International Encyclopedia of Public Health (7 Volumes Set) [1-7, 2 ed.] 9780128036785, 9780128037089

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INTERNATIONAL ENCYCLOPEDIA OF PUBLIC HEALTH SECOND EDITION VOLUME 1 AeCHL

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INTERNATIONAL ENCYCLOPEDIA OF PUBLIC HEALTH SECOND EDITION EDITOR IN CHIEF STELLA R. QUAH Duke-NUS Medical School, Singapore

ASSOCIATE EDITOR IN CHIEF WILLIAM COCKERHAM University of Alabama at Birmingham, Birmingham, AL, USA

VOLUME 1

AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD PARIS • SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier

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EDITORIAL BOARD EDITOR IN CHIEF Stella R. Quah (PhD) is Adjunct Professor at the Duke-NUS Medical School, Singapore. She received her BA in Sociology from the Universidad Nacional de Colombia, her MSc in Sociology from Florida State University as a Fulbright-Hays Scholar, and her PhD in Sociology from the National University of Singapore (formerly University of Singapore). Prior to her current appointment she was Professor at the NUS Department of Sociology where she was a faculty member from 1977 to 2009. Before joining the Sociology Department, she worked at the Department of Social Medicine and Public Health of the Faculty of Medicine, University of Singapore. Her work on Medical Sociology and Public Health has continued throughout her career. She introduced and taught medical sociology at both the Department of Sociology and the Faculty of Medicine. She designed different medical sociology modules for social science students, nursing students, and graduate medical students at the Department of Community, Occupational, and Family Medicine, NUS. When the Graduate School of Medical Studies was set up at the Faculty of Medicine, she taught the medical sociology modules as part of the ‘Foundations of Public Health’ and ‘Lifestyle and Behaviour in Health and Disease’ for the MMed (Public Health). During her long career at NUS, she spent research sabbaticals as Research Associate and Visiting Scholar, by invitation, at the Institute of Governmental Studies, University of California Berkeley (1986–87); the Center for International Studies, MIT, and the Department of Sociology, Harvard University (1993–94), the Harvard-Yenching Institute (1997); the Stanford Program in International Legal Studies, Stanford University (1997); the National Centre for Developmental Studies, Australian National University (2002); and the Walter H. Shorenstein Asia–Pacific Research Center, Stanford University (2006). Her professional activities include her work as Chair of the Medical Sociology Research Committee (RC15) of the International Sociological Association (ISA) 1990–94; ISA Vice President for Research (1994–98); Chairperson of the ISA Research Council (1994–98); and consultant to WHO and UN-ESCAP, among other international and national organizations. She is member of the American Sociological Association and member of several institutional review Boards. On publications, she was Associate Editor of International Sociology (1998–2004) and is member of editorial advisory boards of several international peer-reviewed journals including the British Journal of Sociology; Associate Editor in Chief of the first edition of this Encyclopedia (2008); Coeditor of the Wiley Blackwell Encyclopedia of Health, Illness, Behavior and Society (2014); and Section Editor of Public Health of Elsevier’s Reference Module in Biomedical Sciences. Her areas of research and consultancy include health services utilization; self-medication; health risks behaviors (including smoking, alcohol consumption, and psychoactive substance use); sociocultural factors in infectious diseases, heart disease, and cancer; the governance of epidemics; and the role of family caregivers in mental health. She has published many journal articles and book chapters and has authored nine books; six as sole author. She is also editor and coeditor of 13 books. Her most recent publications include ‘Caring for persons with schizophrenia at home: Examining the link between family caregivers’ role distress and quality of life,’ Sociology of Health and Illness (2013); the Blackwell Encyclopedia of Health, Illness, Behaviour and Society (coeditor and contributor, 2014); ‘Sociology and Psychology in Public Health’ in the Oxford Textbook of Global Public Health (2015); ‘Partnership: The missing link in the process of de-institutionalization of mental health care,’ International Journal of Health Services (2015); Routledge Handbook of Families in Asia (editor and contributor, 2015); and ‘Public Health and Epidemiology: Prevention and surveillance of health risks,’ Elsevier’s Reference Module in Biomedical Sciences (2015).

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ASSOCIATE EDITOR IN CHIEF William Cockerham is Distinguished Professor and Chair of the Department of Sociology at the University of Alabama at Birmingham. He holds a PhD from the University of California at Berkeley. Among his books are Medical Sociology, 13th ed. (Routledge, 2016), with an earlier edition included on the International Sociological Association’s List of 100 Sociology Books of the Century (2000) and Social Causes of Health and Disease, 2nd ed. (Polity, 2013), listed as one of the key books in medical sociology in the twenty-first century in Contemporary Sociology (2014). Other recent books include Sociology of Mental Disorder, 10th ed. (Routledge, 2016) and Medical Sociology on the Move: New Directions in Theory (Springer, 2013). In addition, he is Editor in Chief of the five-volume Encyclopedia of Health, Illness, Behavior, and Society (Wiley-Blackwell, 2014) and Guest Coeditor of a forthcoming special issue of the American Journal of Preventive Medicine. He is also past President of the Research Committee on Health Sociology of the International Sociological Association and has served on the Medical Sociology Council of the American Sociological Association and the Editorial Board of the American Sociological Review.

EDITORIAL BOARD Annette Braunack-Mayer is a bioethicist and Professor of Health Ethics in the School of Public Health at the University of Adelaide. Her research, teaching, and community service focus on combining rigorous and robust analyses of health systems, policies, and practices with the views and experiences of community members. She is passionate about ensuring that the experiences and views of members of communities, including citizens, patients, consumers, and stakeholders, contribute to health services, policies, and systems. She has particular expertise in the use of deliberative methods of engagement with communities, but her research skill set extends across the full range of qualitative research methods. Professor Braunack-Mayer’s current research spans vaccination policy and programs, the appropriate use of big data, obesity prevention, and chronic disease prevention in Aboriginal and Torres Strait Islander communities. She has also completed studies of ethical reasoning among general practitioners, ethics in health technology assessment, and decision-making around the beginning and ending of life. She has published the first and second edition of a text on general practice ethics and over 110 refereed papers and book chapters. Professor Braunack-Mayer chairs a range of health councils and committees, including a government ethics advisory committee and human research and animal ethics committees. She teaches graduate and undergraduate courses in health ethics and qualitative research methods.

Karen Glanz, PhD, MPH, is George A. Weiss University Professor, Professor in the Perelman School of Medicine and the School of Nursing, and Director of the UPenn Prevention Research Center, at the University of Pennsylvania. A globally influential public health scholar whose work spans psychology, epidemiology, nutrition, and other disciplines, her research in community and healthcare settings focuses on obesity, nutrition, and the built environment; reducing health disparities; and health communication technologies. Her research and publications about understanding, measuring, and improving healthy food environments, beginning in the 1980s, has been widely recognized and replicated. Dr Glanz was elected to membership in the Institute of Medicine (IOM) of the National Academy of Sciences in 2013. She was named a Highly Cited Author and one of The World’s Most Influential Scientific Minds 2015 by Thomson Reuters.

Editorial Board

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Davidson H. Hamer, MD, is a graduate of Amherst College and the University of Vermont College of Medicine. After internship and residency in internal medicine at the Washington Hospital Center, he completed a fellowship in infectious disease at Tufts-New England Medical Center. Dr Hamer has a special interest in tropical infectious diseases and has more than two decades of field experience in diarrheal diseases, pneumonia, malaria, and maternal and newborn health. His research interests include emerging infections, neonatal sepsis, antimicrobial resistance, Water, Sanitation and Hygiene (WASH), integrated community case management, interventions for the treatment and prevention of malaria, micronutrient deficiencies, diarrheal disease, and childhood pneumonia. Dr Hamer is a Professor of Global Health and Medicine at the Boston University Schools of Public Health and Medicine, and he holds a position as an Adjunct Professor of Nutrition at the Tufts University Friedman School of Nutrition Science and Policy and adjunct scientist at the Jean Mayer USDA Human Nutrition Research Center on the Aging. Dr Hamer also is the current Principal Investigator for GeoSentinel, a multicountry emerging infections surveillance network.

Japhet Killewo is a professor of Epidemiology at the Muhimbili University of Health and Allied Sciences (MUHAS) in Tanzania. He teaches epidemiology and biostatistics to undergraduate and postgraduate students in the university and offers short courses in data management, research methodology, and monitoring and evaluation to other scholars. He does research in communicable and noncommunicable diseases, and he was the first in Tanzania to design the largest field study for monitoring HIV infection trends and evaluating the impact of HIV interventions in one of the 20 or so regions of Tanzania. He has also worked with the International Center for Diarrheal Disease Research (ICDDRB) in Bangladesh monitoring and evaluating reproductive health interventions in a health and demographic surveillance system. Since 2010 Professor Killewo has been involved in initiating an urban-based health and demographic surveillance system in Tanzania where more than 100,000 residents of all ages are being followed up for in- and out-migration, vital events, socioeconomic status, and food insecurity issues. The population is also being followed up for noncommunicable diseases of various kinds. Professor Killewo has critically reviewed a considerable number of research proposals and manuscripts for various peer-reviewed international journals. Professor Killewo has published widely in local as well as international journals and has written chapters in books and edited a section in the International Encyclopedia of Public Health. He is also the Editor in Chief of the derivative volume on Epidemiology and Demography in Public Health and has more than 80 published articles in journals to his credit.

Jonathan D. Mayer, The overriding emphasis in Professor Mayer’s career has been synthesizing the epidemiologic, geographic, and clinical understanding of health and disease. Health and disease cannot be easily separated into individual disciplines, and so doing may introduce bias into the overall understanding. Professor Mayer’s current position, spanning three different schools at the University of Washington (Public Health, Arts and Sciences, and Medicine) is ideal for this. Similarly, his joint position in Epidemiology and Geography facilitates this. In addition, Professor Mayer has adjunct appointments in two clinical departments: Internal Medicine (Division of Allergy and Infectious Diseases) and Family Medicine, as well as two additional departments in the School of Public Health: Health Services and Global Health. Several leadership positions in the School of Public Health have further facilitated insights into an integrative understanding. Specific interests include (1) diarrheal diseases, especially in sub-Saharan Africa; (2) tuberculosis (TB), especially in densely settled slum areas; (3) vector-borne diseases, including malaria, dengue, and Zika; and (4) emerging infectious diseases – previously unrecognized or genuine de novo diseases, such as Ebola, HIV, Zika, and the emergence of new forms of antimicrobial (‘antibiotic’)-resistant infections. Professor Mayer is particularly interested in understanding the underlying epidemiologic, social, demographic, and political factors underlying disease emergence. Recent attention has been devoted to the epidemiology and geography of pain – especially chronic pain – and the conditions that underlie pain, such as low back pain, postherpetic neuralgia, and injury. Professor Mayer is also interested in health services and the provision of health care. Recent work includes organ transplantation, especially inequities in access to organs; access to pain treatment and pain medications; evolution of hospital systems and consolidation; and, throughout his career; rural health and the urban–suburban–rural inequities in access to care.

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Editorial Board Wayne D. Rosamond, PhD, MS, is a Professor in the Department of Epidemiology, Gillings School of Global Public Health at the University of North Carolina (UNC) at Chapel Hill (USA) and an Adjunct Professor in the Department of Emergency Medicine at UNC. Professor Rosamond is an investigator and teacher in cardiovascular disease (CVD) epidemiology with research expertise in design, conduct, and analysis of community-based surveillance studies and registries of coronary heart disease, heart failure, and stroke. He has also published on the etiology of myocardial infarction, heart failure, sudden cardiac death, venous thromboembolism, and stroke. Dr Rosamond is principal investigator for the North Carolina Stroke Care Collaborative and a coprincipal investigator with the Atherosclerosis Risk in Communities (ARIC) study and Comprehensive Post Acute Stroke Service (COMPASS) trial. Dr Rosamond has collaborated on international CVD epidemiology studies including the WHO-MONICA Project, the Stroke Registry of the Canadian Stroke Network, and the Emerging Risk Factor Collaboration at the University of Cambridge, the United Kingdom. Dr Rosamond is Director of the Cardiovascular Epidemiology NRSA-NIH T32 training grant at UNC. He is past Chair of both the American Heart Association’s (AHA) Statistics and Executive Database Steering Committees and is immediate past President of the Board of Directors of the AHA Mid-Atlantic Affiliate.

Dr Vijay K. Sharma is currently working as Associate Professor at YLL School of Medicine, National University of Singapore, Singapore, and as Senior Consultant, Division of Neurology, National University Hospital, Singapore. He is the current recipient of the prestigious Clinician Scientist Award from National Medical Research Council, Singapore. He has published 187 peerreviewed scientific papers and 19 book chapters. Dr Sharma is Associate Editor for BMC Neurology and serves on the editorial boards of many scientific journals including Stroke, Neural Regeneration Research, Recent Patents on Medical Imaging, Journal of Behavioral and Brain Science, World Journal of Hypertension, ISRN Neurology, American Journal of Cardiovascular Diseases, World Journal of Neurology, Journal of Neurology & Translational Neuroscience (JNTN), International Journal of Medical Sciences and Biotechnology, Advances in Neuroscience Research and Neurological Research and Therapy.

CONTRIBUTORS TO VOLUME 1 Olga Amsterdamska University of Amsterdam, Amsterdam, The Netherlands Harvey Artsob National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada Paolo Aureli Istituto Superiore di Sanità, Rome, Italy Anssi Auvinen School of Health Sciences, University of Tampere, Tampere, Finland Thomas F Babor University of Connecticut School of Medicine, Farmington, CT, USA Megan H Bair-Merritt Boston University School of Medicine, Boston, MA, USA Aaron Bernstein Center for Health and the Global Environment, Harvard T.H. Chan School of Public Health, Boston, MA, USA

Harlal Choudhury National Center for Environmental Assessment, Cincinnati, OH, USA Elise Davis School of Population Health and Global Health, University of Melbourne, Carlton, VIC, Australia Vanessa De la Cruz National Institute of Public Health, Cuernavaca, Mexico Dale A Dickinson School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA Goberdhan P Dimri Northwestern University, Evanston, IL, USA Shira Doron Tufts Medical Center, Boston, MA, USA Jeroen Douwes Massey University, Wellington, New Zealand

Zulfiqar A Bhutta Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON, Canada

Michael Drebot National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada

Peter Boyle International Agency for Research on Cancer, Lyon, France

Tadeusz Dyba DG Joint Research Centre, Institute for Health and Consumer Protection, Public Health e Cancer Policy Support, Ispra, Italy

Freddie Bray Section of Cancer Surveillance, International Agency for Research on Cancer, Lyon, France John H Bryant Johns Hopkins School of Public Health, Baltimore, MD, USA Sally Casswell Massey University, Auckland, New Zealand María Jesús Castaño University Hospital of Albacete, Albacete, Spain Thomas N Chirikos University of South Florida, Tampa, FL, USA

Brian Easton Wellington School of Medicine, University of Otago, Dunedin, New Zealand; and Centre for Social and Health Outcomes, Research and Evaluation (SHORE), Massey University, Palmerston North, New Zealand Kristen Allison Eckert Independent Consultant in Public Health, Tapachula, Chiapas, Mexico Wijnand Eduard National Institute of Occupational Health, Oslo, Norway

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Contributors to Volume 1

Alan J Flisher University of Cape Town, Cape Town, South Africa; and University of Bergen, Bergen, Norway

Luisa A Ikner Water & Energy Sustainable Technology (WEST) Center, The University of Arizona, Tucson, AZ, USA

Anthony Fristachi Battelle Memorial Institute, Columbus, OH, USA

Karen E Iles School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA

Charles P Gerba Water & Energy Sustainable Technology (WEST) Center, The University of Arizona, Tucson, AZ, USA Nancy Gerein University of Leeds, Leeds, UK Angelo P Giardino Baylor College of Medicine, Houston, TX, USA; and Texas Children’s Hospital, Houston, TX, USA Karsten Gjefle The Royal Norwegian Society for Development, Skjetten, Norway Lisa Gold School of Health and Social Development, Deakin University, Burwood, VIC, Australia

Koji Itahana The University of North Carolina, Chapel Hill, NC, USA Harold W Jaffe Centers for Disease Control and Prevention, Atlanta, GA, USA Katherine A James University of Colorado, Denver, CO, USA Casper Jersild Århus University Hospital, Skejby, Denmark Jennifer Kasper University of Arizona, Tuscon, AZ, USA

Jeffrey Goldhagen University of Florida, Jacksonville, FL, USA

Amira M Khan Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON, Canada

Sue Goldstein Soul City Institute for Health and Development Communication, Houghton, South Africa

Caroline Kistin Boston University School of Medicine, Boston, MA, USA

Unni Gopinathan Norwegian Institute of Public Health, Oslo, Norway

Julia Kravchenko Duke University Medical Center, Duke University, Durham, NC, USA

Christoph Gradmann UiO e University of Oslo, Oslo, Norway Valentina Hafner European School of Transfusion Medicine, Milan, Italy Matti Hakama School of Health Sciences, University of Tampere, Tampere, Finland; and Finnish Cancer Registry, Helsinki, Finland Timo Hakulinen Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland Martin Hensher Department of Health, London, UK Linda Hill The Centre for Social and Health Outcomes Research and Evaluation (SHORE), Massey University, Auckland, New Zealand Anette Hjartåker Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

Gerison Lansdown International Consultant on Children’s Rights, London, UK Van Charles Lansingh Instituto Mexicano de Oftalmología, Queretaro, Queretaro, Mexico; Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA; and HelpMeSee, New York, NY, USA Paul E Leaverton College of Public Health, University of South Florida, Tampa, FL, USA Richard A Lemen Rollins School of Public Health, Emory University, Atlanta, GA, USA Morten Lindbæk UiO e University of Oslo, Oslo, Norway Robbin Lindsay National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada

Contributors to Volume 1

David C W Mabey World Health Organization, Geneva, Switzerland; and London School of Hygiene & Tropical Medicine, London, UK Lenore Manderson University of the Witwatersrand, Johannesburg, Gauteng, South Africa

Svetlana Popova Centre for Addiction and Mental Health, Toronto, ON, Canada Roslyn Poulos The University of New South Wales, Sydney, NSW, Australia

G P Marchildon University of Regina, Regina, SK, Canada

Susan Preston-Martin Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

Roberta McKean-Cowdin Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

Pedram Razavi Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

Jaymie R Meliker Stony Brook University, Stony Brook, NY, USA

Jürgen Rehm Centre for Addiction and Mental Health e WHO Collaborating Centre on Mental Health and Addiction, Toronto, ON, Canada

Anthony B Miller University of Toronto, Toronto, ON, Canada Maristela G Monteiro Pan American Health Organization/World Health Organization, NW, Washington, DC, USA Elena Navarro University Hospital of Albacete, Albacete, Spain Eva Negri Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy Jerome O Nriagu University of Michigan, Ann Arbor, MI, USA Paul M O’Byrne McMaster University, Hamilton, ON, Canada David L Parker Park Nicollet Clinic, Minneapolis, MN, USA John Pearn Australian Defence Force and Royal Children’s Hospital, Brisbane, QLD, Australia Claudio Pelucchi Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy Melissa J Perry Milken Institute School of Public Health, The George Washington University, Washington, DC, USA Julian Peto London School of Hygiene and Tropical Medicine, London, UK; and Institute of Cancer Research, Sutton, UK Richard F Pilch Raytheon Intelligence, Information, and Services, Washington, DC, USA

Serge Resnikoff Brien Holden Vision Institute, University of New South Wales, Sydney, NSW, Australia Julius B Richmond Harvard Medical School, Boston, MA, USA Noel R Rose The Johns Hopkins Schools of Medicine and Public Health, Baltimore, MD, USA John-Arne Røttingen Norwegian Institute of Public Health, Oslo, Norway Edgar Sanchez Tufts Medical Center, Boston, MA, USA David J Sencer Centers for Disease Control and Prevention, Atlanta, GA, USA Karri Seppä Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland Teresa Shamah National Institute of Public Health, Cuernavaca, Mexico Vijay K Sharma National University of Singapore and National University Health System, Singapore Roy J Shephard University of Toronto, Toronto, ON, Canada Kevin D Shield Centre for Addiction and Mental Health e WHO Collaborating Centre on Mental Health and Addiction, Toronto, ON, Canada

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Contributors to Volume 1

Kevin D Shield Section of Cancer Surveillance, International Agency for Research on Cancer, Lyon, France Jeremy Shiffman Maxwell School of Syracuse University, Syracuse, NY, USA Gunnar Skov Simonsen UiT e The Arctic University of Norway, Tromsø, Norway; and University Hospital of North Norway, Tromsø, Norway Svein Øivind Solberg AVRDC e The World Vegetable Center, Tainan, Taiwan Javier Solera University Hospital of Albacete, Albacete, Spain Anthony W Solomon World Health Organization, Geneva, Switzerland; and London School of Hygiene & Tropical Medicine, London, UK

Umberto Veronesi European Institute of Oncology, Milan, Italy Salvador Villalpando National Institute of Public Health, Cuernavaca, Mexico Gregory R Wagner National Institute for Occupational Safety and Health, Washington, DC, USA Liang Wang College of Public Health, East Tennessee State University, Johnson City, TN, USA Youfa Wang School of Public Health and Health Professions, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA Petra A Wark London School of Hygiene and Tropical Medicine, London, UK

Mark Stevenson The George Institute for International Health, Sydney, NSW, Australia

Elizabeth Waters School of Population Health and Global Health, University of Melbourne, Carlton, VIC, Australia

Kearsley A Stewart Duke Global Health Institute, Duke University, Durham, NC, USA

Elisabete Weiderpass The Cancer Registry of Norway, Oslo, Norway; Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway; Karolinska Institutet, Stockholm, Sweden; and Genetic Epidemiology Group, Folkhälsan Research Center, University of Helsinki, Helsinki, Finland

Tim Stockwell Centre for Addictions Research of BC, University Victoria, Victoria, BC, Canada Jørund Straand UiO e University of Oslo, Oslo, Norway Stephen B Thacker Centers for Disease Control and Prevention, Atlanta, GA, USA Peter S Thorne University of Iowa, Iowa City, IA, USA Shereen Usdin Soul City Institute for Health and Development Communication, Houghton, South Africa Frances L Vaughn US Department of Health and Human Services (HHS), Office of the Assistant Secretary for Preparedness and Response (ASPR), Washington, DC, USA

Astrid Louise Wester Norwegian Institute of Public Health, Oslo, Norway Lars Wilhelmsen University of Gothenburg, Gothenburg, Sweden Dana Young School of Population Health and Global Health, University of Melbourne, Carlton, VIC, Australia Yiliang Zhu College of Public Health, University of South Florida, Tampa, FL, USA

GUIDE TO USING THE ENCYCLOPEDIA Structure of the Encyclopedia

3.

All articles in the encyclopedia are arranged alphabetically as a series of entries.

A subject classification list has been developed by the editors to group articles under broad topics. This index is useful for making broad connections between articles and locating the relevant article for a topic that is covered in more than one article. This can be found in the front matter of Volume 1.

1.

Alphabetical Contents List

Your first point of reference will likely be the contents. The contents list appears at the front of each volume providing volume and page numbers of the entry. We also display the article title in the running headers on each page so you are able to identify your location and browse the work in this manner. 2.

Cross-references

All articles within the encyclopedia have an extensive list of cross-references which appear at the end of each article, for example: See also: HIV Prevention and Treatment in Children and Adolescents; Mental Health and Substance Abuse; Mental Illness, Historical Views of; Specific Mental Health Disorders: Child and Adolescent Mental Disorders.

4.

Subject Classification List

Index

The index provides the volume and page number for where the material is located, and the index entries differentiate between material that is a whole article; is part of an article, part of a table, or in a figure. This can be found at the rear of Volume 7. 5.

Contributors

A list of volume contributors appears in the front matter of each volume.

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SUBJECT CLASSIFICATION Behavioral Factors in Public Health Anthropological Perspectives on the Health Transition Cultural Competence in Public Health Cultural Contexts of Reproductive Health Cultural Epidemiology Cultural Factors Influencing Therapeutic Practice Cultural Issues and Linguistic Complications in Health Communication Ethnic Conflict and Public Health Gender in Health and Illness Happiness, Health and Altruism Health Behavior and Risk Factors Health Care of Indigenous Peoples/Nations Health Promotion Health-Related Stigma Media and Health Medical Pluralism Medical Sciences and Technology in Socio-Cultural Context New Public Health Patient Empowerment in Health Care Peoples Health Movement Race, Human Variation, and Health, the Interaction of Racism and Health Religion and Healing Risk Communication Social and Cultural Perspectives on Ecology and Health Social Determinants of Health, the United Nations Commission of Social Dimensions of Epidemics Social Dimensions of Infectious Diseases Social Gradients and Child Health Social Science Contributions to Public Health: Overview Sociocultural Construction of Medical Knowledge

Alcohol

Alcohol Consumption: An Overview of International Trends Alcohol Consumption: The Social and Economic Impacts Alcohol Industry Alcohol, Integrated Control of Alcohol: Treatment Burden of Disease and Injury Caused by Alcohol Drugs

Drugs, Illicit e Primary Prevention Strategies Historical and Sociocultural Context of Psychoactive Substance Use Illicit Drugs: Patterns of Use, Dependence, and Contribution to Disease Burden in Developed Countries Illicit Drug Trends Globally Illicit Psychoactive Substance Use and Harm Prevention Mental Health and Substance Abuse Public Health and the Harm Reduction Approach to Illegal Psychoactive Substances Epidemiology of Injuries

Burns and Scalds Disasters and Emergency Planning Drowning Falls Humanitarian Response to Complex Emergencies and Natural Disasters Injury Epidemiology Road Traffic Injuries Sports Injuries Nutrition

Community-Based Nutrition Programmes Epidemiology of Vitamin C

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Subject Classification

Facility-Based Treatment of Severe Malnutrition Fetal Growth Restriction: Causes and Outcomes Food Fortification Functions and Deficiencies of B-Vitamins (and Their Prevention) Infant Malnutrition: Breastfeeding International Dietary Guidelines Iodine Deficiency and Its Prevention Iron Deficiency and Its Prevention Nutrition and HIV Undernutrition and Its Social Determinants Vitamin A Deficiency and Its Prevention Vitamin D

Demography, Epidemiology and Public Health Public Health and Epidemiology: Prevention and Surveillance of Health Risks Compression of Morbidity Demography of Aging Demography, Epidemiology, and Public Health Genetic Epidemiology Population Growth

Environmental and Occupational Epidemiology Clinical Epidemiology

Obesity/Inactivity

Cholesterol and Lipids Diet and Cancer Diet and Heart Disease Fatty Acids Meat Consumption and Cancer Meat Consumption and Cardiovascular Disease Obesity/Overweight: Health Consequences Overweight and Obesity: Prevention and Weight Management Physical Activity and Health Tobacco Use and Public Health

Global Tobacco Industry Preventing Uptake of Smoking Secondhand Smoke Smoking Cessation Smoking, The Burden of Mortality of Tobacco Control: An Integrated Approach Tobacco Harm Minimization Violence

Arms Control Measures Elder Abuse Forced Migration and Health Occupational Injuries and Work Place Violence Serial and Mass Murderers Sexual Violence Suicide and Self-directed Violence Terrorism Violence/Intentional Injuries e Epidemiology and Overview Violence/Intentional Injuries e Prevention and Control Weapons of Mass Destruction Young People and Violence

Clinical Epidemiology Dental Epidemiology

Dental Epidemiology Environmental Public Health

Agricultural Health and Safety Arsenic Asbestos Bioaerosols Biodiversity, Health Implications of Cadmium Carcinogens, Environmental Contaminants Associated with Drinking Water Drinking Water and Sanitation Environmental and Occupational Epidemiology Environmental Health: Overview Environmental Protection Laws Extreme Weather Events and Human Health Famine Hazardous Wastes Human Exposure Science Indoor Air Pollution: Developing Countries Land Use/Land Change and Health Lead Hazards and Poisoning Mercury Natural Disasters Organohalogen Pollutants and Human Health Outdoor Air Pollution: Sources, Atmospheric Transport, and Human Health Effects Pesticides Occupational Public Health

Ergonomics and Musculoskeletal Issues Lung Diseases, Occupational Military Health Issues Occupational Death/Injury Rates

Subject Classification

Occupational Health: Overview Sick Building Syndrome Worker Health and Safety: International Issues

Epidemiology and Public Policy Agenda Setting in Public Health Policy Alma-Ata and Primary Health Care: An Evolving Story Environmental Justice and Health Essential Drugs Policy Evidence-Informed Public Health Policy Food Safety Foundations in Public Health Law Global Health Law: International Law and Public Health Policy Governance Issues in Health Financing Health Policy: Overview Innovative Financing for Health Promotion: A Global Review and Thailand Case Study Interest Groups and Civil Society in Public Health Policy Planning, for Public Health Policy Politics, and Public Health Policy Reform Public and Consumer Participation in Policy and Research Public Health and Law Enforcement Regulation of Drugs and Drug Use Public Health Law and Public Health Policy Relief Operations Role of the State in Public Health Policy Transition to Universal Coverage in Developing Countries

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Leukemia Liver Cancer Lung Cancer Lymphomas Oral Cancer Ovarian Cancer Pancreatic Cancer Pediatric Cancers Prostate Cancer Radiation Therapy Cardiovascular Diseases

Cardiovascular Disease Prevention Coronary Heart Disease Exercise Therapy for Heart Failure Patients in Canada Global Trends in Cardiovascular Disease Heart Failure Hypertension Peripheral Arterial Disease Rheumatic Fever and Rheumatic Heart Disease Risk Factors Sudden Cardiac Arrest Venous Thromboembolism Diabetes Mellitus

Diabetes Mellitus Prevention Diabetes Mellitus Treatment Diabetes Mellitus, Epidemiology Disease Prevention

Disease Prevention: An Overview

Epidemiology of Diseases

Emerging and Re-emerging Diseases

Anemia

Antimicrobial Resistance in a One Health and One World Perspective e Mechanisms and Solutions Emergence of Novel Human Infections: New Insights and New Challenges Epidemiology of the Acquired Immunodeficiency Syndrome HIV Safety Guidelines HIV/AIDS and Tuberculosis HIV/AIDS of the Central Nervous System Lyme Disease Re-emerging Diseases: Overview Severe Acute Respiratory Syndrome (SARS) Transmissible Spongiform Encephalopathies

Anemia Cancer

Bladder Cancer Brain Tumors Breast Cancer Cancer Economics Cancer Epidemiology Cancer Mortality Cancer Prevention Cancer Screening: Theory and Applications Cancer Survival Cancer: Global Burden, Trends, and Projections Colorectal Cancer Esophageal Cancer Future Organization of Cancer Care Gastric Cancer

Infectious Diseases

Adenoviruses Arboviruses Bacterial Infections: Overview

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Subject Classification

Botulism Brucellosis Childhood Infectious Diseases: Overview Chlamydia (Trachoma and Sexually Transmitted Infections) Cholera and Other Vibrioses Dengue Diphtheria Ebola and Other Viral Hemorrhagic Fevers Enteroviruses Escherichia coli Foodborne Diseases Helicobacter pylori Hepatitis, Viral Herpesviruses Infectious Disease Surveillance Influenza Intestinal Infections: Overview Leprosy Measles Mumps Nontuberculous Mycobacteria Pneumonia Poliomyelitis Principles of Infectious Diseases: Transmission, Diagnosis, Prevention and Control Rabies Rhinoviruses Rickettsia Rubella Salmonella Shigellosis Smallpox Streptococcal Diseases Syphilis Tetanus Typhoid Fever Viral Diarrhea Viral Infections, an Overview with a Focus on Prevention of Transmission Waterborne Diseases Yaws, Bejel, and Pinta Yellow Fever Neurological Disorders

Cerebrovascular Disease Head Trauma Huntington’s Disease Late Life Cognitive Disorders Meningitis, Bacterial Metabolic Myopathies Migraine Update Multiple Sclerosis Muscular Dystrophies

Neurodevelopmental Disorders Parkinson’s Disease Seizure Disorders Sleep Disorders Spinal Injury Wilson’s Disease Parasitic Diseases

Ectoparasites Helminthic Diseases: Dracunculiasis Helminthic Diseases: Echinococcosis Helminthic Diseases: Filariasis Helminthic Diseases: Foodborne Trematode Infections Helminthic Diseases: Intestinal Nematode Infections Helminthic Diseases: Onchocerciasis and Loiasis Helminthic Diseases: Schistosomiasis Helminthic Diseases: Taeniasis and Cysticercosis due to Taenia solium Helminthic Diseases: Trichinellosis and Other Helminthic Tissue Helminthic Infections Mycobacterium ulcerans Disease: Buruli Ulcer Parasitic Diseases, an Overview Protozoan Diseases: African Trypanosomiasis Protozoan Diseases: Amebiasis Protozoan Diseases: Chagas Disease Protozoan Diseases: Cryptosporidiosis, Giardiasis, and Other Intestinal Protozoan Diseases Protozoan Diseases: Leishmaniasis Protozoan Diseases: Malaria Clinical Features, Management, and Prevention Protozoan Diseases: Toxoplasmosis Psychological and Psychiatric Disorders

Classification of Mental Disorders: Principles and Concepts Measurement of Psychiatric and Psychological Disorders and Outcomes in Populations Mental Health and Physical Health (Including HIV/ AIDS) Mental Health Epidemiology (Psychiatric Epidemiology) Mental Health Etiology: Biological and Genetic Determinants Mental Health Etiology: Social Determinants Mental Health Policy Mental Health Promotion Mental Health, Morbidity and Impact Principles: Mental Health Resources and Services Principles: Stigma Specific Mental Health Disorders: Depressive and Anxiety Disorders Specific Mental Health Disorders: Eating Disorders

Subject Classification

Specific Mental Health Disorders: Mental Disorders Associated with Aging Specific Mental Health Disorders: Personality Disorders Specific Mental Health Disorders: Psychotic Disorders Specific Mental Health Disorders: Trauma and Mental Disorders Women’s Mental Health Respiratory Diseases

Asthma Chronic Obstructive Pulmonary Disease Cystic Fibrosis Obstructive Sleep Apnea Respiratory Diseases: Overview Respiratory Infections, Acute Respiratory Syncytial Virus Tuberculosis Diagnosis Tuberculosis Epidemiology Tuberculosis Prevention Tuberculosis Treatment Tuberculosis, Public Health Aspects Tuberculosis: Overview Sensory Disorders

Autoimmune Diseases Blindness Endocrine Diseases: Overview Gastrointestinal Disorders: Overview Hearing Disorders Kidney Diseases Lupus Erythematosus: Pathogenesis of Cutaneous Manifestations Sickle-Cell Disease Skin Diseases (Noncancerous)

Ethical and Professional Issues in Epidemiology Anthropological Perspectives in Bioethics Codes of Ethics in Public Health Ethics and Health Promotion Ethics of Immunization Ethics Of Infectious Disease Control Ethics of Organ Transplants Ethics of Public Health Research: Moral Obligations to Communities Ethics of Screening Euthanasia and Public Health Foundations in Public Health Ethics Health and Human Rights: Overview Health Technology Assessment: Ethical, Legal and Social Issues

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Legal Issues in Public Health New Technologies: Ethics of Genomics New Technologies: Ethics of Stem Cell Research Public Health Approaches to Dying, Death, and Loss Reproductive Ethics: Ethical Issues and the Menopause Reproductive Ethics: New Reproductive Technologies Reproductive Ethics: Perspectives on Contraception and Abortion Torture and Public Health Health Inequalities

Community Health Insurance in Low- and MiddleIncome Countries Competition in Health Care Consumerism: Overview Corruption and the Consequences for Public Health Demand for Health Care Determinants of National Health Expenditure Dynamics of the Health-Care Labor Markets Educational Attainment and Health: Survival Energy Use, Health Implications of Equity in Health Financing Health Inequalities Health Information on the Internet Health Insurance Plans and Programs: An Overview Health Literacy International Perspectives on Resource Allocation Literacy and Public Health Provider Payment Methods and Incentives Resource Allocation: Justice and Resource Allocation in Public Health Social Epidemiology

Health Services Acute Care Hospitals Blood Transfusion Services Community Health Workers Disability and Rehabilitation Emergency Medical Technicians Home Care Hospice and Palliative Care Human Resources for Oral Health and Dentistry Immunization Integrative, Traditional and Complementary Medicine Long Term Care in Health Services Long-Term Care Organization and Financing Managed Care Maternal Health Services

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Subject Classification

Nongovernmental Organizations (NGOs) Nurses Primary Health Care Public Health Professionals

Health Systems Canada, Health System of Centers for Disease Control Comparative Health Systems East Asia and Pacific States, Health Systems of Global Issues: Urban Health in Developing Countries Health Systems of Australia and New Zealand Health Systems of Mexico, Central America and the Caribbean Health Systems: United States, Health System of the Health-Care Delivery Systems Japan, Health System of Latin American Social Medicine Mainland China, Hong Kong, and Taiwan, Health Systems of National Health Systems: A Historical Overview One Health Central and Eastern Africa: Historical and future perspectives Public/Private Mix in Health Systems Review of Health Systems of the Middle East and North Africa Region Russia and Former USSR, Health Systems of Scandinavia, Health Systems of South Asia, Health Systems of Southeastern Europe, Health Systems of Traditional Asian Medical Systems United Kingdom, Health System of Urban Health Systems: Overview Western Europe, Health Systems of World Bank World Health Organization

History of Epidemiology and Public Health Epidemiology

Antibiotic Development and Resistance Bacteriology, Historical Epidemiology, Historical

Mental Illness, Historical Views of Plague, Historical Poliomyelitis, Historical Quarantine through History Schools of Public Health Vaccines, Historical World’s Medical Schools: Past, Present and Future Yellow Fever, Historical

Methods and Measurement in Epidemiology Biostatistics Children and Adolescents, Measuring the Quality of Life of Chronic Disease Modeling Clinical Trials Comparative Risk Assessment Cost-Influenced Treatment Decisions and Cost-Effectiveness Analysis Decision Analytic Modeling Disease Classification Economic Models of Hospital Behavior Epidemic Investigation Geographic Information Systems (GIS) in Public Health Global Burden of Disease Health and Disease, Concepts of Health Surveys Human Health Risk Assessment International Classification Systems for Health Life Expectancy Measurements Measurement and Modeling of Health-Related Quality of Life Measurement and Modeling: Infectious Disease Modeling Measurement and Valuation of Health for Economic Evaluation Meta-analysis Observational Epidemiology Quality Adjusted Life Years Surveillance of Disease: Overview Systematic Reviews in Public Health WHO Definition of Health, Rethinking the

Public Health of Population Sub-Groups Public Health

Aging and Public Health

Classic Concepts of Disease History of Malaria and Its Control History of Public Health during Colonialism History of Public Health in the Ancient World Influenza, Historical Leprosy, Historical

Aging, Physical Activity, and Health Aging: Nutrition and the Older Adults Cancer and Senescence Circulatory Diseases and Aging Long Term Care for Aging Populations Longevity of Specific Populations

Subject Classification At-Risk Populations

Populations at Special Health Risk: Children: Children’s Mental Health Services Populations at Special Health Risk: Displaced Populations Populations at Special Health Risk: Homeless Populations at Special Health Risk: Incarcerated Populations at Special Health Risk: Indigenous Populations Populations at Special Health Risk: Men Populations at Special Health Risk: Migrants Populations at Special Health Risk: Rural Populations Populations at Special Health Risk: Women Populations at Special Health Risk: Workers Public Health Dimensions of Disability Stress and (Public) Health Child and Adolescent Health

Adolescents Child Abuse/Treatment Child Labor Child Obesity and Health Child Rights Child Soldiers Child Witness to Violence Children, Media and Health

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HIV Prevention and Treatment in Children and Adolescents Infant Mortality Perinatal Epidemiology School Health Promotion Specific Mental Health Disorders: Child and Adolescent Mental Disorders

Sexual and Reproductive Health Family Planning/Contraception Female Reproductive Physiology/Function Gender Aspects of Sexual and Reproductive Health Gynecological Morbidity Infertility, An Overview Male Reproductive Function Maternal Mortality and Morbidity Menopause Puberty Reproductive Health: Sexually Transmitted Infections e Overview Reproductive Rights Sexual and Reproductive Health: Overview Trends in Human Fertility Unsafe Abortion Violence against Women

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PREFACE TO SECOND EDITION The first edition of the International Encyclopedia of Public Health published in 2008 received the ‘Outstanding Academic Title’ award in the Reference (Science and Technology) category from the American Library Association in 2009. This second edition follows the same essential objective of the first: to offer the state of the art in public health and epidemiology as well as historical accounts of how advances have been accomplished in significant areas of public health and epidemiology. Accordingly, the first edition articles have been thoroughly reviewed for currency, and updated or written anew by their original authors or by invited domain experts when the original authors were not available. In addition, we have included new articles on important emerging issues. This information is provided in the history tagline under the title of each article. Moreover, the multidisciplinary nature of the expertise represented in the first edition continues in this second edition. We have endeavored to convey through the entire Encyclopedia the imperative of scientific collaboration across disciplines and knowledge areas to protect and improve the health of individuals, communities, and nations. Authors are domain experts from a wide range of knowledge fields including biomedicine, public health, epidemiology, medical sociology, health economics, anthropology, bioethics, and biostatistics, among other fields. This principle of multidisciplinary collaboration is implemented not only by the dissemination of knowledge throughout the Encyclopedia but also by the inclusion of articles on knowledge creation (for example, methods and measurement in epidemiology), articles on knowledge application (for example, public health policy and ethical and professional issues), and articles providing knowledge on the substantial sociobehavioral dimensions of public health. This combination of knowledge areas is valuable for the Encyclopedia’s main audiences: graduate students, researchers, clinicians, practitioners, and policy makers. An additional helpful feature for readers is that we offer two types of articles: introductory articles presenting an overview of a given topic and advanced articles discussing details and more complex aspects of the topic. The first edition had six volumes. This second edition has seven volumes comprising new articles and updated and expanded articles to reflect the momentum and scope of knowledge creation in the various subfields of public health and epidemiology since the publication of the first edition. The Encyclopedia covers all the major areas of public health and epidemiology: public health of population subgroups including the aged, adolescents, and at-risk populations; behavioral factors in public health including nutrition, tobacco, alcohol, and psychoactive substance use; epidemiology of injuries; environmental and occupational epidemiology; sexual and reproductive health; health services; health systems; health inequalities, ethical and professional issues in public health; epidemiology and public policy; methods and measurement; demography; history of epidemiology and public health; and epidemiology of diseases. The epidemiology of diseases offers dedicated articles on anemia, diabetes, a wide range of cancer diseases, cardiovascular diseases, infectious and parasitic diseases, respiratory diseases, neurological disorders, sensory disorders, emerging and reemerging diseases, and psychiatry and psychological disorders. What further advantages does the second edition offer to readers? In addition to the authors’ expertise and wide scope of subfields, readers benefit from the multidisciplinary knowledge offered by the Encyclopedia in three other ways: first, through the articles’ evidence-informed analyses supported by tables, figures, and statistics; second, through the connection to extant knowledge by means of comprehensive citations, bibliography, and the list of further readings; and third, through the logical link to related articles in the seven volumes in the form of cross-references at the end of each article. All things considered, it took four years to complete this second edition. A brief historical note is in order. As indicated in the Preface to the first edition, Dr Chris Murray was the original editor in chief and led the

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conceptualization and design of the Encyclopedia. Although Dr Murray withdrew from the project in its early stages of design, he set the basis for its development. Kris Heggenhougen and I worked together on the first edition as editor in chief and associate editor in chief, respectively. The initiative for this second edition was taken in 2013 by Karen Maloney who was then Elsevier’s Publisher Director, in charge of the Major Reference Works Program. The preliminary steps began in the first half of 2013 when Karen approached Kris and me with her idea of a new edition of the Encyclopedia. Kris declined due to his research and writing schedule, but he recommended that I should lead the project. Karen agreed and invited me to be the editor in chief. The process of contacting and inviting all the original authors to update their articles started in 2014 after Elsevier approved the second edition proposal. Unlike the first edition, we already had a body of authors. Yet, reaching the first-edition authors and section editors was a laborious undertaking because of their high mobility in terms of their place of work and their workload. Domain experts are very sought after. Thus many contributors to the first edition had changed their institutional affiliations by the time we began to work on the second edition. This was not surprising given the expansion of scientific research facilities and funding across the globe: experts move across institutions, countries, and continents today with greater ease and frequency than they did a decade ago. Besides changes in institutional affiliation, authors as domain experts face a steady increase in their scientific workload and research responsibilities. It is to their great credit that the invited section editors and authors agreed to participate in the second edition, despite their busy schedules. Although the work of assembling the large team of contributors and section editors was difficult, on the positive side, the mobility of experts and the growth of centers of research excellence around the world led to the rich variety of countries represented in the team of experts working on this second edition of the Encyclopedia. The production process involved several stages. As members of the Editorial Board, the section editors and I assessed the currency of each article in the first edition in collaboration with the respective authors. This was followed by the updating or complete rewriting of articles by the authors. New articles were commissioned. The updated and new manuscripts were reviewed by the respective section editors and editor in chief. Amended articles were reviewed once more before proceeding to two rounds of copyediting where the first and second proofs were checked again by the copy editor, the authors, and the editor in chief. A publication of this magnitude can only be accomplished through the close collaboration of many people. I wish to reiterate my gratitude to all the authors of the 492 articles for contributing their expertise despite their other pressing commitments. Personally, I am also very thankful for the significant cooperation of the eight distinguished domain experts I invited to be section editors and members of the Editorial Board: William C Cockerham, whom I invited to serve also as associate editor in chief; Annette Braunack-Mayer; Karen Glanz; David Hamer; Japhet Killewo; Jonathan D Mayer; Wayne Rosamond; and Vijay Sharma. Professor BraunackMayer, Professor Killewo, Professor Mayer, and Professor Rosamond were members of the first edition’s Editorial Board; and Professor Hamer led the work on the derivative volume on infectious diseases, one of five derivatives we published in 2009e10. All eight section editors have performed their editorial duties with great distinction and collegiality despite their very busy professional schedules, often involving traveling across continents. Summaries of their professional accomplishments are provided in the first volume. Similarly, I have had the benefit of working with a very talented and professional editorial team at Elsevier: Karen Maloney and Erin Hill-Parks (2013); Ginny Mills (2013e15); Susan Dennis, Senior Acquisitions Editor, Major Reference Works; Justin Taylor, Content Project Manager, Major Reference Works; and Katherine Finn, Associate Content Project Manager. I wish to express my sincere gratitude to all of them. Stella R. Quah

FOREWORD I warmly welcome this second edition of the International Encyclopedia of Public Health, with its exceptionally broad coverage that matches the sweep and complexity of today’s health challenges and the multiple disciplines needed to address them. Many of the problems covered are deeply familiar to me, as they are frequently discussed by the World Health Organization’s (WHO’s) 194 Member States during sessions of the World Health Assembly. These are problems that stand in the way of better health in rich and poor countries alike, in tropical and temperate climates, and with causes coming from both ancient and newly emerging threats to health. Ministries of health around the world share the same three never-ending struggles: to hold the volatile microbial world at bay, to change unhealthy behaviors, and to find the human and financial resources needed to meet rising public expectations for health care. All of these struggles have become more difficult since the first edition of the encyclopedia was published in 2008. Concerns about the world’s collective defenses against infectious disease threats have intensified. Two old diseases, transmitted by the Ebola and Zika viruses, caused international public health emergencies when they appeared in new geographical areas and spread explosively through immunologically naive populations. Many common bacterial infections, long considered easy to cure, are no longer responding to available antibiotics. Multidrug-resistant pathogens haunt hospitals in every region of the world. Gonorrhea has become resistant to multiple classes of drugs and may soon be untreatable. An epidemic of multidrug-resistant typhoid fever began rolling across parts of Asia and Africa in 2015. With few replacement products in the pipeline, the world is moving toward a post-antibiotic era in which common infections can once again kill. Health in all regions is being shaped by the same powerful forces: demographic aging, rapid unplanned urbanization, and the globalized marketing of unhealthy products. Under the pressure of these forces, chronic noncommunicable diseases have overtaken infectious diseases as the leading killers worldwide. In this case, economic growth and modernization, long associated with better health outcomes, are actually creating the conditions that allow heart disease, stroke, diabetes, tobacco-related cancers, and diet-related cancers to flourish. Addressing the rise of these complex and costly diseases requires a major shift in the mind-set of public health e from curative care to prevention, and from a strictly biomedical model of health to one that embraces the social and life sciences. It also requires greater financing and numbers of staff to cope with the everincreasing costs of providing care for people living longer, sicker lives. Efforts to change unhealthy behaviors are often thwarted by powerful economic operators: the tobacco, food, sugar-sweetened beverage, and alcoholic beverage industries. The policy environment for enacting change has been distorted by trade agreements that allow corporations to take governments to court when they pass legislation designed to protect their populations from harmful products. Australia’s long legal battle with the tobacco industry, provoked by legislation mandating the plain packaging of cigarettes, provides the most notorious example. Health is further shaped by social inequalities, in income levels and opportunities, which have reached their highest levels seen in more than half a century. The world has 800 million chronically hungry people, but it also has countries where more than 70% of the adult population is obese or overweight. The poverty map has changed. Today, more than 70% of the world’s poor live in middle-income countries. Rising inequality slows the rate at which economic growth reduces poverty, creating a risk that more well-off countries will be largely populated by poor people. Climate change, characterized by more frequent and severe extreme weather events, will likely emerge as the defining health challenge of this century. Many of the same inefficient and polluting energy

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choices that are driving climate change are also devastating health. WHO estimates that, each year, more than seven million deaths worldwide can be attributed to air pollution. Floods destroy lives and livelihoods. Droughts, especially in poor countries dependent on rain-fed agriculture, threaten already precarious food supplies. Diarrheal diseases, including cholera, flourish under conditions of too much and too little water. Insects and other vectors are exquisitely sensitive to variations in heat, humidity, and rainfall. Climate change has already given dengue a vastly expanded geographical range and may do the same for malaria. Other health crises have followed the unprecedented number and scale of protracted armed conflicts, leaving nearly 80 million people in urgent need of essential health services and creating the largest refugee crisis since the end of World War II. In parts of the Middle East, humanitarian agencies have replaced governments as the principal providers of health care. Nor are medical relief workers and their patients safe. In several conflicts, the collapse of law and order extends to blatant violations of international humanitarian law. From 2014 through 2015, WHO documented nearly 1000 deaths following attacks on health facilities in conflict zones. Of the 594 attacks investigated, more than 60% deliberately targeted hospitals. Conflicts can also stall the success of global health campaigns. The poliovirus has found its last sanctuaries in conflict-riddled parts of Afghanistan, Nigeria, and Pakistan. Yet despite all these challenges, advances in global health have been remarkable, spurred in particular by commitment to the health-related Millennium Development Goals (MDGs). At the end of the MDG era, 15 million people living with HIV were receiving antiretroviral therapy, up from just 690,000 in 2000. Deaths from malaria in sub-Saharan Africa dropped by 66%. Between 2000 and 2014, effective diagnosis and treatment of tuberculosis saved an estimated 43 million lives. Worldwide, deaths associated with complications of pregnancy and childbirth declined by 44%. Each day, 19,000 fewer children die than in 1990. Even diseases that affect the poorest of the poor e the neglected tropical diseases e are in retreat. Drug donations by the pharmaceutical industry now allow WHO to reach more than 800 million people each year with preventive therapy for diseases like onchocerciasis, lymphatic filariasis, leprosy, schistosomiasis, and blinding trachoma. Moreover, with the reservoir of infectious agents shrinking year by year, WHO has set targets for eliminating many of these ancient diseases within the next ten years. The 2030 Agenda for Sustainable Development, approved by the United Nations General Assembly in September 2015, aims to transform a world characterized by a catalog of woes: global health threats, more frequent and intense natural disasters, spiraling conflict, violent extremism, terrorism and related humanitarian crises, forced displacement of millions, and a changing climate. The agenda has been praised for its very broad and inclusive approach to development. As with the MDGs, the alleviation of poverty is an overarching objective, but with a difference. As an integrated and interactive agenda, the Sustainable Development Goals (SDGs) aim to tackle poverty, not superficially through handouts, but fundamentally, by addressing its root causes. The emphasis on sustainability encourages the channeling of assistance in ways that build fundamental capacities. In my experience, most developing countries want capacity, not charity. Moreover, enhanced national capacities are the best exit strategy for assistance. I sometimes see articles arguing that health has been short-changed in the SDG agenda, given less prominence than it deserves. After all, three of the eight MDGs were directly focused on health, and two others, on nutrition and water supply and sanitation, addressed major determinants of health. In the new agenda, health is only one in a crowd of 17 goals. As some have argued, such small space undermines the significance of health as an issue that matters profoundly to every person on this planet. I disagree. What the SDGs do especially well is to recognize that health challenges can no longer be addressed by the health sector acting alone. Halting the rise of antimicrobial resistance requires policy support from agriculture. Abundant evidence shows that educated mothers have the healthiest families. Access to modern energy fuels economic growth, but it also reduces millions of deaths from chronic lung disease associated with indoor air pollution. In my view, health occupies pride of place on the new agenda. Health is an end point that reflects the success of multiple other goals. Because the social, economic, and environmental determinants of health are so broad, progress in improving health is a reliable indicator of progress in implementing the overall agenda. In the final analysis, the ultimate objective of all development activities e whether aimed at improving food and water supplies, or making cities safer e is to sustain human lives in good health. Users of this encyclopedia will have a chance to explore the multitude of issues that make work in public health so complex and challenging, and yet ultimately so rewarding. I urge you to consider these issues in the

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context of the overarching need for fair and equitable access to quality health care, always giving priority to unmet needs, and always seeking ways to maximize the efficient use of resources. Apart from serving strong humanitarian and ethical imperatives, doing so furthers the self-interest of all nations. A world that is greatly out of balance in matters of health is neither stable nor secure. Dr Margaret Chan Director-General, World Health Organization

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CONTENTS OF ALL VOLUMES Editorial Board

v

Contributors to Volume 1

ix

Guide to Using the Encyclopedia Subject Classification Preface to Second Edition Foreword

xiii xv xxiii xxv

VOLUME 1 A Acute Care Hospitals Martin Hensher

1

Adenoviruses Luisa A Ikner and Charles P Gerba

5

Adolescents Alan J Flisher and Nancy Gerein

10

Agenda Setting in Public Health Policy Jeremy Shiffman

16

Aging: Nutrition and the Older Adults Julia Kravchenko

22

Aging, Physical Activity, and Health Roy J Shephard

31

Agricultural Health and Safety Melissa J Perry

38

Alcohol Consumption: An Overview of International Trends Maristela G Monteiro, Jürgen Rehm, Kevin D Shield, and Tim Stockwell

45

Alcohol Consumption: The Social and Economic Impacts Brian Easton

58

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Alcohol Industry Linda Hill

62

Alcohol, Integrated Control of Sally Casswell

71

Alcohol: Treatment Thomas F Babor

75

Alma-Ata and Primary Health Care: An Evolving Story John H Bryant and Julius B Richmond

83

Anemia Teresa Shamah, Salvador Villalpando, and Vanessa De la Cruz

103

Anthropological Perspectives in Bioethics Kearsley A Stewart

113

Anthropological Perspectives on the Health Transition Lenore Manderson

122

Antibiotic Development and Resistance Jørund Straand, Christoph Gradmann, Morten Lindbæk, and Gunnar Skov Simonsen

129

Antimicrobial Resistance in a One Health and One World Perspective e Mechanisms and Solutions Astrid Louise Wester, Unni Gopinathan, Karsten Gjefle, Svein Øivind Solberg, and John-Arne Røttingen

140

Arboviruses Harvey Artsob, Robbin Lindsay, and Michael Drebot

154

Arms Control Measures Richard F Pilch

161

Arsenic Katherine A James, Jaymie R Meliker, and Jerome O Nriagu

170

Asbestos Gregory R Wagner and Richard A Lemen

176

Asthma Paul M O’Byrne

183

Autoimmune Diseases Noel R Rose

192

B Bacterial Infections: Overview Edgar Sanchez and Shira Doron

196

Bacteriology, Historical Olga Amsterdamska

206

Bioaerosols Jeroen Douwes, Wijnand Eduard, and Peter S Thorne

210

Biodiversity, Health Implications of Aaron Bernstein

219

Biostatistics Paul E Leaverton, Frances L Vaughn, and Yiliang Zhu

223

Contents of All Volumes

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Bladder Cancer Claudio Pelucchi and Eva Negri

233

Blindness Serge Resnikoff, Van Charles Lansingh, and Kristen Allison Eckert

239

Blood Transfusion Services Casper Jersild and Valentina Hafner

247

Botulism Paolo Aureli

254

Brain Tumors Roberta McKean-Cowdin, Pedram Razavi, and Susan Preston-Martin

263

Breast Cancer Umberto Veronesi and Peter Boyle

272

Brucellosis María Jesús Castaño, Elena Navarro, and Javier Solera

281

Burden of Disease and Injury Caused by Alcohol Kevin D Shield, Svetlana Popova, and Jürgen Rehm

296

Burns and Scalds Roslyn Poulos and Mark Stevenson

310

C Cadmium Anthony Fristachi and Harlal Choudhury

316

Canada, Health System of G P Marchildon

320

Cancer and Senescence Koji Itahana and Goberdhan P Dimri

328

Cancer Economics Thomas N Chirikos

332

Cancer Epidemiology Petra A Wark and Julian Peto

339

Cancer: Global Burden, Trends, and Projections Freddie Bray and Kevin D Shield

347

Cancer Mortality Anette Hjartåker, Elisabete Weiderpass, and Freddie Bray

369

Cancer Prevention Anthony B Miller

381

Cancer Screening: Theory and Applications Anssi Auvinen and Matti Hakama

389

Cancer Survival Karri Seppä, Tadeusz Dyba, and Timo Hakulinen

406

Carcinogens, Environmental Karen E Iles and Dale A Dickinson

422

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Cardiovascular Disease Prevention Lars Wilhelmsen

438

Centers for Disease Control Stephen B Thacker, David J Sencer, and Harold W Jaffe

448

Cerebrovascular Disease Vijay K Sharma

455

Child Abuse/Treatment Angelo P Giardino

471

Child Labor Jennifer Kasper and David L Parker

481

Child Obesity and Health Youfa Wang and Liang Wang

487

Child Rights Jeffrey Goldhagen and Gerison Lansdown

502

Child Soldiers John Pearn

509

Child Witness to Violence Caroline Kistin and Megan H Bair-Merritt

513

Childhood Infectious Diseases: Overview Amira M Khan and Zulfiqar A Bhutta

517

Children and Adolescents, Measuring the Quality of Life of Elise Davis, Dana Young, Elizabeth Waters, and Lisa Gold

539

Children, Media and Health Sue Goldstein and Shereen Usdin

546

Chlamydia (Trachoma and Sexually Transmitted Infections) Anthony W Solomon and David C W Mabey

554

VOLUME 2 Cholera and Other Vibrioses John G Morris, Jr.

1

Cholesterol and Lipids Robert Clarke and Colin Baigent

9

Chronic Disease Modeling J Dik F Habbema, Rob Boer, and Jan J Barendregt

22

Chronic Obstructive Pulmonary Disease Breda Cushen, Ross Morgan, and Ross Summer

28

Circulatory Diseases and Aging Igor Akushevich and Anatoliy I Yashin

36

Classic Concepts of Disease Thomas Schramme

44

Contents of All Volumes

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Classification of Mental Disorders: Principles and Concepts Tevfik Bedirhan Üstün and Roger Ho

51

Clinical Epidemiology David L Sackett and R Brian Haynes

58

Clinical Trials William R Harlan

62

Codes of Ethics in Public Health James C Thomas and Reid Miller

71

Colorectal Cancer Emmanuel Mitry

75

Community Health Insurance in Low- and Middle-Income Countries Maria-Pia Waelkens, Soors Werner, and Criel Bart

82

Community Health Workers Susan B Rifkin

93

Community-Based Nutrition Programmes Kraisid Tontisirin and Lalita Bhattacharjee

103

Comparative Health Systems Hong Wang

111

Comparative Risk Assessment Majid Ezzati

117

Competition in Health Care Paula H Song, Justin D Barlow, Eric E Seiber, and Ann S McAlearney

129

Compression of Morbidity J McCallum and C Mathers

134

Consumerism: Overview Lok Wong and John F P Bridges

142

Contaminants Associated with Drinking Water Hsion-Wen David Kuo and Irene Xagoraraki

148

Coronary Heart Disease Jacqueline Müller-Nordhorn and Stefan N Willich

159

Corruption and the Consequences for Public Health Taryn Vian and Erika L Crable

168

Cost-Influenced Treatment Decisions and Cost-Effectiveness Analysis Marcel Bilger

177

Cultural Competence in Public Health Elizabeth Waters, Lisa Gibbs, Elisha Riggs, Naomi Priest, Andre Renzaho, and Maree Kulkens

181

Cultural Contexts of Reproductive Health Carole H Browner and Robin Root

187

Cultural Epidemiology James A Trostle

191

Cultural Factors Influencing Therapeutic Practice Nina L Etkin, Jonathan D Baker, and Jessica N Busch

198

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Cultural Issues and Linguistic Complications in Health Communication T S Harvey

202

Cystic Fibrosis Garry R Cutting

208

D Decision Analytic Modeling Peter Muenning

211

Demand for Health Care Germano Mwabu

217

Demography, Epidemiology, and Public Health Ollie S Miettinen

223

Demography of Aging Kenneth C Land and Vicki L Lamb

226

Dengue María G Guzman, Omar Fuentes, Eric Martinez, and Ana B Perez

233

Dental Epidemiology Peter G Robinson

258

Determinants of National Health Expenditure A K Nandakumar, Marwa E Farag, Caroline Ly, and Trenton White

264

Diabetes Mellitus, Epidemiology Joan K Bardsley and Helaine E Resnick

274

Diabetes Mellitus Prevention Sabitha R Dasari, Reena Oza-Frank, and K M Venkat Narayan

282

Diabetes Mellitus Treatment Chin Meng Khoo

288

Diet and Cancer Julia S Kravchenko

294

Diet and Heart Disease Frank B Hu

305

Diphtheria Tejpratap S P Tiwari

313

Disability and Rehabilitation Nora Ellen Groce

318

Disasters and Emergency Planning Jennifer Leaning

322

Disease Classification Robert Jakob

332

Disease Prevention: An Overview Anne H Outwater, Sebalda C Leshabari, and Ellen Nolte

338

Drinking Water and Sanitation Michelle V Fanucchi

350

Contents of All Volumes

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Drowning Justine E Leavy, Gemma Crawford, Richard Franklin, Mel Denehy, and Jonine Jancey

361

Drugs, Illicit e Primary Prevention Strategies Michael J McDermott and C F Drescher

366

Dynamics of the Health-Care Labor Markets Edson C Araujo and Gilles Dussault

382

E East Asia and Pacific States, Health Systems of Deoraj Caussy and U Than Sein

387

Ebola and Other Viral Hemorrhagic Fevers Daniel G Bausch and Mikiko Senga

396

Economic Models of Hospital Behavior Satish Joshi and Ranjani Krishnan

410

Ectoparasites Richard J Pollack, Daniel Engelman, Andrew C Steer, and Scott A Norton

417

Educational Attainment and Health: Survival John G Cleland and Jeroen K van Ginneken

429

Effective Alcohol Policy H D Holder

437

Elder Abuse Lia Susana Daichman, Susana Aguas, and Charmaine Spencer

443

Emergence of Novel Human Infections: New Insights and New Challenges Ann Marie Kimball

448

Emergency Medical Technicians Eduardo Romero-Hicks

455

Endocrine Diseases: Overview Peter C Hindmarsh

460

Energy Use, Health Implications of Mike Joffe

468

Enteroviruses José R Romero

474

Environmental and Occupational Epidemiology Neil Pearce and Jeroen Douwes

479

Environmental Health: Overview Dale A Dickinson and Karen E Iles

487

Environmental Justice and Health Carolyn Stephens and Chris Church

499

Environmental Protection Laws Nicholas A Ashford and Charles C Caldart

507

Epidemic Investigation Els Mathieu and Yao Sodahlon

518

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Contents of All Volumes

Epidemiology, Historical Lorentz M Irgens

530

Epidemiology of the Acquired Immunodeficiency Syndrome Malwina N Carrion and Davidson H Hamer

547

Epidemiology of Vitamin C James E Enstrom

559

Equity in Health Financing Diana De Graeve, Ke Xu, and Raf Van Gestel

569

Ergonomics and Musculoskeletal Issues Jack T Dennerlein

577

Escherichia coli Jan T Poolman

585

Esophageal Cancer Linda M Brown, David P Check, and Susan S Devesa

594

Essential Drugs Policy H Haak

603

VOLUME 3 Ethics and Health Promotion Stacy M Carter

1

Ethics of Immunization Marcel Verweij

7

Ethics of Infectious Disease Control Michael J Selgelid

11

Ethics of Organ Transplants Ahmed B Al-Khafaji and Lisa S Parker

17

Ethics of Public Health Research: Moral Obligations to Communities Holly A Taylor, Summer Johnson McGee, Ruth R Faden, and Nancy E Kass

23

Ethics of Screening Niels Nijsingh, Niklas Juth, and Christian Munthe

28

Ethnic Conflict and Public Health Duncan Pedersen and Hanna Kienzler

36

Euthanasia and Public Health Kenneth Chambaere and Joachim Cohen

46

Evidence-Informed Public Health Policy Jana Sisnowski and Jackie M Street

57

Exercise Therapy for Heart Failure Patients in Canada James A Stone, Trina Hauer, Mark Haykowsky, and Sandeep Aggarwal

66

Extreme Weather Events and Human Health Stephanie L Molloy, Erin A Dreelin, and Joan B Rose

70

Contents of All Volumes

xxxvii

F Facility-Based Treatment of Severe Malnutrition Ann Ashworth

77

Falls Anne Tiedemann, Daina L Sturnieks, and Lisa Keay

84

Family Planning/Contraception Anna Glasier and Ailsa Gebbie

92

Famine Marc-André Prost and Alex de Waal

102

Fatty Acids Mohammed H Moghadasian and Fereidoon Shahidi

114

Female Reproductive Physiology/Function Horacio B Croxatto

123

Fetal Growth Restriction: Causes and Outcomes Susan M Sayers, Paul A L Lancaster, and Clare L Whitehead

132

Food Fortification M G Venkatesh Mannar and Annie S Wesley

143

Food Safety Jorgen Schlundt

153

Foodborne Diseases Jean Maguire van Seventer and Davidson H Hamer

160

Forced Migration and Health Pascale Allotey and Sharuna Verghis

174

Foundations in Public Health Ethics Bruce Jennings

183

Foundations in Public Health Law Lawrence O Gostin, Benjamin E Berkman, and John Kraemer

192

Functions and Deficiencies of B-Vitamins (and Their Prevention) Wolfgang Herrmann and Rima Obeid

199

Future Organization of Cancer Care Karol Sikora

204

G Gastric Cancer Suminori Kono

215

Gastrointestinal Disorders: Overview Amanda J MacFarlane and Patrick J Stover

223

Gender Aspects of Sexual and Reproductive Health Jane C Cottingham

233

Gender in Health and Illness Carol Vlassoff

240

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Contents of All Volumes

Genetic Epidemiology Harry Campbell and Niall Anderson

248

Geographic Information Systems (GIS) in Public Health Corinna Keeler and Michael Emch

253

Global Burden of Disease Colin Mathers

256

Global Health Law: International Law and Public Health Policy Allyn L Taylor

268

Global Issues: Urban Health in Developing Countries Carolyn Stephens

282

Global Tobacco Industry George Thomson and Nick Wilson

292

Global Trends in Cardiovascular Disease Usman Khan, Arslan Rafiq, and Jonathan N Bella

301

Governance Issues in Health Financing Phua Kai Hong

330

Gynecological Morbidity Maria Garefalakis, Martha Hickey, and Neil Johnson

342

H Happiness, Health and Altruism Stephen G Post

354

Hazardous Wastes Christopher T De Rosa, M Fay, L S Keith, Moiz M Mumtaz, H R Pohl, M T Hatcher, H E Hicks, James S Holler, P Ruiz, and Barry L Johnson

358

Head Trauma Jared Knopman and Roger Härtl

371

Health and Disease, Concepts of Dina Czeresnia and Teresa C Soares

381

Health and Human Rights: Overview Sofia Gruskin and Daniel Tarantola

385

Health Behavior and Risk Factors Karen Glanz

393

Health Care of Indigenous Peoples/Nations Gerard Bodeker

399

Health Inequalities Catherine Chittleborough

406

Health Information on the Internet Rehema Chande-Mallya, Sydney Enock Msonde, Wulystan Pius Mtega, and Edda Tandi Lwoga

414

Health Insurance Plans and Programs: An Overview Stefan Greß and Juergen Wasem

418

Contents of All Volumes

xxxix

Health Literacy Roy W Batterham, Alison Beauchamp, and Richard H Osborne

428

Health Policy: Overview Calum Paton

438

Health Promotion Maurice B Mittelmark, Ilona Kickbusch, Irving Rootman, Angela Scriven, and Keith Tones

450

Health Surveys Jennifer H Madans

463

Health Systems of Australia and New Zealand Diana M S Hetzel, John D Glover, and Sarah K McDonald

470

Health Systems of Mexico, Central America and the Caribbean Miguel A Gonzalez Block and Sebastian González McQuire

483

Health Systems: United States, Health System of the William C Cockerham

491

Health Technology Assessment: Ethical, Legal and Social Issues Annette Braunack-Mayer

497

Health-Care Delivery Systems Fred C J Stevens, Madelon W Kroneman, and Jouke van der Zee

500

Health-Related Stigma Stella R Quah

508

Hearing Disorders Robert Burkard

512

Heart Failure Véronique L Roger

520

Helicobacter pylori Helena Enroth and Lars Engstrand

527

Helminthic Diseases: Dracunculiasis Philip Willem Downs, Dieudonné P Sankara, and Kojo Yeboah-Antwi

532

Helminthic Diseases: Echinococcosis Donald P McManus and Yang R Yang

545

Helminthic Diseases: Filariasis Pradeep K Das and Ranganatha K Shenoy

552

Helminthic Diseases: Foodborne Trematode Infections Bernard Fried and Jane E Huffman

561

Helminthic Diseases: Intestinal Nematode Infections Lorenzo Savioli, Albis Francesco Gabrielli, and Antonio Montresor

568

Helminthic Diseases: Onchocerciasis and Loiasis Jan H F Remme, Boakye Boatin, and Michel Boussinesq

576

Helminthic Diseases: Schistosomiasis Alan Fenwick and Juerg Utzinger

588

Helminthic Diseases: Taeniasis and Cysticercosis due to Taenia solium Lia P Suazo Hernandez and A Clinton White Jr.

597

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Contents of All Volumes

Helminthic Diseases: Trichinellosis and Other Helminthic Tissue Helminthic Infections Kenneth D Murrell

604

Hepatitis, Viral Samer S El-Kamary and G Thomas Strickland

611

Herpesviruses Sara Oliver and Scott H James

621

VOLUME 4 Historical and Sociocultural Context of Psychoactive Substance Use Stella R Quah

1

History of Malaria and Its Control William J Moss, Snehal N Shah, and Richard H Morrow

5

History of Public Health during Colonialism Alison Bashford

13

History of Public Health in the Ancient World Øivind Larsen

19

HIV/AIDS and Tuberculosis Joseph R Oppong and Kate A Lester

23

HIV/AIDS of the Central Nervous System George Siakallis and Sotirios Tsiodras

33

HIV Prevention and Treatment in Children and Adolescents Sara N Stulac, Milenka Jean-Baptiste, Christina S Mathews, and Joia S Mukherjee

48

HIV Safety Guidelines Neil G Parry

60

Home Care Maxine Duke

64

Hospice and Palliative Care Barbara Gomes, Irene J Higginson, and Elizabeth Davies

69

Human Exposure Science Paul J Lioy and Edo Pellizzari

77

Human Health Risk Assessment Marie Bourgeois, Giffe Johnson, and Raymond Harbison

84

Human Resources for Oral Health and Dentistry Jennifer E Gallagher

95

Humanitarian Response to Complex Emergencies and Natural Disasters Monica Adhiambo Onyango and Malyse Uwase

106

Huntington’s Disease Rahul Rathakrishnan

117

Hypertension Lydia A Bazzano, Ulana Pogribna, and Paul K Whelton

123

Contents of All Volumes

xli

I Illicit Drugs: Patterns of Use, Dependence, and Contribution to Disease Burden in Developed Countries 134 Louisa Degenhardt, Wayne Hall, and Megan Weier Illicit Drug Trends Globally Liesbeth Vandam, João Matias, Rebecca McKetin, Meredith Meacham, and Paul Griffiths

146

Illicit Psychoactive Substance Use and Harm Prevention Stella R Quah

157

Immunization Tracey Goodman, Michel Zaffran, and Bjorn Melgaard

182

Indoor Air Pollution: Developing Countries Majid Ezzati

201

Infant Malnutrition: Breastfeeding Arun Gupta, J P Dadhich, and Shoba Suri

207

Infant Mortality Paul H Wise

216

Infectious Disease Surveillance Jillian Murray and Adam L Cohen

222

Infertility, An Overview Faiza Maryam Gaba and Siladitya Bhattacharya

230

Influenza Paul V Targonski and Gregory A Poland

238

Influenza, Historical Svenn-Erik Mamelund

247

Injury Epidemiology Eleni Th Petridou and Constantine N Antonopoulos

258

Innovative Financing for Health Promotion: A Global Review and Thailand Case Study Viroj Tangcharoensathien, Sakol Sopitarchasak, Shaheda Viriyathorn, Nuttapun Supaka, Kanjana Tisayaticom, Sasirat Laptikultham, Warisa Panichkriangkrai, and Walaiporn Patcharanarumol

275

Integrative, Traditional and Complementary Medicine Gerard Bodeker, Gemma Burford, and Adva Volkov

288

Interest Groups and Civil Society in Public Health Policy Nicholas Mays

296

International Classification Systems for Health T Bedirhan Üstün

304

International Dietary Guidelines Adeline Seow and May C Wang

312

International Perspectives on Resource Allocation Solomon R Benatar and Richard Ashcroft

316

Intestinal Infections: Overview Davidson H Hamer, Christopher J Gill, and Roma Chilengi

322

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Iodine Deficiency and Its Prevention B S Hetzel

336

Iron Deficiency and Its Prevention Paul Whittaker

342

J Japan, Health System of Naoki Ikegami

346

K Kidney Diseases Garabed Eknoyan

353

L Land Use/Land Change and Health Jonathan A Patz and Sarah H Olson

358

Late Life Cognitive Disorders Lisa D Ravdin

364

Latin American Social Medicine Howard Waitzkin

369

Lead Hazards and Poisoning Herbert L Needleman and David C Bellinger

377

Legal Issues in Public Health Stephanie P Kowal and Tania Bubela

384

Leprosy Wim H van Brakel, Erik Post, Paul R Saunderson, and P K Gopal

391

Leprosy, Historical Jo Robertson

402

Leukemia Tracy Lightfoot, Alexandra Smith, and Eve Roman

410

Life Expectancy Measurements David M J Naimark

419

Literacy and Public Health Michael S Wolf, Ruth M Parker, and Scott C Ratzan

432

Liver Cancer Michael C Kew

438

Long Term Care for Aging Populations Eric Stallard

447

Long Term Care in Health Services Jenny Brodsky and A Mark Clarfield

459

Contents of All Volumes

xliii

Longevity of Specific Populations Thomas Theodore Samaras

464

Long-Term Care Organization and Financing Emily Freeman, Martin Knapp, and Ami Somani

469

Lung Cancer Dermot S O’Callaghan and Finbarr O’Connell

477

Lung Diseases, Occupational Mridu Gulati and Mark R Cullen

485

Lupus Erythematosus: Pathogenesis of Cutaneous Manifestations Annegret Kuhn and Peter H Krammer

491

Lyme Disease Zouyan Lu and Jenifer Coburn

495

Lymphomas Marina T van Leeuwen and Claire M Vajdic

504

M Mainland China, Hong Kong, and Taiwan, Health Systems of Gabriel M Leung, Jui-Fen Rachel Lu, and Qingyue Meng

515

Male Reproductive Function H M Behre

529

Managed Care Sherry Glied and Katharina Janus

537

Maternal Health Services Sohinee Bhattacharya and Jacqueline S Bell

543

Maternal Mortality and Morbidity Andrzej Kulczycki

553

Measles Gustavo H Dayan and Huong Q McLean

565

Measurement and Modeling of Health-Related Quality of Life Ron D Hays and Bryce B Reeve

570

Measurement and Modeling: Infectious Disease Modeling Mirjam Kretzschmar

579

Measurement and Valuation of Health for Economic Evaluation John Brazier and Julie Ratcliffe

586

Measurement of Psychiatric and Psychological Disorders and Outcomes in Populations Traolach S Brugha and Howard Meltzer

594

Meat Consumption and Cancer Amanda J Cross and Rashmi Sinha

604

Meat Consumption and Cardiovascular Disease Martha L Daviglus, Amber Pirzada, and Ka He

612

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VOLUME 5 Media and Health Francesco Taroni

1

Medical Pluralism Elisabeth Hsu

8

Medical Sciences and Technology in Socio-Cultural Context Stacy Leigh Pigg

13

Meningitis, Bacterial M C Brouwer and D van de Beek

21

Menopause David W Sturdee

26

Mental Health and Physical Health (Including HIV/AIDS) Ashraf Kagee and Melvyn Freeman

35

Mental Health and Substance Abuse Benedetto Saraceno, Michelle Funk, and Vladimir B Poznyak

45

Mental Health Epidemiology (Psychiatric Epidemiology) Grayson S Norquist and Kathryn M Magruder

54

Mental Health Etiology: Biological and Genetic Determinants Stephen J Glatt, Stephen V Faraone, and Ming T Tsuang

63

Mental Health Etiology: Social Determinants Alex Cohen and Harry Minas

69

Mental Health, Morbidity and Impact Oye Gureje and Bibilola D Oladeji

73

Mental Health Policy Rachel Jenkins

81

Mental Health Promotion Helen Herrman, Rob Moodie, Shekhar Saxena, Takashi Izutsu, and Atsuro Tsutsumi

93

Mental Illness, Historical Views of David Pilgrim

106

Mercury Philippe Grandjean

110

Meta-analysis Athina Tatsioni and John P A Ioannidis

117

Metabolic Myopathies M Tarnopolsky

125

Migraine Update Jonathan Jia Yuan Ong

132

Military Health Issues Susan P Proctor

138

Multiple Sclerosis Dimitrios Karussis

145

Contents of All Volumes

xlv

Mumps Paul Gastañaduy and Amy Parker Fiebelkorn

180

Muscular Dystrophies Mina Astejada, May Christine Malicdan, and Ichizo Nishino

183

Mycobacterium ulcerans Disease: Buruli Ulcer Richard O Phillips, Mark Wansbrough-Jones, and Kingsley B Asiedu

193

N National Health Systems: A Historical Overview Nicholas Goodwin

201

Natural Disasters Abhaya S Prasad and Louis Hugo Francescutti

215

Neurodevelopmental Disorders Ester Klimkeit, Nicole Rinehart, Tamara May, and John Bradshaw

223

New Public Health John R Ashton and Miranda N Thurston

231

New Technologies: Ethics of Genomics Benjamin Capps

240

New Technologies: Ethics of Stem Cell Research Rachel A Ankeny

248

Nongovernmental Organizations (NGOs) Helen Yanacopulos

251

Nontuberculous Mycobacteria Todd P Primm and Joseph O Falkinham, III

257

Nurses Judith A Oulton and Patricia Caldwell

264

Nutrition and HIV Henrik Friis, Mette Frahm Olsen, and Suzanne Filteau

271

O Obesity/Overweight: Health Consequences Shari S Bassuk and JoAnn E Manson

277

Observational Epidemiology Jennifer L Kelsey and Ellen B Gold

295

Obstructive Sleep Apnea Silke Ryan

308

Occupational Death/Injury Rates Tim Driscoll and Marilyn A Fingerhut

315

Occupational Health: Overview Rosemary K Sokas and Nancy L Sprince

325

Occupational Injuries and Work Place Violence Nancy A Stout, Dawn N Castillo, Harlan E Amandus, and Timothy J Pizatella

334

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Contents of All Volumes

One Health Central and Eastern Africa: Historical and Future Perspectives Japhet Killewo, William Bazeyo, and Robinson Mdegela

342

Oral Cancer Crispian Scully and Narendran Andrew Robinson

348

Organohalogen Pollutants and Human Health Prasada Rao S Kodavanti and Bommanna G Loganathan

359

Outdoor Air Pollution: Sources, Atmospheric Transport, and Human Health Effects George D Thurston

367

Ovarian Cancer L C Woodhouse and R J Edmondson

378

Overweight and Obesity: Prevention and Weight Management Elizabeth H Baker

383

P Pancreatic Cancer D S Michaud

390

Parasitic Diseases, an Overview Malwina N Carrion, Davidson H Hamer, and Darin Evans

399

Parkinson’s Disease Amos D Korczyn, Yacov Balash, and Tanya Gurevich

409

Patient Empowerment in Health Care John F P Bridges, Svetla Loukanova, and Percivil M Carrera

416

Pediatric Cancers Charles A Stiller

426

Peoples Health Movement Claudio Schuftan

438

Perinatal Epidemiology Martha S Wingate, Anne E Epstein, and Fatimah Oluwakemi Bello

442

Peripheral Arterial Disease Ioanna Tzoulaki and F Gerry R Fowkes

449

Pesticides Claudio Colosio, Federico Maria Rubino, and Angelo Moretto

454

Physical Activity and Health Graham A Colditz, Nhi Nguyen, and Hank Dart

463

Plague, Historical Ole J Benedictow

473

Planning, for Public Health Policy Tolib N Mirzoev and Andrew T Green

489

Pneumonia Stephen R C Howie, Davidson H Hamer, and Stephen M Graham

500

Poliomyelitis Ondrej Mach, Roland W Sutter, and T Jacob John

509

Contents of All Volumes

xlvii

Poliomyelitis, Historical Hans van Vliet, Harrie van der Avoort, and Marina Conyn-van Spaendonck

519

Politics, and Public Health Policy Reform Amanda Glassman and Kent Buse

527

Population Growth Kaja Jurczynska and Bernice Kuang

533

Populations at Special Health Risk: Children: Children’s Mental Health Services Beth Doll

541

Populations at Special Health Risk: Displaced Populations Samantha L Thomas, Stuart D M Thomas, Debbi Long, and Paul A Komesaroff

548

Populations at Special Health Risk: Homeless Daniel B Herman and Jennifer I Manuel

556

Populations at Special Health Risk: Incarcerated Alexandria Macmadu, Manasa Reddy, Anna Tomasulo, Andrew Coyle, and Josiah D Rich

563

Populations at Special Health Risk: Indigenous Populations John Douglass Whyte, Ian P S Anderson, and Sue Crengle

573

Populations at Special Health Risk: Men Alan White

583

Populations at Special Health Risk: Migrants Oliver Razum and Florence Samkange-Zeeb

591

Populations at Special Health Risk: Rural Populations John S Humphreys and Geoff Solarsh

599

Populations at Special Health Risk: Women Jenifer E Allsworth and Marlene B Goldman

609

Populations at Special Health Risk: Workers Carles Muntaner, Faraz Vahid Shahidy, Il-Ho Kim, and Joan Benach

617

VOLUME 6 Preventing Uptake of Smoking Konrad Jamrozik

1

Primary Health Care David Sanders, Nikki Schaay, and Suraya Mohamed

5

Principles: Mental Health Resources and Services Pratap Sharan and Vimal Krishnan

15

Principles of Infectious Diseases: Transmission, Diagnosis, Prevention, and Control Jean Maguire van Seventer and Natasha S Hochberg

22

Principles: Stigma Lawrence Yang, Arthur Kleinman, and Junko Morita

40

Prostate Cancer Graham G Giles

51

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Protozoan Diseases: African Trypanosomiasis Pere P Simarro and Jose R Franco

60

Protozoan Diseases: Amebiasis Shinjiro Hamano

64

Protozoan Diseases: Chagas Disease Sergio S Estani and Elsa L Segura

70

Protozoan Diseases: Cryptosporidiosis, Giardiasis, and Other Intestinal Protozoan Diseases Saul Tzipori and Justyna J Jaskiewicz

79

Protozoan Diseases: Leishmaniasis Adrienne J Showler and Andrea K Boggild

97

Protozoan Diseases: Malaria Clinical Features, Management, and Prevention Adrienne J Showler, Kevin C Kain, and Andrea K Boggild

103

Protozoan Diseases: Toxoplasmosis Eskild Petersen, Daniel Ajzenberg, Laurent Mandelbrot, and Jorge Enrique Gomez-Marin

114

Provider Payment Methods and Incentives Randall P Ellis, Bruno Martins, and Michelle McKinnon Miller

133

Puberty Sonia R Grover and Anurag Bajpai

143

Public and Consumer Participation in Policy and Research Gillian Stokes and Sandy Oliver

148

Public Health and Epidemiology: Prevention and Surveillance of Health Risks Stella R Quah

158

Public Health and Law Enforcement Regulation of Drugs and Drug Use Craig L Fry

164

Public Health and the Harm Reduction Approach to Illegal Psychoactive Substances Brian Emerson and Mark Haden

169

Public Health Approaches to Dying, Death, and Loss Allan Kellehear

184

Public Health Dimensions of Disability Donald J Lollar and Willi Horner-Johnson

190

Public Health Law and Public Health Policy Sonia Allan

200

Public Health Professionals Poonam Dhavan and K Srinath Reddy

210

Public/Private Mix in Health Systems Christopher R Keane and Manuj C Weerasinghe

217

Q Quality Adjusted Life Years Joshua A Salomon

224

Quarantine through History Andrea A Conti

229

Contents of All Volumes

xlix

R Rabies Henry Wilde, Supaporn Wacharapluesadee, Thiravat Hemachudha, Veera Tepsumethanon, and Boonlert Lumlertdacha

236

Race, Human Variation, and Health, the Interaction of Alan H Goodman

245

Racism and Health Yin Paradies

249

Radiation Therapy Francesc Casas, Sherif Abdel-Wahab, Nenad Filipovic, and Branislav Jeremic

260

Re-emerging Diseases: Overview Mary E Wilson

269

Relief Operations Jo Rose and Phil O’Keefe

278

Religion and Healing Lance D Laird and Linda L Barnes

286

Reproductive Ethics: Ethical Issues and the Menopause Sheryl de Lacey

291

Reproductive Ethics: New Reproductive Technologies Rachel A Ankeny

297

Reproductive Ethics: Perspectives on Contraception and Abortion Ea Mulligan and Margie Ripper

301

Reproductive Health: Sexually Transmitted Infections e Overview Bradley Stoner

306

Reproductive Rights Andrzej Kulczycki

315

Resource Allocation: Justice and Resource Allocation in Public Health Rosamond Rhodes

320

Respiratory Diseases: Overview Neil J Brennan

328

Respiratory Infections, Acute Mark Rogan

332

Respiratory Syncytial Virus Sonja Junge, D James Nokes, Eric A F Simões, and Martin W Weber

337

Review of Health Systems of the Middle East and North Africa Region Kedar Mate, Caitlin Bryan, Nigel Deen, and Jesse McCall

347

Rheumatic Fever and Rheumatic Heart Disease Praveg Goyal and Rajesh Vijayvergiya

357

Rhinoviruses Ann R Falsey and Angela R Branche

363

Rickettsia David H Walker

370

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Contents of All Volumes

Risk Communication Ralph J DiClemente and Jerrold M Jackson

378

Risk Factors Rachel R Huxley, Richard Taylor, and Annette Dobson

383

Road Traffic Injuries Rebecca Ivers, Katherine Brown, Robyn Norton, and Mark Stevenson

393

Role of the State in Public Health Policy Benjamin Hawkins and Arturo Alvarez-Rosete

401

Rubella H Cody Meissner and Davidson H Hamer

410

Russia and Former USSR, Health Systems of Dina Balabanova, Erica Richardson, and Richard Coker

414

S Salmonella John A Crump and John Wain

425

Scandinavia, Health Systems of Karsten Vrangbæk

434

School Health Promotion Oddrun Samdal

439

Schools of Public Health David Evans

447

Secondhand Smoke Sarah M McGhee and Anthony J Hedley

455

Seizure Disorders Steven C Schachter

459

Serial and Mass Murderers Dennis L Peck and Robert B Jenkot

465

Severe Acute Respiratory Syndrome (SARS) Kenneth W Tsang

477

Sexual and Reproductive Health: Overview Mahmoud F Fathalla and Mohamed M F Fathalla

481

Sexual Violence Rachel Jewkes and Elizabeth Dartnall

491

Shigellosis Sujit K Bhattacharya and Dipika Sur

499

Sick Building Syndrome Janis Jansz

502

Sickle-Cell Disease Cage S Johnson

506

Skin Diseases (Noncancerous) Levi E Fried, Sulochana Bhandarkar, and Jack L Arbiser

513

Contents of All Volumes

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Sleep Disorders Antonio Culebras

519

Smallpox Mary G Reynolds and Inger K Damon

524

Smoking Cessation Marewa Glover and Hayden McRobbie

534

Smoking, The Burden of Mortality of Majid Ezzati and Alan D Lopez

545

Social and Cultural Perspectives on Ecology and Health Glenn A Albrecht, Nick Higginbotham, Linda Connor, and Neville Ellis

551

Social Determinants of Health, the United Nations Commission of Alec Irwin, Orielle Solar, and Jeanette Vega

557

Social Dimensions of Epidemics Stella R Quah

562

Social Dimensions of Infectious Diseases Johannes Sommerfeld

569

Social Epidemiology Landon Myer, Ezra Susser, Bruce G Link, and Chelsea Morroni

574

Social Gradients and Child Health Barbara Starfield

586

Social Science Contributions to Public Health: Overview Jeannine Coreil and Karen E Dyer

599

Sociocultural Construction of Medical Knowledge Atwood D Gaines

612

VOLUME 7 South Asia, Health Systems of Brian Chin, Manju Rani, and Sekhar Bonu

1

Southeastern Europe, Health Systems of Nertila Tavanxhi, Genc Burazeri, and Ulrich Laaser

10

Specific Mental Health Disorders: Child and Adolescent Mental Disorders Melvyn W B Zhang and Roger C M Ho

22

Specific Mental Health Disorders: Depressive and Anxiety Disorders Ian B Hickie

29

Specific Mental Health Disorders: Eating Disorders Sherrie S Delinsky, Jennifer L Derenne, and Anne E Becker

43

Specific Mental Health Disorders: Mental Disorders Associated with Aging Ingmar Skoog

48

Specific Mental Health Disorders: Personality Disorders Kirsten Barnicot and Mike J Crawford

55

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Contents of All Volumes

Specific Mental Health Disorders: Psychotic Disorders R Thara, Mubeen Taj, and Srinivasan Tirupati

60

Specific Mental Health Disorders: Trauma and Mental Disorders Derrick Silove, Angela Nickerson, and Richard A Bryant

69

Spinal Injury Bruce W Martin and Omar Amin

74

Sports Injuries Corey Joseph and Caroline F Finch

79

Streptococcal Diseases Gursharan S Chhatwal and Rikki Graham

87

Stress and (Public) Health Ulf Lundberg

98

Sudden Cardiac Arrest Grant Fletcher and Thomas Rea

106

Suicide and Self-directed Violence Diego De Leo and Karolina Krysinska

115

Surveillance of Disease: Overview Angela Chow and Yee-Sin Leo

124

Syphilis Ian Simms

139

Systematic Reviews in Public Health Rebecca Armstrong, Jodie Doyle, Helen Roberts, Laurie Anderson, Sandy Oliver, and Mark Petticrew

147

T Terrorism Barry S Levy and Victor W Sidel

152

Tetanus Tejpratap S P Tiwari

158

Tobacco Control: An Integrated Approach Ron Borland

164

Tobacco Harm Minimization Richard J O’Connor and K Michael Cummings

169

Torture and Public Health Linda Piwowarczyk and Michael Grodin

178

Traditional Asian Medical Systems Elisabeth Hsu and Ron L Barrett

187

Transition to Universal Coverage in Developing Countries Tim Ensor

195

Transmissible Spongiform Encephalopathies Ermias D Belay

206

Trends in Human Fertility John G Cleland

212

Contents of All Volumes

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Tuberculosis Diagnosis Peter D O Davies

219

Tuberculosis Epidemiology Giovanni Sotgiu, Philippe Glaziou, Charalambos Sismanidis, and Mario Raviglione

229

Tuberculosis: Overview Terry M O’Connor

241

Tuberculosis Prevention Jennifer S Landry and Dick Menzies

246

Tuberculosis, Public Health Aspects Giovanni B Migliori, Rosella Centis, Alimuddin Zumla, Ziad A Memish, and Mario C Raviglione

252

Tuberculosis Treatment Payam Nahid and Philip C Hopewell

267

Typhoid Fever Laura Saporito, Claudia Colomba, and Lucina Titone

277

U Undernutrition and Its Social Determinants Vundli Ramokolo, Wanga Zembe-Mkabile, and David Sanders

284

United Kingdom, Health System of Rebecca Surender, Karen Matsuoka, and Pavel Ovseiko

293

Unsafe Abortion Anibal Faúndes and Laura Miranda

301

Urban Health Systems: Overview Danielle C Ompad, Sandro Galea, and David Vlahov

311

V Vaccines, Historical Husein Moloo and Andrew W Artenstein

318

Venous Thromboembolism Damon Houghton and Nigel S Key

330

Violence against Women Claudia Garcia-Moreno and Heidi Stöckl

337

Violence/Intentional Injuries e Epidemiology and Overview Alison Rutherford

344

Violence/Intentional Injuries e Prevention and Control Dinesh Sethi and Alexander Butchart

351

Viral Diarrhea Gagandeep Kang

360

Viral Infections, an Overview with a Focus on Prevention of Transmission Vincent Chi-Chung Cheng, Jasper Fuk-Woo Chan, Ivan Fan-Ngai Hung, and Kwok-Yung Yuen

368

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Contents of All Volumes

Vitamin A Deficiency and Its Prevention Susanne H Wedner and David A Ross

378

Vitamin D Reinhold Vieth

383

W Waterborne Diseases Jeffrey K Griffiths

388

Weapons of Mass Destruction Victor W Sidel and Barry S Levy

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Western Europe, Health Systems of Achim Schmid and Richard Freeman

408

WHO Definition of Health, Rethinking the Sissela Bok

417

Wilson’s Disease Amit Kulkarni and Vijay Kumar Sharma

424

Women’s Mental Health Prabha S Chandra, Meiya Varghese, and T A Supraja

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Worker Health and Safety: International Issues Leslie London and Sophie Kisting

444

World Bank Jennifer P Ruger

453

World Health Organization Uzor C Ogbu and Onyebuchi A Arah

461

World’s Medical Schools: Past, Present and Future Markley H Boyer

468

Y Yaws, Bejel, and Pinta Oriol Mitjà and Kingsley Asiedu

476

Yellow Fever Elizabeth D Barnett

484

Yellow Fever, Historical John T Cathey and John S Marr

491

Young People and Violence Iris Wagman Borowsky, Timothy P Capecchi, Rachel Widome, and Michael D Resnick

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Index

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A Acute Care Hospitals Martin Hensher, Department of Health, London, UK Ó 2017 Elsevier Inc. All rights reserved.

Introduction Acute care can be defined as the short-term care and treatment of patients suffering an episode of serious illness or who have sustained an injury. Across the world, the preferred location for the delivery of this form of care is the hospital. Hospitals are a ubiquitous human institution, common to all modern societies. However, the form and organization of hospitals varies greatly from country to country, reflecting different cultural, medical, and economic traditions.

Origins and History of Acute Hospitals A number of European hospitals can trace their roots back to the twelfth century. These were typically founded by religious orders, and usually formed part of an almshouse for the poor and infirm. By the late eighteenth century, similar institutions were becoming more common in larger towns and cities as the process of urbanization and industrialization began to gather pace in Europe and North America. However, these hospitals were still seen as places of death, disease, and destitution from which few emerged alive, and were shunned by the wealthy (who were treated at home by their physicians and surgeons). This bleak picture was transformed during the nineteenth century as the concepts of hygiene and antisepsis and the beginnings of modern anesthesia delivered startling improvements in patient survival, so that hospitals began to be seen as a place of safety and healing, rather than a place for the indigent to die. This transformation was complete by the middle of the twentieth century, as effective antimicrobials greatly reduced the risks of infection, and advances in therapeutic technology steadily improved the clinical outcomes that patients could expect to receive from hospital treatment. Indeed, by the end of the twentieth century, calls for a reduced reliance on hospital care and a concern that acute hospitals may overmedicalize the natural processes of birth, aging, and dying, had become commonplace in many countries.

1. To provide the fixed physical and technological infrastructure required to support care for acutely ill patients, much of which could not be provided (for technical or economic reasons) at a smaller scale of institution or in the patient’s home. 2. To concentrate personnel with specialized and scarce skills onto the same location, allowing them to provide 24-h care for many patients simultaneously, and to give acutely ill patients rapid access to a wide set of diagnostic and therapeutic skills should their condition change. Both of these functions fundamentally reflect the existence of some degree of economies of scale and of scope (Posnett, 2002) in the care of acutely sick patients. However, these economies are not fixed; over time and across continents technologies, processes, and costs will vary substantially. Certainly the mix of patients likely to present at an ‘acute’ hospital of notionally similar size (and the care that can be provided for them) might differ wildly between Canada and Cameroon, for example. While resource availability will dictate exactly what activities are carried out, any acute hospital will provide the following basic services: Initial assessment and stabilization of the acutely ill patient; Provision of more definitive diagnosis; l Immediate/urgent treatment. l l

What happens next for a patient with a given condition may, however, vary more substantially between different health systems. In some, patients may be hospitalized for longer, receiving treatment and rehabilitation as inpatients in the acute hospital; in others, they may be discharged to home or nonacute facilities to receive treatment and rehabilitation outside the acute setting. In some systems, a single acute hospital may provide both urgent and planned care (e.g., elective surgery), while in others planned follow-up care may be provided by different organizations.

Specific Functions

Roles and Functions of Acute Care Hospitals Common Functions An acute hospital is instantly recognizable as such anywhere in the world. Yet the precise nature of the conditions they treat,

International Encyclopedia of Public Health, 2nd edition, Volume 1

the staff who work in them, and their place within the wider health-care system vary substantially. At their most generic level, the common functions of all acute hospitals can be described as follows:

Beyond the most basic function of providing a clinically and economically viable platform for round-the-clock care for acutely ill patients, acute hospitals may often perform a range of other very important roles within the health-care system.

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In most countries, acute hospitals form part of a referral system, which allows patients to be referred to increasingly specialized levels of care – allowing escalation and de-escalation of care from initial contact with generalist first-contact providers up to highly specialized centers of expertise. In many developing country health systems, an acute hospital may well be the first level of care at which any qualified physicians might be encountered. Many acute hospitals also play an important role in the education and training of health professionals, providing practical training opportunities for many different staff groups. However, this role can vary substantially from country to country, reflecting traditions and customs as much as deliberate design. For example, practically every acute hospital in the United Kingdom’s National Health Service (NHS) is a training hospital – because almost all NHS hospitals rely heavily on junior doctors who are still in training posts for 2 years after initial qualification to provide much of their basic nonspecialist medical cover, and upon specialist registrars (i.e., more experienced doctors who are training for accreditation as specialists) to provide much of their specialist care. In many other countries, these doctors would be concentrated in a much smaller proportion of hospitals, which are explicitly designated as university or teaching hospitals.

The Organization of Acute Hospitals Service Mix Two related factors have together exerted a substantial influence on the specific organization and service mix of acute hospitals seen in different countries and contexts. The first is the underlying service model to which hospitals and health systems aspire; crudely, this can be considered along an axis ranging from ‘fully comprehensive’ (i.e., each acute hospital should provide a full and clearly defined range of services) to ‘fully networked’ (i.e., different hospitals provide quite different service ranges, supporting and complementing each other through network arrangements to ensure that a local health system – rather than any one hospital – provides a comprehensive service range to patients). Closely linked is the extent to which local health services are systematically planned, or are driven by market forces. The ideal of specifying a comprehensive service model, and then planning and investing actively to ensure that hospitals conform to this model, has had a powerful influence on health planning in many countries. The basis of this conceptual model was clearly stated in the United Kingdom’s Hospital Plan of 1962, but has been restated in many other countries since then: Each health district should contain a single district hospital, providing a defined set of acute care services capable of dealing with the vast majority of acute care needs that might present themselves from a defined district population (often specified in terms of an ideal or typical population size). In this model, local acute hospitals serve a defined population as a ‘natural monopoly’ provider; patients requiring more specialized care are referred up a clearly specified referral system. Such an approach is still an important force in health planning, for example, in the recent development of district and regional hospital packages of care in the South African public health

system (Department of Health, 2002). By contrast, many other systems have taken a less directive approach to the service mix offered by acute hospitals. An individual hospital may offer whatever mix of service it believes it can sustain given likely local demand, revenue, and market factors (within certain regulatory constraints); funders or planners focus their efforts on ensuring that a full range of services are provided to a defined population (be they members of a particular insurance fund or inhabitants of a geographical area) from a collection of different providers. These providers might find themselves in competition with one another for certain services, yet mutually dependent for others. This more ‘laissez faire’ approach is a hallmark of systems with higher degrees of private insurance funding (e.g., the United States, urban areas of India) and/or nonstate ownership of health facilities, but also appears in many social health insurance systems (e.g., France, Germany). Although a copious and inconclusive literature has examined the issues of competition and markets versus planned approaches to health care over many years, it is interesting to note that very little attention has been paid to studying the real differences in service mix observed across different systems. Clearly, the precise service mix of an ‘acute’ hospital will vary tremendously according to context and setting. Tertiary sub-specialists at hospitals such as Massachusetts General or University College Hospitals London provide acute hospital care; yet so does a medical officer at a district hospital in Africa, single-handedly providing medical, pediatric, obstetric, and surgical care to a rural population hundreds of kilometers from any other hospital. Attempts have periodically been made to specify particular service packages that should be provided by acute hospitals in different countries (see NHS National Leadership Network, 2006) for a recent exercise in England), yet such an approach cannot possibly yield results applicable in all settings. Certain trends in overall service mix can clearly be pointed to, however. Chief among these has been a consistent downward trend in the number of acute hospital beds available and in the duration of hospital stay across all developed economies (Hensher et al., 1999a). Acute hospitals have increasingly focused their efforts and activities on the sickest patients at the most acute phase of their illness, as technological and infrastructural advances have allowed patients to be discharged ever earlier and to be cared for safely and effectively at home. This trend has physically reshaped the acute hospital infrastructure across Europe and North America, as bed and hospital numbers have shrunk from their peak in the 1950s. In many countries, another visible trend has been the separation of planned care from emergency or unplanned care. Routinely scheduled care (primarily but not exclusively surgery) increasingly takes place in different facilities (in separate theaters, wards, or even entirely different hospitals) to ensure it is not disrupted by the unpredictable demand for emergency care and to maximize productive efficiency. Some writers (e.g., Herzlinger, 1997) have suggested that the future may lie in ‘focused factories’ – hospitals specializing in one specific condition or organ system – to generate maximum expertise and efficiency. Actual movement toward this model seems altogether more limited; indeed, single-specialty hospitals were arguably more common 20 years ago than they are

Acute Care Hospitals today, as they were an important feature of Soviet bloc health systems.

Relationship with Primary Health-care Services It has been recognized for many years that high-quality and efficient acute care requires effective coordination between acute hospitals and the primary health-care services that provide most of us with the overwhelming majority of the health care we will require throughout our lifetimes. The caricature of the hospital as the centerpiece of the health system has – especially in developing countries – given way to an alternative caricature of the hospital as a drain on primary care, sucking resources into attempts to rescue the sickest patients and away from cost-effective primary care and public health programs. Yet, in developed countries, a great deal of care is now delivered in community settings, care that previously would only have been delivered within an acute hospital, and much effort has been devoted to re-engineering systems and care pathways to minimize the need for hospitalization. Developments in pharmaceutical and diagnostic technology have greatly facilitated this shift, but concerted efforts have also been made to move key staff into community-based settings. Such processes will clearly have limits at any given point in time, especially in the presence of economies of scale (see Roland et al., 2005; for a careful study of the scope for and limitations on shifting care from hospital to primary care settings in the UK). Great care and pragmatism is required when considering this issue in developing countries. Despite their many faults and failings, acute hospitals are often the most functionally effective and intact components of health systems in poor countries; dismantling them in the name of primary care principles should not be advocated without the most serious consideration and technical challenge. Indeed, the idea of a deep divide between primary care and acute care is arguably an artifact of particular organizational models, particularly those that differentiate sharply between primary care and hospital physicians. Thus, in some systems, general practitioners handle primary care activity, and hospital doctors are employed by and work in hospitals – and never the twain shall meet. Yet in other systems, specialist physicians frequently practice both in the hospital and in office-based practice in the community, whereas general practitioners may well have admitting rights in acute hospitals, where they will admit and care for their patients using hospital resources. The export and import of novel models of care integration often does not pay enough attention to the profound differences between systems in the underlying models of physician employment and the incentives that flow from them.

Recent and Emerging Trends The long-term historical trend toward a smaller number of acute hospital beds and a reduced reliance on acute inpatient care has already been noted. It has perhaps been most pronounced in the United States, but is clearly visible in all high-income and many middle-income countries. This trend has been less clear in developing countries, due in part to

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more limited data availability, and also to the very low baseline of health service provision in more countries – services that are inadequate to meet current needs would hardly be expected to shrink. In richer countries this trend has been driven by multiple factors – better treatments and outcomes, reduced length of stay, significant substitution of acute hospital stays with stays in nursing homes, rapid growth in the ability to offer interventions on an ambulatory care basis, and explicit economic incentives (see Hensher et al., 1999b; for a fuller discussion). A parallel trend visible more recently has been a tendency to concentrate more complex interventions (particularly, but not exclusively, specialized surgery) onto a reduced number of centers. This trend has reflected growing evidence that surgical and other outcomes are related to the volume of specific procedures undertaken by an individual practitioner. For many procedures, there is now evidence that outcomes are poor when practitioners undertake only small volumes; perhaps most far-reaching in its implications has been evidence indicating that outcomes are poorer in trauma surgery outside specialized major trauma centers. As a result, many health systems have attempted (via differing mechanisms) to ensure that less common procedures are concentrated into specialist centers. When combined with the parallel shift of simpler activity out of hospital and into ambulatory care, this raises the prospect of a subset of hospitals (primarily smaller general hospitals, without specialist centers of expertise) being left with too small a core of inpatient services to remain economically viable. Were such hospitals to close, then local communities may face significant reductions in their ability to access basic acute care – a trade-off sometimes not explicitly addressed in discussions of the benefits of service concentration of specialized procedures.

The Future of Acute Hospitals – Challenges and Risks A growing challenge for acute hospitals has been the steady rise in the incidence of drug-resistant health-care-acquired infections (HCAIs), such as methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile. HCAIs have, in many developed countries, become endemic in acute care hospitals, with around 9% of hospital patients in England infected with an HCAI at any one time (Public Accounts Committee, 2005). HCAIs lead directly to the death of some patients; undermine care outcomes for many more; lead to increased resource utilization and costs in the care of infected patients; and undermine patient and public confidence in hospitals and health care more generally. Pharmaceutical solutions to HCAIs seem not to be forthcoming; HCAIs are therefore likely to continue to require greater attention to infection control, effective case finding, using ambulatory care to avoid admission to hospital in the first place, and even changes to the physical design of hospitals if they are to be controlled effectively. In the worst case, a failure to deal effectively with HCAIs could turn the clock back significantly on acute hospital care – the long downward trend in hospital stays could be reversed, and the public may cease to view hospitals as places of safety – reverting to their pre-twentieth-century status as risky environments in which only those who cannot afford other forms of

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care would willingly enter. It is also possible that recent patterns of acute hospital care may be challenged in adapting to a low-carbon future. Service models that are reliant on long or frequent journeys for either patients or staff might need to be reconsidered if transportation costs start to rise significantly, due either to carbon taxes or increasing fuel scarcity. There is little doubt that – barring truly extraordinary scientific breakthroughs – the acute hospital will still be with us in a 100 years’ time. Even if its physical form has changed, and the treatments provided within its walls have changed completely from those we know today, the future hospital as a social institution would still be clearly recognizable to us. The challenge for health systems is to seek a continuous rebalancing of care provision and location to reflect changing technologies, capabilities, and relative costs. The designers of acute hospital systems for the future – whether in rich or poor countries – will need to strive constantly to ensure that hospitals provide only that appropriately specialized acute care that cannot be more cost effectively delivered in other settings – but that they also support primary health care integrally through the wider distribution of information, expertise, and skills.

See also: Antimicrobial Resistance in a One Health and One World Perspective – Mechanisms and Solutions; Comparative Health Systems; Competition in Health Care; Long-Term Care Organization and Financing; National Health Systems: A Historical Overview; Planning, for Public Health Policy; Primary Health Care; World’s Medical Schools: Past, Present and Future.

References Department of Health, 2002. A District Hospital Service Package for South Africa: A Set of Norms and Standards. Department of Health, Pretoria, South Africa. Hensher, M., Edwards, N., Stokes, R., 1999a. International trends in the provision and utilisation of hospital care. Br. Med. J. 319, 845–848. Hensher, M., Fulop, N., Coast, J., Jefferys, E., 1999b. Better out than in? Alternatives to acute hospital care. Br. Med. J. 319, 1127–1130.

Herzlinger, R., 1997. Market-Driven Healthcare: Who Wins, Who Loses in the Transformation of America’s Largest Service Industry. Addison-Wesley, Reading, MA. NHS National Leadership Network Local Hospitals Project, 2006. Strengthening Local Services: The Future of the Acute Hospital. National Health Service, London. Posnett, J., 2002. Are bigger hospitals better? In: McKee, M., Healy, J. (Eds.), Hospitals in a Changing Europe. Open University Press, Buckingham, UK, pp. 100–118. Public Accounts Committee, 2005. Public Accounts – Twenty-Fourth Report. House of Commons, London. http://www.publications.parliament.uk (accessed March, 2008). Roland, M., McDonald, R., Sibbald, B., et al., 2005. Outpatient Services and Primary Care: A Scoping Review of Research into Strategies for Improving Outpatient Effectiveness and Efficiency. National Primary Care Research and Development Centre, Manchester, UK.

Further Reading Barnum, H., Kutzin, J., 1993. Public Hospitals in Developing Countries: Resource Use, Cost, Financing. Johns Hopkins University Press, Baltimore, MD. Centre for Reviews and Dissemination, 1996. Effective Health Care Bulletin: Hospital Volume and Health Care Outcomes, Costs and Patient Access. NHS Centre for Reviews and Dissemination, New York, UK. English, M., Lanata, C.F., Ngugi, I., Smith, P.C., 2006. The district hospital. In: Jamison, D.T., Breman, J.G., Measham, A.R., et al. (Eds.), Disease Control Priorities in Developing Countries, second ed. Oxford University Press, New York, pp. 1211–1228. Hensher, M., Price, M., Adomakoh, S., 2006. The referral hospital. In: Jamison, D.T., Breman, J.G., Measham, A.R., et al. (Eds.), Disease Control Priorities in Developing Countries, second ed. Oxford University Press, New York, pp. 1229–1244. McKee, M., Healy, J. (Eds.), 2002. Hospitals in a Changing Europe. Open University Press, Buckingham, UK. Risse, G.B., 1999. Mending Bodies, Saving Souls: A History of Hospitals. Oxford University Press, New York.

Relevant Websites http://www.kznhealth.gov.za/norms.pdf – Department of Health, (Pretoria, South Africa). http://www.dcp2.org – Disease Control Priorities Project (DCPP). http://www.jointcommission.org/PublicPolicy/future.html – The Joint Commission ‘Hospital of the Future’ Project. http://www.mapofmedicine.com – Map of Medicine. http://www.institute.nhs.uk – The NHS Institute for Innovation and Improvement.

Adenoviruses Luisa A Ikner and Charles P Gerba, Water & Energy Sustainable Technology (WEST) Center, The University of Arizona, Tucson, AZ, USA Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Charles P. Gerba, R.A. Rodriguez, volume 1, pp. 28–33, Ó 2008, Elsevier Inc.

Introduction Adenoviruses infect a variety of vertebrate species. In human hosts, adenoviral illnesses manifest most commonly in children and young adults as respiratory and eye infections, and gastroenteritis. Enteric serotypes of the virus are a major cause of gastroenteritis among children worldwide, and respiratory strains have been implicated in outbreaks of acute respiratory disease among military trainees. Obesity among both children and adults has also been correlated with seropositivity to adenovirus 36. Although adenovirus infections in healthy persons are largely either asymptomatic or self-limiting, immunocompromised individuals (e.g., transplant patients, AIDS patients) are more susceptible to severe symptomology and outcomes, with mortality rates ranging from 2% to 70% for those infected (Echavarría, 2008). Adenoviruses are classified under the viral family Adenoviridae, which is further subdivided into five genera: Mastadenovirus, Aviadenovirus, Atadenovirus, Siadenovirus, and Ichtadenovirus (Harrach et al., 2011). The genus Mastadenovirus is comprised of all known adenoviruses known to infect humans, as well as serotypes infecting bovine, canine, equine, murine, ovine, porcine, and simian species in addition to tree shrews. Members of the Aviadenovirus genus only infect birds, while those in Atadenovirus infect bovine and ovine species as well as ducks, possums, and snakes. Siadenovirus is characterized by three known hosts (frogs, turkeys, and raptors), and the white sturgeon is the only known host in the Ichtadenovirus genus. The natural host range of adenovirus serotypes is generally limited to a single species or a closely related species. There are currently 56 identifiable human adenovirus serotypes, which are also commonly referred to as ‘types.’ These are divided into seven subgroups (A–G) and four hemagglutination groups (I–IV). Each adenovirus type is differentiated by a lack of cross-reactivity to antisera of other known serotypes. Adenoviruses are further characterized by their oncogenic potential and ability to agglutinate rhesus monkey and

Table 1

rat erythrocytes. The current classification scheme for human adenovirus serotypes is outlined in Table 1.

Structure and Physical/Chemical Properties Adenoviruses are 70–90 nm in diameter. They are comprised of an icosahedral, nonenveloped nucleocapsid that encases a single linear, double-stranded DNA genome. The nucleocapsid consists of 252 capsomer proteins in total – 240 nonvertex hexon capsomers and 12 penton base vertex capsomers. For the majority of adenovirus serotypes, a single fiber of varying length (which is unique per serotype) extends from each penton base, with the exception of enteric serotypes 40 and 41 which project two fibers per penton base. Adenoviruses may remain infectious outside of host cells for extended periods of time. Environmental factors including temperature, humidity, and the presence of organic matter such as feces contribute to inactivation rates on both porous and nonporous surfaces (Boone and Gerba, 2007). The ability to maintain infectivity outside of host cells may facilitate transmittance of adenoviruses to human hosts from inanimate objects in the environment. They are also able to maintain stability in the presence of a number of physical and chemical agents including elevated temperatures and surfactant-based disinfectant solvents, respectively. However, they are generally susceptible to oxidizing agents. While infectivity is optimal within a neutral pH range of 6.5–7.4, adenoviruses, in general, can tolerate pH levels from 5.0 to 9.0. Heat sensitivity varies among the genera and is dependent on temperature and exposure time. Adenoviruses also maintain infectivity after freezing.

Illnesses Adenovirus serotypes causing respiratory illness are transmitted from person to person largely by way of infective aerosols, and

Human adenovirus serotype classification

Subgroup

Serotype group

Hemagglutination

A B C D

12, 18, 31 3, 7, 11, 14, 16, 21, 34, 35, 50, 55 1, 2, 5, 6 8–10, 13, 15, 17, 19, 20, 22–30, 32, 33, 36–39, 42–49, 51, 53, 54, 56 4 40, 41 52

IV (little or no agglutination) I (complete agglutination of rhesus monkey erythrocytes) III (partial agglutination of rat erythrocytes) II (complete agglutination of rat erythrocytes)

E F G

III III N.D.

N.D., Not determined.

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Adenoviruses

enteric forms via the fecal–oral route. Transmission may also occur via contaminated inanimate environmental surfaces (i.e., fomites). Viruses can be transferred to hands by touching the contaminated hands of others or fomites. Self-inoculation then follows into the mouth, nose, or ocular conjunctiva of permissive human hosts. The majority of the 56 known human serotypes are believed to cause asymptomatic infections, while 30% are associated with human disease (Table 2). Adenoviruses have a broad tissue tropism and cause a variety of infections in the human body. The most frequently reported illnesses are upper (pharyngitis and tonsillitis) and lower (bronchitis, bronchiolitis, and pneumonia) respiratory infections, conjunctivitis, cystitis, and gastroenteritis. These infections may also become systemic and affect the bladder, liver, pancreas, myocardium, or central nervous system. Enteric adenoviruses are a leading cause of acute gastroenteritis worldwide in infants and young children following rotavirus and noroviruses (Lanata et al., 2013). The majority of ailments caused by adenoviruses are acute and self-limiting. Diarrhea is a symptom of infection by several adenovirus types; however, infectious virions can be shed in the feces whether they are characterized as diarrhea or not. Shedding of adenoviruses in the feces can continue for extended periods after symptoms have subsided. Occurrence studies have found that up to 20% of asymptomatically infected persons may also expel viruses in solid excreta. Subgenera C serotypes may be excreted for several months or years following initial onset of disease. Member serotypes of subgenera B and E cause higher rates of respiratory distress, while most infections caused by A and D generally are asymptomatic. Adenovirus latency in the tonsils, lymphocytes, and adenoidal tissues of human hosts can last for years, with reactivation occurring due to particular conditions such as a change in immune status. The long-term effects of latent adenovirus infections remain unknown. Immunity is serotype-specific. Antibodies produced as a response to a previous infection usually confer protective immunity upon reexposure to the same serotype, and symptoms rarely manifest in the host. Certain serotypes of human adenoviruses from subgenera A and B are oncogenic when introduced into an animal model. For example, human adenovirus 12 is able to cause undifferentiated tumors in hamsters following subcutaneous or intramuscular injection (Doerfler, 2009). However, no human cancers have been linked to infection by any of the known 56 serotypes, and pursuits for tumor antigens and DNA sequences remain negative.

Table 2

Respiratory Infections Adenovirus serotypes 1–6 are causative agents of acute respiratory diseases (ARDs) worldwide, particularly in children. Serological surveys have estimated that 10–25% of respiratory infections in children are attributable to adenoviruses (Fox et al., 1969; Bezerra et al., 2011). Respiratory adenovirus infections are also well documented in adults. Symptoms of adenovirus ARD include fever, chills, headache, malaise, and myalgia. Secondary attack rates in households can be upwards of 50% due to fecal–oral transmission that is likely enhanced by high levels of viral shedding in excreta. Infectious adenoviruses can be recovered from the throat or stools of an infected child for up to 3 weeks. Adenovirus serotypes 1–7 are largely associated with mild to moderate respiratory illnesses including pharyngitis, tonsillitis, and the common cold. Type 7 has also been implicated as a cause of pneumonia in children and military recruits (Moro et al., 2009). Infants and children infected with adenoviral pneumonia suffer severe, and at times, fatal, outcomes. Other lower respiratory infections attributable to adenoviruses include bronchitis and bronchiolitis.

ARD of Military Recruits ARD is an infection typified by nasal congestion, coryza (nasal discharge), and a cough coupled with fever, chills, malaise, myalgia, and headache. Progressive disease usually results in pneumonia, which can be fatal. It spreads via infective aerosols among individuals subjected to fatigue and crowding. The earliest recognized cases were among military recruits during World War II. An investigative commission was assembled at the time in effort to characterize the illness and determine its etiology. Following analysis of data provided by human volunteers and epidemiologic profiling, the disease was classified as ARD. It was distinguished from other infectious respiratory disease agents at the time as a filterable agent (i.e., virus), and by an incubation period of 5–6 days. Adenovirus types 4 and 7 were initially identified as the infectious viral agents causing ARD. The US military initiated an immunization program in 1971 targeting these serotypes. It continued through 1996, at which time the sole manufacturer of the vaccine ceased production. An ARD epidemic caused by adenovirus 4 soon followed, and more than 1000 military trainees were infected. Although deaths from adenoviral ARD pneumonia are rare, they do still occur. A survey of

Common illnesses associated with human adenoviruses

Disease

Individuals at risk

Principal serotypes

Acute febrile pharyngitis Pharyngoconjunctival fever Acute respiratory disease Pneumonia Epidemic keratoconjunctivitis Follicular conjunctivitis Gastroenteritis/diarrhea Urinary tract colon hepatitis

Infants, young children School-aged children School-aged children, military recruits, elderly Infants, young children, military recruits Any Infants, young children Infants, young children Bone marrow, liver, or kidney transplant recipients, AIDS patients, or immunosuppressed

1–3, 5–7 3, 7, 14 3, 4, 7, 11, 14, 16, 21 1–4, 6, 7, 14, 16, 55 8–11, 13, 15, 17, 19, 20, 22–29, 37, 54, 56 3, 7, 53 18, 31, 40, 41, 52 1, 2, 5, 34, 35, 42–51

Adenoviruses US military trainees from 1998 to 2010 documented eight deaths from ARD-related pneumonia (Potter et al., 2012). Adenovirus serotypes 4, 7, and 14 were isolated from the afflicted military members. Other sources of risk from adenoviral ARD include college dormitories, children’s institutions, and childcare facilities.

Pharyngoconjunctival Fever Subgenera B adenoviruses mostly cause pharyngoconjunctival fever (PCF). PCF is a syndrome comprised of unilateral or bilateral conjunctivitis, pharyngitis, rhinitis, and spiking fever up to 104  F. The illness generally lasts from 5 to 7 days. The most common etiologic agent is adenovirus 3, although serotypes 4, 7, 11, and 14 have also been associated with the disease. Children are the most commonly afflicted, with direct transmission to the eyes or upper respiratory tract occurring due to contact with the contaminated waters of swimming pools, water reservoirs, and small lakes. Outbreaks of PCF are frequent in childcare centers, schools, and summer camps. Secondary spread to caretaking adults is common, although symptoms tend to be less severe (e.g., mild conjunctivitis).

Eye Infections Adenoviruses account for 65–95% of viral conjunctivitis cases worldwide (Pelino et al., 2015). A number of adenovirus serotypes including 8, 11, 19, and 37 can cause epidemic keratoconjunctivitis (EKC), a highly contagious disease in which the conjunctiva becomes infiltrated, chemotic, and hyperemic. Most major epidemics of EKC have historically been associated with types 8, 19, and 37, with more recent large-scale outbreaks in Asia caused by emergent adenovirus serotypes 54 and 56. Sporadic cases have also been reported worldwide in Europe, North America, Asia, and Australia, with serotype 8 responsible for the greatest total number of cases (Adhikary and Banik, 2014). Transmission occurs via direct contact with eye secretions from an infected person and through contact with contaminated fomites, eye instruments, ophthalmic solutions, and the towels or hands of medical personnel. Eye trauma can increase the risk of infection. Large-scale outbreaks have mostly involved adults, although smaller outbreaks have been reported among pediatric and neonatal units in hospital settings (Centers for Disease Control and Prevention, 2013). The first large-scale outbreak occurred during World War II among shipyard workers in Hawaii and was called ‘shipyard eye’ or ‘shipyard’ conjunctivitis. The causative agent was later identified as human adenovirus serotype 8. Other outbreaks have involved contaminated ophthalmic solutions and a roller towel used for drying faces and hands. Outbreaks of EKC are commonly reported from the offices of ophthalmologists. Transmission is thought to be facilitated by inadequate sterilization of equipment or contact lenses, direct manipulation of the eye, or by use of eye solutions and ointments. Although secondary spread between infected children and family members has been documented, direct inoculation into the eye appears to be necessary for disease onset. Follicular conjunctivitis is a less severe form that primarily affects the clear membrane coating, the inner aspect of the eyelids, and the outer surface of the eye. Most cases are mild

7

and followed by complete recovery. It is transmitted from person to person and often contracted by swimming in inadequately chlorinated swimming pools or bodies of freshwater during the summer. Cases occur on an individual basis or may occur in large groups of people. The first documented outbreak of adenoviral follicular conjunctivitis occurred in 1955 when swimmers frequenting a local pool became infected. Adenovirus serotypes 3 and 7 are most commonly isolated for this condition, although a number of other types are capable of causing the associated symptomology.

Gastroenteritis Enteric adenoviruses are a leading cause of childhood gastroenteritis after rotavirus and noroviruses. The worldwide incidence of adenoviral gastroenteritis in children has ranged from 3.1% to 13% (Biçer et al., 2011). Adenoviruses 40 and 41 are the most common etiologic agents and cause diarrhea accompanied by fever usually lasting for 2 weeks. It has been estimated that serotypes 40 and 41 contribute to 5–20% of hospitalizations for diarrhea in developed countries. Young children are the most vulnerable to infection and are more likely to present with respiratory symptoms in conjunction with gastroenteritis when infected with enteric adenoviruses (Wiegering et al., 2011). Serotypes 18, 31, and 52 can also cause gastroenteritis. Amino acid sequence characterization revealed that adenovirus 31 is closely related to adenoviruses 40 and 41. Adenovirus 31 is more closely associated with diarrhea than the other nonenteric adenoviruses.

Obesity ‘Infectobesity’ refers to the ability of viral agents to cause obesity in infected hosts. Several studies have demonstrated a causal relationship between adenovirus 36 and obesity in animal models including chickens, mice, and nonhuman primates. A higher prevalence of serum antibodies to adenovirus 36 in obese children and adults has been observed worldwide. The metabolic and molecular mechanisms of how adenovirus infections eventuate in obesity have yet to be determined. Since increased food intake alone cannot adequately explain observed increases in adiposity (tendency to store fat), it has been suggested that adenovirus 36 may induce metabolic changes. One proposed mechanism involves the influence of adenovirus 36 on the differentiation of preadipocyte cells and/or the accumulation of lipids by adipocytes (cells that accumulate fat in the body). Increased glucose uptake has also been correlated with adenovirus 36–stimulated Ras signaling for infected human adipose-derived stem cells and human skeletal muscle cells (Rogers et al., 2008). In addition, mice lacking a monocyte chemoattractant protein (MCP-1) were protected against adenovirus 36–induced inflammation and obesity relative to wild-type mice (Na and Nam, 2012).

Morbidity and Mortality Adenovirus is not a reportable disease agent. Therefore, there are no national- or population-based morbidity and mortality figures available. The majority of epidemiological data comes

8

Adenoviruses

from the study of select populations that are most affected by adenovirus infections. Such groups include children in hospitals and childcare centers, military trainees, immunocompromised persons, and groups of families. In the 1950s, adenoviral ARD infections were common among military personnel with as many as 10% infected. Complications from pneumonia accounted for 90% of associated hospitalizations. With the implementation of a vaccine schedule against serotypes 4 and 7 in the 1970s, the number of cases subsided. However, the sole manufacturer of the vaccine ceased its production in 1996, and a resurgence in morbidity (10–12%) and mortality rates among previously healthy military recruits occurred during the first decade of the twenty-first century. Beginning in 2011, a live nonattenuated oral vaccine against serotypes 4 and 7 was mandated for use by military members. Rates of adenoviral ARD illness and mortality have since been in decline.

Impact on the Immunocompromised The immune status of an infected individual is a strong predictor of adenoviral disease severity. Adenovirus infections and outcomes in immunocompromised hosts have therefore been well documented. In immunocompetent persons, nonenteric adenovirus infections usually produce moderate, selflimiting illness. Immunocompromised hosts, however, are at increased risk for serious and potentially fatal systemic disease. In immunocompromised hosts, adenoviruses more readily disseminate into any body system. Severe illnesses can develop including pneumonitis, meningoencephalitis, hepatitis (particularly in liver and bone marrow transplant patients), and hemorrhagic cystitis (especially in kidney transplant patients), eventuating in death for some infected persons (Table 3). Enteric adenovirus serotypes are rarely isolated from immunocompromised patients with gastroenteritis or diarrhea.

Adenoviruses are commonly detected in raw and disinfected secondary sewage due to their high levels of excretion in human feces. They have been suggested as index organisms for other enteric viral pathogens (e.g., noroviruses) in water quality monitoring, in part, due to their high levels of persistence in the environment. Adenoviruses were detected in 100% of the wastewater and combined sewage overflow discharge samples collected in Michigan over a 1-year period, with enteric serotype 41 comprising most of the isolates (Fong et al., 2010). Comparative studies have demonstrated that adenoviruses usually outnumber enteroviruses in surface waters. There is very little information regarding the occurrence and persistence of adenoviruses in groundwater. A study conducted in France of confined and unconfined aquifers detected adenoviral genomic material using real-time PCR, thereby indicating presence or occurrence (Ogorzaly et al., 2010). Due to a lack of cell culture data, however, the infectious state of the isolates could not be ascertained.

Survival in the Environment

Mortality ratio (%)

References

15 19

Murtagh et al. (2009) Schilham et al. (2002)

Resistance to Disinfectants

75 50

Symeonidis et al. (2007) Lion (2014)

All serotypes of adenovirus are excreted in the feces. Therefore, contaminated water is a potential source of exposure by way of ingestion, inhalation, or direct contact with the eyes. A number of adenovirus outbreaks due to recreational water exposure have been documented over the years, with a majority originating in swimming pools prior to 1980 (Sinclair et al., 2009). More than half of the outbreaks were linked to adenovirus 3, Table 3 Mortality ratios associated with adenovirus illnesses in subpopulations

Children 100 mg l
1) in Bangladesh has led to substantial adverse and systemic health outcomes ranging from cardiovascular disease, cancer, dermal diseases, diabetes, and all-cause mortality (Yunus et al., 2011). These outcomes are not limited to adults with children showing increased risk for skin abnormalities and lung diseases (Majumder et al., 2012). Recent years have seen incredible efforts to identify the most efficient remediation technique for tube-wells in Bangladesh given that 60% of them are contaminated with inorganic arsenic 10 mg l
1) potentially exposing more than 80 million people. Many technologies have been investigated for efficiency at arsenic removal from drinking water in Bangladesh however complicating this is that for a technology to be applied in a developing country such as Bangladesh, it needs to be low cost, adaptable and transferrable (Jiang, 2012). As of 2012, oxidation, co-precipitation, and flocculation along with bio-organisms have been determined most appropriate for remediating tube-wells in Bangladesh (Jiang, 2012). Current research is also investigating technologies to reduce tube-well contamination by understanding sources and mobilization of inorganic arsenic. In addition to drinking water, food is a major source of arsenic exposure (Figure 2). The major sources of inorganic arsenic exposure in food are (1) plant material (vegetables) irrigated with contaminated water in arsenic-endemic areas such as Bangladesh, (2) rice, which can accumulate inorganic arsenic (55–97 ng g
1) through cooking in contaminated water or

SW Finland British Columbia, Canada Bavaria, Germany Western, Central, and Northeastern, United States

Xinjiang, China

Inner Mongolia, China Fukuoka, Japan

Spain Danube Basin

Taiwan

Ghana Antofagasta Region, Chile NW Argentina Chaco-Pampean Palin, Argentina

Bengal Delta Mekong, Red Rever Deltas New South Wales, Australia Victoria, Australia

Figure 1 Aquifers with elevated arsenic concentrations around the world. Adapted from Barringer, J.L., Reilly, P.A., 2013. Arsenic in Groundwater: A Summary of Sources and the Biogeochemical and Hydrogeologic Factors Affecting Arsenic Occurrence and Mobility. USGS. http://dx.doi.org/10. 5772/55354; Smedley, P.L., Kinniburgh, D.G., 2002. A review of the source, behavior, and distribution of arsenic in natural waters. Appl. Geochem. 17, 517–568.

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Arsenic Table 1

Estimates of worldwide population exposed to arsenic in drinking water

Country

Population exposed to As  300 mg l
1

Population exposed to As  50 mg l
1

Population exposed to As  10 mg l
1

Bangladesh West Bengal, India Nepal Taiwan Mainland China Vietnam Argentina Chile Mexico United States Hungary Total

5 000 000 1 000 000 ? 150 000 1 000 000 3 000 000 ? ? ? ? ? 10 000 000

57 000 000 4 200 000 ? 900 000 5 600 000 3 000 000 3 000 000 500 000 400 000 350 000 29 000 70 000 000

80 000 000 26 000 000 2 500 000 1 800 000 14 600 000 6 000 000 ? 1 800 000 ? 13 000 000 450 000 150 000 000

Chanpiwat, P., Sthiannopkao, S., Cho, K.H., Kim, K.-W., San, V., Suvathong, B., Vongthavady, C., 2011. Contamination by arsenic and other trace elements of tubewell waters along the Mekong River in Lao PDR. Environ. Pollut. 159, 567–576; Hoang, T.H., Bang, S., Kim, K.-W., Nguyen, M.H., Dang, D.M., 2010. Arsenic in groundwater and sediment in the Mekong River delta, Vietnam. Environ. Pollut. 158, 2648–2658; Nicolli, H.B., Bundschuh, J., Blanco, M., Del, C., Tujchneider, O.C., Panarello, H.O., Dapeña, C., Rusnasky, J.E., 2012. Arsenic and associated trace-elements in groundwater from the Chaco-Pampean plain, Argentina: Results from 100 years of research. Sci. Total Environ. 429, 36–56; Sancha, A.M. O’Ryan, R., 2008. Managing hazardous pollutants in Chile: arsenic. Rev. Environ. Contam. Toxicol. 196, 123–146.

however arsenic in seafood is in the form of organic arsenic compounds (arsenobetaine and arsenosugars) which are believed to be relatively nontoxic to humans. However, in arsenic-endemic areas the concern toxicologically is exposure to inorganic arsenic in vegetables, rice, and meat which can account for 10–40% of the arsenic exposure through food. Inorganic arsenic exposure through food is highly variable across populations due to differentials in inorganic arsenic concentrations in water used for irrigation or cooking of plant material with vegetable concentrations ranging between 15%) and those with the lowest ( 0.05. The observed sample difference is said to be not statistically significant at the 0.05 level. The above examples are a simple illustration of the difference between a statistically significant difference and one that Table 1 Coronary heart disease (CHD) incidence rates: 2  2 table

Smokers Nonsmokers Total

CHD

Non-CHD

Total

20 10 30

20 30 50

40 40 80

Biostatistics is not statistically significant. The probability statements are made, assuming that the null hypothesis is true. It should be kept in mind that a statistically significant difference refers only to the reality of a difference. In a statistical test of which the chi-square test is but one of many examples, nothing is said about the magnitude of the difference. Clearly, there are statistically significant differences that are real but too small to be clinically or practically important. That is why a confidence interval should always accompany the results of such a significance test. The accompanying point and interval estimates clarify the likely size of the difference. Actually, if a 95% confidence interval includes the null value, one may use the interval as an equivalent test of H0. If the null value (zero difference) is included in the 95% confidence interval, we accept H0. If it is outside the range of the confidence interval we would reject H0, at the 0.05 level. Because of this fact, some scientists have called for the abandonment of significance testing and the use of P-values in the evaluation of study results. Rather, they argue, the confidence interval gives everything one needs. However, there are more complex statistical tests in which a confidence interval is not so easily calculated or interpreted. Tests of significance have become a regular part of data analyses and most scientists seem to prefer the computation of both significance tests and confidence intervals. There are several ways in which a 2  2 table may arise in research. The above example is one in which two groups of subjects are followed for a period of time to see if illness rates differ in two groups exposed to a suspected causal factor (cigarettes in this case). This is the most elementary example of a cohort epidemiological study. In such an instance an attack rate or incidence rate may be computed for the two groups being compared. From Table 1, we can see that the two rates are 50% and 25%. Each of these figures could be construed as the risk of contracting the defined illness in the study’s time frame. The two percentages are estimates of the absolute risk. The ratio of the two is labeled the relative risk (RR), a bedrock statistic in epidemiology. In our simple example, the RR is 20/40 divided by 10/40, or 2.0. That is, one is twice more likely to contract CHD when exposed to cigarettes than if there was no such exposure. From our chi-square test, we know that this RR is statistically significant at the 0.05 level. We may wish to construct a confidence interval for our RR estimate as well. It is important to note the relationship between confidence intervals and tests of hypotheses. If our confidence interval contains the null value, then the null hypothesis is accepted. If our confidence interval excludes the null value, then the null hypothesis is rejected. Thus one may always use the confidence interval as both an indication of how accurate our point estimate is and also to test H0.

An Example of Hypothesis Testing with Two Sets of Continuous Data Suppose that we have drawn two random samples not from binomial populations but from two populations of continuous measurements. We have the same two populations as in the previous binomial example, but now (instead of asking a yes/no question) we record a measurement on each member in our two samples. Our single measurement in this case is a simple fasting total cholesterol value. The hypothesis to be

229

tested is that the population mean, m, is the same in both populations. That is, the two samples essentially come from the same population. Symbolically, we write the null hypothesis, H0: m1 ¼ m2 ¼ m (the common population mean). Naturally, to investigate this null hypothesis, the first thing to look at is the two sample means. If they are identical, we immediately conclude that the data support H0. But, of course, this almost never happens. The real question is how far apart must the two sample means be before we reasonably conclude with a precise probability statement that they could not likely have been drawn from the same population? We know that the two samples were actually drawn from two different groups but, if the population means (m) were identical, then, for our purposes, we are dealing with only one population. To assess this probability we calculate a summary statistic called the t-statistic. Knowing the distribution of this t-statistic under H0 allows us to test H0, creating a t-test, as was the case with the chi-square test with binomial data. The t-statistic is a ratio of the difference in the two sample means divided by an estimate of the standard deviation of this difference, called the SE of the mean difference. If this calculated t-value is close to zero, obviously we are more likely to accept H0. If the t-value is large (i.e., the sample means are far apart relative to their standard deviation), then we are more likely to reject H0 and conclude that the samples came from two different populations; that is, we would reject H0. Again, such statements are placed in a probabilistic basis, just as was the case with the chi-square test. The same inferences are drawn with respect to H0 and its likelihood of yielding our observed datadtwo sets of measurements in this case.

Other Tests of Hypotheses The previous two examples are among the simplest and most common tests of hypotheses: comparing percentages (discrete data) between two groups and comparing sample means (continuous data) between two groups. Obviously, there are numerous other situations in which a hypothesis may be tested. We may have several groups of means we want to compare. The technique known as the analysis of variance is usually employed in that instance. If we wish to investigate the association between two continuous variables, the methods of regression and correlation are used. The same principles apply; the null hypothesis is stated and a statistic is calculated by which to make a probability statement (test of significance) about the likelihood that our data could have resulted from a situation in which our null hypothesis was true. The same interpretation is used for the resulting significance tests. (For an excellent source of statistical software, including tutorials, for conducting many tests, see under the section titled Relevant Websites.)

Sample Size and Statistical Significance If a properly conducted test for statistical significance reveals a statistically significant result, we trust the probability statement, regardless of the sample size. All tests take into account the size of the samples. As just stated, the researcher must then decide if the difference is large enough to be important.

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However, if a test result shows that an observed difference is not statistically significant (P > 0.05), this result is interpreted as meaning that the observed difference could easily have arisen by chance alone (H0, true), that is, more than 5% of the time. Is it possible that there is a real difference and that the testing procedure missed it? Are we wrong in accepting H0 in such cases? Whereas our probability statement is correct, the answer is maybe. It is possible to miss real and possibly important differences between the two groups being studied. This can easily happen if our sample size is too small. Although it is beyond the scope of this article, the relationships among the sample size, size of the difference, and the statistical power (probability of rejecting H0) to detect real differences must be considered in study planning. Sample size calculations should be undertaken as part of the study planning process to ensure that the sample sizes are adequate to detect important differences with a reasonable degree of probability. (See some of the biostatistics references listed for computational details under the section titled Further Reading.)

Biostatistics in Public Health Epidemiology and Clinical Trials Most epidemiological research is involved in the search for associations, for potential cause-and-effect relationships among variables. Before following up on an observed association, it must first be demonstrated that it could not easily have arisen by chance alone. Obviously, this is where a biostatistical approach is mandated. If you cannot convince your peers that your result is not easily explained by chance, you will not have much success in engendering support for further investigation. Tests of hypotheses and confidence intervals play a basic role in such evaluations. Once it has been determined that observed differences or associations are unlikely to have been the result of chance alone (i.e., statistically significant), the epidemiologist must evaluate the possibility that the association may be causal. Of course, as we have pointed out, real associations do not imply that two variables are causally related. The surest way to establish causation is by means of an experiment. As we have noted, using human volunteers in an experiment is called a clinical trial. Most clinical trials conducted are in the area of clinical medicine, that is, testing and comparing treatments for persons already diagnosed with an illness. However, in recent years, there have been an increasing number of clinical trials in epidemiology known as prevention trials. The difference between the two approaches is not trivial. Few question the ethics of using volunteers in an experimental search for improved therapies. But if preliminary epidemiological research implicates a possible cause of a disease, it seems unethical to directly test this hypothesis in an experiment. Such a study would mean that some healthy individuals would be subjected to a variable suspected of causing illness. Despite the ethical issues involved, there now have been many clinical trials examining the possible cause and effect of variables believed to cause illness. One approach is to find a volunteer population that is already exposed to a suspected cause and randomly remove, or greatly reduce, the exposure to that cause in half of them. Following both groups until

some new illnesses occur and comparing the two rates is a logical test of the causal hypothesis. This certainly was the approach in the early cholesterol reduction trials. Such trials showed experimentally that cholesterol reduction was an effective way to reduce the incidence of CHD. Another aspect of clinical trials among healthy, symptomfree persons is that the time period from initial observation to an adverse health event is usually much longer than would be the case in clinical trials of sick patients. Sample size requirements are correspondingly much higher. And the time of such trials is much longer. One approach to ameliorating this situation is to select volunteers from high-risk subjects, the logic being that such a group would yield more cases of illness in a shorter period of time than from the general population. Thus, when epidemiological research (i.e., an observed association) indicated that beta-carotene supplementation might possibly reduce the risk of lung cancer, trials were begun among smokers who were cancer free. A trial using volunteers from the general population would have been prohibitively expensive and lengthy because the incidence of lung cancer is very low. However, among cigarette smokers, the expected number of cases is much higher. Two well-conducted major trials examining the protective effect of beta-carotene in smokers actually revealed that this supplement was not beneficial and likely increased the risk of lung cancer in smokers. These trials once again demonstrated the need for experimentation to verify a suspected cause-and-effect relationship. It is too easy to assume such a relationship when it has not been proven with sound experimentation.

Software Used in Biostatistics The remarkable developments of computer science and engineering during the past few decades have transformed statistical analyses in all areas of science. The speed of computing and the ability to store massive amounts of data have both undergone a quantum leap and continue to increase. Routine calculations that previously required many hours may now be conducted in fractions of seconds. And some newer methods of analyses that once could not have even been contemplated are now in routine use. This includes Markov chain Monte Carlo methods to derive Bayes posterior distributions that are of high dimension or cannot be specified in closed form. In such cases, tens of thousands of repeated samplings are drawn, and analyzed, to conduct inference in a specific context. As a result, an abundance of statistical software packages have emerged and are now available for data analyses. The most popular include SAS, SPSS, R, Stata, and Epi Info. SAS is a system of programs created by the Statistical Analysis System Institute (Schlotzhauer and Littell, 1997). The system has involved into an enterprise data system, including not only statistical analysis packages, but also packages for file management, data storage, and warehousing. It is widely used by larger corporations, in almost all areas of health sciences. SPSS, initially developed as a ‘statistical package for social sciences,’ is now a part of IBM’s software group and has an expanded capacity for survey and marketing research, and data mining. A product of StataCorp of College Station,

Biostatistics Texas, Stata, a package mostly run on a personal computer, has a full capability for data analysis, graphics, and simulations. R is a language and environment for statistical computing and graphics (Ihaka and Gentleman, 1996). It is a GNU project and its use is free of charge. Many user-contributed methods can be first found in R, some eventually migrate to commercial software years later. The development of statistical methods and algorithms for omics data is a good example of such community-participatory software development. R has an advantage for users who would like to program for data processing and data analysis, and to develop new methods or modify existing methods. Epi Info is another free software developed from the Centers for Disease Control and Prevention. With a suite of lightweight tools, Epi Info aims to help health researchers with simple tools for rapid creation of data collection instruments and data analysis, visualization, and reporting, without the complexity or expense of large, enterprise applications (see Relevant Websites).

‘Big Data’ and Biostatistics ‘Big Data’ refers to an emerging phenomenon in which data are generated in great volume, great velocity, and great variety (Laney, 2001). Some now use additional V’s such as veracity to characterize Big Data. These V’s make Big Data acquisition, access, analytics, and application within a specific time frame difficult using traditional IT technologies and data analytic techniques (Tien, 2014). Unlike data collected from a planned experiment, these ‘Big Data’ are likely to be unstructured, making conventional statistical methods for designed studies less applicable. ‘Big Data’ likely will impact public health in the decades to come, and its analysis faces challenges and will require analytic approaches including statistical methods and their efficient implementation for systematic applications (National Research Council, 2013). In the future it may not be economically feasible to conduct many of the cohort studies and clinical trials implied by emerging hypotheses, and there are wicked problems that are unlikely to be addressed through single designed studies. New ways of exploiting large sets of data not collected for a specific purpose may be called for as an alternative. One exacerbating factor is the coding of the human genome. The gene– environmental interaction will point to subsets of persons who may respond quite differently to environmental exposures or new drugs. The sheer magnitude of evolving issues and data sets almost certainly will provide the impetus for developing new methods for not only individual genes but also disease pathways or biological systems analyses. Biostatistics will be a major player in this new enterprise because accurate probability statements will be the major goal for most such analyses, although disciplines outside of biostatistics will play contributing roles. An eminent group of epidemiologists has called for ‘integrating Big Data science into the practice of epidemiology’(Khoury et al., 2013). There is also additional attention to Big Data in health-care management (Bates et al., 2014). Privacy considerations are of paramount concern, of course, when using patient databases at any level. Nevertheless, such data sets appear to have good potential to improve health-care decision-making. A summary of Big Data and public health is provided by Khoury and Ioannidis (2014).

231

Combining Evidence from Multiple Studies The statistical methods described in this article utilize the conventional approach that a particular data set is analyzed independently as a stand-alone investigation. The evaluation of overall evidence generated from similar investigations examining the same general problem can be handled in a review. A formal, quantitative, method of combining evidence is called meta-analysis. This is a process by which the common form results (e.g., odds ratio) from several studies addressing essentially the same hypothesis are pooled to provide an overall assessment of the hypothesis. Additionally, this method provides a measure of the variation between studies. This procedure may include several epidemiologic investigations, clinical trials, or both. Naturally, attention must be paid to the quality of each study, including potential bias. See for example Metaanalysis in Medicine and Health Policy (Stangl and Barry, 2009). All of the methodologies described in this article are based upon the relative frequency distribution of outcome measures. Bayesian inference, built on the pioneering work of Thomas Bayes, attempts to quantify and update the degree of belief in a hypothesis upon observing additional evidence. The degree of belief in the hypothesis is specified in a prior probability before additional data evidence is seen and is updated to a posterior probability after the data evidence is incorporated. The Bayes theorem is a classic example demonstrating applications in disease screening or health decision-making scenarios. Assume the prevalence of prostate cancer to be 15% among men 55 years of age and above (prior probability). Further assume that the prostate-specific antigen (PSA) test would detect a PSA value in blood greater than 4 ng ml1 for individuals with prostate cancer 21% of the time (sensitivity), but has a 6% false positive rate. If a patient’s test result is greater than 4 ng ml1, the (posterior) probability of detecting prostate cancer is 40.5% using the formula below: PrðProstate CancerjHigher PSAÞ ¼ PrðHigher PSAjProstate CancerÞ PrðProstate CancerÞ=PrðHigher PSAÞ ¼ 0:21  0:15=ð0:21  0:15 þ 0:06  0:85Þ ¼ 0:405: Breslow’s paper, ‘Biostatistics and Bayes’ (Breslow, 1990), provides a good summary of the various Bayesian methods. With increasing computing power and powerful computation algorithms, Bayes inference methods such as multilevel or hierarchical models (Bryk and Raudenbush, 2002) and Markov chain Monte Carlo (Geyer, 1992) are widely used in problems involving nested, complex model structures and a large number of unknown parameters.

Some Common Errors in Biostatistics Reasoning Assuming an Observed Association Implies Causality

Epidemiology, the search for variables suspected of being in the causal pathway of disease and disability, is the cornerstone of public health. When such causal variables are found, many public health activities are devoted to reducing their impact. Several successful public health interventions have taken place. These include the reduction of cigarette smoking, serum cholesterol levels, and blood pressure levels. These reductions have

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had an impact on several diseases seen at the population level, particularly in the area of CHD. In these cases an association was noted between levels of the suspected variables and the onset of disease. However, one cannot be certain that some other, perhaps, genetic variable may play a role in both the suspected causal variable and a disease. Usually, clinical trials must be employed to rule out other than causal hypotheses. Of course, there are times when a public health decision must be made in the absence of experimental evidence of causality (i.e., clinical trials). The classic example of such an action is documented in the famous 1964 Surgeon General’s Report on cigarette smoking as a cause of lung cancer (U.S. Department of Health, Education, and Welfare, 1964). It is neither ethical nor logistically feasible to conduct the definitive trial in this situation. However, the sum of the evidence from many nonexperimental studies was consistent enough to result in stating that the association likely was causal and public health action was required. The magnitude of the population effect necessitated this particular action. In most cases, however, experimental evaluation would be required.

Assuming Statistical Significance Equates to Practical Significance

As we have emphasized, statistical testing relates only to the reality of a group or treatment difference, not to the magnitude of any difference. What does it matter if an analgesic dissolves 5 s faster than a competing brand in terms of affecting a headache? That is why many persons prefer to emphasize confidence intervals in biostatistics, rather than statistical tests. A confidence interval allows one to examine the magnitude of an estimated difference along with a significance test. If the interval does not include the null value, the null hypothesis may be rejected.

Assuming Relative Risk Is More Important Than Absolute Risk

A pharmaceutical advertisement may state simply that the use of their drug will reduce the risk of a heart attack by 25%. By itself, this statement is meaningless. Among what population and over what time period are the first clarifications that come to mind. However, even more important may be the contrast of a reduction in RR versus a reduction in absolute risk. Suppose that the untreated risk of an attack were 4 per 1000 men in a year, and that the treated risk was reduced to 3 per 1000 men in a year. This is an RR reduction of (43)/4, or 25%. But the absolute reduction is 1 per 1000 men or 0.1% in a year, which is not as impressive as the RR reduction. Obviously, both risks must be considered and weighed in making a decision about a cost/benefit evaluation regarding embarking on a drug regimen. Oftentimes, the absolute risk is ignored.

See also: Clinical Trials; Health Surveys.

Bryk, S.W., Raudenbush, A.S., 2002. Hierarchical Linear Models: Applications and Data Analysis Methods. Sage Publications, Thousand Oaks, CA. Blackwell, D.L., Lucas, J.W., Clarke, T.C., 2012. Summary health statistics for U.S. adults: national health interview survey. National center for health statistics. Vital Health Stat. 10, 260. Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS), 2014. National Health and Nutrition Examination Survey Questionnaire. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Hyattsville, MD. Committee on the Analysis of Massive Data, Committee on Applied and Theoretical Statistics, Board on Mathematical Sciences and Their Applications, Division on Engineering and Physical Sciences, National Research Council, 2013. Frontiers in Massive Data Analysis. The National Academies Press. Geyer, C.J., 1992. Practical markov chain monte carlo. Stat. Sci. 7, 473–483. Havlik, R.J., Feinleib, M. (Eds.), 1979. Proceedings of the Conference on the Decline in Coronary Heart Disease Mortality. National Heart, Lung, and Blood Institute, Washington, DC. October 24–25, 1978. NIH Publication No. 79–1610. Huff, D., 1993. How to Lie with Statistics. W.W Norton, New York. Ihaka, R., Gentleman, R., 1996. A language for data analysis and graphics. J. Comput. Gr. Stat. 5 (3), 299–314. Khoury, M.J., Lam, T.K., Ioannidis, J.P., et al., April 2013. Transforming epidemiology for 21st century medicine and public health. Cancer Epidemiol. Biomarkers Prev. 22 (4), 508–516. Khoury, M.J., Ioannidis, J.P., 2014. Big data meets public health. Science 346, 1054–1055. Laney, D., 2001. 3D Data Management: Controlling Data Volume, Velocity, and Variety. Technical Report. META Group. http://blogs.gartner.com/doug-laney/files/2012/ 01/ad949-3D-Data-Management-Controlling-Data-Volume-Velocity-and-Variety. pdf (last accessed 18.01.15.). Miniño, A.M., 2013. Death in the United States, 2011. NCHS Data Brief, No 115. National Center for Health Statistics, Hyattsville, MD. National Center for Health Statistics, 2014. Health, United States, 2013: With Special Feature on Prescription Drugs. Hyattsville, MD. National Research Council, 2013. Frontiers in Massive Data Analysis. Committee on the Analysis of Massive Data and Committee on Applied and Theoretical Statistics. The National Academies Press, Washington DC. Rosner, B., 2006. Fundamentals of Biostatistics, sixth ed. Brooks/Cole, Belmont, CA. Schlotzhauer, S., Littell, R., 1997. SAS System for Elementary Statistical Analysis, second ed. SAS Institute Inc, Cary, NC. Stangl, D., Barry, D.A., 2009. Meta-analysis in Medicine and Health Policy. CRC Press, Boca Raton, FL. Tien, J., 2014. Overview of big data: a US perspective. Bridge 44, 12–19. U.S. Department of Health and Human Services. Office of Disease Prevention and Health Promotion, 2015. Healthy People 2020. Washington, DC. U.S. Government Smoking and Health, 1964. Report of the Advisory Committee to the Surgeon General of the Public Health Service. U.S. Department of Health, Education and Welfare, Washington, DC. World Health Organization, 2014. World Health Statistics. Geneva, Switzerland.

Further Reading National, Center for Health, Statistics (NCHS), 2006. Health, United States, 2006: With Chartbook on Trends in the Health of Americans. NCHS, Hyattsville, MD. Pagano, M., Gauvreau, K., 2000. Principles of Biostatistics, second ed. Duxbury, Pacific Grove, CA. U.S. Department of Health and Human Services, 2000. Healthy People 2010: Understanding and Improving Health, second ed. U.S. Government Printing Office, Washington, DC. World Health, Organization, 2006. The World Health Report 2006 – Working Together for Health. WHO, Geneva, Switzerland.

References

Relevant Websites

Bates, D.W., Saria, S., Ohno-Machado, L., Shah, A., Escobar, G., 2014. Big data in health care: using analytics to identify and manage high-risk and high-cost patients. Health Aff. 33, 1123–1131. Breslow, N., 1990. Biostatistics and Bayes. Stat. Sci. 5, 269–284.

http://www.cdc.gov/nchs – CDC. http://www.cdc.gov/DataStatistics – CDC, Data and Statistics. http://www.cdc.gov/epiinfo – CDC Epi Info, What Is Epi Info? http://www.healthypeople.gov/LHI – Healthy People, Leading Health Indicators.

Bladder Cancer Claudio Pelucchi and Eva Negri, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 1, pp. 311–317, Ó 2008, Elsevier Inc.

International Encyclopedia of Public Health, 2nd edition, Volume 1

8 Deaths per 100 000

Bladder cancer is three to four times more frequent in men than in women in most populations (Parkin et al., 1999). This is mainly due to men’s higher exposure to the two main recognized risk factors for bladder cancer: tobacco smoking and aromatic amines. Transitional-cell carcinoma (TCC) is the most common histological type of bladder cancer, although the distribution of histologies varies in different populations. TCC accounts for over 95% of bladder cancers in white populations, for about 85% in black American populations, and for a lower proportion in Middle East populations, among whom squamouscell type is frequent. Tobacco smoking and occupational exposures are the main determinants for both TCC and nonTCC bladder tumors. As concerns the subsite of origin within the bladder, in a large U.S. investigation about 43% of bladder cancers occurred at an unspecified subsite, and 13% arose in more than one subsite. Of bladder cancers occurring in a single subsite, most occurred on one of the bladder walls (40% on lateral walls, 11% on the posterior wall, and 3% on the anterior wall). Less common subsites included the ureteric orifice (17%), followed by the trigone (13%), dome (9%), and neck (7%). Substantial variability exists in the rates recorded in various cancer registries, partly reflecting different diagnostic criteria, since the distinction between benign and malignant tumors is not straightforward. Thus, bladder cancer incidence rates and trends are difficult to interpret. These cautions notwithstanding, the highest incidence rates are recorded in Europe and North America, although Northern Africa and Western Asia are high-risk areas, too (Parkin et al., 1999). Mortality rates are more informative. Data on mortality are available from the World Health Organization in a uniform and standardized format for most of Europe, and for selected extra-European countries, including the United States and Japan. In most European countries, male bladder cancer mortality rates (age-standardized, world standard population) in early 2000 ranged between 5 and 8/100 000, whereas rates for women varied between 1 and 2/100 000, the highest rates being observed in Denmark (2.6) and the UK (1.8). In the United States, bladder cancer mortality rates were 3.7/100 000 in men and 1.1 in women; corresponding values in Japan were 2.5/ 100 000 in men and 0.7/100 000 in women. Bosetti et al. (2005) provided mortality data for some countries of Central and South America, where bladder cancer mortality rates in the year 2000 varied between 1.0 (in Ecuador) and 4.6 (in Argentina) in men and between 0.6 (in Ecuador and Mexico) and 1.1 (in Chile, Cuba, and Puerto Rico) in women. These marked differences across South American countries probably reflect different smoking habits and patterns, such as use of black tobacco, which is strongly associated with bladder cancer, in Argentina and Cuba.

With reference to trends over time, male rates (Figure 1(a)) in the European Union (EU) were 6.7/100 000 in 1970–74, peaked at 7.4 in 1985–89, and declined thereafter to 6.1/ 100 000 in 2000–01. Important differences, however, existed in different regions, as mortality rates were still increasing in many countries of Eastern Europe, including Bulgaria, Poland, and Romania. In the United States, male bladder cancer mortality rates rose until the mid-1970s to a value of 5.1/ 100 000, and then started to decline (Bosetti et al., 2005), that is, about 10–15 years prior to the EU, whereas in Japan the rates were stable around a value of 2.4/100 000 between 1970 and 2001. For women (Figure 1(b)), mortality rates from bladder cancer in the EU were 1.5/100 000 in 1970–74, 1.6 in 1975–79, and declined thereafter to 1.3 in 2000–01. In the United States, female rates increased to 1.5/100 000 during the 1970s and then declined, as observed in men. In Japan, female mortality rates constantly tended to decrease between 1970 and 1995, and then leveled off (from 0.9/ 100 000 in 1970–74 to 0.7 in 2000–01). Data on mortality trends from Central and South America are less clear, with some countries showing declining rates from the 1970s (e.g.,

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Figure 1 Trends in age-standardized (adjusted to the world standard population) death certification rates per 100 000 for bladder cancer (all ages), 1970–2001. (a) Males; (b) females. O European Union, , United States, B Japan. Data from the World Health Organization.

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Argentina and Venezuela), others with fairly constant levels, and a few others that showed a steep increase in male rates after 1995 (e.g., Cuba, Costa Rica, Puerto Rico), possibly reflecting the patterns of tobacco smoking for subsequent generations of American men (Bosetti et al., 2005). Although problems of case ascertainment and death certification may have affected bladder cancer mortality certification, the trends observed in Europe and other developed areas of the world are probably real, and well reflect the pattern of exposure to tobacco smoking – and to a lesser extent occupational carcinogens – of subsequent generations of men. The pattern of mortality from bladder cancer is similar to that of lung cancer, with downward trends over the last decade in several southern and northern European countries – 10 to 15 years later than in the United States – and still appreciably upward in some Eastern European countries, where tobacco control is less implemented.

Symptoms and Diagnosis The main signs of bladder cancer are hematuria (often frank and painless), frequent and/or urgent urination, and painful urination. Although these symptoms are frequently related to other urinary tract conditions, such as cystitis and bladder stones, their medical evaluation is critical, particularly for gross hematuria. Classic methods to diagnose bladder neoplasms include cystoscopy (passing a tube through the urethra to examine the inner lining of the bladder), urine culture and cytology, followed by transurethral biopsy/resection. Histological analyses of small samples of tissue provide the diagnosis. Although many urinary markers showed promising results as diagnostic or screening tools for bladder cancer, none has yet been proven sufficient for diagnosing or excluding bladder neoplasms. Screening practices are currently not recommended for bladder cancer, even in high-risk groups (e.g., occupationally exposed subjects), due to high proportions of false-positive results. Clinical studies of screening have failed to demonstrate a beneficial effect on outcome or mortality (Silverman et al., 2006).

Risk Factors Several epidemiological studies investigated in different populations the role of potential risk factors in bladder carcinogenesis, and a few etiological agents are now established. Known or potential etiological factors for bladder cancer are summarized in Table 1, and are discussed in the following sections.

Tobacco Cigarette smoking is the main recognized cause of bladder cancer in both developed and developing countries for which data are available. The risk in smokers is two to four times that of nonsmokers, and increases with number of cigarettes per day and duration of smoking. Risk is up to fivefold higher in heavy and in long-term smokers as compared to neversmokers. Smokers of unfiltered, high-tar, or black (air-cured) tobacco cigarettes (i.e., those with higher levels of aromatic amines) are at higher risk than smokers of filtered, low-tar, or

blond (flue-cured) tobacco ones. It has been suggested that bladder cancer risk may be higher in women than in men who smoke comparable numbers of cigarettes, but recent investigations and combined reanalysis of earlier studies did not support this hypothesis. Cessation of smoking led to a 30–60% decrease in risk as compared to current smokers. Though the risk declines with increasing time since quitting, it does not approach that of never-smokers even after 25 or more years since cessation of the habit. There is some evidence that pipe and cigar smoking are also associated with bladder cancer risk, though not all findings were consistent, whereas there is no evidence from epidemiological data that link smokeless tobacco consumption (i.e., chewing tobacco and snuff) to bladder neoplasms. To date, only a small number of studies have provided information on the relation between exposure to environmental tobacco smoke and bladder carcinogenesis, finding inconsistent results.

Occupation Control of occupational carcinogens has been an important contributor to the recent reduction in bladder cancer mortality, particularly among males. Exposure to some aromatic amines, and particularly 2-naphthylamine and benzidine, is the most important determinant of the excesses of bladder cancer observed in workers from several types of industries. An excess bladder cancer risk was in fact reported more than a century ago among workers employed in dyestuff manufacture, including aromatic amines, whose production has been dramatically reduced since the 1950s. A number of other occupations have been associated with increased risk of bladder cancer, including rubber manufacture, aluminum industry, painting, leather industry, and truck and other drivers, although their risk quantification is mostly undefined. Hair dyes used during the early 1970s contained some mutagenic aromatic amines, and thus occupational use of hair dyes gathered a wide interest and was largely investigated over the last decades in relation to bladder carcinogenesis. In a reanalysis of 10 cohort studies including over 81 000 occupationally exposed subjects, it was estimated that there was an overall 40% increased risk of bladder cancer, which was stronger in men (þ60%) than women (þ10%) (La Vecchia and Tavani, 2001). It is unclear whether the risk difference between genders is real or due to other exposures in males (such as to brilliantine) or confounding from smoking or other lifestyle factors. On the other hand, a combined reanalysis of available data excluded any association between personal use of hair dyes and bladder cancer.

Diet Several substances contained in foods and their metabolites are excreted through the urinary tract, and thus a role of dietary factors in bladder carcinogenesis is plausible. Consumption of fruit and vegetables, on the one hand, reduced the risk of bladder cancer in a major fraction of studies that investigated the issue. On the other hand, there is some evidence suggesting a direct relation with fat intake. In 2000, Steinmaus et al. (2000) conducted a meta-analysis of 38

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Summary of potential risk factors for bladder cancer

Risk/protective factor

Effect

Carcinogen or mechanism of carcinogenesis

Possible evaluation

Cigarette smoking

Direct

Real

Occupation l Aromatic amine manufacture l Dyestuff manufacture l Rubber industry l Painting l Leather industry l Aluminum industry l Truck drivers and other drivers l Hairdressers Fluid intake

Direct

Exposure to aromatic amines and other carcinogens (tobacco hydrocartoons, tar) Exposure to aromatic amines and other chemical carcinogens Diesel exhausts or reduced bladder voiding (drivers)

Carcinogens In drinking water (chlorination by-products, arsenic) Coffee Artificial sweeteners Diet l Vegetables and fruit Urinary tract diseases l Schistosoma haematobium l Cystitis l Other urinary tract infection l Kidney or ureter stones Drugs l Phenacetin l Cyclophosphamide l Phenobarbital Family history of bladder cancer Genetic polymorphism of genes involved in detoxification of aromatic amines (NATI/NAT2, GSTM1)

Inverse Direct Direct Direct Inverse Direct

Direct Direct Inverse Direct Direct when NAT2 deleted

Dilution of carcinogens, increase of voiding frequency Direct carcinogenic action

Real (for exposure to aromatic amines)

Possible Possible

Carcinogenic metabolites in urine Undefined in humans Antioxidant or other properties of vitamins, minerals, or other compounds

Controversial Inadequate Possible

Chronic inflammation/altered metabolism

Real for Schistosoma haematobium, possible for other

Genetic predisposition Inefficient detoxification of aromatic amines with consequent increased production of carcinogenic metabolites

Possible Possible

Pelucchi, C., Bosetti, C., Negri, E., Malvezzi, M., La Vecchia, C., 2006. Mechanisms of disease: the epidemiology of bladder cancer. Nat. Clin. Pract. Urol. 3, 327–340 (Table 2). Reprinted by permission from Macmillan Publishers Ltd, Ó 2006.

studies on six dietary variables that gave a relative risk (RR) of 0.7 for high vegetable, 0.8 for high fruit, and 1.4 for high fat intake, whereas no significant association was found for meat (RR ¼ 1.0), retinol (RR ¼ 1.0) or beta-carotene intake (RR ¼ 0.9). Recent cohort studies conducted in Eastern Asia found that a high intake of soy was associated with a more than twofold excess bladder cancer risk. Considering micronutrient intake, results on vitamin A and carotenoids were inconsistent, whereas an inverse association was reported between selenium intake and bladder cancer risk. Long-term use of vitamin E, but not vitamin C, supplements were found to reduce bladder cancer mortality. With reference to the use of artificial sweeteners, laboratory tests found that large quantities of saccharin cause bladder cancer in rats. In the 1970s, considerable public concern followed the results of an epidemiological study reporting a 60% increased risk of bladder cancer in men (but not women) who used artificial sweeteners (Howe et al., 1977). Nevertheless, large and informative studies conducted thereafter excluded an association with ever use of artificial sweeteners, both in men and women, and according to type or form of sweeteners.

Although it is difficult to separate the effects of single artificial sweetener substances, as these are usually combined in food products, the epidemiologic evidence does not support an association between saccharin and other artificial sweeteners and bladder cancer. Thus, the International Agency for Research on Cancer changed the evaluation of saccharin from group 2B (possibly carcinogenic to humans) to group 3 (not classifiable as to its carcinogenicity to humans).

Fluid Intake Fluid intake may dilute metabolites in the urine and increase the frequency of voiding, thus reducing contact of carcinogens with the bladder epithelium. According to an opposite theory, the risk of bladder cancer rises with total intake of fluids, as these may contain carcinogenic contaminants too. Consistently with the first hypothesis, data from the Health Professionals Follow-up Study found that men in the highest fluid intake category had half the risk of bladder cancer as compared to those in the lowest level, and such protection was observed for water as well as for consumption of other

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fluids (Michaud et al., 1999). However, epidemiological findings on the issue are largely inconsistent, with a majority of case–control studies reporting a direct relation with bladder cancer risk. The issue remains unsettled, due to the extreme difficulties in undertaking and interpreting such studies. According to the second hypothesis, besides the amount of fluids ingested, the type of beverage and the source of drinking water would be most important. Indeed, a meta-analysis of studies on consumption of chlorinated drinking water found a 40% increased risk for long-term users (Villanueva et al., 2003), and pooled data from six case–control studies gave a higher risk of bladder cancer for consumption of tap water, but no association with non-tap water. High concentrations of arsenic in drinking water, such as those reported in some regions of Taiwan, Bangladesh, Argentina, and Chile, are associated with large increases in risk and incidence of bladder and other cancers, whereas in areas characterized by lower levels of exposure – as the United States and Finland – the pattern of risk is less clear and may be modified by smoking habits.

approximately twofold excess risk in patients with (recurrent) urinary tract infections, although bladder cancer cases may recall previous urinary diseases more accurately than healthy controls, and thus some of this excess may be explained by recall bias. There is some evidence from both epidemiological and laboratory studies that a history of kidney or urinary stones may moderately increase bladder cancer risk. Microsatellite alterations have been reported in urinary sediments from patients with cystitis and bladder cancer. Recent prospective and retrospective studies found that subjects with a history of gastric ulcer could share an increased risk of bladder cancer (Michaud et al., 2004). The low antioxidant levels and the bacterial colonization of the stomach occurring during chronic gastritis may explain the association observed, as they lead to endogenous production and subsequent excretion through the urinary bladder of nitrosamines, which are known bladder carcinogens in animals. However, no association emerged with history of duodenal ulcer.

Drugs Beverages A potential association between coffee drinking and bladder cancer has been investigated since the early 1970s in a large number of epidemiological studies. In 2001, a meta-analysis estimated summary odds ratios (ORs) of 1.26 (95% confidence interval (CI), 1.09–1.46) from studies of male, 1.08 (95% CI, 0.79–1.46) of female, and 1.18 (95% CI, 1.01–1.38) of male and female coffee drinkers combined, after adjustment for smoking (Zeegers et al., 2001). Thereafter, other European cohort and case–control studies have reported consistent results that supported these estimates as well as the presence of gender differences in risk. Besides this feature, several studies reported no trend with dose or duration of coffee drinking, and thus coffee is probably not causally related with bladder cancer, although at the same time it may represent an indicator of risk. Epidemiological findings on a possible relation between alcohol drinking and bladder cancer are compatible with no association or a moderate positive one. The results obtained from various studies are generally inconsistent, and this has been attributed to the fact that various populations have different drinking patterns, as well as different correlates (including coffee and diet) of alcohol drinking. As for coffee consumption, a possible explanation of the moderate increase in risk observed in some studies may be linked to residual confounding by smoking, which is usually directly correlated with both alcohol and coffee consumption, or to an association between alcohol, coffee, and a yet unidentified risk factor.

Urinary Tract and Other Diseases Bladder cancer is frequent in areas (such as Northern Africa) with a high prevalence of infection with Schistosoma haematobium, which is responsible for chronic irritation of the urothelium. In these areas, a consistent relation between bladder schistosomiasis and cancer has been reported, and the percentage of squamous cell type carcinoma is high (Bedwani et al., 1998). Chronic irritation of the bladder epithelium caused by urinary tract infections and stones may also increase bladder cancer risk. Various case–control studies reported an

The current epidemiological knowledge on the relation between drug use and risk of bladder cancer support an inverse association with non-steroidal anti-inflammatory drugs, a direct association with heavy consumption of phenacetin-containing analgesics (a similar link also emerged with renal cell carcinoma), whereas no consistent relation has been reported for paracetamol. Studies of animal models reported a preventive effect of nonsteroidal anti-inflammatory drugs in bladder carcinogenesis. Further, there is some evidence that patients treated with cyclophosphamide for non-Hodgkin’s lymphoma had an increased risk of developing bladder cancer, whereas in a few – but not all – studies, treatment with phenobarbital was inversely associated with bladder cancer risk, particularly among smokers.

Family History of Bladder Cancer Various retrospective studies consistently reported a 1.5- to 2fold increased risk of bladder cancer in individuals with a history of the same neoplasm in first-degree relatives. These studies were also generally concordant in suggesting that bladder cancer risk is higher when the relatives of bladder cancer patients are diagnosed at early age. Otherwise, a potential involvement of an X-linked susceptibility gene was suggested by findings of higher risks in siblings, and particularly in brothers of young probands, than in offspring of bladder cancer cases, but not all studies found consistent results, and the issue is therefore open to discussion. There is no evidence in support of an interaction between smoking and familial factors in bladder carcinogenesis, as available data suggest independent effects on risk.

Biomarkers of Bladder Cancer Susceptibility Polymorphic distribution of the enzymes involved in the activation and/or deactivation of aromatic amines in humans is an important determinant of individual susceptibility to their carcinogenic effects. N-acetyltransferase (NAT) is an enzyme whose activity may result in the detoxification of aromatic amines. Its activity in

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humans is coded by two distinct genes named NAT1 and NAT2. The NAT2 enzyme has long been known to be polymorphic, and in about half of Caucasians, termed slow acetylators, its activity is reduced. Various studies suggested that the slow NAT2 genotype could be a risk factor for bladder cancer, specifically by interacting with occupational exposures to aromatic amines or cigarette smoking, but generally the power to identify significant gene–environment interactions was limited. A first meta-analysis of 22 case–control studies reported an overall RR of bladder cancer for NAT2 slow acetylators of 1.4 (95% CI, 1.2–1.6), as compared to rapid acetylators (Marcus et al., 2000a). Despite significant heterogeneity across studies, this meta-analysis suggested that in most populations slow NAT2 acetylation status is associated with a modest increase in bladder cancer risk. Further, Marcus et al. (2000b) reviewed the relation between cigarette smoking and NAT2 acetylation status in a subsequent meta-analysis of case series that found an interaction between slow acetylation status, tobacco smoking, and bladder cancer risk (RR ¼ 1.3, 95% CI, 1.0–1.6). There is also a variant polyadenylation signal of the NAT1 gene (NAT1*10 allele) associated with higher enzyme activity (Bell et al., 1995). The activity of NAT1 is reported to be higher than that of NAT2 in the bladder and may increase the formation of DNA binding metabolites of aromatic amines within the target organ. However, less is known about NAT1 polymorphism than about NAT2, and the NAT1 genotype has not been associated with increased risk of bladder cancer. The enzyme glutathione S-transferase M1 (GSTM1) is involved in the detoxification of a number of carcinogens. About 50% of Caucasians have an inherited deletion of two copies of the gene coding for GSTM1, and several – but not all – studies suggested that individuals homozygous for the deleted genotype (GSTM1 0/0) have an increased risk of bladder cancer. A large Spanish case–control study found RRs of 1.2 (95% CI, 0.8–1.7) and 1.9 (95% CI, 1.4–2.7) for individuals with deletion of one or two copies of the GSTM1 gene, respectively (Garcia-Closas et al., 2005). The same study also confirmed an increased risk of bladder cancer for NAT2 slow acetylators that was stronger among current smokers. Most studies do not, however, have adequate power to address the interaction between NAT2, GSTM1, cytochrome P4501A2, environmental factors, and bladder cancer risk. A recent cohort study from Los Angeles provided valuable results highlighting that NAT2 slow acetylators who used permanent hair dyes had an RR of bladder cancer of 2.9 (95% CI 1.2– 7.5), and that among lifelong non-smokers, the RR for permanent hair dye use was 6.8 (95% CI 1.7–27.4) for non-NAT1*10 subjects (Gago-Dominguez et al., 2003). Both the estimates were, however, based on few subjects, and much larger studies are required to confirm the associations in subgroups. Therefore, this point is at present unsettled.

cancer, tobacco smoking, is also the factor to which a large fraction of bladder cancer cases are attributable in most countries, both in men and women. In men, estimates of PAR of bladder cancer related to tobacco smoking varied from 50% in some areas of the United States and in the Netherlands to 70% in Southern Europe and Egypt and to 80% in the UK, whereas in women the PARs were around 30% in developed countries and very low in studies conducted in world areas where tobacco smoking is infrequent in women (such as Egypt). With reference to gene–environment interactions, assuming an RR of bladder cancer of 2.5 for smokers in a predominantly male European population, the PAR was about 35% for slow acetylators who had ever smoked. It has been estimated that the risk of bladder cancer attributable to occupational factors is between 4% and 7% in Western European countries, and similar results (PARs between 5% and 10%) were previously reported in studies from Great Britain and North America. As the control of occupational exposure to carcinogens improved widely in the last decades in developed countries, the proportion of cases attributable to occupational exposures has probably been declining during recent years. Scanty information is available from other areas of the world, however, where measures to reduce occupational hazard may still be inadequate. Little information is available on the proportion of cases of bladder cancer attributable to other risk factors, as data are often inadequate to provide useful indications for prevention. Nevertheless, it was estimated that schistosomiasis, a parasitic disease caused by flatworms of the genus Schistosoma, could be responsible of 28% of bladder cancer cases occurring in an urban population of Zimbabwe. Control of schistosomiasis is based on drug treatment, control of freshwater snails that release larval forms of the parasites, improved sanitation, and health education. Thus, reduction of Schistosoma haematobium infection is one of the major preventable causes of bladder neoplasms in various areas of Africa and Middle East. If the association between exposure to chlorination by-products in tap water and bladder cancer is real, the estimated PAR in a Canadian population would be around 15%, while the proportion of bladder cancers attributable to familial and heritable factors was estimated to be relatively low, for example, between 2% and 7%. In conclusion, there is ample information for prevention and control of bladder cancer. Avoidance of tobacco smoking, close surveillance of occupational exposures to aromatic amines and other chemical agents, and control of bladder and other urinary tract infections would considerably reduce the incidence of bladder cancer worldwide.

Population-Attributable Risks

References

The population-attributable risk (PAR, i.e., the proportion of bladder cancer attributable to each etiological factor) depends not only on the RR, but also on the frequency of exposure to each factor, and therefore it varies across geographical areas and time periods. The major recognized risk factor for bladder

Bedwani, R., Renganathan, E., El-Khwsky, F., et al., 1998. Schistosomiasis and the risk of bladder cancer in Alexandria, Egypt. Br. J. Cancer 77, 1186–1189. Bell, D.A., Badawi, A.F., Lang, N.P., et al., 1995. Polymorphism in the Nacetyltransferase 1 (NAT1) polyadenylation signal: association of NAT1*10 allele with higher N-acetylation activity in bladder and colon tissue. Cancer Res. 55, 5226–5229.

See also: Cancer Epidemiology; Carcinogens, Environmental; Diet and Cancer; Pesticides; Smoking, The Burden of Mortality of.

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Bosetti, C., Malvezzi, M., Chatenoud, L., et al., 2005. Trends in cancer mortality in the Americas, 1970–2000. Ann. Oncol. 16, 489–511. Gago-Dominguez, M., Bell, D.A., Watson, M.A., et al., 2003. Permanent hair dyes and bladder cancer: risk modification by cytochrome P4501A2 and Nacetyltransferases 1 and 2. Carcinogenesis 24, 483–489. Garcia-Closas, M., Malats, N., Silverman, D., 2005. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 366, 649–659. Howe, G.R., Burch, J.D., Miller, A.B., et al., 1977. Artificial sweeteners and human bladder cancer. Lancet 2, 578–581. International Agency for Research on Cancer, 1999. IARC Monographs on the evaluation of the carcinogenic risks to humans. In: Some Chemicals that Cause Tumours of the Kidney or Urinary Bladder in Rodents, and Some Other Substances, vol. 73. International Agency for Research on Cancer, Lyon, France. La Vecchia, C., Tavani, A., 2001. Hair dyes and bladder cancer: an update. Eur. J. Cancer Prev. 10, 205–208. Marcus, P.M., Vineis, P., Rothman, N., 2000a. NAT2 slow acetylation and bladder cancer risk: a meta-analysis of 22 case–control studies conducted in the general population. Pharmacogenetics 10, 115–122. Marcus, P.M., Hayes, R.B., Vineis, P., et al., 2000b. Cigarette smoking, Nacetyltransferase 2 acetylation status, and bladder cancer risk: a case-series meta-analysis of a gene-environment interaction. Cancer Epidemiol. Biomarkers Prev. 9, 461–467. Michaud, D.S., Spiegelman, D., Clinton, S.K., et al., 1999. Fluid intake and the risk of bladder cancer in men. N. Engl. J. Med. 340, 1390–1397. Michaud, D.S., Mysliwiec, P.A., Aldoori, W., Willett, W.C., Giovannucci, E., 2004. Peptic ulcer disease and the risk of bladder cancer in a prospective study of male health professionals. Cancer Epidemiol. Biomarkers Prev. 13, 250–254. Parkin, D.M., Pisani, P., Ferlay, J., 1999. Estimates of the worldwide incidence of 25 major cancers in 1990. Int. J. Cancer 80, 827–841. Silverman, D.T., Devesa, S.S., Moore, L.E., Rothman, N., 2006. Bladder cancer. In: Schottenfeld, D., Fraumeni Jr., J.F. (Eds.), Cancer Epidemiology and Prevention, third ed. Oxford University Press, New York, pp. 1101–1127. Steinmaus, C.M., Nunez, S., Smith, A.H., 2000. Diet and bladder cancer: a metaanalysis of six dietary variables. Am. J. Epidemiol. 151, 693–702. Villanueva, C.M., Fernandez, F., Malats, N., Grimalt, J.O., Kogevinas, M., 2003. Metaanalysis of studies on individual consumption of chlorinated drinking water and bladder cancer. J. Epidemiol. Community Health 57, 166–173. Zeegers, M.P., Tan, F.E., Goldbohm, R.A., van den Brandt, P.A., 2001. Are coffee and tea consumption associated with urinary tract cancer risk? A systematic review and meta-analysis. Int. J. Epidemiol. 30, 353–362.

Further Reading Brockmöller, J., Kerb, R., Drakoulis, N., Staffeldt, B., Roots, I., 1994. Glutathione Stransferase M1 and its variants A and B as host factors of bladder cancer susceptibility: a case–control study. Cancer Res. 54, 4103–4111. International Agency for Research on Cancer, 1987. IARC monographs on the evaluation of the carcinogenic risks to humans. In: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs, vols. 1–42 (Suppl. 7). International Agency for Research on Cancer, Lyon, France. International Agency for Research on Cancer, 2004. IARC monographs on the evaluation of the carcinogenic risks to humans. In: Tobacco Smoke and Involuntary Smoking, vol. 83. International Agency for Research on Cancer, Lyon, France. Kogevinas, M., ’t Mannetje, A., Cordier, S., et al., 2003. Occupation and bladder cancer among men in Western Europe. Cancer Causes Control 14, 907–914. Levi, F., Lucchini, F., Negri, E., Boyle, P., La Vecchia, C., 2004. Cancer mortality in Europe, 1995–1999, and an overview of trends since 1960. Int. J. Cancer 110, 155–169. National Research Council, 2001. Board on Environmental Studies and Toxicology. Subcommittee to Update the 1999 Arsenic in Drinking Water, Report, Committee on Toxicology. Arsenic in Drinking Water: 2001 update. National Academy Press, Washington, DC. Pereg, D., Lishner, M., 2005. Non-steroidal anti-inflammatory drugs for the prevention and treatment of cancer. J. Intern. Med. 258, 115–123. Van der Meijden, A.P., 1998. Bladder cancer. Br. Med. J. 317, 1366–1369. Vogelstein, B., Kinzler, K.W., 2004. Cancer genes and the pathways they control. Nat. Med. 10, 789–799. Zeegers, M.P., Kellen, E., Buntinx, F., van den Brandt, P.A., 2004. The association between smoking, beverage consumption, diet and bladder cancer: a systematic literature review. World J. Urol. 21, 392–401.

Relevant Websites http://www.nlm.nih.gov/medlineplus/bladdercancer.html – MedlinePlus, U.S. National Library of Medicine and National Institutes of Health: Bladder Cancer (last accessed 12.04.16.). http://www.who.int/schistosomiasis/en/ – World Health Organization: Schistosomiasis (last accessed 12.04.16.).

Blindness Serge Resnikoff, Brien Holden Vision Institute, University of New South Wales, Sydney, NSW, Australia Van Charles Lansingh, Instituto Mexicano de Oftalmología, Queretaro, Queretaro, Mexico; Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA; and HelpMeSee, New York, NY, USA Kristen Allison Eckert, Independent Consultant in Public Health, Tapachula, Chiapas, Mexico Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by S. Resnikoff, R. Pararajasegaram, volume 1, pp. 318–324, Ó 2008, Elsevier Inc.

Blindness is a health and social concern of significant public health dimensions that, until recently, has not received the attention it warrants on the global health agenda. As will be seen, the majority of the global population with blindness live in developing regions and in the impoverished regions of rapidly economically developing countries. The trends in global blindness have transitioned from infectionand nutrition-related causes of blinding eye diseases to those of a chronic nature that generally stem from noncommunicable disorders, referred to as the ‘epidemiological transition.’ This is in keeping with the demographic transition that is occurring at an enhanced pace in the developing regions of the world, consequent to their inevitable population momentum. These transitions have far-reaching consequences for population eye health, with all its implications in terms of underdevelopment, social costs, and poverty alleviation in general, and the quality of life of affected individuals and communities, in particular. The lowered life expectancy consequent to becoming blind is an illustrative example.

What Is Blindness? There is no simple answer. The reason for this is that, until recently, there has been great variation in the definition of blindness from one country to another. This is despite the availability of a definition and classification dating back to 1972 that has found international acceptance and was included in the 10th revision of the WHO International Statistical Classification of Diseases Injuries and Related Health Problems. In this classification, blindness is defined as presenting visual acuity of less than 3/60 (20/400 or 0.05). For categories of visual impairment, moderate and severe visual impairment is now used instead of low vision so as not confuse nonblinding visual impairment with functional low vision. Moderate visual impairment is defined as presenting visual acuity of less than 6/18 (20/70 or 0.30) but equal to or greater than 3/60 (20/200 or 0.1). Severe visual impairment is defined as a presenting visual acuity of less than 6/60 (20/200 or 0.1), but equal to or greater than 3/60 (20/400 or 0.05). The WHO defines functional low vision as visual acuity of less than 6/18 (or 20/60) but greater than or equal to light perception in the better eye that is untreatable and uncorrectable. In the above definitions, ‘presenting’ visual acuity is now used instead of ‘best corrected,’ because the former more accurately reflects the true magnitude of uncorrected refractive error as a cause of blindness and visual impairment.

International Encyclopedia of Public Health, 2nd edition, Volume 1

Epidemiology There are some limitations inherent in describing the epidemiology of visual impairment and blindness. These stem from the use of different definitions and visual cutoff points for the different categories of visual impairment in different studies. However, current standardized epidemiological methodologies, such as the rapid assessment of avoidable blindness, use more standardized definitions. As such, the recent estimation would more closely reflect the real situation.

Magnitude and Causes of Visual Impairment The WHO estimates that the global magnitude of visual impairment in relation to the 2010 world population is 285 million people, of whom 39 million have blindness (Pascolini and Mariotti, 2012). The Vision Loss Expert Group of the 2010 Global Burden of Disease Study performed a more complex estimation using hierarchical regression models that account for variation between blindness and visual impairment over time (Stevens et al., 2013). According to this study, there were 32.4 million people with blindness and 191 million with moderate to severe visual impairment in 2010. The Global Burden of Disease study revealed interesting global trends in blindness and moderate to severe visual impairment. From 1990 to 2010, there were approximately 18 million cases of averted blindness, although, due to the rapidly aging global population, the number of people with blindness increased by 0.6 million from 1990 to 2010. The increase may have been as high as 19 million people for moderate to severe visual impairment. However – and more important for public health – the global prevalence of blindness and moderate to severe visual impairment both significantly decreased, from 3.0% and 14.3%, respectively, in 1990 to 1.9% and 10.4%, respectively, in 2010.

Causes of Visual Impairment and Blindness According to the WHO estimates (2010) (in, Pascolini and Mariotti, 2012), the global causes of visual impairment, including blindness, are cataract, 33%; uncorrected refractive errors, 42%; glaucoma, 2%; age-related macular degeneration, 1%; trachoma, 1%; corneal opacities, 1%; diabetic retinopathy, 1%; childhood blindness (various causes), 1%; and other causes, 18%. The WHO estimates the following global causes of blindness: cataract, 51%; glaucoma, 8%; age-related macular degeneration, 5%; childhood blindness (various causes), 4%; corneal opacities, 4%; uncorrected refractive error, 3%; trachoma, 3%; diabetic retinopathy, 1%; and other causes, 21%.

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Figure 1 Global causes of blindness (presenting visual acuity), based on 2010 Global Burden of Disease data (Bourne, R.R., Stevens, G.A., White, R.A., et al., 2013. Causes of vision loss worldwide, 1990–2010: a, systematic analysis. Lancet Glob. Health 1 (6), e339–e349.). DR, diabetic retinopathy; URE, uncorrected refractive errors.

According to the Global Burden of Disease estimates (2010) (in, Bourne et al., 2013), the global causes of blindness are as follows: cataract, 39%; uncorrected refractive errors, 20%; glaucoma, 4%; macular degeneration, 5%; diabetic retinopathy, 2%; trachoma, 3%; and other causes, 27%. The Global Burden of Disease estimates the global causes of moderate to severe visual impairment are as follows: uncorrected refractive error, 51%; cataract, 26%; macular degeneration, 2%; glaucoma, 1%; diabetic retinopathy, 1%; trachoma, 1%; and other causes, 18%. The proportions of blindness and moderate to severe visual impairment due to cataract and trachoma decreased from 1990 to 2010, while the proportions of blindness and moderate to severe visual impairment due to uncorrected refractive error, glaucoma, age-related macular degeneration, diabetic retinopathy increased. Figure 1 depicts the causes of blindness and their relative magnitude from a global perspective.

Inequity in Eye Health Status and Causes of Visual Impairment There is wide variation in both the prevalence and underlying causes of visual impairment and blindness based on geographical location, demographic structure, gender, socioeconomic status, and health system development. An estimated 90% of the global population with visual impairment live in developing parts of the world. Figure 2 illustrates the geographical distribution of global blindness.

Vision Impairment across the Life Spectrum Visual impairment is not equally prevalent across various age groups of the population. For instance, 84.6% of all people with blindness are 50 years and older (Stevens et al., 2013). However, this cohort currently represents only 19% of the

global population. Those persons 50 years and older therefore bear a disproportionate load of blindness. At the other end of the life spectrum, blindness in childhood has a lower absolute prevalence, with the WHO estimating that 4% of global blindness is due to childhood blindness and corneal opacities, which affect approximately 1.6 million children (Pascolini and Mariotti, 2012). A child going blind in early childhood and surviving to 50 years of age (as an example) has many years of blindness ahead. Therefore, in terms of ‘years of blindness,’ childhood blindness ranks second to blindness from cataract in adults and merits to be addressed as a global priority in public health ophthalmology.

Gender/Sex Disparities The majority of people with blindness (60%) and moderate and severe visual impairment (57%) are women (Stevens et al., 2013). Sex and gender variations have been reported in all age groups and in all regions of the world. Consistently, for reasons such as limited access and uptake of eye care services, women are at a higher risk than men of being visually impaired or blind. The fact that women have a higher life expectancy also puts them at greater risk for age-related eye diseases (Ulldemolins et al., 2012). In fact, age primarily contributes to vision disparities in women in the United States (Clayton and Davis, 2015). For vision disparities related to sex, evidence supports that most ocular diseases affect female patients (in terms of prevalence) disproportionately compared to male patients. For example, refractive errors are more prevalent in women. There have been associations reported between hormonal effects and women’s risk of developing cataract and glaucoma (Clayton and Davis, 2015). For vision disparities related to gender, in addition to general problems of limited access to health services and behaviors that make women less likely to seek preventive care, gender-defined

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Figure 2 Regional distribution of age-standardized prevalence of visual impairment, based on 2010 Global Burden of Disease data (Stevens, G.A., White, R.A., Flaxman, S.R., et al., 2013. Global prevalence of vision impairment and, blindness: magnitude and temporal trends, 1990–2010. Ophthalmology 120 (12), 2377–2384.).

roles increase a woman’s risk for blindness, especially in developing countries. For example, women in developing countries are three times more likely to have blinding trachoma because of their primary caretaker role at home, exposing them more frequently to the pathogen (Clayton and Davis, 2015). There is a great need, not only for more research based on sex and gender in eye health to better understand and resolve the vision disparities in women, but also for policy changes to promote and ensure equity in eye health.

Biological Determinants Many of the causes that result in visual impairment and blindness have biological determinants such as genetic background, age, and gender. These are nonmodifiable, and prevention or treatment of these are related to biomedical interventions. These include treatment for cataract and trichiasis (in trachoma) or a mix of interventions, as in glaucoma and diabetic retinopathy. Where underlying ecological determinants prevail, such as in onchocerciasis and trachoma, medical treatment together with interventions such as vector control, personal hygiene (e.g., face washing), and environmental improvement are employed.

Social Determinants Social determinants of health drive health differences or inequalities among social groups and include race, ethnicity, gender, socioeconomic status, geographic inequalities, and having a specific health condition (Ulldemolins et al., 2012). An understanding of the underlying social determinants of eye health is a necessary prerequisite not only for an understanding of the public health dimensions of the problem, despite the availability of appropriate knowledge, technology,

and skills, but also for preventing and controlling the many determinants and diseases that lead to visual impairment. However, when dealing with these conditions as factors of vision impairment and blindness in a population setting, the existence of social determinants is often overlooked. These include various barriers to uptake of services. Health illiteracy, poverty along with its related deprivations, physical and social distance from health facilities, and cultural beliefs and barriers predominate. In addition to supporting that women are at greater risk for blindness and visual impairment (as explained above), a review of social determinants of eye health (Ulldemolins et al., 2012) found three other important findings: a higher socioeconomic status is protective from blindness and visual impairment; l ethnicity was associated – but not exclusively – with visual impairment; l living in a rural area (a geographic factor) was related to income and visual impairment. l

In general, these factors determine the availability, accessibility, and affordability of services even when they are provided. Compounding these determinants of visual impairment is the inequitable distribution of service in terms of geographic distribution, quality, cost, and accountability.

Prevention of Blindness: What Can Be Done? Cataract Cataract remains the leading cause of blindness, accounting for nearly half of all cases, as shown in Figure 1, except in the most developed countries. This is certainly not due to the lack of an effective intervention.

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Evidence-based, cost-effective interventions are practiced to deal with the surgical management of cataract (Baltussen et al., 2004). Removal of the affected lens of the eye and replacement with a synthetic posterior chamber intraocular lens (IOL) is standard practice the world over. Refinements in technology and approaches in IOL material and design ensure a near normal restoration of vision for the large majority of patients. In low- and middle-income countries, it has been estimated that the cost-effectiveness ratios of these surgical interventions are below US$200 per disability-adjusted life year (DALY) averted and less than US$24 000 in high-income countries. Another study demonstrated that cataract surgery was very cost effective, with cost utility ranging from US$3.5 to US$834 per quality-adjusted life year (QALY) in developing countries and from US$159 to US$1356 per QALY in developed countries (Lansingh and Carter, 2009). However, to be able to minimize the magnitude of cataract as a cause of blindness, interventions must go beyond technology to outcome-oriented interventions that vigorously address the various social determinants that predicate the high prevalence of cataract and other blinding conditions in developing countries. Even in these countries, studies have demonstrated the wide disparity in cataract surgical rates (defined as the number of cataract surgeries carried out per one million population annually), surgical outcome, and population coverage, not only between countries but also between regions in the same country. The equitable provision of efficient and effective health systems delivering eye care should be an essential public health priority for all developing countries.

Trachoma The SAFE strategy (surgery, antibiotics, facial cleanliness, environmental improvement) is an integrated approach based on the principles of primary health care recommended by WHO to help eliminate blinding trachoma in a sustainable manner. The four elements complement each other and comprise a mix of primary, secondary, and tertiary preventive interventions, with strong community involvement and educational activities. Studies on the cost effectiveness of these interventions are limited. However, the few reported studies point to a range of approximately US$4–82 per DALY averted across trachomaendemic areas, in the case of trichiasis surgery. In the case of antibiotic treatment, it has been estimated that across the endemic regions studied, the cost per DALY averted ranged between US$4000 and US$220 000, depending on whether the drug is part of a donation program or is calculated at the market price.

Diabetic Retinopathy Diabetic retinopathy, already a leading cause of blindness in working-age populations in developed countries, is fast assuming epidemic proportions worldwide with the upsurge of diabetes mellitus even in developing countries. The causes of vision loss are multifactorial and closely linked to the duration of diabetes. Other risk factors include uncontrolled blood sugar, high blood pressure, and increased blood lipids. Besides controlling the disordered metabolic state, available interventions include periodic examination of the ocular

fundus through dilated pupils, early identification of sightthreatening lesions, and treatment with laser photocoagulation and/or antivascular endothelial growth factors (VEGF) intravitreal injections, especially in diabetic macular edema. Health promotion and patient education are important supportive interventions. A multidisciplinary team approach to care of these patients is essential. Extended follow-up with careful monitoring and tracking of patients is important. In patients with some residual vision that is not amenable to further treatment, low-vision care should be offered.

Glaucoma This comprises a group of conditions that may lead to the primary cause of irreversible vision loss and blindness through damage to the optic nerve (optic neuropathy). WHO has estimated that 3.1 million persons are blind due to glaucoma (Pascolini and Mariotti, 2012). Published projections indicate that by 2020, 76 million people will have glaucoma and 65.5 million people will have primary open angle glaucoma (Tham et al., 2014; Kapetanakis et al., 2016). Significant improvement in treatment interventions has been made in recent years, such as laser therapy, medication, and surgery to prevent vision loss from glaucoma. However, given the fact that the tools currently required for the identification, assessment, and management of early glaucoma are often lacking, particularly in the developing world, the management of glaucoma at a community level holds many challenges.

Childhood Blindness Childhood blindness results from a number of causes that range from genetically determined and congenital conditions to micronutrient deficiency (vitamin A) and infective conditions (measles, ophthalmia neonatorum, rubella) to conditions requiring specialized surgical treatment such as childhood cataract, glaucoma, and retinopathy of prematurity. In developed and rapidly economically developing regions of the world, retinopathy of prematurity is more than an emerging problem. With increased survival of low birth weight and low gestational age infants, there is already an upsurge in vision loss from this cause. Considerable regional variations between and within countries exist with regard to the magnitude and causes of childhood blindness. Services for children are arranged through vision screening in schools and community centers with follow-up assessment and provision of spectacles. A concerted primary eye care approach could control and minimize causes related to poverty and deprivation such as malnutrition, measles, and harmful traditional practices. Other causes such as cataract, glaucoma, and retinopathy of prematurity require specialized surgical care and management, including lowvision care and inclusive education of affected children.

Uncorrected Refractive Errors These include conditions such as myopia (nearsightedness), hyperopia (farsightedness), and astigmatism. Age-related presbyopia also falls within this category. According to the Global

Blindness Burden of Disease Study, there are an estimated 108 million persons with visual impairment due to uncorrected refractive errors (with presenting visual acuity less than 6/18 in the better eye), of whom, 6.8 million are blind (Stevens et al., 2013). In 2011, there were an estimated 1.3 billion global cases of presbyopia; 244 million were uncorrected or undercorrected among the population over 50 years of age (Frick et al., 2015). Uncorrected refractive error comprises the commonest cause of visual impairment. The proportion of uncorrected refractive errors varies based on cultural norms, gender, and availability and affordability of services. Uncorrected refractive errors comprise a significant cause of pediatric vision impairment, particularly in low-income countries. These have implications for child development and education, future employment prospects, and performance. Services to correct disabling refractive errors should include identification of persons requiring correction, assessment and prescription of appropriate correction, and the provision of spectacles that are affordable and cosmetically acceptable.

Age-Related Macular Degeneration This condition presents an emerging challenge given the rapidly escalating number of older populations globally. It is already the major cause of blindness in the developed countries. While there is greater knowledge regarding the cause and pathophysiology of the disease, efforts at prevention and treatment have not been promising. There are two forms of agerelated macular degeneration, the neovascular, wet form and dry age-related macular degeneration, with most patients developing the latter form. The management of wet age-related macular degeneration is based on the use of anti-VEGF drugs such as ranibizumab, bevacizumab, and aflibercept (Yonekawa et al., 2015). Dry age-related macular degeneration is, conversely, among the most difficult therapeutic target indications in ophthalmology. The gold standard management strategy has been antioxidant vitamin supplementation to delay disease progression, but there are no approved therapies available that can prevent vision loss or prevent geographic atrophy. Ongoing research has suggested the potential value of newer treatment modalities in experimental stages, including neuroprotective drugs, visual cycle modulators, anti-inflammatory drugs, vascular drugs, and stem cell therapy, but the outcome of such treatments on a large scale has yet to be determined (Nowak, 2014; Singer, 2014). In the interim, much can be gained through the provision of low-vision care to improve the functioning and quality of life of these patients.

Low Vision The following definition was agreed upon to identify persons who could benefit from low-vision care: A person with low vision is someone who, after medical, surgical, and/or standard refractive intervention, has a corrected visual acuity in the better eye of less than 6/18 down to and including light perception or a central visual field of less than 20 degrees, but who uses or has the potential to use vision for the planning and/or execution of a task.

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Currently there are no global estimates of the number of people with low vision who would benefit from low-vision services. Based on WHO data, it can be assumed that there are an estimated 68.5 million people in the world with functional low vision (Pascolini and Mariotti, 2012). However, with the advancing age of the population and a concomitant increase in age-related chronic diseases such as glaucoma, diabetic retinopathy, and macular degeneration, the unmet need for low-vision services could rapidly escalate. The coverage of low-vision services currently is extremely sparse, even in developed countries. Low-vision care needs to be developed in close collaboration with the correction of uncorrected refractive errors, and follow the same principles, such as affordability and acceptability.

Concepts of Primary Eye Care and the Domains of Prevention of Blindness in Terms of Universal Health Coverage The basic principles of primary health care, as enshrined in the Alma Ata declaration (1978) and subsequent World Health Assembly (WHA) resolutions, provide the basic framework for the development of health systems that could provide equitable, comprehensive, and sustainable eye care as an integral part of health care. In 2005, the WHA passed Resolution WHA58.33, Sustainable health financing, universal coverage and social health insurance, which urges WHO member states to provide health care, with financial risk protection, to all their citizens. The WHO defined the goal of universal health coverage (in, WHO, 2013) as “to ensure that all people obtain the health services they need – prevention, promotion, treatment, rehabilitation, and palliation – without risk of financial ruin or impoverishment, now and in the future.” Recently, Resolution WHA66.4 (2013), Toward universal eye health: a global action plan 2014–19 (hereafter referred to as the WHO GAP), includes a set of activities for member states to strengthen eye care within their health systems with the aim to provide universal coverage in eye care. Since the approval of Resolution WHA66.4, numerous WHO regions have also ratified regional action plans that incorporate the objectives and activities of the WHO GAP within regional context. Primary health care, of which prevention of blindness needs to be an integral part, consists of the following: Essential health care based on practical, scientifically sound, and socially acceptable methods and technology made universally accessible to individuals and families in the community through their full participation and at a cost that the community and country can afford to maintain at every stage of their development in the spirit of self-reliance and self-determination.

Primary eye care comprises a simple but comprehensive set of promotive, preventive, curative, and rehabilitative activities that can be carried out by suitably trained primary healthcare workers, who in turn are supported by a referral system that ought to comprise secondary and tertiary level of services and, in some regions, provide mobile services.

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Available Primary Eye Care Interventions to Eliminate Avoidable Blindness Cataract, glaucoma, corneal opacities (from various causes), diabetic retinopathy, age-related macular degeneration, trachoma, and onchocerciasis lend themselves to potential health promotion, prevention, treatment, and rehabilitative strategies. Similar interventions are possible in most of the cases of childhood blindness. Another area in which primary-level services could provide effective support is in vision screening, early detection, and appropriate referral of persons of all age groups with uncorrected refractive error. This constitutes a large segment of the population across the life spectrum that could benefit from appropriate corrective services.

Economic Implications of Visual Impairment and Blindness Studies on the economic losses to individuals and society from visual impairment and the economic gains from the application of cost-effective interventions to prevent blindness and restore sight provide supportive evidence or investment in blindness-prevention programs. The economic burden of avoidable visual impairment includes the direct costs in terms of resources spent in individual and community care, including the various components of the eye care system at all levels, and the indirect costs, which comprise a range of productivity losses, with their far-reaching implications, social and rehabilitative expenses, impaired quality of life, and premature death. Studies have been published to highlight the economic aspects of some of the commoner individual blinding conditions such as cataract, trachoma, onchocerciasis, glaucoma, and diabetic retinopathy. Most of these have been carried out in developed countries. For instance, an Australian study (Taylor et al., 2004) assessed the overall economic impact of the five most prevalent visually impairing conditions (75% of all causes) in Australia (Figure 3). These included cataract, age-related macular degeneration, glaucoma, diabetic retinopathy, and refractive errors. The economic analysis predicted an estimated direct cost of US$1.3 billion. Indirect costs were estimated to add a further

US$5.6 billion to the annual eye care budget for 2004. These estimates cannot be easily extrapolated to other parts of the world, however, due to different disease patterns, health-care costs, work force wage structures, and social security systems. The most comprehensive global cost of visual impairment to date was a study that included direct and indirect costs of visual impairment for every region of the world to estimate that the global cost was $3 trillion in 2010 (Gordois et al., 2012). However, this study did not include the cost of productivity loss, as data were incomplete. The Fred Hollows Foundation (2013) has recently released a series of reports with Pricewaterhouse Coopers based on the global costs and benefits of eliminating avoidable blindness. After adding the dollar amount of productivity gains for working age (15–65 years), deadweight loss, and health systems savings, they found the value of the benefits (US$843.5 billion) are 2.1 times the costs of the global elimination effort (US$294.2 billion). Furthermore, in developing countries, the benefits (US$517.1 billion) were quadruple the costs (US$128.1 billion). An annual investment of US$5.70 per person on average, which in developing countries is as low as US$2.20 per year, is all that would be needed to eliminate avoidable blindness and visual impairment.

Partnerships for Prevention of Blindness Global and Regional Initiatives Onchocerciasis Control Program This program was established in West Africa in 1974. The objectives of this international collaboration were to eliminate onchocerciasis in the 11 countries covered by the program and consequently improve the socioeconomic condition of the people, who largely comprised an agrarian society. The program was closed in December 2002 after stopping the transmission of onchocerciasis in 10 participating countries; operations had been interrupted in Sierra Leone due to civil war. The Onchocerciasis Control Program (OCP) ended with impressive achievements. In now-controlled areas, an estimated 600 000 cases of blindness were prevented, 18 million children were spared from the risk of the disease, and 25 million hectares of land were made safe for cultivation and resettlement.

Figure 3 Cost of eye diseases, 2004, in US dollars (millions), by condition. AMD, age-related macular degeneration. Source: Taylor, H., Keeffe, J., Mitchell, P., 2004. Clear Insight: The Economic Impact and Cost of Vision Loss in Australia. Center for Eye Research Australia, Melbourne.

Blindness African Program for Onchocerciasis Control From December 1995 through December 2015, African Program for Onchocerciasis Control (APOC) was implemented with the sole aim of eliminating onchocerciasis from the African countries where the disease continued to be endemic. The region covered extended to 11 countries beyond those included in OCP, with 31 endemic countries, nongovernmental developmental organizations, foundations, and private sector partners participating. While WHO served as the executing agency, the fiscal agency was the World Bank, and the program is considered a model of public–private partnership in public health. The primary strategic objective was to create, by 2007, a system of community-directed distribution of ivermectin, as a microfilaricidal agent, donated at no cost by Merck, to prevent an annual 40 000 cases of blindness. By 2014, 100 million annual ivermectin treatments were provided, and APOC contributed to elimination efforts of other coexisting neglected tropical diseases, such as trachoma and lymphatic filariasis. APOC closed in 2015 in anticipation of the 2016 launch of its successor, the Expanded Special Project for the Elimination of Neglected Tropical Diseases, which will target the elimination of onchocerciasis, lymphatic filariasis, trachoma, schistosomiasis, and soil-transmitted helminthiasis.

Onchocerciasis Elimination Program for the Americas This program was initiated in 1991 as a regional initiative for Brazil, Colombia, Ecuador, Guatemala, Mexico, and Venezuela. The goals are to eliminate morbidity and to interrupt transmission of river blindness. This is a partnership program, including the six countries, the Pan American Health Organization, the private sector, specialized institutions, and international nongovernmental developmental organizations. The program strategy is to provide sustained mass distribution of ivermectin every 6 months, with the aim of reaching at least 85% of the atrisk population. Onchocerciasis Elimination Program for the Americas has been very successful with 11 of the 13 endemic foci of the Americas having eliminated or interrupted transmission of onchocerciasis. Colombia, Ecuador, and Mexico have received official WHO verification of the elimination of onchocerciasis, while Guatemala has halted disease transmission and is pending WHO verification of elimination. Transmission of onchocerciasis is only ongoing in the Yanomami area of the Amazon rainforest on the border of Brazil and Venezuela, where the migratory population and the difficult terrain have challenged operational efforts. The population at risk for onchocerciasis in the Americas has been reduced by more than 95%.

WHO Global Alliance for the Global Elimination of (Blinding) Trachoma 2020 Global Elimination of (Blinding) Trachoma 2020 (GET 2020) was constituted in 1997 to provide support and technical assistance to endemic countries by a number of partners (nongovernmental development organizations, research institution and industry) working toward elimination of blinding trachoma as a public health problem, using the SAFE strategy. The alliance meets on an annual basis and involves concerned

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member state representatives. The agenda includes the sharing of information on the progress of national programs, research initiatives and results, future plans, and reports on available financial and in-kind resources. The Alliance is supported by the International Coalition for Trachoma Control, a coalition of nongovernmental organizations, private sector and academic organizations, which is strongly involved in coordination and resource mobilization.

VISION 2020: The Right to Sight In 1999, WHO launched the Global Initiative for the Elimination of Avoidable Blindness under the title ‘VISION 2020: The Right to Sight.’ The initiative was spurred by the dismal global data on blindness that became available in the mid-1990s. These data were compounded by the predicted near-doubling of the global magnitude of visual impairment and blindness by the year 2020, with many of the underlying causes being preventable or treatable. These predictions were based on demographic projections and a presumed relatively unchanged eye care delivery as part of national health-care systems. Such a scenario was then likely to be realistic in the developing countries, where the problem was greatest and the resources for eye care are severely limited. Moreover, these countries were beset with competing demands for resources from limited health budgets to control other priority diseases such as HIV/AIDS, malaria, tuberculosis, and childhood diseases. The initiative was thus seen not only as a health challenge but also as a moral imperative that needed to be urgently addressed. VISION 2020 is a collaborative effort conceived by the WHO and the International Agency for the Prevention of Blindness and its constituent members. The objective is to support member countries by providing technical and financial support to realign and strengthen existing national programs or to initiate and develop new national programs aimed at the collective achievement of the common goal of eliminating avoidable blindness globally. The initiative identified three strategic components as the framework for action: cost-effective disease control; human resource development; and l infrastructure, including appropriate technology. l l

The overarching supportive elements included advocacy, public awareness campaigns, resource mobilization, and improved governance and management of health systems, including monitoring and evaluation for quality assurance. Partnership development was a key factor. The underlying guiding principle was delivering eye care as an integral part of primary health care. Global political commitment to VISION 2020 was forthcoming in 2003, 2006, and 2013 through the adoption by the WHO member states of resolutions WHA56.26, Elimination of Avoidable Blindness, WHA59.25, Prevention of Avoidable Blindness and Visual Impairment, and WHA66.4, the current WHO GAP, respectively. By signing the WHO GAP, countries have committed to implement prevention of blindness activities that aim to reduce the prevalence of blindness by 25% by 2019, based on the 2010 baseline.

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At the national level, a number of countries have signed national declarations of support, and outcome-oriented national action plans have been formulated and are being implemented. Overall, there is greater global awareness of the dimension of the problem of visual impairment, including blindness, as a public health concern. This has led to the all-important political commitment at all levels to eliminate avoidable blindness as a public health problem globally before 2020. It has also led to the development of, partnerships among a variety of partners, such as WHO, member countries, international nongovernmental developmental organizations and institutions, academia, the corporate sector, and civil society. The ultimate goal is to establish a sustainable, equitable, and comprehensive eye care system as an integral part of national health systems based on the principles of primary health care.

Nowak, J.Z., 2014. AMDdthe retinal disease with an unprecised etiopathogenesis: in search of, effective therapeutics. Acta Pol. Pharm. 71 (6), 900–916. Pascolini, D., Mariotti, S.P., 2012. Global estimates of visual impairment: 2010. Br. J. Ophthalmol. 96 (5), 614–618. Singer, M., 2014. Advances in the management of macular degeneration. F1000Prime Rep. 6, 29. Stevens, G.A., White, R.A., Flaxman, S.R., et al., 2013. Global prevalence of vision impairment and, blindness: magnitude and temporal trends, 1990–2010. Ophthalmology 120 (12), 2377–2384. Taylor, H., Keeffe, J., Mitchell, P., 2004. Clear Insight: The Economic Impact and Cost of Vision Loss in Australia. Center for Eye Research, Melbourne, Australia. Tham, Y.C., Li, X., Wong, T.Y., et al., 2014. Global prevalence of glaucoma and projections of, glaucoma burden through 2040: a systematic review and metaanalysis. Ophthalmology 121 (11), 2081–2090. Ulldemolins, A.R., Lansingh, V.C., Valencia, L.G., et al., 2012. Social inequalities in blindness and, visual impairment: a review of social determinants. Indian J. Ophthalmol. 60 (5), 368–375. World Health Organization, 2013. Universal Eye Health: A Global Action Plan 2014– 2019. http://www.who.int/blindness/AP2014_19_English.pdf?ua¼ (accessed 04.01.16.). Yonekawa, Y., Miller, J.W., Kim, I.K., 2015. Age-related macular degeneration: advances in, management and diagnosis. J. Clin. Med. 4 (2), 343–359.

References

Further Reading

Baltussen, R., Sylla, M., Mariotti, S.P., 2004. Cost effectiveness analysis of cataract, surgery: a global and regional analysis. Bull. World Health Organ. 82 (5), 338–345. Bourne, R.R., Stevens, G.A., White, R.A., et al., 2013. Causes of vision loss worldwide, 1990–2010: a, systematic analysis. Lancet Glob. Health 1 (6), e339–e349. Clayton, J.A., Davis, A.F., 2015. Sex/gender disparities and women’s eye health. Curr. Eye Res. 40 (2), 102–109. Frick, K.D., Joy, S.M., Wilson, D.A., et al., 2015. The global burden of potential productivity loss, from uncorrected presbyopia. Ophthalmology 122 (8), 1706–1710. The Fred Hollows Foundation, 2013. Investing in Vision – Comparing the Costs and Benefits of, Eliminating Avoidable Blindness and Visual Impairment. Pricewaterhouse Coopers, Australia. Gordois, A., Cutler, H., Pezzullo, L., et al., 2012. An estimation of the worldwide economic and health burden of visual impairment. Glob. Public Health 7, 465–481. Kapetanakis, V.V., Chan, M.P., Foster, P.J., et al., 2016. Global variations and time trends in the, prevalence of primary open angle glaucoma (POAG): a systematic review and meta-analysis. Br. J. Ophthalmol. 100 (1), 86–93. Lansingh, V.C., Carter, M.J., 2009. Use of global visual acuity data in a time trade-off approach to, calculate the cost utility of cataract surgery. Arch. Ophthalmol. 127 (9), 1183–1193.

Johnson, G.J., Minassian, D.C., Weale, C.A., West, S.K. (Eds.), 2003. The Epidemiology of Eye Diseases, second ed. Arnold, London. World Health Organization, 2010. The World Health Report 2010. Health Systems Financing: The Path to Universal Coverage. http://www.who.int/whr/2010/en/ (accessed 07.01.16.).

Relevant Websites http://www.cehjournal.org/ – Community Eye Health Journal (last accessed on 19.06.16.). http://www.icoph.org/ – International Council of Ophthalmology (last accessed on 19.06.16.). http://www.nei.nih.gov/ – National Eye Institute (last accessed on 19.06.16.). http://www.v2020.org/ – Vision 2020: The Right to Sight (last accessed on 19.06.16.). http://www.who.int/blindness/en/ – WHO, Prevention of Blindness and Visual Impairment (last accessed on 19.06.16.).

Blood Transfusion Services Casper Jersild, Århus University Hospital, Skejby, Denmark Valentina Hafner, European School of Transfusion Medicine, Milan, Italy Ó 2017 Elsevier Inc. All rights reserved.

Definitions and Approaches ‘Blood’ is a fluid tissue, composed from various cells with complex functions (erythrocytes, red cells – oxygen carriers; leucocytes, white cells – immune response to disease; and thrombocytes – cytoplasmic fragments of larger cells/megakaryocytes, activated when bleeding occurs), which are carried by plasma (over 90% water, plus proteins, minerals, etc.). Blood is vital as carrying oxygen, nutrients, and other essential elements to the tissues and removing residues of cellular metabolism. It also carries various clotting factors which normally intervene when bleeding occurs. ‘Blood donation’ is a benevolent gesture of offering blood for patients in need. Every healthy individual 18–65 years of age can donate blood, about 7 ml per kg body weight, up to a maximum of 450 ml whole blood per donation. To ensure donor availability, some countries have lowered the donation age to 17 and allowed blood donation after 65 years of age, if all donor health criteria are fulfilled. The interval between two whole blood donations has to be at least 72 days. Voluntary nonremunerated blood donation is considered a cornerstone of blood safety and it is advocated and supported by many international bodies, such as World Health Organization, the International Federation of Red Cross and Red Crescent Societies, the International Federation of Blood Donor Organizations, and the International Society for Blood Transfusion (see Relevant Websites). ‘Blood transfusion’ is a medical treatment in which donated blood (collected and prepared from a healthy person – a donor) is administered to the patient being treated, in the form of blood components, blood derivatives, or in rare and very specific situations as whole blood. The most appropriate blood transfusion therapy should provide for the missing or reduced element. Transfusion of whole blood can be lifesaving in situations such as massive blood loss due to trauma, burns, or extensive surgery. Blood component therapy is used to treat conditions in which the specific element is missing; for example, packed red cell administration in the case of severe anemia (a reduction in oxygen supply to vital organs) or platelet concentrates transfused for an abnormal decrease in the number of platelets. People suffering from sickle-cell disease may require frequent transfusion of red cell concentrates. In the case of hemophilia, the administration of the missing clotting factor (Factor VIII or IX concentrate or alternative recombinants) is required. Blood transfusion treatment is usually performed in health-care settings. ‘Blood transfusion service’ deals with various aspects of the blood transfusion chain, from the potential donor (information and selection of donors, blood collection, blood testing, blood processing, blood storage, blood transportation) to the potential recipient (selection and distribution of appropriate components for transfusion), and should link to the clinical interface and patient follow-up. It is important to note that

International Encyclopedia of Public Health, 2nd edition, Volume 1

donor promotion and awareness to blood donation is also part of blood service activities. This complex work is usually carried out by dedicated organizations/institutions or departments that operate at national, regional, or local level. In some countries blood services are hospital based. The range of responsibilities of the blood services (hospital or nonhospital based) varies, according to the organization of the national health-care system. Usually, the hospital blood service is a transfusion department that bears the responsibilities of storage, selection (compatibility testing), and administration of blood components according to medical prescription. ‘Blood components’ result from the separation of collected whole blood through centrifugation at various speeds. Components include red cells, white cells, thrombocytes, and plasma. Each component has specific characteristics, including a special storage temperature and shelf life (e.g., thrombocytes must be stored at þ21  C; plasma must be frozen at 40  C). The time between preparation and storage has direct consequences on the quality of active factors in the respective unit for transfusion or fractionation. Blood components can also be collected from the individual donor through apheresis procedures (separation of the required component from collected blood during the donation procedure, with the remaining being returned to the donor at the end of the separation process). The procedure can be fully or partially automated. ‘Blood derivatives’ are obtained through industrial fractionation procedures from raw plasma. These procedures must follow the pharmaceutical current good manufacturing practices (cGMP) so that resulting products comply with required safety standards. The purified and concentrated coagulation factors (e.g., Factor VIII, Factor IX), human albumin (usually prepared as 5% or 20% solutions), and immune globulins are the most frequently used blood derivatives. Technological progress has been achieved in developing pharmacologic alternatives to transfusion therapy, which include volume replacement solutions and plasma expanders, recombinant coagulation factors, erythropoiesis (red cell production) stimulation factors, in the continuous strive to cover patients’ therapeutic needs and identify measures addressing an insufficient blood supply, increasingly exposed to safety threats. To further respond to blood availability challenges, increasing attention is given to the development of blood substitutes and oxygen carriers.

Safety Aspects of Blood Transfusion Being a complex but undeniable life source, blood has been given historically mythical attributes. After unsuccessful transfusions of blood from animals to humans, and sometimes from humans to humans as well, it was only after 1900, when Karl Landsteiner discovered the ABO major blood groups, that blood transfusion therapy became possible. The

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history of blood transfusion has shown that once the blood group compatibility barrier had been overcome, there are infectious threats to which increased attention must be given. (For a more comprehensive overview of the history of blood transfusion, see Starr, 1998.) Blood-borne pathogens can be transferred with the donor’s blood to the recipient patient. Such pathogens may be viruses (e.g., HIV/AIDS, hepatitis B and C), parasites (e.g., malaria, Chagas’ disease), bacteria (e.g., syphilis, brucellosis), or prions (e.g., vCJD). In the late 1980s the transmission of the HIV by blood, blood components, and by pharmaceutically manufactured blood derivatives raised important concerns. A large number of patients chronically depending on therapy with blood components or derivatives were proven to be infected with HIV and other blood-borne pathogens. These findings led to more firm regulations of the entire blood transfusion area, with patient protection being of central importance. Other crisis situations, such as the variant Creutzfeldt–Jakob disease (vCJD) infections (mad cow disease), severe acute respiratory syndrome, avian flu epidemics, seasonal malaria and West Nile virus transmission, and the recent Ebola virus outbreak, have strongly affected the availability of the national blood supplies at times. Climate change and increased cross-border movement have led to revised geographical distributions of emerging and reemerging pathogens transmittable through blood. Extensive screening of donors and donations, and postprocessing treatment of blood products (including pathogen inactivation technologies) became part of the quality management and quality assurance operations. A nonexhaustive list of infectious agents which can be transmitted by blood transfusion is presented in Table 1. These agents in their early stage of infection may induce a healthy carrier state with few or no symptoms of disease. It is important to note that even if this list is under continuous development and scrutiny, not all agents are being tested for each donation. As of today, mandatory testing of blood donations concerns HIV-1, -2; hepatitis B and C viruses; and syphilis, to which locally significant testing requirements are added. By locally significant, in context, one should understand the local epidemiology (incidence and prevalence of specific infections in the populations) and links with its seasonal variations when applicable. Considering the limitations of testing procedures (infections are not identified during their initial phase – window period, new infectious agents for which tests have not been developed, quality of tests, and testing algorithm in place), the appropriate selection of potential blood donors should be given its full importance in maintaining safe blood supplies. The public and political attention focused on the infectious safety risks, led to more sophisticated and numerous testing procedures, and increasingly complex donor selection criteria. This placed on the second line the noninfectious safety concerns that become today in the high and medium human development index (HDI) countries, the leading causes of transfusion-related incidents and adverse events. Of physical (such as volume overload) or immunologic causality (such as allergic reactions, hemolytic reactions, transfusion-related acute lung injury, graft-versus-host disease), the intrinsic mechanisms of noninfectious safety risks related to blood transfusion including immune modulation require close monitoring, and some are still being explored. Hence, the vital

Table 1 Nonexhaustive list of infectious agents that (can) adversely affect the availability and safety of blood supplies Infectious agent Viruses Influenza viruses

Hepatitis viruses: A, B, C, D, E Herpesviruses: Epstein–Barr virus, human cytomegalovirus, human herpesvirus 8

Retroviruses: human immunodeficiency virus (HIV-1 and HIV-2), human T cell lymphotrophic virus (HTLV-I and HTLV-II) Erythroviruses: parvovirus B19

Mosquito-borne viruses: West Nile virus (WNV), chikungunya virus, dengue virus Bacteria Treponema pallidum Borrelia burgdorferi Brucella melitensis Coxiella burnetii Parasites Plasmodium species: P. falciparum, P. vivax, P. ovale, P. malariae Trypanosoma cruzi Toxoplasma gondii Leishmania donovani Babesia microti Nonconventional agents Prions

Observations Major impact on donor availability, to date no published reports of transmission of influenza viruses through transfusion Hepatitis B and C viruses are part of the basic mandatory screening of donors and donated blood With particular relevance for transfusion in patients with reduced immune protection capacity (neonates, conditions associated with immune deficiency) HIV-1 and HIV-2 are part of the basic mandatory screening of donors and donated blood HIV1 (with three genetic groups, nine known subtypes and recombinants) accounts for over 90% of HIV infections worldwide Documented transmission through transfusion of untreated pooled components and organ transplantation Increasing geographic spread in recent decades, mandatory seasonal testing for WNV introduced in affected areas Syphilis, part of the basic mandatory screening of donors and donated blood Lyme disease Brucellosis Q fever Malaria, reemergence due to climate change in recent years, donor deferral policies and available immunological testing Chagas’ disease Toxoplasmosis Leishmaniosis Babesiosis Variant Creutzfeldt–Jakob disease

importance of ABO/D blood grouping, and extended compatibility testing, required for every unit to be transfused. A nonexhaustive list of noninfectious hazards related to blood transfusion is presented in Table 2.

Present Situation The safety, availability of and access to adequate blood supplies are still challenged in many parts of the world.

Blood Transfusion Services Table 2 Nonexhaustive list of noninfectious risks related to blood transfusion Condition Immunologic mechanisms Acute occurrence l Allergic reactions

l

Hemloytic reactions

White blood cell incompatibility l Transfusion-related lung injury (TRALI) l

Delayed occurrence Alloimunization

l

l

Graft-versus-host disease

l

Posttransfusion purpura

Notes

Different degrees of severity (mild febrile and chills, urticarial reactions, anaphylaxis); recipient antibodies to donor plasma proteins Red cell incompatibility (ABO/D blood groups), recipient irregular antibodies to donor erythrocytes antigens Recipient antibodies against HLA antigenic system on donor white cells Severe and potentially lethal complication, transfusion of all blood components reported to be involved in TRALI (high level of specific antibodies in donor/donation involved) Antibodies anti-RBC and HLA antigens developed in patient, with impact on future administration of blood components Severe but rare complication, donor antibodies (T lymphocytes) target recipient tissues, occurring in patients with immune deficiency Recipient developing antiplatelet antibodies, with resulting thrombocytopenia

Nonimmunologic mechanisms Acute occurrence l Circulatory overload Follows rapid or massive transfusion (large quantities of fluids) l Hemolytic reactions Related to storage length and quality of the transfused product l Metabolic disturbances Acute hypotensive reactions, hypothermia, metabolic alkalosis in massive transfusions, hyperkalemia, hypocalcemia Delayed occurrence l Iron overload In patients subject to chronic transfusions (i.e., major thalassemia patients) l Metabolic disturbances Delayed hypoglycemia following exchange transfusion

According to the latest WHO global database for blood safety summary report, drawing from 2008 data reported by 164 countries, an estimate of 91.8 million blood donations are collected annually (WHO GDBS Summary report, 2011). Analysis of blood donations in relation to the HDI showed that almost half of these blood donations are collected in high-income countries. 85% of the world’s population, which lives in low and medium HDI countries, has access to only 52% of the total blood supply. This has a dramatic impact on the capacity to respond to various health needs of the population, and the strong links between blood availability and maternal mortality rates have been demonstrated.

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The differences in blood donation rates (that globally range between 0.4 and 64.6 per 1000 population) reflect not only the degree of awareness and involvement of the population with respect to blood donation and blood transfusion (local culture and health education) but also the level of development of health care in which the blood service is embedded. With mounting safety requirements and technological progress, blood transfusion services have become an increasingly expensive component of public health. In countries with limited resources, the safety of blood transfusion is of particular concern. In addition to the gaps in terms of technological progress available in the field, there are often high prevalence rates of HIV, hepatitis B and C, and other particular bloodborne diseases (see Relevant Websites of WHO, CDC). There is no generic formula for the calculation of what an appropriate blood supply would mean in size and constituency, and a relative value is usually calculated for planning purposes, based on retrospective analysis of covered and actual patient unmet needs in transfusion therapy. An appropriate blood supply can be defined as a situation in which no patient will die due to lack of appropriate treatment with blood, blood components, and/or blood derivatives and subsequently varies from one country to another. The sequence of steps undertaken to collect, produce, and administer a therapeutic blood unit is presented in a simplified manner in Figure 1.

Essentials in Blood Safety Important components of blood safety are: l l l l l

Organization, coordination, and regulatory framework for the blood transfusion services; Safe blood donors – education, recruitment, screening, retention, and medical follow-up; Safe blood units – collection, testing, further processing, and storage; Safe transfusion therapy – appropriate use of blood and blood components at the clinical site; Hemovigilance – reporting and follow-up on safety issues and transfusion outcomes.

WHO promotes an integrated strategy for blood transfusion safety, recommending (1) national coordination of specialized services to ensure that harmonized practices, safety standards, and quality management systems are uniformly applied in all areas, (2) regular voluntary nonremunerated blood donors from low-risk populations as primary source for the national blood supply, (3) appropriately tested (for blood-borne pathogens, blood grouping, and compatibility testing), processed, stored, distributed, and (4) adequately used at the hospital site including postdonation and posttransfusion follow-up for donor and recipient respectively. Preventive measures to reduce transfusion therapy needs and use, including availability of alternatives to transfusion, are part of enforcing strategies for blood supply management. A 15% increase in national blood policy development, with overall 58% countries having specific legislation in place for 2008 was reported to the WHO Global Database on Blood safety (Summary report, 2011).

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Figure 1

Blood Transfusion Services

Simplified flow of the blood donation and transfusion process.

Organization and Supportive Frameworks for the Blood Transfusion Services The blood transfusion service should be integrated with the health-care system of a country. Its appropriateness depends on the strength of public health interventions, the development level of health service delivery (preventive and curative medicine), and the health status of the population it serves. Experience has shown that the organization of blood services on a nationally coordinated basis ensures harmonized quality standards along the blood chain and increases consistency in delivery of products, information, and statistics. In addition, such organization has been proven to be more cost-effective owing to economies of scale. The blood transfusion service usually functions under government responsibility. A national blood policy and plan should define the vision and the steps required for strengthening quality, safety, availability, and access to adequate blood supplies. A national blood program for defined periods of time will allow addressing priorities and monitoring progress in the field. Constantly updated, dedicated, legal provisions and regulatory frameworks are part of the supportive mechanisms to implementation. Appropriate resources, including sustainable funding mechanisms, are needed for its appropriate functioning. The blood service organization and functioning should be looked at horizontally bridging the involvement of the various stakeholders and related interventions. A dedicated national commission with mixed representation can play an advisory function at a high decision-making level with respect to blood

safety issues, as well as enhance dialog among interested parties, such as blood transfusion specialists, clinicians, and patients. National Regulatory Authorities have the mandate to evaluate and monitor compliance of blood service operations with agreed quality standards, and the way supportive quality management systems ensure that products meet the standards in use. Quality and safety standards for the blood services operations are grounded in more general standards, such as the ISO 9000-series standards and the cGMP guidelines for medicinal products for human and veterinary use. Resulting from concerted efforts and combined expertise of national experts and international organizations, these common standards are subject to periodic review to ensure they keep pace with advances in science and technology development, and adequately respond to safety challenges and patient needs. Monitoring the compliance to defined standards is part of a regular process of quality assessment and control.

Safe Blood Donors According to data available from various sources and studies, voluntary nonremunerated regular blood donors recruited from low-risk populations carry a much lower risk of infections. Safe donor selection criteria, which reflect the education to healthy lifestyles, proved to be highly effective in the prevention of HIV/AIDS transmission. The ‘Club 25’ initiative in Africa (youth initiative promoting lifestyles and regular blood donation, aiming for about 20 blood donations by

Blood Transfusion Services the age of 25) led to a dramatic decrease in transfusiontransmitted infections and related risks, to the mutual benefit of donors and recipient patients. The safe blood donors are the cornerstone of a safe blood supply and therefore an important and central point in WHO recommendations as well as other international organizations concerned. Establishing a pool of safe blood donors requires long-term commitments to education, information, and social involvement. Efforts in this respect have been particularly enhanced with the World Blood Donor Day, launched in 2004, and endorsed by the World Health Assembly in 2005 as global annual event. Cosponsored by WHO, the International Federation of Red Cross and Red Crescent Societies (IFRCRCS), International Federation of Blood Donor Organizations (IFBDO/ FIODS), and International Society of Blood Transfusion (ISBT), it aims to increase awareness toward blood donation and enhance the different steps in the process of education, recruitment, and retention of low-risk donors and establishment of youth donor programs. The theme of World Blood Donor Day 2014 was dedicated to safe motherhood. In the current epidemiological context (i.e., blood safety potential threats) and extended cross-border movement, donor selection criteria have become more stringent with the aim to reduce residual risks. There is a constant debate on how far the donor screening and selection procedures should go, considering their impact on actual donor availability, blood supplies, and patient safety. The Melbourne declaration on 100% voluntary nonremunerated blood donation of blood and blood components (2009) and the Rome declaration on achieving selfsufficiency in safe blood and blood products based on voluntary nonremunerated blood donations (2013) emphasize the vital importance of safe blood donations (i.e., voluntary nonremunerated) in preserving adequate and sustainable national blood supplies and healthy populations.

Testing and Processing of Blood Collected blood needs to be screened for blood-borne pathogens prior to transfusion. Basic screening includes tests for HIV, hepatitis B, hepatitis C, and syphilis. In some parts of the world, additional tests are necessary for local epidemiological threats. It is the responsibility of health authorities to outline a national strategy for screening of all donated blood and specify the most appropriate testing and diagnostic algorithms to be used. In addition, testing for ABO and RhD blood groups, as well as screening for irregular antibodies, is performed to avoid an incompatible (hemolytic) transfusion reaction. Reliable testing of blood units requires the following: 1. Uninterrupted supply of high-quality test systems; this includes procurement, supply, central storage, and distribution of reagents and materials to ensure continuity of testing; 2. Maintenance of a quality assurance system and good laboratory practice, including the use of standard operating procedures for all aspects of blood screening and processing; 3. Continuous training of staff members in all aspects of blood screening and processing of blood units, including storage and transportation of blood products.

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Collected whole blood can be stored for a time depending on the mixture of anticoagulant preservation solution used. The whole blood unit may be separated into major blood components – packed red cell, fresh frozen plasma, and platelet concentrate – to increase efficiency of use. Processing of donated blood into its different components reduces the occurrence of adverse transfusion reactions and tailors therapeutic response to the particular needs of the patient. Since each blood component can be stored according to its specific requirements, effectiveness is increased and shelf-life adjusted. Time interval between collection, separation, and storage at the correct temperature also influences the quality and expected transfusion efficiency of the separated component. In what fresh frozen plasma is concerned, separation should be done within 6 h from collection and at not more than 18 h if refrigerated. Separated plasma should be subject to fast freezing (less than 1 h) at below 30  C. Fresh frozen plasma can be stored at 40  C for 36 months, pooled platelets suspended can be stored at þ20 to 24  C for 3–5 and up to 7 days depending on the suspension media, and red cells suspended in an additive solution (SAG-MAN or ADSOL) can be used up to 45 days if stored at þ4  C. Raw plasma for industrial fractionation (obtained from separated whole blood donations or apheresis procedures) has to comply to specific quality and safety requirements and is subject to standardized testing, industrial processing (extraction and purification) following pharmaceutical GMP and results in several individualized protein fractions, such as Factor VIII, IX concentrates; albumin and immune globulins (most frequently produced). Considering the life saving role of transfusion therapy when needed, blood components and blood derivatives have been recently included in the WHO list of essential medicines.

Appropriate Clinical Use of Blood Blood is a scarce resource and should always be used with care. As with any medical procedure, it carries also a measurable risk to the recipient patient. In evaluating the indication for blood transfusion therapy, the benefits for the patient should outweigh the risks. Several international recommendations and guidelines have been developed in this respect, but these are not always available or used, and in many circumstances the process continues to rest on historically based practices and the clinical experience of the attending physicians. Several studies have shown important differences in usage of blood transfusion therapy within and between countries, for similar clinical pathologies. The training of clinical users in the adequate use of blood is an important endeavor which requires constant updates not only regarding scientific progress and technologies but also the availability of and access to alternatives to transfusion therapy (pharmaceutical products, clinical prevention, and procedures). Strengthening the collaboration and coordination with different levels of health care may help reduce blood usage through (1) prevention and education to health; (2) early diagnosis and treatment of diseases or conditions which may lead to the need for blood transfusion (obstetric antenatal care, iron substitution, etc.); (3) use of evidence-based latest therapeutic guidelines and microinvasive/bloodless surgical technologies;

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(4) replacement therapies where applicable (preoperative blood collection for autotransfusion; intraoperative normovolemic hemodilution; preoperative and postoperative blood salvage). Optimization of therapeutic blood usage is required not only by the scarcity of this natural reserve but also on maintaining an appropriate balance between related risks and benefits. In recent years, the concept of patient blood management (PBM), based on the earlier enumerated principles for reducing the clinical use of blood, has gained more and more attention and adherence in the clinical community of mainly high and medium HDI. The three pillars of PBM focus on optimization of red cell mass, reduction of blood loss/bleeding and optimization of the physiological reserve of anemia (see Isbister, 2013). Explaining the benefits and risks of transfusion therapies to patients and families is an important element in creating the necessary understanding of this apparently simple procedure. An informed patient will be knowledgeable of the residual risks related to the transfusion if given (no zero risk), as well as be involved in the informed choice of alternatives. The expert patient will be equally able to observe if safety steps such as appropriate identification, skin disinfection, etc., are followed and contribute to reducing the potential occurrence of transfusion-related hazards. The Network for Advancement of Patient Blood Management, Haemostasis and Thrombosis collects and promotes evidence-based interventions supporting these concepts, altogether with several (inter)national initiatives and web-based platforms for information exchange.

Hemovigilance ‘Hemovigilance,’ ‘pharmacovigilance,’ and ‘materiovigilance’ find their application in blood transfusion safety, as a set of complementary surveillance (‘vigilance’) procedures covering the whole transfusion chain (from the collection of blood and its components to the follow-up of the transfused patient), to monitor, record, and analyze occurring deviations to quality and safety standards and practices, and their impact on donor safety, patient safety, or health-care worker safety. The aim of hemovigilance is to collect all information of unexpected, undesirable, or serious adverse events in donors or in patient recipients of blood transfusion therapy in order to correct their cause, prevent recurrence, and improve the safety of blood collection and transfusion. It also looks into donor epidemiological follow-up, as part of organized surveillance procedures. Adverse reactions are defined as reactions which are unintended and occur during collection or transfusion procedures. Reporting of serious adverse events related to transfusion therapy appears to be one of the oldest reporting systems in place. However, the development of national hemovigilance systems poses increasing challenges. These relate to how hemovigilance is regulated in terms of accountability and responsibilities for reporting donation/transfusion-related events, to the various taxonomies in use and how the degree of severity and the reporting trigger are defined, the limited resources for supportive information technologies, and, mainly, the communication between blood services and hospital services (reporting, route cause analysis of reported events and feedback).

Several websites provide data on hemovigilance (national and regional). The International Haemovigilance Network (formed in 2009) collects information from national operational hemovigilance systems and provides a forum for shared information and best practices in the field. Drawing from collected data, IHN has developed the International Surveillance of Transfusion Associated Reactions and Events (ISTARE) that can be used for benchmarking as well as monitoring progress and trends. Hemovigilance is to be seen as a safety tool fostering reporting and learning. The increasing role of the patient in this process is expected to strengthen hemovigilance at its operational level.

See also: Brucellosis; Hepatitis, Viral; History of Malaria and Its Control; HIV/AIDS and Tuberculosis; Lyme Disease; Protozoan Diseases: Malaria Clinical Features, Management, and Prevention; Protozoan Diseases: Toxoplasmosis; Social Dimensions of Epidemics.

References AABB, 2011. In: Roback, J., et al. (Eds.), Technical Manual, seventeenth ed. AABB Press, Bethesda, MD. Barbara, J., Regan, F.A.M., Contreras, M., 2008. Transfusion Microbiology. Cambridge University Press, Cambridge, UK. European Directorate for the Quality of Medicines & HealthCare, 2013. Council of Europe Publishing, Guide to the Preparation, Use and Quality Assurance of Blood Components, seventeenth ed. Council of Europe, Strasbourg, France. Goodnough, L.T., Shander, A., 2008. Risks and complications of blood transfusions: optimizing outcomes for patients with chemotherapy induced anemia. Adv. Stud. Med. 8 (10), 357–362. Hillyer, C.D., Silberstein, L.E., Ness, P.M., Anderson, K.C., Roback, J.D., 2006. Blood Banking and Transfusion Medicine. Basic Principles and Practice, second ed. Elsevier, London. Improving blood safety worldwide. Editorial. Lancet 370 (9585), 2007, 361. http:// dx.doi.org/10.1016/S0140-6736(07)61167-2. Elsevier Ltd. Isbister, J.P., 2013. The three pillar matrix of patient blood management – an overview. Best Pract. Res. Clin. Anaesthesiol. 27, 69–84. Kitchen, A., Barbara, J., 2008. Current information on the infectious risks of allogeneic blood transfusion. Transfus. Alter. Transfus. Med. 10 (3), 102–111. Klein, H.G., Anstee, D.J., 2014. Mollison’s Blood Transfusion in Clinical Medicine, twelfth ed. Wiley-Blackwell, Oxford, UK. Lozano, M., Contreras, M., Blajchman, M., 2006. Global Perspectives in Transfusion Medicine. AABB Press, Bethesda, MD. Melbourne declaration on 100% Voluntary Non-Remunerated Donation of Blood and Blood Components. Available online. Rome declaration on Achieving Self-sufficiency in Safe Blood and Blood Products, Based on Voluntary Non-Remunerated Blood Donation. Available online. Starr, D., 1998. Blood: An Epic History of Medicine and Commerce. Knopf, New York. Sen, S., Gupta, P., Sinha, S., Bahmbani, P., 2014. Haemovigilance and transfusion safety: a review. Sch. J. App. Med. Sci. 2 (1A), 85–90. Van Aken, W.G., 2006. Gift or good? Transfus. Clin. Biol. 13, 196–199. Van der Poel, C.L., Seifried, E., Schaasberg, W.P., 2002. Paying for blood donations: still a risk? Vox Sanguinis 83, 285–293. Wislow, R.M., 2006. Blood Substitutes. Elsevier, San Diego, CA. WHO, June 2011. Global database on blood safety. In: Summary Report 2011. Available online at: www.who.int/blood safety. World Health Organization, 2001. Blood Transfusion, Safety, the Clinical Use of Blood: Handbook. WHO, Geneva, Switzerland.

Relevant Websites http://www.aabb.org/ – AABB. http://www.redcross.org/ – American Red Cross.

Blood Transfusion Services http://www.edqm.eu/ – European Directorate for the Quality of Medicines & HealthCare, Council of Europe. http://www.eur-lex.europa.eu/ – EUR-Lex. http://www.fiods.org/ – International Federation of Blood Donor Organizations. http://www.ifrc.org/ – International Federation of Red Cross and Red Crescent Societies. www.ihn-org.com/ – International Haemovigilance Network. http://www.isbt.org – International Society for Blood Transfusion.

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www.ihn-org.com/haemovigilance-databases/istare-2/ – International Surveillance of Transfusion Associated Reactions and Events. http://www.nataonline.com/ – Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis. http://www.thalassaemia.org.cy/ – Thalassemia International Federation. http://www.wfh.or/ – World Federation of Haemophilia. http://www.who.int/bloodsafety/ – World Health Organization: Blood Transfusion Safety.

Botulism Paolo Aureli, Istituto Superiore di Sanità, Rome, Italy Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Paolo Aureli, Giovanna Franciosa, Lucia Fenicia, volume 1, pp. 329–337, Ó 2008, Elsevier Inc.

Introduction Botulism is a rare, severe, neuroparalytic disease caused by accidental or intentional exposure to eight distinct botulinum toxins (BoNTs, A–H types) that affect humans and a variety of domestic and wild lower animals. The disease is characterized by symmetrical cranial nerve palsies that may be followed by descending, symmetric flaccid paralysis of voluntary muscles, which may lead to death because of respiratory or heart failure. Botulinum toxins are neurotoxins of extreme potency and lethality (they can be lethal at doses as low as 1 mg kg 1 orally) released by vegetative cell death and lysis. Four toxigenic anaerobic Gram-positive spore-forming bacteria of the genus Clostridium produce the botulinum toxins: the classic Clostridium botulinum that produces type A, B, C, D, E, F, and H toxins (BoNT/A–F, H), C. argentinense that produces type G toxin (BoNT/G), and two rare strains of C. butyricum and C. baratii that produce types E and F botulinum-like toxins, respectively. From the first years of the twentieth century, the potent toxicity of neurotoxins and their specific action have drawn the attention of many researchers and promoted the growth of research in different fields. The understanding of the environmental distribution of the organism, the mechanism of spore germination and heat resistance, the chemical and physical factors controlling the survival and growth of the vegetative form, and the production, release, and stability of the toxin have allowed the development of technology to produce safe food and strategies to manage the disease efficiently. Botulism that follows the consumption of preformed neurotoxin in an improperly preserved food (foodborne or ‘classic’ botulism) has now become relatively rare in developed countries, although sporadic outbreaks continue to occur from homemade food. Furthermore, this deadly food poison has been recognized as a potent therapeutic agent for many human syndromes caused by hyperactivity of cholinergic nerve terminals and, more recently, as a popular cosmetic useful to reduce or eliminate wrinkles on the face and neck as an alternative to cosmetic surgery. Nevertheless, because even a single case of botulism represents both a public health emergency that requires immediate intervention to prevent additional cases and a medical emergency that requires prompt provision of botulinum antitoxin and prolonged intensive care among affected persons, it has mandated intensive surveillance and control measures (prompt reporting, epidemiological investigation, and diagnostic confirmation) in developed countries to determine the source. Over the past 50 years, several ‘new’ or emergent forms of botulism have been recognized and described. These occur after the absorption of the botulinum neurotoxin produced in vivo when the spores of toxin-producing Clostridia have contaminated a wound associated with trauma (wound botulism; Merson and Dowell, 1973) or sniffing/injecting drugs, or

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from infection of the intestine of small babies (infant botulism; Midura and Arnon, 1976; Pickett et al., 1976) or adults (adult infantlike botulism; Chia et al., 1986) who have altered intestinal flora that allows germination and growth of Clostridia spores occasionally present in food. The two last forms were recently grouped under the term ‘intestinal toxemia botulism.’ Another form of botulism (inhalational botulism; Holzer, 1962) was described among German laboratory workers as a consequence of accidental exposure during animal experiments. Because of the presumption that the disease may be caused by aerosolized toxin, C. botulinum and its toxins are classified as major agents in biological weapons or bioterrorism attack (‘Class A agents’ by the Centers for Disease Control and Prevention (CDC)). Finally, one form of botulism with local or generalized weakness (iatrogenic botulism) has been reported after the injection of higher doses of toxins as therapeutic agents in patients with neuromuscular conditions resulting from abnormal, excessive, or inappropriate muscle contractions (Bakheit et al., 1997) or of unlicensed, highly concentrated botulinum toxin for cosmetic purposes (Chertow et al., 2006). In conclusion, humans may be affected by four accidental or ‘natural’ forms of botulism (foodborne botulism, wound botulism, infant botulism, and adult infantlike botulism) and by two intentional ones (iatrogenic botulism and inhalational botulism), all of those associated with toxin types A, B, E, and, sometimes, C, F, and H. Botulism affects mammals, birds, and fish by neurotoxins produced by C. botulinum. Animal botulism occurs in three accidental forms: (1) ingestion of preformed toxins produced by the growth of C. botulinum in decaying crops, vegetation (forage), free-floating macrophytic green algae, or carcass material, or (2) gastrointestinal, or (3) wound infection resulting from proliferation of C. botulinum in situ. Forage botulism occurs when the pH (>4.5), moisture, and anaerobic conditions within the forage allow proliferation of C. botulinum. Carrion-associated botulism occurs when the carcass of a dead animal is invaded by C. botulinum, generally types C and D strains, and the toxin is produced. Recently, in shoreline birds with botulism, it was demonstrated that macroalga Cladophora provides a habitat for C. botulinum type E. Presently the relationship between this bacterium and the alga, and how this interaction potentially contributes to botulism outbreaks in birds (Chun et al., 2013) need to be elucidated. Disease in farm animals is produced primarily by types A (cattle and horses), B (swine, cattle, horses), C (wild and domestic bird, minks, and, sometimes, cattle, sheep, and horses), D (cattle, wild and domestic birds), and E (fish, wild and domestic birds). Birds may harbor type D–producing strains in the gut without showing symptoms. The signs and symptoms of human botulism are essentially the same for all forms of the disease (except the presence of

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Botulism fever in patients with wound botulism), whereas it is not clear which of the animal exposures is the more important or whether there is a difference in clinical features.

Etiologic Agents: The Toxins Designation The eight toxin types have been assigned the letters A through H as convenient clinical and epidemiological markers. The designation of the botulinum toxin is identical to the designation of the producing strain. Because some rare C. botulinum strains are capable of producing the major type-specific toxin as well as a minor toxin of another type, the capital letter is to designate the major typespecific toxin. These strains are termed ‘bivalent’ and include those with the dual toxicities of Ab, Ba, Af, and Bf, as well as AB strains that produce equivalent amounts of both toxins. The new BoNT/H toxin is produced by a bivalent strain from group I, which predominantly synthetizes BoNT/B. This new toxin type has been established only on the basis of sequence analysis of the gene encoding it and because of the absence of neutralization with antisera against the previously identified BoNT types (Barash and Arnon, 2014; Dover et al., 2014). Finally, a specific strain of C. botulinum, which produced a DC mosaic botulinum neurotoxin formed by 2/3 of BoNT/D and 1/3 of BoNT/C, was discovered recently (Nakamura et al., 2010). The new neurotoxin was called BoNT/DC and resulted in high lethality in mice (1.1  10 9 LD50 mg 1 protein) compared with other types of neurotoxins. This strain is added to another strain producing a CD mosaic neurotoxin formed by 2/3 of BoNT/C and 1/3 of BoNT/D (Takeda et al., 2005). One of two letters is bracketed when one of two botulinum toxin genes is unexpressed (‘silent’ gene). A single strain of C. botulinum, which produces three enzymatically active neurotoxins, was recently described (Kalb et al., 2014).

Structure Botulinum neurotoxins are released from vegetative cell death and lysis as progenitor toxins that contain a 150-kDa relatively inactive single-chain polypeptide of similar structure as well as a variable number of associated nontoxic proteins, which include the nontoxic nonhemagglutin (NTNHA) protein and three hemagglutinins (HAs), HA1, HA2, and HA3. NTNHA protects BoNTs from stomach acid and intestinal proteases forming a minimally functional progenitor toxin complex (M-PTC) (290 kD) (Gu et al., 2012). M-PTC associates with the HAs to form the large PTC (L-PTC) (760 kD), which exhibits up to 30-fold greater oral toxicity. They dissociate from the progenitor toxins when the complexes reach the small intestine, which is the main site of absorption of BoNTs into the bloodstream, where they translocate from the apical to the basolateral side of the polarized epithelial monolayer. The single-chain polypeptides become fully active after a specific proteolytic cleavage within a surface-exposed loop subtended by a highly conserved disulfide bridge. Several

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bacterial and tissue proteinases are able to generate two polypeptide chains: a 100-kDa heavy (H) chain and a 50-kDa light (L) chain linked by a single disulfide bond organized in four domains, which are functionally linked to the different steps of the mechanism of neuron intoxication. The N-terminal domain (the L-chain, 50 kDa), which acts as a zinc-dependent endopeptidase, cleaves the proteins involved in acetylcholine vesicle docking and fusion to the presynaptic membrane. The L-chain is disulfide-linked to the domain HN (50 kDa), which is implicated in the transmembrane translocation of the L-chain from the lumen of endosomal vesicles into the neuronal cytosol (Montal, 2010). The third domain (HCeN, 25 kDa) is linked to HN and its function is presently unknown; this domain is linked to the C-terminal domain (HCeC, 25 kDa), which is responsible for the neurospecific binding of the BoNTs via a double interaction mediated by two binding sites. One site is very similar among serotypes and isoforms and binds the oligosaccharide portion of a polysialoganglioside. The second one varies among serotypes and binds different receptors (Binz and Rummel, 2009). Although all of the neurotoxin types inhibit acetylcholine release from the nerve terminal, their intracellular target proteins, their characteristics of action, and their potencies vary substantially.

Genetics and Toxicogenesis Genes encoding components of the botulinum neurotoxin complexes are arranged in clusters. The structure and composition of the neurotoxin gene clusters of C. botulinum vary, some clusters possessing genes (ha) encoding the HAs, such as those of types B, C, D, and G, and other clusters lacking these genes (types A2, A3, A4, E, and F). The type A1 gene can be located in either clusters, depending on the strain. All botulinum toxin gene clusters include a ntnh gene; in addition, all, except for those containing the bont/e gene in all C. botulinum type E and C. butyricum type E strains, and those containing the bont/f gene in nonproteolytic C. botulinum type F and in neurotoxigenic C. baratii type F strains, contain a gene (botR) for an alternative RNA polymerase factor, that positively regulates the synthesis of the botulinum neurotoxin complexes. The expression of BotR (encoded by botR) is likely regulated by other factors; hence the positive regulation of the synthesis of the botulinum toxin complexes is a cascade process. In addition, evidence of negative regulation has been achieved, yet the factors directly involved in these mechanisms still remain to be elucidated. The mechanisms that regulate the expression of BoNT/E and BoNT/F in the C. botulinum strains lacking the botR gene are still unknown. The nucleotide sequences of genes encoding the different botulinum toxin gene types have been determined, and the derived amino acid sequences compared. Despite a high degree of homology in regions involved in similar structure/function, a certain gene and protein sequence variability has been recognized among the different serotypes and even within each serotype (Peck et al., 2011). Since sequence variation influences the biological properties of the neurotoxins (including receptor binding affinity, substrate recognition and cleavage efficiency, and antibody

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binding) (Popof and Bouvet, 2013), each botulinum neurotoxin is divided into subtypes (BoNT/A1-5, BoNT/B1-8, BoNT/E1-9, BoNT/F1-7, mosaic BoNT/CD, and BoNT/DC), which differ one from another by at least 2.6% in the amino acid composition. Recently, Dover et al. (2013) identified a C. botulinum strain that contains 3 BoNT gene clusters consisting of BoNT subtypes A2, F4, and F5. This was the first report of a clostridial organism containing more than two neurotoxin gene clusters. Botulinum neurotoxin gene types E and F from neurotoxigenic C. butyricum and C. baratii have also been sequenced: they show high relatedness with the corresponding BoNT genes from C. botulinum strains of 97% and 70–74%, respectively, which are indicative of lateral gene transfer among progenitor strains. The possibility that botulinum neurotoxin genes are mobile is substantiated by the existence of C. botulinum strains harboring two different neurotoxin genes and by the mosaic sequences observed in some neurotoxin genes of type C and D. In addition, the genomic location of the neutotoxin gene clusters within potentially mobile genetic elements, including plasmids, bacteriophages, and remnants of transposons, in a number of C. botulinum strains provides further evidence that the toxin gene clusters have been transferred among Clostridia during evolution.

Mechanism of Action In foodborne and infectious botulism, the orally ingested or in situ-produced toxin must pass through the intestinal epithelial barrier to enter the systemic circulation from the gut lumen. Recently, it has been shown that the HA component of toxin directly binds epithelial cadherin (E-cadherin) and thereby disrupts E-cadherin–mediated cell-to-cell adhesion and, in turn, the epithelial barrier facilitating the transepithelial delivery of BoNT (Sugawara et al., 2010; Lee et al., 2014). After absorption, the toxin passes into the bloodstream and is transported to the nerve tissue, where it paralyzes the cholinergic neuromuscular junction via four sequential steps (Arnon et al., 2001): 1. rapid and specific binding by the H chains to receptors on the presynaptic membrane of the cholinergic nerve terminals; 2. internalization inside a vesicle endowed with an ATPase proton pump; 3. membrane translocation triggered by acidification of the vesicular lumen into the cytosol; and 4. enzymatic cleavage by the L-chain, a zinc-dependent endopeptidase of SNARE (soluble NSF, N-ethyl maleimidesensitive factor, attachment receptors, proteins essential for regulated exocytosis) of the complex of proteins (VAMP, SNAP-25, and syntaxin) required for fusion of the synaptic vesicle with the presynaptic plasma membrane. In particular, vesicle-associated membrane protein (VAMP), also referred to as synaptobrevin, plasma membrane synaptosome-associated proteins (SNAP-25), and syntaxin form a trimeric complex by winding one around the other two.

This forms a stable, four-helical, coiled-coil structure that brings the synaptic vesicle membrane and the plasma membrane close enough to permit fusion and subsequent release of the vesicle neurotransmitter content (acetylcholine) into the synaptic cleft. Cleavage of any one of these proteins prevents the SNARE complex formation, which in turn inhibits acetylcholine release and results in flaccid paralysis. Each toxin cleaves the specific component of the synaptic vesicle fusion machinery at a single site: the L-chains of BoNT/A, C, and E cleave SNAP-25; the L-chains of BoNT/B, D, F, and G cleave synaptobrevin (VAMP). Only BoNT/C cleaves two proteins: syntaxin other than SNAPS-25. Within a few days, the affected nerve terminals are no longer capable of neurotransmitter exocytosis, but newly formed sprouts release acetylcholine, forming a functional synapse. In conclusion, the different spectrum of symptoms exhibited by patients derives from different sites of intoxication, rather than from a different molecular mechanism of action.

Toxicity The mouse LD50 values of the seven BoNTs vary between 1 and 5 ng of toxin per kg of body weight; in humans, for whom corresponding values are not available, the LD50 for a 70-kg person has been estimated to be similar or lower, approximately 40 U/kg or about 2500–3000 U (1U is 1 mouse LD50 for a 20-g Swiss strain mouse). Clinical observations have indicated that type A neurotoxin is often associated with higher mortality than botulism from types B and E and causes the longest lasting disease. The estimated lethal doses for purified crystalline toxin type A extrapolated from studies on primates are 0.09–0.15 mg for a 70-kg person when administrated intravenously, 0.80–0.90 mg by inhalation, and 70 mg when introduced orally.

Duration of Inhibitory Effect The duration of the effect of the BoNTs may be several weeks to months (from 4–6 weeks for type E to 3–6 months for the other types) and is dependent on the toxin serotype, the dose, the type of cholinergic nerve terminal affected, the amount of toxin ingested, and the animal species. After several weeks/months, the original terminal resumes acetylcholine exocytosis. Weakness and autonomic dysfunction may persist for more than 1 year. Since BoNTs have also been shown remarkably effective as therapeutics in treating many neuronal and neuromuscular disorders, its long persistence in patients is considered a positive hallmark. Different subtypes of toxin A exhibit a remarkable dissimilar duration of intracellular enzymatic activity. The mechanisms for this persistence are currently unclear.

Commercial Preparations Since botulinum toxin has become a powerful therapeutic tool for a growing number of human diseases (such as those caused

Botulism by hyperfunction of cholinergic terminals and, more recently, diseases of the autonomic nervous system, pain, and migraine), different preparations have been commercially available. The first one was type A botulinum toxin, marketed as BOTOX (Allergan, Inc., USA). Other preparations of botulinum toxin currently available for therapeutic purposes include other botulinum toxin type A, such as Dysport (Beaufour-Ipsen, Dreux, France), ‘Hengli’ (Lanzhou Institute of Biological Products, Lanzhou, China), Linurase (Prollenium, Inc., Canada), Xeomin (Merz Pharma, Germany), Puretox (Mentor Corporation, USA), Neuronox (Medy-Tox, Inc., South Korea); and one botulinum toxin type B named Myobloc (Elan Pharmaceuticals, USA). The above list is likely incomplete, since the number of licensed botulinum toxins is expanding, due to the successful use of botulinum toxin for cosmetic treatments. Available botulinum toxins are approved for specific uses depending on the country. In some patients, formation of antibodies against botulinum neurotoxins A and B may occur, leading to treatment failure. As a consequence, the therapeutic potential of other types of botulinum neurotoxins has been evaluated as an alternative to the most widely used botulinum toxin type A.

Sensitivity and Immunity Different animal species show a great range of sensitivity to the different BoNTs. Animals that may obtain oxygen through the skin are poorly sensitive, while highly sensitive are mammalians and birds that depend heavily from the muscle contraction driven internal pulmonary respiration. Humans, carrion-eating carnivores, swine, cattle, sheep, mink, and horses are sensitive, whereas snakes and amphibians are rather resistant. Birds are sensitive to BoNT/A and very sensitive to BoNT/C and BoNT/E, whereas invertebrates are not sensitive to BoNTs. Cattle are believed to be more sensitive to the effects of botulinum toxin than birds. For reasons that remain uncertain, not all exposed persons manifest symptoms of botulism. Besides the uneven distribution of the toxin in contaminated foods, host factors may play a role, because at least one person has had demonstrable levels of toxin in circulation without manifesting any clinical symptoms (Kalluri et al., 2003). An attack of food botulism does not produce an immunological response in human populations. The absence of immunity probably results because the quantities of neurotoxins causing foodborne disease may be smaller than an immunizing dose. In contrast, antibody to neurotoxin has been detected in a small number of patients receiving multiple exposures to neurotoxin, whether in adult intestinal toxemia botulism, infant botulism, or after receiving doses of injected type A botulinum toxin as therapy. Also, the administration of a toxoid that contains formalin-activated toxins of types A–E (pentavalent A–E botulinum toxoid) yields botulism-immune globulins and is recommended for protecting laboratory workers who work with cultures of C. botulinum or its toxins. Active immunization of cattle in high-risk herds, of animals grown for their fur, and of ducks with a bivalent formalininactivated toxoid is a current option.

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Stability Botulinum toxins are heat sensitive; types A, B, E, and F neurotoxins are inactivated by heating at 79  C for 20 min or 85  C for 5 min. However, if a food contains the botulinum toxin, higher temperature and time conditions may be necessary to completely eliminate it, depending on the presence of food matrix compounds that may protect the toxin. The toxins are stable at pH 5. Botulinum toxins can persist in carrion for at least 1 year.

Botulinum Neurotoxin-Producing Clostridia Until recently, the ability of a Clostridium strain to produce botulinum neurotoxin was necessary and sufficient to include it in the botulinum species. Upon phenotypic and genotypic characterization of C. botulinum strains, however, it became evident that the species encompasses a group of very diverse organisms; in addition, organisms taxonomically identifiable as species other than botulinum, such as C. butyricum and C. baratii, can produce botulinum toxin types E and F, respectively. Polyphasic taxonomic approaches relying on 16S and 23S rRNA gene sequencing, in addition to traditional phenotypic characterization and DNA hybridization studies, have identified at least six (I–VI) distinct groups of botulinum neurotoxin-producing Clostridia. Group I includes all C. botulinum types A and H strains, and the strains of C. botulinum types B and F capable of hydrolyzing complex proteins such as those of meat and milk (proteolytic strains); the strains of C. botulinum types B and F that do not digest complex proteins, and all strains of C. botulinum type E are included in group II (nonproteolytic strains); group III consists of the C. botulinum types C and D strains; and C. argentinense, C. butyricum type E, and C. baratii type F fall into groups IV, V, and VI, respectively.

Habitat Clostridium botulinum occurs naturally in the environment and is commonly found in soil, dust, fresh water and marine sediments, vegetation, free-floating algal mats, and wild and domestic animals. Recently, it has been demonstrated that the digestates from biogas fermentation used as fertilizers are a low risk source for the dissemination of C. botulinum spores. Environmental reports show that a relationship exists between the incidence of different C. botulinum types and geographic areas. Specifically, C. botulinum type B is predominant in Europe and the eastern United States; C. botulinum type A predominates in the western United States, South America, and China; C. botulinum type E is widely spread in northern areas of the world, such as Scandinavia, Canada, and Alaska, and in several Asian and Middle East countries. Accordingly, most cases of botulism in the same regions are caused by the predominant toxin types. C. butyricum type E and C. baratii type F seem to be less ubiquitous, the former having been associated with botulism only in Italy, India, USA, UK, and China, and the latter only in the United States, Spain, and Hungary.

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Environmental sources of these organisms have not been identified, except for numerous lake sediments in China found positive for C. butyricum type E.

Control Factors in Foods Because of the environmental ubiquity of C. botulinum, food can become contaminated with the microorganism at any stage of the ‘farm-to-fork’ food chain. Although the application of hygienic practices can generally decrease the level of microbial contaminants in a food, the presence of C. botulinum spores cannot be ruled out. Foodborne botulism occurs (1) when the food contaminated with C. botulinum spores is processed and stored under conditions permissive for the survival and proliferation of the organism, with (2) consequent toxin synthesis in the food, and (3) when the food containing the botulinum neurotoxin is not cooked before consumption. Hence, eliminating C. botulinum in foods, controlling its growth, and destroying the toxin eventually produced in the food are the most effective tools to prevent foodborne botulism. Heat treatment is commonly applied to inactivate C. botulinum spores in foods. The most largely used heat resistance parameters in thermal settings of low acidic, ambient stable products are the D-value (time required to have a 10-fold decrease of the spore count at a certain temperature) and the z-values (temperature increase to have a 10-fold decrease of D-values). Spores of Group I are more heat resistant than those of Group II, as demonstrated by their higher D-value, and they represent a threat in the canning process of low-acid, high-moisture foods. According to a meta-analysis of D-values of proteolytic C. botulinum and its surrogate strain Clostridium sporogenes PA 3679 (Diao et al., 2014), the D-value and the z-value are similar. The mean D-values at the reference temperature of 121.1  C, in liquid media and pH neutral, were estimated to 0.19 and 1.28 min for C. botulinum and C. sporogenes, respectively. On the other hand, the mean z-values of the two species were similar: 11.3 and 11.1  C for C. botulinum and C. sporogenes, respectively. Based on the assumption that the D 121  C value of C. botulinum is equal to 0.204 min, a 5D (five decimal) thermal process is industrially employed to consider canned food safe, which in practice consists of heat treatment at 121  C for 5 min (sterilization). Milder temperature and time conditions, such as those of pasteurization processes, are not lethal to botulinum spores. In order to minimize the loss of nutrients and organoleptic quality caused by the sterilization processes, the use of high-hydrostatic pressure in combination with temperatures > 70  C has been investigated for the inactivation of C. botulinum spores, because they are insensitive to pressure treatment at ambient temperatures. A few data are available on the efficacy on the inactivation of C. botulinum spores of other physical methods, such as gamma irradiation, pulsed electrical field technology, and microwave. In those food matrixes that can be affected by the sterilization conditions, control of C. botulinum is achieved through inhibition, rather than destruction. Clostridium botulinum grows well in foods with high free-water (water activity > 0.94), low acid (pH > 4.6), and low salt (20% of tumor cells) are important predictors of complete pathological response to six courses of primary chemotherapy. Disease-free survival is substantially longer for patients with endocrineresponsive disease than for patients who do not express steroidhormone receptors, even though patients with endocrineunresponsive disease are at least four times more likely to obtain a pathological complete remission after primary chemotherapy (Colleoni et al., 2004). Anthracyclines and taxanes are usually used for patients with both operable and locally advanced disease (Nowak et al., 2004). Anthracycline-based primary chemotherapy has been reported to yield a large proportion of responses in small-sized tumors with a high proliferation index (Ki67) or grade, and with simultaneous overexpression of HER-2/ neu and topoisomerase II, whereas mutation of p53 has been associated with a reduced response rate to chemotherapy. Chemotherapy regimens that do not contain anthracycline (that have vinorelbine, platinum, and fluorouracil) were also reported to be effective, especially for patients

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with endocrine-unresponsive disease, with or without inflammatory features.

Conclusions Breast cancer is the most common type of tumor in women in most parts of the world. Although stabilized in Western countries, its incidence is increasing in other continents. Prevention of breast cancer is difficult because the causes are not well known. We know of many risk factors such as nulliparity, late age at first pregnancy, little or no breastfeeding, which, however, are linked to the historic development of human society. On the contrary, a great effort is needed to improve early detection of the tumor. Screening programs among the female population should therefore be implemented. The early discovery of a small breast carcinoma leads to a very high rate of curability and entails very mild types of treatment, with preservation of the body image. Treatments are improving, but a strict interdisciplinary approach is essential. It is conceivable that in all countries specialized centers or units for breast cancer management should be set up.

Acknowledgments We wish to acknowledge Professor Roberto Orecchia, Professor Aron Goldhirsch, and Professor Giuseppe Viale for their precious scientific contribution.

See also: Cancer Epidemiology; Cancer Mortality; Cancer Screening: Theory and Applications; Cancer Survival; Future Organization of Cancer Care; Populations at Special Health Risk: Women; Radiation Therapy.

References Burbank, F., Parker, S.H., Fogarty, T.J., 1996. Stereotactic biopsy: improved tissue harvesting with the Mammotome. Am. Surg. 62, 738–744. Cho, E., Spiegelman, D., Hunter, D.J., et al., 2003. Premenopausal fat intake and risk of breast cancer. J. Natl. Cancer Inst. 95 (14), 1079–1085. Colleoni, M., Viale, G., Zahrieh, D., et al., 2004. Chemotherapy is more effective in patients with breast cancer not expressing steroid hormone receptors: a study of preoperative treatment. Clin. Cancer Res. 10, 6622–6628. Coombes, R.C., Hall, E., Gibson, L.J., et al., 2004. Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N. Engl. J. Med. 350, 1081–1092. Cuzick, J., Powles, T., Veronesi, U., et al., 2003. Overview of main outcomes in breast cancer prevention trials. Lancet 361, 296–300. Ferlay, J., Bray, F., Pisani, P., Parkin, D.M., 2004. Globocan 2002: Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No. 5, version 2$0. IARC Press, Lyon, France. Fisher, B., Costantino, J.P., Wickerham, D.L., et al., 1998. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and Bowel project p1study. J. Natl. Cancer Inst. 90, 1371–1388. Hong, W.K., Sporn, M.B., 1997. Recent advances in chemoprevention of cancer. Science 278, 1073–1077. Nowak, A.K., Wilcken, N.R., Stockler, M.R., Hamilton, A., Ghersi, D., 2004. Systematic review of taxane-containing versus non-taxane containing regimens for adjuvant and neoadjuvant treatment of early breast cancer. Lancet Oncol. 5, 372–380.

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O’Shaughnessy, J.A., Ljung, B.M., Dooley, W.C., et al., 2002. Ductal lavage and the clinical management of women at high risk for breast carcinoma: a commentary. Cancer 94, 292–298. Tavassoli, F.A., Devilee, P. (Eds.), 2003. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Tract. IARC Press, Lyon, France. Tripathy, D., Slamon, D.J., Cobleigh, M., et al., 2004. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J. Clin. Oncol. 22, 1063–1070.

Veronesi, U., Paganelli, G., Viale, G., et al., 2003. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N. Engl. J. Med. 349, 546–553. Veronesi, U., Boyle, P., Goldhirsch, A., Orecchia, R., Viale, G., 2005. Breast cancer. Lancet 365, 1727–1741. Veronesi, U., Mariani, L., Decensi, A., et al., 2006. Fifteen-year results of a randomized phase III trial of fenritinide to prevent second breast cancer. Ann. Oncol. 17, 1065–1071.

Brucellosis Marı´a Jesu´s Castan˜o, Elena Navarro, and Javier Solera, University Hospital of Albacete, Albacete, Spain Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Javier Solera Santos, Maria Jesús Castaño Aroca, volume 1, pp. 357–369, Ó 2008, Elsevier Inc.

Introduction Historically, brucellosis has been known as undulant fever, Gibraltar fever, rock fever, Mediterranean fever, and Malta fever for humans, and Bang’s disease, swine brucellosis, or contagious abortion for animals. It is a highly transmissible zoonosis affecting a wide variety of mammals. Human infections arise through direct contact with infected animals or their products. Human-to-human transmission is rare. Brucella melitensis is the most common agent causing human brucellosis and results in more severe infections than Brucella abortus. Failure to diagnose brucellosis, which frequently presents as a chronic disease, is largely due to a lack of clinical awareness. In addition, the bacterium that causes the disease is fastidious and not easily detected in clinical samples. Brucellosis has important effects on both public health and animal health and is widespread in many areas of the world. The control of human disease is affected by control of animal disease through vaccination, testing, and slaughter of infected herds and by pasteurization of milk products. Brucellae represent a significant aerosol biohazard to laboratory workers and others at occupational risk such as veterinarians, abattoir workers, and farmers. The interest in brucellosis has increased since Brucella spp. have been considered as a potential biological weapon.

Historical Aspects In 1859, Marston, a British army physician, while working on the island of Malta, described for the first time the clinical manifestation of human brucellosis as ‘Mediterranean gastric remittent fever.’ The causative organism for Malta fever was discovered in 1887 by Sir David Bruce, who named it Micrococcus melitensis. It was isolated from the spleen of a British soldier who had died of the disease. In 1897, Almroth Wright applied the newly discovered bacterial agglutination test to the diagnosis of Malta fever. In 1905, Zammit was the first to isolate Brucella in goat blood, and Major William Horrocks, also on the Mediterranean Fever Commission, found the organism in milk, thus demonstrating its zoonotic nature (Vasallo, 1996). This important discovery led to a total ban on consumption of goat’s milk by the military in order to eradicate the disease. This discovery also helped to explain the epidemiology of the disease. For example, officers were three times more likely to become ill because they drank more milk than private soldiers, and large numbers of cases were found in hospitals where milk was widely distributed. A Danish physician and veterinarian, Bernhard Bang, discovered Brucella abortus in 1897 while investigating contagious abortion that had been affecting cattle in Denmark for over a century. He also discovered that the organism affected horses, sheep, and goats. Thus the disease became known as “Bang’s disease.” The connection between animals and humans was discovered in the 1920s by Alice Evans, an American bacteriologist,

International Encyclopedia of Public Health, 2nd edition, Volume 1

who renamed the genus Brucella to honor Sir David Bruce. The morphology and pathology of the organism was very similar between Bang’s Bacterium abortus and Bruce’s M. melitensis. The name of Sir David Bruce has been carried on in today’s nomenclature of the organisms. The third most common Brucella species related to undulant fever in humans is B. suis, historically associated with swine herds. In 1947, Brucella neotomae was first isolated in the United States from desert wood rats. Brucella ovis was isolated in 1953 from sheep with ram epididymitis in New Zealand and Australia. Brucella canis was discovered in 1966 from dogs, caribou, and reindeer. In 1994, the first Brucella strain isolated from an aborted fetus of a bottlenose dolphin (Tursiops truncatus) was described. Since then, several Brucella strains have been isolated from marine mammals, including seal (Brucella pinnipedialis), dolphin, porpoise, and whale (Brucella ceti). Brucella microti, isolated for the first time in the common vole during an epizootic in the Czech Republic in 2001, has also been found in the red fox and soil (Scholz et al., 2008a,b, 2009). The latest species of Brucella described, Brucella inopinata, has been isolated from an infected human breast implant (Scholz et al., 2010). Recently, a 100% identity of 16S rRNA sequencing to B. inopinata has been seen in bacterial isolates from frogs which suggest a potentially novel Brucella species (Einsberg et al., 2012).

Epidemiology Routes of Transmission Sheep, goats, cattle, camels, swine, dogs, and other mammals are the principal reservoirs for human infection. The placenta, fetal fluids, and vaginal discharges expelled by infected animals after abortion induced by Brucella are important sources of infection for man and other animals. Brucellosis is transmitted directly by infected aerosols, via the gastrointestinal tract, or wounds in skin and mucosae. After entry into the body, the organisms arrive at the lymph nodes before bacteremia occurs. Bacteremia often leads to the invasion of the uterus, udder, mammary glands, and sometimes the spleen. Products derived from infected animals and environmental conditions are secondary routes of transmission just as important as the route related to abortion. Survival of Brucella in such situations is summarized in Table 1. In 1983, Stantic-Pavlinic described the first uncommon case of human-to-human transmission when a laboratory worker probably transmitted the disease to his wife. Rare cases of acquisition through organ transplantation, sexual contact, breastfeeding, the transplacental route, contaminated cosmetic derivates, and exchange transfusion have been described (Meltzer et al., 2010; Pappas et al., 2005; Grave and Sturn, 1983). In industrialized countries, there is a clear correlation between animal brucellosis and an occupational hazard to persons engaged in certain professions (shepherds, abattoir workers, veterinarians, and dairy-industry professionals),

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Brucellosis Table 1

Survival of Brucella spp. in the environment

Environment

Survival time


Direct sunlight (2 months 60 days 7 years 3–44 days 4 months Several days to months For 100 days 16 h 10 min 15 min Several days 3 months

whereas in developing countries the disease is related to people who consume unpasteurized or uncooked animal products. Microbiology laboratory personnel and physicians are also at risk.

Prevalence and Incidence This zoonosis has important repercussions for both public health and the economies of less undeveloped countries. To date, only 18 countries have been declared officially brucellosis free as concerns cattle, sheep, and goats. Sweden was the first country declared officially free of brucellosis in bovine herds in 1957. Since then, effective government-supported vaccination programs for slaughter of infected animals and control of homemade animal products have almost eradicated or steadily decreased the number of brucellosis cases in most industrialized countries. Recently, Latvia has joined the bovine-free brucellosis status. Nevertheless, bovine brucellosis has become a reemerging disease in France and Belgium (Table 2).

Table 2 Countries and year reporting last declared case of brucellosis in domestic animals due to Brucella abortus, Brucella melitensis, and Brucella suis Country

B. abortus

B. melitensis

B. suis

Andorra Australia Austria Barbados Botswana Belarus Belgium Brazil Bulgaria Canada Czech Republic Chile Croatia Denmark Dominican Republic Eritrea Estonia Ethiopia Finland Former Republic of Macedonia France French Polynesia Ghana Georgia Germany Greece Guyana Hungary Israel Italy Jamaica Japan Korea (Democratic People’s Republic of) Latvia Lithuania Luxembourg

2001 1989 2003 1978 . 1984 2000 (reemerging in 2012) . 1958 1989a 1964 . 1965 1962 . 2011 1961 . 1960 . 2003 (reemerging in 2012) 1984 . . 2000 . 1995 (ND) 1985 1984 . ND 2002 (new cases in 2007) 2008 1963 1992 1995

2001 2004 2003 NR 1995 1997 . 2001 2002 2003 1996 1975 1996 (new cases in 2007) 2006 1998 (ND) 2002 1996 . 2004 . 2006 (reemerging in 2012) 2003 ND 1997 . . ND 2001 (new cases in 2012) . . Before 1997 1949 ND 1997 1997 2003

2006 . NR (reemerging in 2010) NR NR NR New cases in 2012 2003 2003 NDb 1996 (reemerging in 2006) 1987 . 1994 ND ND 1988 Before 2008 Before 2006 ND . . Before 2006 1995 . 2001 ND . Before 2006 ND (new cases after 2008)c Before 2006 Before 2006 1995 (ND) 1994 (reemerging in 2010) 1992 Before 2006

Brucellosis

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Table 2 Countries and year reporting last declared case of brucellosis in domestic animals due to Brucella abortus, Brucella melitensis, and Brucella suisdcont'd Country

B. abortus

B. melitensis

B. suis

Malta Moldova Myanmar Netherlands New Zealand Norway Panama Poland Romania Russia Serbia and Montenegro Slovakia Slovenia Singapore South Africa Sri Lanka Swaziland Sweden Switzerland Syria Taipei China Togo Turkmenistan Uganda Ukraine United Kingdom United States of America Uzbekistan Vanuatu Zimbabwe

1996 ND . 1996 1989 1953 . 1980 1969 . ND 1964 1998 ND . . . 1957 1996 1999 (new cases in 2009) 1990 ND 2002 . 1992 1978 (new cases in 2008) . ND 1992 .

2001 2003 . 2004 2004 2004 2001(ND) 2004 Before 1998 . . 2003 2003 1998 ND 1998 2003 2004 1985

Before 2006 2002 2002 1973 Before 2006 Before 2006 2001(ND) 2003 . 2003 2003 1992 1997 1989 ND 1998 Before 2006 1957 2002 (reemerging in 2009) Before 2006 Before 2006 ND ND 2001 (ND) 2002 (reemerging in 2008) Before 2007 . 1995 (ND) Before 2006 Before 2006

2003 (ND) 2003 (ND) 2004 (ND) . 2004 2006 2004 2008 (ND) Before 1997 1996

ND, no information available; NR, never reported. a New cases in American bison in 2012. b New cases in wild species in 2009. c New cases in wild boar after 2010. Data obtained from http://www.oie.int.

The real incidence of brucellosis may be higher because of the inability of status reporting from many countries, because some cases are treated as if they were other infectious diseases, and also because in some countries the current investment in diagnosis is inexistent and/or inaccurate. The current worldwide prevalence of all forms of brucellosis is in practice limited to Latin America, the Middle East, the Balkan area, Mongolia, Russia, China, and certain Mediterranean countries. Brucellosis in small ruminants caused by B. melitensis is the most common form of the disease in developing countries, and it is almost always associated with clinically apparent disease in humans. The 15 main countries in terms of the number of brucellosis cases registered in 2012 are summarized in Table 3. There is a connection between countries with the highest number of cases of the disease in animals and rates of disease in humans. As regards human brucellosis, Mexico is the country with the highest incidence rate. Mexico has experienced a deep increase in recent years: from 3993 human cases in 2005 (rate per 100 000 population 3.7598) to 127 756 in 2012 (rate per 100 000 population 3.1986). The high prevalence of brucellosis registered in both human and small ruminants

in Mexico may be due to the lack of control measures such as screening, surveillance, border control, vaccination, and slaughter of sick animals. However, Syria has experienced a steep decrease in recent years: from 39 838 human cases in 2007 (rate per 100 000 population 215.9387) to 1452 cases in 2012 (rate per 100 000 population 7.8705). Although both animal and human disease occurrence seems to have decreased in years, sustained incidence of human disease is still present. In 2012, 197 792 new cases were reported in humans worldwide (OIE). Although rare, porcine brucellosis is widely spread internationally. In 2012, the highest numbers were registered in Spain, Hungary, and French Polynesia (Table 3). The epidemiologic pattern of human brucellosis has changed in the United States in the last 60 years as a result of veterinary control efforts. In 1947, the number of human cases was the highest ever reported. Thanks to successful brucellosis eradication programs consisting in vaccination of young animals and slaughter of sick animals or older animals with serologic evidence of infection, the annual incidence has been lowered to fewer than 100 cases in the past two decades. These few cases are situated in Texas and California and are

284

Brucellosis Table 3

Main 15 countries in number of brucellosis cases registered in 2012

Human brucellosis

Brucella abortusa

Brucella melitensisb

Brucella suisc

Mexico (127 756) China (39 515) Iran (8610) Turkey (6759) Algeria (5298) Iraq (3668) Kyrgyzstan (2296) Syria (1452) Russia (465) Tunisia (278)

Mexico (22 728) Russia (9627) Guatemala (>8281) Brazil (5167) South Africa (5041) Italy (3860) Kyrgyzstan (2338) Turkey (2346) Cuba (2287) Korea (Democratic People’s Republic of) (1497) Paraguay (1126) Algeria (1044)

China (56 255) Italy (15 059) Spain (4722) Turkey (1270) Tajikistan (1232) Egypt (1023) Iran (907) Thailand (823) Russia (795) Iraq (756)

Spaind (107) Hungary (83) French Polynesia (46) Italyd (31) Croatia (18) Cuba (17) Uruguay (10) Nicaragua (6) Thailand (4) Belgiume (1)

Azerbaijan (275) Argentina (246) Israel (183) Oman (148) Palestinian Autonomous Territories (148)

Honduras (893) Chile (753) Bolivia (733)

Kuwait (663) Palestinian Autonomous Territories (514) Bosnia (401) Jordan (372) Israel (259)

a

Infecting cattle, sheep, goats, dogs, equidae, swine, buffaloes and wild species (common dolphin in Costa Rica and American bison in Canada). Infecting cattle, sheep, goats, dogs, buffaloes, cammelidae and wild species (chamoix and ibis in France and western roe deer, red deer, fallow deer and spanish ibex in Spain). c Infecting cattle, swine and wild boar. d Only wild boar. e Infecting cattle. Data obtained from http://www.oie.int/hs2/report.asp?lang¼es. b

probably due to the illegally imported animals and dairy products from Mexico.

Causative Organism Taxonomy of Brucella Species Based on phylogenetic analysis of their 16S rRNA sequences, Brucella spp. belong to the Class I. Alphaproteobacteria class. nov., order IV Rhizobiales ord. nov. (Banai and Corbel, 2010). Historically, Brucella species were named based on their phenotypic characteristics and primary host species. The description of novel Brucella species is also based on molecular analysis. There are currently 10 recognized species within this genus Table 4

which vary in host preference and grade of virulence for humans. Characteristics of the classical six species are summarized in Table 4. Since 1994, when two new species from marine mammals (temporary called Brucella pinnipediae and Brucella cetaceae) were isolated, only three cases of acquired human infection with these strains have been reported. In recent years, an important controversy has developed concerning the taxonomy of the genus Brucella. Several molecular genotyping methods have been used to show that all Brucella species including the recently isolated marine mammal strains share a high degree of DNA relatedness which feed the controversy of considering a single monospecific genus, B. melitensis and that the other species should be considered as biovars. Moreover, the close relationship between the genera

Species and biovars of Brucella, natural host, and pathogenicity to humans

Species

Biovar

Preferred host

Human pathogen

Virulence

Infective dose

Brucella melitensis Brucella abortus Brucella suis

1–3 1–5, 6, 9 1–5

Yes Yes Yes

þþþþ þþ þþþ

1–10 100 000 1000–10 000

Brucella canis Brucella ovis Brucella neotomae Brucella ceti Brucella pinnipedialis Brucella microti Brucella inopinata

None None None ND ND ND ND

Sheep and goats Cattle and Bovidae Biovar 1: swine Biovar 2: swine, hare, roer deer, armadillos Biovar 3: swine Biovar 4: reindeer Biovar 5: wild rodents Canids Sheep Desert wood rat Cetaceans Pinnipeds Vole (Microtus arvalis) Unknown

Yes No No Yes (laboratory adquisicion) Not described in humans Not described in humans Breast implant infection

þ – – ND ND ND ND

1 000 000 None None ND ND ND ND

ND, no data.

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Brucellosis Ochrobactrum and Brucella has been recently sustained by the study of the genetic diversity among Ochrobactrum strains. Leal-Klevezas et al., 2005 suggest that the family Brucellaceae should be revised, and only Brucella and Ochrobactrum should be included.

Description of Brucella Species Brucellae are aerobic, gram negative, coccobacilli 0.6–1.5 mm long by 0.5–0.7 mm in width. They are nonmotile, nonhemolytic, non-spore-forming, nontoxigenic, and non-capsule-forming bacteria. Their metabolism is largely oxidative. Brucella species are catalase-positive and usually oxidase-positive; most strains reduce nitrate to nitrite (except B. ovis and some B. canis strains), and some may also reduce nitrite to nitrogen gas. All species are indole-negative and Voges Proskauernegative. Brucella spp. may occur either as smooth (S) or rough (R) strains depending on the presence of fully or reduced lipopolysaccharide (LPS). Normally, except for B. ovis and B. canis, rough strains contain little or no LPS and are less virulent than smooth strains. The identification of cultured Brucella spp. carries an array of 25 phenotypic features, including serological typing for the A and M antigens, phage typing, requirement for elevated CO2 atmosphere, and metabolic process. Lysis by Brucella phages is a useful tool to confirm the identity of Brucella species. Brucella biovars are differentiated by their

Table 5

requirement for CO2 for growth, production of urease which varies from fast to very slow, H2S production, sensitivity to the dyes, basic fuchsine and thionine, and seroagglutination in serum (Table 5). Penicillin is used for the routine differentiation of the vaccinal strain B. abortus species biovar 1 strain 19, and streptomycin for B. melitensis biovar 1 strain Rev.1.

The Genome The genomes of seven Brucella species have recently been sequenced: B. melitensis (Del Vecchio et al., 2002), B. suis, B. abortus, B. microti, B. pinnipedialis, B. canis, and B. ceti (Ancora et al., 2014). Brucella has no plasmids. With the exception of B. suis biovar which has a single circular chromosome, the genome of Brucella spp. is composed of two circular chromosomes, a large chromosome of 2.12 Mb and a small chromosome of 1.8 Mb. It typically encodes 3200 to 3500 open reading frames with an average GC content of 57%. The size of the genome varies between the 3.25 Mb of most Brucella spp. and the 3.10 Mb of B. suis biovar 3.

Virulence and Immunity Response Characteristics of virulence and pathogenesis of Brucella are not well understood. In contrast to other intracellular pathogens, Brucella species do not produce exotoxins, antiphagocytic

Biovar differentiation of Brucella species Growth on dyesa

Species

Colony morphology

Brucella melitensis

Smooth

Brucella abortus

Smooth

Brucella suis

Smooth

Brucella canis Brucella ovis Brucella neotomae Brucella ceti Brucella pinnipedialis Brucella microti Brucella inopinata

Rough Rough Smooth Smooth Smooth Smooth Smooth

Biovar 1 2 3 1 2 3 4 5 6 9 1 2 3 4 5

Agglutination in serum

CO2 requirement

H2S production

Urease activity

Oxidase activity

Basic fuchsin (20 mg)

Thionin (40 mg)

A

M

R

– – – þ/v þ/v þ/v þ/v – – þ/ – – – – – – þ – – þ

– – – þ þ þ þ – – þ þ – – – – – – þ – –

þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ – þ þ þ

þ þ þ þ þ /v þ þ þ þ þ þ þ þ þ þ – – þ þ

þ þ þ þ – þ þ/v þ þ þ /v – þ /v – /v /v – þ þ

þ/v þ þ – – þ – þ þ þ þ þ þ þ þ þ þ – þ/v þ

– þ þ þ þ þ – – þ – þ þ þ þ – – – þ þ þ

þ – þ – – – þ þ – þ – – – þ þ – – – /v /v

– – – – – – – – – – – – – – – þ þ – – –

– –

– þ

þ þ (fast)

þ þ

þ þ

þ þ

– –

þ þ

– –

þ, positive; , negative; þ/v or /v, variable; A, monospecific Brucella abortus antiserum; M, monospecific Brucella melitensis antiserum; R, antirough Brucella serum. a Dye concentration in serum dextrose medium: 20 mg ml1.

286

Brucellosis

capsules or thick cell walls, resistant forms or fimbriae, and do not show antigenic variation. Brucella pathogenesis relies mostly on three aspects. Firstly, Brucella can survive, replicate, and persist within host cells. Secondly, Brucella can hide from cellular bactericidal mechanisms. And finally, Brucella can modulate the host immune response. The preferential reproductive niches of Brucella are macrophages, dendritic cells, and placental trophoblasts. In other professional phagocytes, such as polymorphonuclear neutrophils, Brucella does not replicate, although it is able to resist the killing action of these short-living inflammatory cells and avoid degranulation (Martirosyan et al., 2011). Moreover, a recent study has reported the ability of B. pinnipedialis to enter an epithelial cell line in vitro (Larsen et al., 2013). The phagocytosed Brucella first resists digestion and avoids lysosomal fusion, before moving to the endoplasmic reticulum, which is a suitable niche of replication. This property is related to the structure of its cell envelope which is highly hydrophobic in comparison to other intracellular gramnegative bacteria. The Brucella outer membrane contains a LPS molecule with special features which contribute to the overall reduction of negative charges on the surface of the smooth bacterium. Consequently, it has a remarkable set of properties such as resistance to binding by antimicrobial peptides and proteins, low complement activation, low stimulation of cells triggering the cytokine network, and low toxicity for the cells where the bacterium grows. It has long been observed that smooth Brucella can dissociate into rough mutants that are cytotoxic to macrophages. However, the in vivo biological significance and/or mechanistic details of Brucella dissociation and cytotoxicity remain incomplete (Pei et al., 2014). One virulence factor required in the control of intracellular trafficking and survival is VirB, encoding a type IV secretion system. It translocates Brucella effector proteins into host cells and is critical for both survival and replication of Brucella in infected host cells (Poester et al., 2013). In addition to this secretion system, a small periplasmic protein unique to the genus Brucella called BvfA (for Brucella virulence factor A) has been described. The BvfA deletion mutant made from B. suis was highly attenuated both in in vitro macrophage infection assays and in in vivo murine models of brucellosis. It was shown that the expression of this factor is induced within macrophages by phagosome acidification and coregulated with the B. suis virB operon, suggesting that it too may play a role in the establishment of the intracellular niche (Detilleux et al., 1990). Another molecule required for controlling the intracellular trafficking of Brucella is the b-cyclic 1,2-glucan which is secreted into the periplasm and plays a role in the osmoregulation of the cell envelope in several a-proteobacteria, including Brucella. The greater number of virulence genes required for chronic infection versus acute disease may reflect the requirement for additional adaptations to ensure long-term persistence, such as those which prevent clearance of B. abortus by the host immune system (Jones and Winter, 1992). Protection of humans against infection by Brucella depends on the development of an adequate response from Th1 cells which involve mainly antigen-presenting cells, natural killer cells, and CD4 and CD8 lymphocytes (Rodriguez-Zapata and Solera, 2014). After phagocytosis, Brucella does not promote activation of macrophages and protects these cells from

apoptosis. Dendritic cells, which also internalize Brucella, do not become mature and activated. Polymorphonuclear leukocytes do not degranulate; consequently, there is not a significant release of mediators to the extracellular media. Brucella does not activate the complement cascade through direct action or through activated granulocytes, resulting in very little tissue damage mediated by these cells. Due to the lack of leukocyte and complement activation, the concomitant synthesis of liver proinflammatory proteins, such as fibrinogen and fibrinopeptides, which promote the permeabilization of blood vessels, does not occur. As a result, Brucella does not induce significant hematological changes such as leukocytosis, neutrophilia, and thrombocytopenia, and coagulopathies are rare during the incubation period (Martirosyan et al., 2011).

Clinical Manifestations of Human Brucellosis The clinical complexity of human brucellosis is shown in Figure 1. Not everyone who has contact with Brucella specimens develops active brucellosis. For example, more than 50% of slaughterhouse workers and up to 33% of veterinarians have high anti-Brucella antibody titers, but no history of recognized clinical infection. Persons who develop acute, symptomatic brucellosis can manifest a wide spectrum of symptoms including fever, sweating, malaise, anorexia, headache, arthralgias, myalgias, backache, and weight loss (Table 6). Fever may become undulant (recurrent) if left untreated, with periods with and without fever. Examination frequently shows nothing abnormal, apart from fever, but lymphadenopathy, splenomegaly, and hepatomegaly are found in some cases (Table 6). Complications of brucellosis can occur anywhere in the body. Complications include spondylitis, sacroiliitis, osteomyelitis, meningitis, and orchitis (Table 7). The main cause of mortality, however, is endocarditis. Moreover, the most important contributor to a poor outcome is probably a delay in instituting effective antibiotic treatment. Brucellosis must be distinguished from other endemic acute and subacute febrile illnesses. Influenza, malaria, deep abscesses, tuberculosis, amebic liver abscess, encephalitis, dengue, leptospirosis, infectious mononucleosis, endocarditis, typhoid fever, typhus, visceral leishmaniasis, toxoplasmosis,

Focal disease

Therapy intensity

Clinical brucellosis

Asymptomatic infection

Exposure without infection

Figure 1

The complexity of human brucellosis.

Disease severity

Brucellosis Table 6 Frequency of symptoms and signs in patients with brucellosis according to eight major series Symptoms

Frequency (range %)

Fever Chills Diaphoresis Headache Back pain Fatigue Arthralgia Myalgia Anorexia and weight loss Abdominal symptoms (including pain, nausea, emesis, constipation, or diarrhea) Respiratory symptoms (including chest pain, cough, or sputum)

62–100 32–86 12–96 16–77 24–73 20–73 14–77 40 16–62 16–50

Signs Fever Hepatomegaly Splenomegaly Lymphadenopathy Osteoarticular findings (arthritis, spine, and joint tenderness) Orchitis/epididymitis Skin rash Neurologic abnormalities Relative bradycardia

0–25 Frequency (range %) 84–96 6–46 7–42 8–25 12–43 0–10 0–5 0–5 0–10

lymphoproliferative disease, and connective tissue diseases should be considered. For patients in countries where brucellosis is not endemic, a travel history is crucial.

287

compared to bone marrow. Blood may be cultured using the biphasic method of Castaneda which uses both a solid and a liquid medium in the same container. The modern semiautomatic culture systems have somewhat improved the speed of detection. Brucella, however, is a slow-growing organism, and cultures are rarely positive before the third day of incubation. Usually cultures become positive in the first week, but should be kept for at least 3 weeks before the culture can be concluded to be negative for Brucella. Blind subculture is recommended at the end of the third week of incubation. Isolation of the organism in culture has also been performed using synovial, pleural, peritoneal, and cerebrospinal fluids, urine, and biopsies of various tissues (liver, spleen, lymph nodes). The sensitivity of body fluid and tissue cultures depends on the amount of material used; however, the positivity rate is lower than that of blood cultures. Brucella is isolated on most standard media (e.g., sheep blood, chocolate, tryptic soy agars). The optimum pH for growth varies from 6.6 to 7.4, and the temperature is 36– 38
C. Brucella requires biotin, thiamin, and nicotinamide. The growth is improved by serum or blood, but hemin (Vfactor) and nicotinamide-adenine dinucleotide (X-factor) are not required. The growth of most Brucella strains is inhibited on media containing bile salts, tellurite, or selenite. Growth is poor in liquid media unless culture is vigorously agitated. On suitable solid media, colonies can be visualized after 4 days as pinpoint, 1–2 mm in diameter, smooth borders, translucent, and a pale honey color. CO2 enhances growth of some biovars of B. abortus. Smooth Brucella cultures, especially B. melitensis cultures, tend to change to rough forms, and sometimes to mucous forms. Colonies are then less transparent with granular surface and the color changes from matt white to brown.

Serological Diagnosis

Management Diagnosis The absence of specific symptoms or signs makes the clinical diagnosis of human brucellosis difficult. The diagnosis of brucellosis requires a combination of clinical and laboratory findings. Definitive diagnosis requires isolation of the organism from blood or other clinical samples of infected patients. Nowadays, the diagnosis of brucellosis is usually performed by a combination of methods: bacteriological, serological, or/and molecular.

Isolation of Brucella Blood cultures are still the standard diagnostic method. They are positive in 60–80% of patients with acute brucellosis. The sensitivity of blood cultures is highest in the first weeks of the illness, is reduced by prior use of antibiotics, and increases with the volume of blood cultured. Culture of bone marrow is more sensitive. Results are positive in 80–95% of patients with brucellosis, even in patients who have been taking antibiotics for several days, regardless of the duration of the infection. Blood cultures are less sensitive than bone marrow cultures because of the lower numbers of microorganisms in blood as

Most serological tests rely on the unique antigenic properties of LPS that are shared among the three Brucella species that cause disease in humans. The use of LPS as an antigen causes crossreactivity with organisms such as Vibrio and Yersinia enterocolitica that share common features of the LPS. More important in the use and interpretation of LPS-based testing is the fact that in endemic areas a large proportion of the population may have developed antibodies due to previous disease or exposure. The standard tube agglutination test measures antibodies to B. abortus antigen. This test equally detects antibodies to B. abortus, B. suis, and B. melitensis but not to B. canis (deficient in LPS O-chain). SAT is performed by mixing serial dilutions of serum, usually 1:20 through 1:2560, with Brucella antigen in test tubes or in wells of an enzyme-linked immunosorbent assay (ELISA) plate. After overnight incubation, agglutination is read either by the unaided eye or under a binocular. A presumptive case is one in which the agglutination titer is positive (>1:160) in single or serial specimens, with symptoms consistent with brucellosis. In endemic areas the diagnostic threshold value will have to be set at least one titer step higher (1:320) to provide a sufficiently high specificity as many asymptomatic individuals will have titers equal to the lower threshold level of 1:160. The use of the

288 Table 7

Brucellosis Clinical Syndromes and Focal Complications of brucellosis

Type

Comment

Skeletal: Arthritis, spondylitis, sacroiliitis, osteomyelitis, bursitis, tenosynovitis

Occur in about 20–85% of patients. In children, arthritis of hip and knee joints is most common. Unilateral sacroiliitis is common in young adults. Spondylitis is the most serious complication, and paraspinal and epidural abscess is not infrequent. Occur in about 2–5% of patients. Cerebrospinal fluid examination reveals a lymphocytic pleocytosis with an elevated protein and normal or low glucose level. Gram’s stain and culture have low sensitivity. Computerized tomography may demonstrate basal ganglia calcification and abscesses. Unilateral epididymo-orchitis is frequent in young men. Renal involvement is uncommon although interstitial nephritis, pyelonephritis, immunoglobulin A and membranous glomerulonephritis, massive proteinuria, and caseating granulomas have all been reported in the literature. Increased rates of spontaneous abortion, premature delivery, and intrauterine infection with fetal death have been described among pregnant women with clinical evidence of brucellosis. Endocarditis occurs in 99%), but the specificity can be disappointingly low. As a result, the positive predictive value of the test is low, and a positive test result thus requires confirmation by a more

Surgical drainage of localized suppurative lesions and splenectomy may be of value if antimicrobial treatment is ineffective. Cough and other pulmonary symptoms in about 15–25% of patients. Less than 40% of patients with a cough have normal chest X-rays. More common in patients with Brucella melitensis. Occur in about 5% of patients. Many transient and often nonspecific skin lesions have been described. Ophthalmologic complications of Brucella infection include uveitis, keratitis, endophthalmitis, dacryo-cystitis and optic neuritis. Brucellosis could involve any organ or organ system. Many other rare complications have been described.

specific test. The negative predictive value of RB though is high, and a negative test result excludes active brucellosis with a high degree of certainty. To increase the specificity and the positive predictive value of RB, the test may be applied to a serial dilution (1:2 through 1:64) of the serum sample. The specificity of the RB increases when higher dilutions agglutinate, and titers of 1:8 or 1:16 and above may be regarded as positive. This approach, however, inevitably results in a lower sensitivity. The Coombs anti-Brucella test was simplified by Otero et al. in 1982. This test detects specific incomplete antibodies (IgG and IgA) which remain high (>1:160) for years after appropriate antibiotic treatment, making it difficult to distinguish between active infection and cured infection. ELISA has been used to identify and quantify separately different kinds of anti-Brucella immunoglobulin and follow their evolution throughout the infectious process, showing extraordinary sensitivity and specificity. The IgM-ELISA test has a very high correlation with serum agglutination,

Brucellosis especially in the first months of evolution. By contrast, the ELISA-IgA and especially ELISA-IgG show a high correlation with the Coombs test. The detailed and reliable information provided by ELISA, together with an acceptable cost and the possibility of being introduced on a large scale without great difficulty, suggested that the ELISA-IgM would replace the agglutination test and ELISA-IgG Coombs test for the routine diagnosis of brucellosis. However, in recent years, the widespread and routine use of this test has encountered a lack of adequate standardization of commercial systems. In fact, laboratories using this method often provide confusing results that are difficult to interpret. Thus, their widespread use is not recommended until a well-established standardization occurs. The BrucellaCapt is an immunocapture agglutination test which detects agglutinating and nonagglutinating antibodies with very high sensitivity. Several authors have found a similar specificity and sensitivity to the Coombs test. Some other authors have reported greater specificity and sensitivity, showing that titers of both tests have a very high correlation. This test has been suggested as a possible substitute for the Coombs test in the diagnosis of human brucellosis, although in some cases of relapse and chronic forms of the disease, the Coombs test shows better results. Dipstick and lateral flow assays described by Smits et al. in 1999 and 2003, respectively, are highly sensitive and specific for the diagnosis of brucellosis. In addition, these tests are easy to use and do not require specialized personnel or equipment, they are easy to perform and to read, and their components are stable without refrigeration. Therefore, these tests are ideal for use in rural and suburban areas where brucellosis is endemic. Dipstick is a colorimetric test, which identifies specific IgM Brucella antibodies with similar sensitivity to the SAT test, but it is easier and faster to perform. However, the sensitivity of this assay quickly begins to be negative after starting antibiotic treatment and is negative in patients with chronic brucellosis and in patients with focal complications. The lateral flow assay is a simplified version of the ELISA. This test is a chromatographic immunoassay which allows detection of IgM/IgG antibodies to Brucella. Briefly, the technique consists of applying serum or whole blood to Brucella LPS antigen immobilized on a nitrocellulose membrane; the development is done by adding antihuman antibodies labeled with colloidal gold particles of red. A positive result shows a red line indicating the presence of Brucella antibodies in the sample. Other serological tests have shown to be highly sensitive and specific in the diagnosis of brucellosis although their use is not widespread for various reasons. Immunofluorescence described by Moody et al. in 1961 is technically complex, and it does not provide more information than that obtained with the Coombs test. The gel precipitation techniques, which determine antibodies against LPS-S, native hapten, B polysaccharide, and soluble Brucella proteins, require wellcharacterized soluble antigenic extracts to interpret the results correctly. The classic most widely used assays are RB, tube agglutination, and the Coombs test. The negative results of these three tests virtually exclude the diagnosis of brucellosis. In areas with low prevalence of brucellosis, the main diagnostic difficulty is the lack of suspicion of the disease. By contrast, in

289

endemic areas, suspected brucellosis is automatically included in the differential diagnosis, but the difficulty lies in the interpretation of serological results. Serological tests may not be useful (1) in early stages of the disease when antibody levels are low, (2) during reinfection and relapse in endemic areas, (3) occupational exposures, and (4) in patients with chronic brucellosis where antibody levels may remain high.

Molecular Diagnosis PCR (polymerase chain reaction) represents one of the few diagnostic tests with the potential to detect infections caused by all of the known species of Brucella. Over the last two decades, PCR has been applied in the diagnosis of infectious diseases where conventional techniques are too slow or insensitive. Since Fekete et al. described in 1990 the first study on the detection of Brucella by standard PCR, there has been substantial development of molecular diagnostics for human brucellosis. PCR (single and multiplex format) based on identification of different parts of the Brucella species genome has been developed for diagnosis of both animal and human brucellosis or screening of food products. Most assays typically differentiate Brucella species by amplicon size and have been designed using different DNA targets. Several studies have described the standard PCR as a fast, sensitive, and specific technique to the blood culture and serology in the diagnosis of brucellosis, both at diagnosis and at relapse, and focal disease states. Real-time quantitative PCR (qPCR) has revolutionized the way clinical microbiology laboratories diagnose many human microbial infections. qPCR detects and quantifies DNA targets by monitoring PCR product production, measured by increased fluorescence during cycling, rendering postamplification manipulations unnecessary. Sample processing is automated, thus minimizing the risk of carry-over contamination and reducing time for analysis. In 2001, Redkar et al. reported the first assay of qPCR to detected DNA of B. melitensis, B. abortus, and B. suis in pure culture. Currently, numerous studies have been published using qPCR in the molecular diagnosis of human brucellosis in various clinical specimens (Queipo-Ortuño et al., 2005; Debeaumont et al., 2005; Navarro et al., 2006; Kattar et al., 2007; Vrioni et al., 2008). The most important features of these assays are shown in Table 8. Other studies have been published using the qPCR in clinical samples from patients with brucellosis, employing any of the assays described above or with slight modifications or using the RoboGene Brucella Detection Kit (Qiagen, Hilden, Germany) (Surucuoglu et al., 2009). Navarro et al. (2006) detected for the first time B. melitensis DNA in the blood of patients with brucellosis throughout treatment and posttreatment follow-up, despite apparent recovery from infection, using qPCR. The data suggest that brucellosis may be a chronic, relapsing disease comparable with those caused by intracellular pathogens such as Mycobacterium tuberculosis. These data have been confirmed by other authors (Maas et al., 2007; Vrioni et al., 2008; Castaño and Solera, 2009). The sensitivities and specificities of PCR assays for detection of Brucella spp. DNA in different clinical specimens from patients with suspected brucellosis or brucellosis are shown in Table 9.

290 Table 8

Brucellosis Real-time polymerase chain reaction assays for the diagnosis of human brucellosis on clinical specimens

Author

Detected

Gene template/ Fragment (bp)

Patients/samples Sample type

Clinical sensitivity/ Clinical specificity

Detection chemistries

Queipo-Ortuño (2005)

Brucella spp.

bcsp31a/223

93.3/94.6

SYBR Green I

Debeaumont (2005)

Brucella spp.

bcsp31/169

64.7/100

Hybridization probe (FRET)

Navarro (2006)

Brucella melitensis

IS711b/251

100/100c (97.8)d

Hydrolysis probe (TaqMan)

Kattar (2007)

Brucella spp.

16S-23S ITSe/147

66.7/99.7

Hybridization probe (FRET)

Vrioni (2008)

Brucella spp.

bcsp31/207

59/60 Serum 17/17 Serum 18/180 Blood 340/251 Blood 39/130 Serum/blood

100/100

Hybridization probe (FRET)

a

Gene that codes for the synthesis of an immunogenetic membrane protein specific for Brucella spp. Insertion element, specific for Brucella melitensis. c Control group: healthy blood donors. d Control group: healthy individuals with no history of brucellosis or exposure to Brucella spp. and patients with febrile syndromes, initially suggested a differential diagnosis with brucellosis. e Ribosomal 16S-23S internal transcribed spacer (ITS) region is present in all Brucella spp. b

Table 9

Sensitivities and specificities of PCR assays for detection of Brucella spp. DNA in different clinical specimens from patients with brucellosisa

Clinical specimen

Number of patients included (range)

Number of studies included

Median % sensitivity (range)

Reported % specificity (range)

Conventional PCR Blood

(10–263)

12

84.35 (50–100)

95.43 (60–100)

Serum

(25–243)

3

89.67 (79–96)

100

CSF Synovial fluid Pus abscesses Urine Bone Sputum Renal cyst fluid Pleural fluid Renal tissue Thyroid tissue Real-Time PCR Blood Serum

1 8 5 5 4 2 2 1 1 1

1 1 1 1 1 1 1 1 1 1

100 87.5 100 100 100 100 100 100 100 100

100 100 100 100 100 100 100 100 100 100

18 (17–60)

1 3

100 81.77 (64.7–91.7)

100 96.13 (93–100)

CSF Lung Bone biopsy specimen SF

6 1 1 1

1 1 1 1

100 100b 100 100

100 100b 100c/(97.8)d 100b/(97.8)c

References Matar et al. (1996) Queipo-Ortuño et al. (1997) Navarro et al. (1999) Morata et al. (1999) Zerva et al. (2001) Al-Nakkas et al. (2002) Nimri (2003) Morata (2003) Vrioni et al. (2004) Queipo-Ortuño et al. (2005) Al-Nakkas et al. (2005) Elfaki et al. (2005) Zerva et al. (2001) Vrioni et al. (2004) Elfaki et al. (2005) Elfaki et al. (2005) Morata et al. (2001) Morata et al. (2001) Morata et al. (2001) Morata et al. (2001) Morata et al. (2001) Morata et al. (2001) Morata et al. (2001) Morata et al. (2001) Morata et al. (2001) Navarro et al. (2006) Debeaumont et al. (2005) Queipo-Ortuño et al. (2005) Queipo-Ortuño et al. (2005) Colmenero et al. (2005) Theegarten et al. (2008) Navarro-Martínez et al. (2008) Castaño et al. (2009)

CSF, cerebrospinal fluid; PCR, polymerase chain reaction; SF, synovial fluid. a Only studies published in English in MEDLINE. b Sensitivity/specificity in strains. c Control group: healthy blood donors. d Control group: healthy individuals with no history of brucellosis or exposure to Brucella spp. and patients with febrile syndromes initially suggested a differential diagnosis with brucellosis.

Brucellosis Despite the large number of PCR assays currently described, none of them have been standardized yet. The scientific community should focus on validating a PCR assay and a universal standard of Brucella DNA as well as verifying interlaboratory reproducibility, as has already been done for other pathogens. With these genus or species-specific qPCR assays, clinical laboratories can quantify the bacterial load present in any sample for the diagnosis of Brucella spp. infections.

Treatment Antimicrobial therapy is useful for shortening the natural course of the disease, decreasing the incidence of complications, and preventing relapse. Appropriate antibiotics should have high in vitro activity and good intracellular penetration. Tetracyclines, especially doxycycline and minocycline, are the most effective drugs for brucellosis treatment. These drugs are inexpensive, widely available, and rarely associated with side effects. In randomized controlled trials, these drugs have proven safe in all age groups. They produce rapid relief of symptoms, with defervescence usually occurring within 2–7 days; however, 6 weeks of treatment are required, and adherence over this period may be low. The rate of treatment failure rate is 1–5%, relapse rate is 5–10%, and cure rate exceeds 80% when an appropriate duration is used. Tetracyclines are usually combined with aminoglycosides, rifampicin, trimethoprim–sulfamethoxazole (TMP-SMZ), or quinolones. Recommendations for therapy of brucellosis are provided in Table 10 (Solera, 2010). Decisions regarding brucellosis therapy often require the provider to present various options to the patient with a discussion of short- and long-term goals. The age of the patient, severity of disease, likelihood of Table 10

291

response, and potential for adherence are all important factors to consider. According to three meta-analyses (Solera et al., 1994; Skalsky et al., 2008; Solís García del Pozo and Solera, 2012), the most effective regimen in adults without complications is combined doxycycline for 45 days with streptomycin for 14 days or gentamicin for 7 days. The alternative is a combination of doxycycline and rifampicin for 45 days. Other combinations such as ofloxacin and rifampicin have similar efficacy as well as fewer side effects. However, they are more expensive. Combined doxycycline-co-trimoxazole could also offer a lowcost alternative. Triple therapy with doxycycline-rifampicinaminoglycoside cannot be recommended in view of current data.

Treatment of Acute Brucellosis in Adults without Complications or Focal Disease The preferred regimen is combination therapy with doxycycline 100 mg orally twice daily for 45 days and streptomycin 1 g intramuscularly once daily for the first 14 days. Gentamicin 5 mg kg1 day can be substituted for streptomycin. Alternative treatment consists of the same doses and duration of doxycycline plus rifampicin 600–900 mg daily for 45 days (Solera et al., 1997). For patients in whom tetracyclines are contraindicated, no other antibiotic combination offers a consistent treatment option that is as effective as doxycycline–streptomycin or doxycycline–rifampicin in the treatment of acute brucellosis.

Therapy in Patients with Focal Disease The most common complications of brucellosis are summarized in Table 7. Except for a few localized forms for which surgery is necessary, the basic treatment for focal brucellosis consists of the administration of antimicrobial agents. The

Treatment of brucellosisa

Clinical syndromes

Recommended

Alternative

Acute brucellosis adults and children >8 years

Doxycycline 100 mg PO bid  45 days plus either streptomycin 15 mg kg1 IM daily  14–21 days or gentamicin 3–5 mg kg1 IV daily  7–14 days Or Doxycycline 100 mg PO bid  45 days plus rifampin 600–900 mg PO daily  45 days TMP-SMZ 5 mg kg1 (of TMP component) PO bid  45 days plus gentamicin 5–6 mg kg1 IV daily  7 days Doxycycline 100 mg PO bid and rifampin 600 mg PO daily  6–52 weeks plus either streptomycin 1 g IM daily or gentamicin 3–5 mg kg1 IV daily  14–21 days

Rifampin 600 mg PO daily  42 days plus quinolone (ofloxacin 400 mg PO bid or ciprofloxacin 750 mg PO bid)  42 days Or Doxycycline 100 mg PO bid plus TMP-SMZ 1 DS tablet bid  2 months Rifampin 15 mg kg1 PO daily  45 days plus gentamicin 5–6 mg kg1 IV daily  7 days

Children 0

[1]

Burden of Disease and Injury Caused by Alcohol

301

Table 2 Relative risks for alcohol-attributable diseases and injuries by consumption stratum (reference group is ‘current abstainers’) for globally available disease categories Condition

ICD 10 code

New WHO code

Old WHO code

Infectious and parasitic diseases Tuberculosis

A15-A19

3

IA1

B20-B24

10

IA3

Lönnroth et al. (2008), for causal relationship see Rehm et al. (2009b) Gmel et al. (2011)

61 62 63 66 78 70 65

IIA IIA1 IIA2 IIA5

Baan et al. (2007), International Agency for Research on Cancer, (2010) (based on relative risks from Corrao et al. (2004))

E10-E14

80

IIC

Baliunas et al. (2009)

F10.0, F10.3-F10.9 F10.1 F10.2 G40-G41

86

IIE4

I10-I15 I20-I25

97 110 112 113

IIF3 IIH IIH2 IIH3

100% AAF per definition 100% AAF per definition 100% AAF per definition Samokhvalov et al. (2010a)

I47-I49 I60-I62 I63-I66

116 114 114

IIH6 IIH4 IIH4

K70, K74 K85, K86.1

121 123 125

IIJ IIJ2

J10.0, J11.0, J12-J15, J18

39

IB1

Samokhvalov et al. (2010c)

P05-P07

50

ID1

Patra et al. (2011)

152 153 154 155 156 157 159

IIIA IIIA1 IIIA2 IIIA3 IIIA4 IIIA5 IIIA7

160 161 162

IIIB IIIB1 IIIB2

Human immunodeficiency virus/acquired immune deficiency syndrome Malignant neoplasms Mouth and oropharynx cancers Esophageal cancer Liver cancer Laryngeal cancer Breast cancer Colon cancer Rectal cancer Diabetes Diabetes mellitus Neuropsychiatric conditions Alcoholic psychoses (part of AUD) Alcohol abuse (part of AUD) Alcohol dependence (part of AUD) Epilepsy Cardiovascular disease Hypertensive disease Ischemic heart disease Cardiac arrhythmias Ischemic stroke Hemorrhagic and other nonischemic stroke Digestive diseases Cirrhosis of the liver Acute and chronic pancreatitis Respiratory infections Pneumonia Conditions arising during the prenatal period Low birth weight: as defined by the global burden of disease Unintentional injuries Motor vehicle accidents Poisonings Falls Fire Drowning Other unintentional injuries

Intentional injuries Self-inflicted injuries Homicide a

C00-C14 C15 C22 C32 C50 C18 C20

a

X40-X49 W00-W19 X00-X09 W65-W74 b Rest of V-series and W20-W64, W 75-W99, X10-X39, X50-X59, Y40-Y86, Y88, and Y89 X60-X84 and Y87.0 X85-Y09, Y87.1

Sources for relative risks

IIA9 IIA4

Taylor et al. (2009) Roerecke and Rehm, (2012) for volume, Roerecke and Rehm, (2010) for pattern Samokhvalov et al. (2010b) Patra et al. (2010) Patra et al. (2010) Rehm et al. (2010c) Irving et al. (2009)

Taylor et al. (2010) for relative risk, methodology adopted from Taylor et al. (2011)

Taylor et al. (2010) for relative risk, methodology adopted from Taylor et al. (2011)

V021–V029, V031–V039, V041–V049, V092, V093, V123–V129, V133–V139, V143–V149, V194–V196, V203–V209, V213–V219, V223–V229, V233–V239, V243–V249,V253–V259, V263–V269, V273– V279, V283–V289, V294–V299, V304–V309, V314–V319, V324–V329, V334–V339, V344–V349, V354–V359, V364–V369, V374–V379, V384–V389, V394–V399, V404–V409, V414–V419, V424–V429, V434–V439, V444–V449, V454–V459, V464– V469, V474–V479, V484–V489, V494–V499, V504–V509, V514–V519, V524–V529, V534–V539, V544–V549, V554–V559, V564–V569, V574–V579, V584–V589, V594–V599, V604–V609, V614–V619, V624–V629, V634–V639, V644–V649, V654– V659, V664–V669, V674–V679, V684–V689, V694–V699, V704–V709, V714–V719, V724–V729, V734–V739, V744–V749, V754–V759, V764–V769, V774–V779, V784–V789, V794–V799, V803–V805, V811, V821, V830–V833, V840–V843, V850– V853, V860–V863, V870–V878, V892. b Rest of V ¼ V-series minus the ICD 10 codes present in motor vehicle accidents; AUD ¼ alcohol use disorder.

302 Table 3

Burden of Disease and Injury Caused by Alcohol Countries of the WHO regions

Region

Countries

African Region (AFR)

Algeria, Angola, Benin, Botswana, Burkina Faso, Burundi, Cabo Verde, Cameroon, Central African Republic, Chad, Comoros, Congo, Côte d’Ivoire, Democratic Republic of the Congo, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mozambique, Namibia, Niger, Nigeria, Rwanda, Sao Tome and Principe, Senegal, Seychelles, Sierra Leone, South Africa, Swaziland, Togo, Uganda, United Republic of Tanzania, Zambia, and Zimbabwe Antigua and Barbuda, Argentina, Bahamas, Barbados, Belize, Bolivia (Plurinational State of), Brazil, Canada, Chile, Colombia, Costa Rica, Cuba, Dominica, Dominican Republic, Ecuador, El Salvador, Grenada, Guatemala, Guyana, Haiti, Honduras, Jamaica, Mexico, Nicaragua, Panama, Paraguay, Peru, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and the Grenadines, Suriname, Trinidad and Tobago, United States of America, Uruguay, and Venezuela (Bolivarian Republic of) Afghanistan, Bahrain, Djibouti, Egypt, Iran (Islamic Republic of), Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, Somalia, South Sudan, Sudan, Syrian Arab Republic, Tunisia, United Arab Emirates, and Yemen Albania, Andorra, Armenia, Austria, Azerbaijan, Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Georgia, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Luxembourg, Malta, Monaco, Montenegro, Netherlands, Norway, Poland, Portugal, Republic of Moldova, Romania, Russian Federation, San Marino, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Tajikistan, the former Yugoslav Republic of Macedonia, Turkey, Turkmenistan, Ukraine, United Kingdom, and Uzbekistan Bangladesh, Bhutan, Democratic People’s Republic of Korea, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, and Timor-Leste Australia, Brunei Darussalam, Cambodia, China, Cook Islands, Fiji, Japan, Kiribati, Lao People’s Democratic Republic, Malaysia, Marshall Islands, Micronesia (Federated States of), Mongolia, Nauru, New Zealand, Niue, Palau, Papua New Guinea, Philippines, Republic of Korea, Samoa, Singapore, Solomon Islands, Tonga, Tuvalu, Vanuatu, and Vietnam

Region of the Americas (AMR)

Eastern Mediterranean Region (EMR) European Region (EUR)

South-East Asia Region (SEAR) Western Pacific Region (WPR)

where Pabs represents the proportion of ‘lifetime abstainers,’ Pform the proportion of ‘former drinkers,’ and Pcurrent(x) the probability distribution (grams of pure alcohol per day) function for current drinkers. RRform represents the RR for ‘former drinkers’ and RRcurrent(x) the RR function for a given average daily alcohol consumption in grams per day. A cap at an exposure of 150 g of pure alcohol was used as a conservative measure, as very few individuals consume more than this amount on a daily basis for an extended period of time.

Alcohol and the Risk of Ischemic Heart Disease

The alcohol PAF for ischemic heart disease takes into consideration binge alcohol consumption and is calculated using the same formula as the one used for an average volume of alcohol consumption. However, for current drinkers who are also heavy episodic consumers (both chronic heavy episodic drinkers (people who consume five or more international standard alcoholic drinks per day (60 g of pure alcohol or more)) or nonchronic heavy episodic drinkers (people who do not consume on average five or more international standard drinks per day, but do so on at least one occasion monthly)) the RR for ischemic heart disease is 1 when compared to lifetime abstainers.

Alcohol and the Risk of Injury

The alcohol PAFs for injuries were based on a time-at-risk model, taking into account the prevalence of current drinkers and the average alcohol consumption and binge alcohol consumption among current drinkers (see Shield et al., 2012). This model calculated the time a person was at risk

during both average drinking days and heavy drinking days (based on how much the person consumed during those days and on metabolism data (Shield et al., 2012)) and combined this calculation with the severity of the risk of an injury, compared to if the person did not drink (based on how much the person consumed during those days). The alcohol PAFs for injuries was then calculated based on the risk of injury for the entire population (using the risk information estimated as outlined above) as compared to a population where no one consumed alcohol. With respect to the WHO estimates of the burden of alcohol consumption (World Health Organization, 2014b), injuries to others caused by motor vehicle accidents were not calculated as data on passengers killed in motor vehicle accidents were not available.

Alcohol and Mortality from HIV/AIDS

Alcohol has been shown to decrease adherence to highly active antiretroviral therapy (HAART) among people who have HIV/AIDS (Hendershot et al., 2009) and, therefore, the mortality from HIV/AIDS attributable to alcohol consumption was estimated based on the increased mortality that occurs when people do not adhere to their HAART. This calculation used data on the mortality rates of people who have HIV/AIDS who either adhered or did not adhere to their medication regimes, the percentage of people who were in need of HAART and received HAART, and the mortality rate of people who received HAART compared to those who did not receive HAART (see Gmel et al., 2011) for more information on the estimation of the alcohol PAF for HIV/AIDs mortality).

Burden of Disease and Injury Caused by Alcohol Estimating the Alcohol-Attributable Burden of Disease and Injury

The alcohol-attributable burden of disease and injury was derived using eqn [2]. AA burden ¼

nðzÞ X nðyÞ X nðiÞ X

PAFzyi  Burdenzyi

[2]

z¼1 y¼1 i¼1

where AAburden represents the burden caused by alcohol consumption (either deaths, YLLs or YLDs); PAFzyi represents the alcohol PAF for gender z (male or female), age group y, and disease i; and Burdenzyi represents the burden (in either deaths, YLLs, or YLDs) of gender z, age group y, and disease i. The AAburden estimates were summed across countries to estimate the alcohol-attributable burden for both WHO regions and globally (World Health Organization, 2014a). All estimates of the alcohol-attributable burden are for 2012, using predicted country-level 2012 per capita alcohol consumption data. Most countries did not have data for the estimation of alcohol consumption and, therefore, predictions were based on per capita alcohol data from 2000 to 2010 using fractional polynomial regression with the year as the independent variable.

Consumption and the Alcohol-Attributable Burden: A Global Overview Global Patterns of Drinking Table 4 provides an overview of adult per capita consumption for 2012 by WHO region. There is wide variation in alcohol consumption from the global average of 6.8 l of pure alcohol consumed per adult per year (the equivalent of 14.7 g of pure alcohol per day). The countries with the highest overall consumption are Belarus, Moldova, Russia, and Ukraine, but other areas of Europe (EUR) also have high overall consumption. The Americas region (AMR) has the next highest overall consumption. Intermediate levels of consumption are found in the Western Pacific Region (WPR) and the African Region (AFR), while the lowest consumption levels are found in the South-East Asia Region (SEAR) and particularly in the Eastern

Table 4

303

Mediterranean Region (EMR). Furthermore, worldwide, almost one-quarter (22.8%) of all alcohol consumed is in the form of unrecorded alcohol. The percentage of all alcohol consumption from unrecorded sources also varied by region, with the EMR having the greatest proportion of all such alcohol (52.3%), followed by the SEAR (41.0%). In 2012, 61.9% of all adults globally (53.0% of men and 70.9% of women) did not consume alcohol in the past 12 months (Table 4). Furthermore, almost one-half of the global adult population (48.3%) had never consumed alcohol, while 38.1% of the global adult population had consumed alcohol within the past year. The prevalence of abstainers, former drinkers, and current drinkers varied by region, with Belarus, Moldova, Russia, and Ukraine having the highest prevalence of current drinkers, followed by EUR (excluding Belarus, Moldova, Russia, and Ukraine), and the AMR. The prevalence of past year abstention was the highest in the EMR, with 94.5% of adults abstaining from alcohol in the past year, followed by the SEAR, with 86.5% of adults abstaining from alcohol in the past year. Table 5 outlines the prevalence of heavy episodic drinkers by WHO region among adults in 2012. Worldwide, approximately 11.4% of adult drinkers engaged in heavy episodic drinking and approximately 4.3% of all adults engaged in heavy episodic drinking. Belarus, Moldova, Russia, and Ukraine had the highest prevalence of heavy episodic drinking, with 14.0% of all adults and 20.5% of all adult drinkers engaging in heavy episodic drinking, followed by EUR (excluding Belarus, Moldova, Russia, and Ukraine) and by the AMR. The EMR had the lowest prevalence of heavy episodic drinking, with less than 0.1% of all adult drinkers and less than 0.01% of all adults engaging in heavy episodic drinking.

Burden of Disease and Injury Attributable to Alcohol Consumption In 2012 the number of deaths caused by alcohol consumption far exceeded the number prevented. Table 6 outlines the deaths attributable to alcohol consumption by cause for 2012. While 5.9% of all global deaths in 2012 were attributable to alcohol,

Per capita consumption of alcohol and prevalence of lifetime abstainers, former drinkers, and current drinkers for 2012 by WHO region

WHO region Africa Americas Eastern Mediterranean Europe Excluding (BLR, MDA, RUS, and UKR) Only (BLR, MDA, RUS and UKR) South-East Asia Western Pacific World

Percentage of lifetime abstainers

Percentage of former drinkers

Percentage of current drinkers

Adult total per capita alcohol consumption (in liters of pure alcohol)

Unrecorded consumption (In liters of pure alcohol)

Adult population (1000s)

Men

513 073 723 380 402 642

45.8% 68.9% 10.8% 26.7% 86.5% 93.3%

57.5% 14.0% 11.5% 19.0% 18.5% 20.6% 89.8% 6.0% 3.4%

12.7% 40.2% 19.6% 19.6% 70.7% 52.7% 4.8% 7.5% 3.3%

29.8% 5.9 61.4% 8.4 5.5% 0.7

1.8 1.2 0.4

574 673

15.9% 29.9%

23.2% 11.3% 11.2%

11.3% 72.7% 58.8%

65.6% 9.3

1.2

171 044

6.9%

18.0%

13.0% 18.0% 19.1%

18.6% 75.2% 62.8%

68.4% 14.8

4.0

1 302 773 1 492 484 5 186 326

63.8% 89.9% 24.9% 49.8% 38.4% 58.2%

76.7% 14.5% 5.1% 37.2% 16.3% 17.9% 48.3% 14.6% 12.7%

9.9% 21.7% 5.0% 17.1% 58.8% 32.3% 13.6% 47.0% 29.1%

13.5% 4.0 45.7% 8.4 38.1% 6.8

1.6 1.7 1.5

Women Total

Men

Women Total

Men

Women Total

304

Burden of Disease and Injury Caused by Alcohol Prevalence of heavy episodic drinkers by WHO region for 2012

Table 5

WHO region Africa Americas Eastern Mediterranean Europe Excluding (BLR, MDA, RUS, and UKR) Only (BLR, MDA, RUS, and UKR) South-East Asia Western Pacific World

Table 6

Heavy episodic drinkers among current drinkers

Heavy episodic drinkers (total population)

Adult population (1000s)

Men

Women

Total

Men

Women

Total

513 073 723 380 402 642

11.6% 21.2% 0.1%

3.1% 7.5% 0.0%

7.3% 14.1% 0.1%

4.7% 15.0% 0.0%

0.6% 3.9% 0.0%

2.2% 8.7% 0.0%

574 673 171 044 1 302 773 1 492 484 5 186 326

25.3% 32.3% 3.2% 14.5% 16.8%

10.8% 10.7% 0.1% 1.9% 6.1%

17.9% 20.5% 1.7% 8.2% 11.4%

18.4% 24.3% 0.7% 8.5% 7.9%

6.3% 6.7% 0.0% 0.6% 1.8%

11.7% 14.0% 0.2% 3.8% 4.3%

Deaths (in 1000) attributable to alcohol consumption globally in 2012

Disease category

Men

Women

Total

Tuberculosis HIV/AIDS Lower respiratory infections Preterm birth complications Neoplasms Mouth and oropharynx cancers Esophagus cancer Colon and rectum cancers Liver cancer Pancreas cancer Breast cancer Other malignant neoplasms Diabetes mellitus Alcohol use disorders Epilepsy Cardiovascular diseases Hypertensive heart disease Ischemic heart disease Hemorrhagic stroke Ischemic stroke Other circulatory diseases Digestive diseases Cirrhosis of the liver Other digestive diseases Injuries Road injury Poisonings Falls Fire Drowning Other unintentional Self-harm Interpersonal violence Total alcohol-attributable deaths ‘caused’ Total alcohol-related deaths ‘prevented’ Net alcohol-attributable deaths ‘caused’

93 18 81 2 306 80 78 50 72 9 0 17 2 86 18 499 70 112 246 64 7 375 355 20 778 174 30 101 24 46 138 161 104 2257 2 2255

16 4 50 2 103 10 11 22 15 4 41 1 29 21 5 629 25 417 133 46 8 158 154 4 70 13 4 9 5 4 15 14 7 1059 29 1031

109 22 132 3 410 90 89 72 86 13 41 18 31 107 24 1128 95 529 379 110 15 533 509 24 849 187 34 109 29 50 154 175 111 3316 31 3285

the percentage of such deaths was higher among men (7.6%) than among women (4.0%). This difference in mortality between men and women is expected given the differences observed in the average volume of consumption and the

Men % of all AA deaths

Women % of all AA deaths

Total % of all AA deaths

4.1% 0.8% 3.6% 0.1% 13.6% 3.6% 3.5% 2.2% 3.2% 0.4% 0.0% 0.8% 0.1% 3.8% 0.8% 22.2% 3.1% 5.0% 10.9% 2.9% 0.3% 16.6% 15.8% 0.9% 34.5% 7.7% 1.4% 4.5% 1.1% 2.0% 6.1% 7.1% 4.6%

1.6% 0.4% 4.9% 0.1% 10.0% 0.9% 1.1% 2.1% 1.4% 0.4% 4.0% 0.1% 2.8% 2.1% 0.5% 61.0% 2.4% 40.5% 12.9% 4.5% 0.8% 15.3% 14.9% 0.4% 6.8% 1.3% 0.4% 0.9% 0.4% 0.3% 1.5% 1.4% 0.6%

3.3% 0.7% 4.0% 0.1% 12.5% 2.7% 2.7% 2.2% 2.6% 0.4% 1.3% 0.6% 0.9% 3.3% 0.7% 34.3% 2.9% 16.1% 11.5% 3.4% 0.5% 16.2% 15.5% 0.7% 25.8% 5.7% 1.0% 3.3% 0.9% 1.5% 4.7% 5.3% 3.4%

prevalence of heavy episodic drinking; men consumed more alcohol than did women and in a much more harmful manner. The top contributors to the mortality burden caused by alcohol were cardiovascular diseases (34.3%), injuries (25.8%),

Burden of Disease and Injury Caused by Alcohol Table 7

305

Years of life lost (YLLs) (in 1000) attributable to alcohol consumption globally in 2012

Disease category

Men

Women

Total

Tuberculosis HIV/AIDS Lower respiratory infections Preterm birth complications Neoplasms Mouth and oropharynx cancers Esophagus cancer Colon and rectum cancers Liver cancer Pancreas cancer Breast cancer Other malignant neoplasms Diabetes mellitus Alcohol use disorders Epilepsy Cardiovascular diseases Hypertensive heart disease Ischemic heart disease Hemorrhagic stroke Ischemic stroke Other circulatory diseases Digestive diseases Cirrhosis of the liver Other digestive diseases Injuries Road injury Poisonings Falls Fire Drowning Other unintentional Self-harm Interpersonal violence Total alcohol-attributable YLLs ‘caused’ Total alcohol-related YLLs ‘prevented’ Net alcohol-attributable YLLs ‘caused’

3 382 870 2 119 178 8 904 2 624 2 081 1 241 2 220 238 0 500 37 3 339 891 11 720 1 628 2 365 6 330 1 288 108 13 562 12 793 769 35 060 8 156 1 335 3 314 1 067 2 154 5 861 7 393 5 781 37 80 026 79 989

630 206 1 096 139 2 861 300 255 507 385 88 1 304 22 649 777 235 11 153 635 6 407 3 308 714 89 5 043 4 909 134 2 789 587 151 239 179 151 575 585 323 649 24 929 24 280

4 012 1 076 3 216 317 11 764 2 924 2 336 1 748 2 605 326 1 304 523 686 4 116 1 126 22 873 2 263 8 772 9 638 2 002 197 18 605 17 702 903 37 850 8 743 1 486 3 553 1 245 2 305 6 436 7 978 6 104 686 104 955 104 269

digestive diseases (16.2%), and neoplasms (12.5%); however, the amount each cause of death contributed to the total mortality burden attributable to alcohol differed by sex, with cardiovascular deaths accounting for the most alcoholattributable deaths among women (61.0%) and injury deaths accounting for the most alcohol-attributable deaths among men (34.5%). The global burden of alcohol-attributable YLLs for 2012 is outlined in Table 7. In 2012, 5.2% of all YLLs were attributable to alcohol consumption, with 7.1% of all YLLs attributable to alcohol consumption among men and 2.8% of all YLLs attributable to alcohol consumption among women. Furthermore, the top contributing causes to the burden of alcoholattributable YLLs in 2012 differed from the top contributing causes for alcohol-attributable deaths. In 2012, injuries were the leading causes of all alcohol-attributable YLLs (36.3%), followed by cardiovascular diseases (21.9%), digestive diseases (17.8%), and neoplasms (11.3%). The differing contributions of these causes to the burden of alcohol-attributable YLLs are dependent on the time of death; injuries due to alcohol tend

Men % of all AA YLLs

Women % of all AA YLLs

Total % of all AA YLLs

4.2% 1.1% 2.6% 0.2% 11.1% 3.3% 2.6% 1.6% 2.8% 0.3% 0.0% 0.6% 0.0% 4.2% 1.1% 14.7% 2.0% 3.0% 7.9% 1.6% 0.1% 17.0% 16.0% 1.0% 43.8% 10.2% 1.7% 4.1% 1.3% 2.7% 7.3% 9.2% 7.2%

2.6% 0.8% 4.5% 0.6% 11.8% 1.2% 1.1% 2.1% 1.6% 0.4% 5.4% 0.1% 2.7% 3.2% 1.0% 45.9% 2.6% 26.4% 13.6% 2.9% 0.4% 20.8% 20.2% 0.6% 11.5% 2.4% 0.6% 1.0% 0.7% 0.6% 2.4% 2.4% 1.3%

3.8% 1.0% 3.1% 0.3% 11.3% 2.8% 2.2% 1.7% 2.5% 0.3% 1.3% 0.5% 0.7% 3.9% 1.1% 21.9% 2.2% 8.4% 9.2% 1.9% 0.2% 17.8% 17.0% 0.9% 36.3% 8.4% 1.4% 3.4% 1.2% 2.2% 6.2% 7.7% 5.9%

to occur in people who are relatively young, and cardiovascular diseases due to alcohol typically affect people who are older. In 2012, men experienced approximately 3.3 times more alcohol-attributable YLLs than did women. There are, however, also proportional variations by sex in how much each disease category contributed to the overall alcohol-attributable burden of YLLs. Specifically, cardiovascular diseases, liver cirrhosis, and lower respiratory infections contributed proportionally more to the alcohol-attributable burden of YLLs for women than these causes contributed to the burden of YLLs for men. This difference is due to the burden of injuries in men contributing proportionally much more to the alcohol-attributable burden of disease and injury among men than this cause did among women. Additionally, the amount of YLLs prevented among women in 2012 was over 10 times the number of YLLs prevented among men. In 2012, 5.1% of DALYs lost were attributable to alcohol, with 7.4% of all DALYs lost among men being attributable to alcohol and 2.3% of all DALYs lost among women being attributable to alcohol. Table 8 outlines the global

306

Burden of Disease and Injury Caused by Alcohol Table 8

Disability-adjusted life years (DALYs) lost (in 1000) attributable to alcohol consumption globally in 2012

Disease category

Men

Women

Total

Tuberculosis HIV/AIDS Lower respiratory infections Preterm birth complications Neoplasms Mouth and oropharynx cancers Esophagus cancer Colon and rectum cancers Liver cancer Pancreas cancer Breast cancer Other malignant neoplasms Diabetes mellitus Alcohol use disorders Epilepsy Cardiovascular diseases Hypertensive heart disease Ischemic heart disease Hemorrhagic stroke Ischemic stroke Other circulatory diseases Digestive diseases Cirrhosis of the liver Other digestive diseases Injuries Road injury Poisonings Falls Fire Drowning Other unintentional Self-harm Interpersonal violence Total alcohol-attributable DALYs ‘caused’ Total alcohol-related DALYs ‘prevented’ Net alcohol-attributable DALYs ‘caused’

4 238 928 2 178 184 9 047 2 675 2 097 1 284 2 236 239 0 516 90 27 021 1 621 11 776 1 655 2 094 6 417 1 344 267 13 742 12 927 815 39 136 9 423 1 379 4 975 1 183 2 182 6 608 7 431 5 954 90 109 871 109 781

761 220 1 135 145 2 976 307 257 526 388 89 1 387 23 1,261 4 986 521 11 087 651 6 278 3 286 719 154 5 157 5 011 146 3 502 758 157 600 202 155 703 592 336 1,261 30 490 29 230

4 999 1 148 3 313 329 12 023 2 982 2 354 1 810 2 623 328 1 387 539 1,351 32 007 2 142 22 863 2 306 8 372 9 703 2 063 420 18 899 17 938 961 42 638 10 181 1 537 5 575 1 385 2 337 7 310 8 022 6 291 1,351 140 361 139 011

alcohol-attributable DALYs lost by cause for 2012. The greatest difference between alcohol-attributable deaths, YLLs, and DALYs lost is the high contribution of alcohol use disorders to the overall alcohol-attributable burden of DALYs lost. Alcohol use disorders are the second greatest contributor to the alcohol-attributable burden of DALYs lost (23.0% of all alcohol-attributable DALYs lost were due to injuries: 24.6% of all alcohol-attributable DALYs lost among men and 17.1% of all alcohol-attributable DALYs lost among women), with injuries being the top contributor. However, it should be noted that the number of DALYs lost due to alcohol use disorders among men was 5.4 times the number of DALYs lost caused by alcohol use disorders among women.

Burden by WHO Region Among people of all ages, Belarus, Moldova, Russia, and Ukraine in 2012 had the greatest percentage of all deaths, YLLs, and DALYs that were attributable to alcohol consumption, with 31.6% of all deaths, 30.2% of all YLLs, and 34.9% of all DALYs lost being attributable to alcohol consumption

Men % of all AA DALYs

Women % of all AA DALYs

Total % of all AA DALYs

3.9% 0.8% 2.0% 0.2% 8.2% 2.4% 1.9% 1.2% 2.0% 0.2% 0.0% 0.5% 0.1% 24.6% 1.5% 10.7% 1.5% 1.9% 5.8% 1.2% 0.2% 12.5% 11.8% 0.7% 35.6% 8.6% 1.3% 4.5% 1.1% 2.0% 6.0% 6.8% 5.4%

2.6% 0.8% 3.9% 0.5% 10.2% 1.0% 0.9% 1.8% 1.3% 0.3% 4.7% 0.1% 4.3% 17.1% 1.8% 37.9% 2.2% 21.5% 11.2% 2.5% 0.5% 17.6% 17.1% 0.5% 12.0% 2.6% 0.5% 2.1% 0.7% 0.5% 2.4% 2.0% 1.2%

3.6% 0.8% 2.4% 0.2% 8.6% 2.1% 1.7% 1.3% 1.9% 0.2% 1.0% 0.4% 1.0% 23.0% 1.5% 16.4% 1.7% 6.0% 7.0% 1.5% 0.3% 13.6% 12.9% 0.7% 30.7% 7.3% 1.1% 4.0% 1.0% 1.7% 5.3% 5.8% 4.5%

in these countries. The burden in these countries was far greater than the alcohol-attributable burden globally, where in 2012, 5.9% of all deaths, 5.2% of all YLLs, and 5.1% of all DALYs lost were caused by alcohol consumption. Figure 2 outlines the percentage of all deaths, YLLs, and DALYs lost attributable to alcohol consumption by WHO region for 2012. The EMR had the lowest percentage of all deaths, YLLs, and DALYs lost attributable to alcohol consumption, with 0.9% of all deaths, 0.7% of all YLLs, and 0.6% of all DALYs lost in 2012 being attributable to alcohol consumption. Proportionally, the percentage of the total burden of deaths, YLLs, and DALYs lost that were attributable to alcohol consumption in 2012 was higher among people 0–69 years of age than it was for people of all ages, particularly in the case of deaths attributable to alcohol consumption, with 6.7% of all deaths, 5.2% of all YLLs, and 5.2% of all DALYs lost among people 0–69 years of age being attributable to alcohol consumption. Figure 3 outlines the percentage of all deaths, YLLs, and DALYs attributable to alcohol consumption by region for 2012 for people 0–69 years of age. The difference in the percentage of all deaths attributable to alcohol

307

Burden of Disease and Injury Caused by Alcohol

Percent of burden aributable to alcohol consumpon

40.0% 34.9% 35.0% 31.6%

30.2%

30.0% 25.0% 20.0% 15.0% 10.0% 5.9% 3.3%

5.0%

4.7%

4.6%

4.6%

5.9%

7.1%

Figure 2

2.4% 0.6%

YLLs AMR

AFR

EMR

DALYs

EUR (except BLR, MDA, RUS and UKR)

BLR, MDA, RUS and UKR

SEAR

WPR

Percentage of total health burden attributable to alcohol consumption by WHO region in 2012.

40.0% Percent of burden aributable to alcohol consumpon

6.6%

5.6% 4.0%

0.7%

Deaths World

6.7% 5.1%

4.4% 2.4%

0.9% 0.0%

6.8%

6.7%

5.2%

36.5%

35.0% 29.3%

28.9%

30.0% 25.0% 20.0% 15.0% 10.0% 5.0%

9.6%

8.6% 6.7%

8.9% 5.6%

9.4%

8.9% 5.2%

3.3%

4.6% 2.3%

0.9%

8.1%

8.0%

7.7%

7.2%

5.2%

4.2% 2.4%

0.7%

0.6%

0.0% Deaths

YLLs

DALYs

Burden World

Figure 3

AFR

AMR

EMR

EUR (except BLR, MDA, RUS and UKR)

BLR, MDA, RUS and UKR

SEAR

WPR

Percentage of total health burden attributable to alcohol consumption by WHO region for those 0–69 years of age in 2012.

consumption among those 0–69 years of age was the most pronounced in EUR (excluding Belarus, Moldova, Russia, and Ukraine), where the percentage of all alcohol-attributable deaths in this age group was 2.1 times the percentage of all alcohol-attributable deaths among people of all ages, followed by the AMR where the percentage of all alcohol-attributable deaths among people 0–69 years of age was 1.8 times the percentage of all alcohol-attributable deaths among people of all ages.

Conclusions and Implications Alcohol creates a large burden of deaths, YLLs, and DALYs lost globally, and its role as one of the most important risk factors for the global burden of disease and injury needs to be addressed. The burden of alcohol consumption in 2012 was caused primarily by injuries, cardiovascular diseases, digestive

diseases, neoplasms, and alcohol use disorders. The average volume of alcohol consumption and heavy episodic drinking show wide variations by gender and by region. Additionally, the resulting health burden caused by alcohol consumption shows wide variation by cause of death, YLLs, and DALYs lost, and by gender and region. Given current trends in exposure, with expected increases in alcohol consumption in developing countries (Shield et al., 2011), and increases in the burden of outcomes that are causally related to alcohol consumption, such as the burden caused by noncommunicable diseases (Parry et al., 2011; World Health Organization, 2011), the detrimental impact of alcohol is expected to increase in the future in developing countries and effective interventions should be introduced in these countries.

See also: Alcohol Consumption: An Overview of International Trends; Alcohol Consumption: The Social and Economic Impacts; Alcohol Industry; Alcohol: Treatment.

308

Burden of Disease and Injury Caused by Alcohol

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A systematic review of the epidemiology of unrecorded alcohol consumption and the chemical composition of unrecorded alcohol. Addiction 109, 880–893. http://dx.doi.org/10.1111/ add.12498. Rehm, J., Mathers, C., Popova, S., Thavorncharoensap, M., Teerawattananon, Y., Patra, J., 2009a. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol use disorders. Lancet 373, 2223–2233. Rehm, J., Samokhvalov, A.V., Neuman, M.G., Room, R., Parry, C.D., Lönnroth, K., Patra, J., Poznyak, V., Popova, S., 2009b. The association between alcohol use, alcohol use disorders and tuberculosis (TB). A systematic review. BMC Public Health 9, 450. Rehm, J., Rehn, N., Room, R., Monteiro, M., Gmel, G., Jernigan, D., Frick, U., 2003a. The global distribution of average volume of alcohol consumption and patterns of drinking. Eur. Addict. Res. 9, 147–156. Rehm, J., Room, R., Graham, K., Monteiro, M., Gmel, G., Sempos, C., 2003b. The relationship of average volume of alcohol consumption and patterns of drinking to burden of disease – an overview. Addiction 98, 1209–1228. Rehm, J., Room, R., Monteiro, M., Gmel, G., Graham, K., Rehn, N., Sempos, C., Jernigan, D., 2003c. Alcohol as a risk factor for global burden of disease. Eur. Addict. Res. 9, 157–164. Rehm, J., Room, R., Monteiro, M., Gmel, G., Graham, K., Rehn, N., Sempos, C.T., Frick, U., Jernigan, D., 2004. Alcohol use. In: Ezzati, M., Lopez, A.D., Rodgers, A., Murray, C.J.L. (Eds.), Comparative Quantification of Health Risks: Global and Regional Burden of Disease Attributable to Selected Major Risk Factors. World Health Organization, Geneva, Switzerland, pp. 959–1109. Rimm, E.B., Williams, P., Fosher, K., Criqui, M.H., Stampfer, M.J., 1999. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ 19, 1523–1528. Rockhill, B., Newman, B., 1998. Use and misuse of population attributable fractions. Am. J. Public Health 88, 15–19. Roerecke, M., Rehm, J., 2010. Irregular heavy drinking occasions and risk of ischemic heart disease: a systematic review and meta-analysis. Am. J. Epidemiol. 171, 633–644. Roerecke, M., Rehm, J., 2012. The cardioprotective association of average alcohol consumption and ischaemic heart disease: a systematic review and meta-analysis. Addiction 107, 1246–1260.

Burden of Disease and Injury Caused by Alcohol Samokhvalov, A.V., Irving, H., Mohapatra, S., Rehm, J., 2010a. Alcohol consumption, unprovoked seizures and epilepsy: a systematic review and meta-analysis. Epilepsia 51, 1177–1184. Samokhvalov, A.V., Irving, H.M., Rehm, J., 2010b. Alcohol as a risk factor for atrial fibrillation: a systematic review and meta-analysis. Eur. J. Cardiovasc. Prev. Rehabil. 17, 706–712. Samokhvalov, A.V., Irving, H.M., Rehm, J., 2010c. Alcohol consumption as a risk factor for pneumonia: systematic review and meta-analysis. Epidemiol. Infect. 138, 1789–1795. Samokhvalov, A.V., Popova, S., Room, R., Ramonas, M., Rehm, J., 2010d. Disability associated with alcohol abuse and dependence. Alcohol. Clin. Exp. Res. 34, 1871–1878. Seitz, H.K., Becker, P., 2007. Alcohol metabolism and cancer risk. Alcohol Res. Health 30, 38–47. Shield, K., Rehm, J., 2012. Difficulties with telephone-based surveys on alcohol in high-income countries: the Canadian example. Int. J. Methods Psychiatr. Res. 21, 17–28. Shield, K., Rehm, M., Patra, J., Sornpaisarn, B., Rehm, J., 2011. Global and country specific adult per capita consumption of alcohol, 2008. Sucht 57, 99–117. Shield, K.D., Gmel Jr., G., Patra, J., Rehm, J., 2012. Global burden of injuries attributable to alcohol consumption in 2004: a novel way of calculating the burden of injuries attributable to alcohol consumption. Popul. Health Metr. 10, 9. Sun, F., Tsuritani, I., Honda, R., Ma, Z.Y., Yamada, Y., 1999. Association of genetic polymorphisms of alcohol-metabolizing enzymes with excessive alcohol consumption in Japanese men. Hum. Genet. 105, 295–300. Sun, F., Tsuritani, I., Yamada, Y., 2002. Contribution of genetic polymorphisms in ethanol-metabolizing enzymes to problem drinking behavior in middle-aged Japanese men. Behav. Genet. 32, 229–236. Takeshita, T., Morimoto, K., 1999. Self-reported alcohol-associated symptoms and drinking behavior in three ALDH2 genotypes among Japanese university students. Alcohol. Clin. Exp. Res. 23, 1065–1069. Taylor, B., Irving, H.M., Baliunas, D., Roerecke, M., Patra, J., Mohapatra, S., Rehm, J., 2009. Alcohol and hypertension: gender differences in dose-response relationships determined through systematic review and meta-analysis. Addiction 104, 1981–1990. Taylor, B., Irving, H.M., Kanteres, F., Room, R., Borges, G., Cherpitel, C., Greenfield, T., Rehm, J., 2010. The more you drink, the harder you fall: a systematic review and meta-analysis of how acute alcohol consumption and injury or collision risk increase together. Drug Alcohol Depend. 110, 108–116. Taylor, B., Shield, K., Rehm, J., 2011. Combining best evidence: a novel method to calculate the alcohol-attributable fraction and its variance for injury mortality. BMC Public Health 11, 265.

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United Nations, 2013. World Population Prospects: The 2012 Revision. United Nations, New York, USA. http://esa.un.org/wpp/. World Health Organization, 2004. Global Status Report on Alcohol 2004. World Health Organization, Geneva, Switzerland. World Health Organization, 2009. Global Health Risks. Mortality and Burden of Disease Attributable to Selected Major Risks. World Health Organization, Geneva, Switzerland. World Health Organization, 2011. Prevention and Control of NCDs: Priorities for Investment. World Health Organization, Geneva, Switzerland. World Health Organization, 2014a. Global Health Estimates 2013: Deaths by Cause, Age and Sex, by Country, 2000–2012. World Health Organization, Geneva, Switzerland. World Health Organization, 2014b. Global Status Report on Alcohol and Health. World Health Organization, Geneva, Switzerland. Zaridze, D., Brennan, P., Boreham, J., Boroda, A., Karpov, R., Lazarev, A., Konobeevskaya, I., Igitov, V., Terechova, T., Boffetta, P., Peto, R., 2009. Alcohol and cause-specific mortality in Russia: a retrospective case-control study of 48,557 adult deaths. Lancet 373, 2201–2214.

Further Reading English, D., Holman, C., Milne, E., et al., 1995. The Quantification of Drug Caused Morbidity and Mortality in Australia 1995. Commonwealth Department of Human Services and Health, Canberra, Australia. Ezzati, M., Lopez, A.D., Rodgers, A., et al., 2004. Comparative Quantification of Health Risks. Global and Regional Burden of Disease Attributable to Selected Major Risk Factors. WHO, Geneva. Lopez, A.D., Mathers, C.D., Ezzati, M., et al., 2006. Global Burden of Disease and Risk Factors. Oxford University Press and The World Bank, New York & Washington. Rehm, J., Room, R., Monteiro, M., et al., 2004. Alcohol use. In: Ezzati, M., Lopez, A., Rodgers, A., Murray, C. (Eds.), Comparative Quantification of Health Risks, Global and Regional Burden of Disease Attributable to Selected Major Risk Factors, vol. 1. WHO, Geneva, pp. 959–1108. Ridolfo, B., Stevenson, C., 2001. The Quantification of Drug-Caused Mortality and Morbidity in Australia 1998. Australian Institute of Health and Welfare, Canberra.

Relevant Website www.who.int/globalatlas/alcohol – WHO, Global Atlas, Alcohol.

Burns and Scalds Roslyn Poulos, The University of New South Wales, Sydney, NSW, Australia Mark Stevenson, The George Institute for International Health, Sydney, NSW, Australia Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 1, pp. 370–376, Ó 2008, Elsevier Inc.

Introduction Burns are caused by thermal energy arising from exposure to sources of flames (flame burns), hot liquids (scalds), and hot surfaces (contact burns). Injury occurs when some or all of the different layers of cells in the skin are destroyed (Latarjet, 1995). Skin injuries resulting from exposure to electricity, chemicals, ultraviolet and ionizing radiation, as well as respiratory insults from smoke inhalation are also regarded as fire and burn injuries (Latarjet, 1995). Burn severity depends on a number of factors including the size and depth of the burn, the location of the burn, the age and previous health condition of the victim, and the severity of associated injuries such as respiratory damage from smoke inhalation. The size of the burn is usually described in terms of the percent of total body surface area affected. The depth of the burn is dependent on both the temperature of the heat source and the duration of exposure. Burn depth has often been described in terms of first, second, and third degree to reflect increasing depth, but more recently classification of burns as partial or full-thickness has become common. Burn injuries are a major public health problem worldwide, especially in developing countries, where the risk is greatest and access to specialist care limited. Burns can result in devastating injury causing death or significant long-term morbidity and disability. Burn injuries represent a significant cost to society both in terms of human suffering and health-care costs. Fire and burn injuries accounted for about 2% of the total cost of injuries occurring in the United States in 2000, equating to a cost of US$7.5 billion dollars (Finkelstein et al., 2006). The focus of this article will be on unintentional burn injuries arising from flames, hot liquids, and hot surfaces. A brief reference to intentional burn injuries is made at the end of the article.

Surveillance of Burn Injuries Systematic surveillance is the essential first step in the public health approach to the prevention of disease and injuries. Most high-income countries have formal surveillance systems capable of providing reliable data on mortality and hospitalization due to burn injury, but few low- and middle-income countries do, with data significantly underestimating the incidence. Most countries code data using the World Health Organization’s International Classification of Disease Codes (ICD), the latest version of which is ICD-10. Under this system, the article titled ‘External Causes of Morbidity and Mortality’ permits the classification of the manner (the intent) and the mechanism of the burn injury. For example, in the case of unintentional injury, codes X00–X09 represent exposure to smoke, fire, and flames, and X10–X19 represent contact with heat and hot substances.

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Health and vital statistics do not provide all the information necessary to understand burn epidemiology or to set priorities in burn prevention, so other sources of data are required. These include data from presentations to accident and emergency departments, data from individual hospitals and burn units, and specific epidemiological studies.

Epidemiology The relative importance of different burn sources varies with age, gender, and geographic location. Globally, fire-related burns (that is, flame burns and respiratory damage due to smoke inhalation) account for 5% of injury mortality (Peden et al., 2002). In 2000, the World Health Organization estimated that fire-related burns caused 238 000 deaths, over 95% of which occurred in low- and middle-income countries (Peden et al., 2002). South Asia accounted for just over half of all fire-related deaths, with females in this region suffering the highest burn mortality rates in the world (11.3 per 100 000). Figure 1 shows fire-related burn mortality rates by WHO region. Globally, children aged less than 5 years of age and adults aged over 70 years are most at risk of death from fire-related burns. Table 1 shows fire-related burn mortality rates in WHO regions by age and sex. Fatal and nonfatal outcomes from injury can be reflected in disability-adjusted life years (DALYs). This is a measure that accounts for the years of life lost from premature death, and the years of life lived with disability, with one DALY representing 1 lost year of healthy life. Fire-related burns account for 6% of the global burden of injury; over 50% of the total number of disability-adjusted life years lost are among children aged 0–14 years (Peden et al., 2002). The available global data on burns concentrates on fire-related burns, particularly fire-related mortality (Peden et al., 2002). An understanding of nonfatal burn injuries, or burn injury from other mechanisms, requires the analysis of individual studies or the data collected by individual countries or jurisdictions. Forjuoh (2006) undertook a review of over 100 studies reporting on burns in low- and middle-income countries. The majority of these were hospital- or clinic-based studies. He found that scalding from hot liquid accounted for one-third to one-half of all burns for all age groups, followed by hot objects and flame in children, and by flame in adults. Children under 4 years were most at risk for burns, with another peak occurring in older adolescence due to occupational exposure and improper use of flammable materials. Most studies in children reported a preponderance in males, but gender differences in older age groups varied across different countries.

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Mortality rate (per 100 000) No data 4.81−8.30 4.01−4.80 1.18−4.00 1.00−1.17

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.Dotted lines on maps represent legal status of any country, territory, city or its authorities, or concerning the approximate border lines for which there may not yet be full agreement. © WHO 2002, All rights reserved

Africa LMIC 5.5

Fire-related burn mortality rates (per 100 000 population) in WHO regions, 2000 Eastern Americas South-East Asia Europe Western Pacific Mediterranean HIC LMIC India Other LMIC HIC LMIC HIC LMIC HIC China Other LMIC 1.3 1.17 8.3 8.2 1.0 4.0 1.5 4.8 1.5 1.1 2.0

HIC, High-income countries: LMIC, Low- and middle-income countries. Figure 1 Global fire-related burn mortality. From Peden, M., McGee, K., Sharma, G., 2002. The Injury Chart Book: A Graphical Overview of the Global Burden of Injuries. World Health Organization, Geneva, Switzerland.

Table 1

Fire-related burn mortality rates (per 100 000 population) in WHO regions by age group and sex, 2000 World

Africa

Americas

Southeast Asia

Europe

Eastern Mediterranean

Western Pacific

Age group (years)

Both sexes

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

All ages 0–4 5–14 15–29 30–44 45–59 60–69 70–79 80

3.9 6.6 2.5 3.9 3.5 3.1 4.2 6.9 12.5

3.4 7.6 1.6 2.4 3.1 3.7 4.3 7.1 12.5

4.5 5.7 3.6 5.5 3.9 2.5 3.9 6.3 13.3

6.6 23.6 3.4 1.1 2.1 3.8 11.1 25.0 5.1

4.4 9.3 2.3 2.3 2.0 3.7 10.0 20.0 41.2

1.5 2.6 0.5 1.0 1.1 1.7 4.5 7.7 8.3

1.0 2.6 0.4 0.4 0.5 0.7 1.0 2.4 5.4

5.5 4.4 2.3 5.5 6.9 6.6 8.8 12.5 25.0

11.3 7.1 9.3 15.6 12.1 6.8 10.8 16.7 40.0

3.5 3.8 0.6 1.0 4.1 5.4 5.4 4.5 14.3

1.8 4.0 0.5 1.1 1.0 1.3 2.2 2.9 6.3

3.7 11.4 1.6 2.9 2.3 4.0 2.7 6.5 5.1

6.4 9.1 3.3 7.7 5.0 4.3 4.6 25.0 35.6

1.3 1.4 0.7 0.9 1.0 1.5 1.9 3.8 14.3

1.1 1.6 0.7 1.0 0.5 0.8 1.9 3.1 8.3

From Peden, M., McGee, K., Sharma, G., 2002. The Injury Chart Book: A Graphical Overview of the Global Burden of Injuries. World Health Organization, Geneva, Switzerland.

In high-income countries, children also have the highest rates of admission for burns. Scalds are the most common form of burns in children, and result from exposure to hot tap water and other sources of hot fluid, such as hot food and drink. Contact burns, often the result of contact with hot household appliances, are common as well. The incidence of scald injuries also increases in older people, possibly the result of their decreased mobility and other comorbidities. Some countries show a peak in admissions for burns among

young males in their teens and early adult years, probably reflecting occupational exposures and their greater risk-taking behaviors. There are a number of differences in the risk factors for burns between high-, low-, and middle-income countries, and this has important implications for burn prevention. For example, sources of open flames are common in many households in low- and middle-income countries, particularly in rural areas without electricity. Flame sources include open

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fires, kerosene and naphtha stoves and lanterns, and candles, which are a risk for fire-related burns due to (Barss et al., 1998): the lack of enclosures for open fires, and the location of fires and stoves at floor level; l the physical instability of candles, small stoves, and lanterns which can easily tip over; l the use of volatile, highly flammable fuels; l the structure of housing (flammable materials, insufficient exits). l

In these settings, certain clothing styles (such as saris, which are loose and flowing) put women at particular risk as they lean over open flames while cooking; and children can readily fall or crawl into open fires or be scalded by hot water from unstable, open pots on the fire. Not surprisingly, Forjuoh’s (2006) review found that the vast majority of childhood and adult female burns occurred in the home, with the kitchen being the most common location. Two peak times of the day for burn events were identified: late morning and evening, these being periods when food is prepared, cooked, and served. A higher incidence of burns was reported in winter months in those places with seasonal variations. Identified risk factors for burns in children included the factors listed above, as well as the presence of a preexisting impairment in a child (such as mobility impairment, epilepsy, or blindness), the history of burn in a sibling, insufficient supervision of children, low maternal education, overcrowding, and housing location (slum areas). In high-income countries, smoking materials and lighters, heating appliances and electrical faults, cooking, and children playing with matches are the cause of most residential fires (Liao and Rossignol, 2000). Groups at increased risk of fire-related injury or death in the United States include young children and older adults, African Americans, Native Americans, the poor, and those living in substandard housing. Alcohol misuse is an important risk factor. A seasonal variation is evident, with most residential fires occurring during winter. Similar socioeconomic and seasonal factors have been identified in other developed countries. The significant role of hot tap water in scalds in high-income countries was not appreciated until the 1970s when Feldman et al. (1977) demonstrated that tap water scalds accounted for between 7% and 17% of all childhood scald burns requiring hospitalization. Subsequent studies have confirmed the importance of scald injuries due to hot tap water in children, as well as in persons aged 60 years and older. Childhood exposure often results from falling, or being placed, into a hot bathtub or sink, or turning on the hot tap while left unattended in the bathtub. For adults, scald injuries may result from falling or losing consciousness in a bath or shower. Despite differences between high-, low-, and middleincome countries, risk factors for burns in both settings can be understood in terms of the classic epidemiologic triad of agent, host, and environment. In this case, the agent refers to the thermal energy and its source; the host refers to the individual at risk and intrinsic factors (such as age, sex, or behavior) that affect his or her likelihood of exposure to thermal energy; and the environment refers to the setting or context in which

burn injury occurs. This includes risk factors in both the physical environment (e.g., an open fire place, or an accessible cup of coffee) and the social environment (e.g., overcrowding, lack of parental supervision, and poverty).

Burn Prevention Effective burn prevention requires an understanding of the epidemiological characteristics and the risk factors associated with burn injuries. Continued research in these areas has resulted in significant achievements in burn prevention in many high-income countries, and subsequent declines in deaths and hospitalization for burn injuries (Brigham and McLoughlin, 1996). Strategies for burn prevention can be divided into three main types (Liao and Rossignol, 2000): education, which requires behavioral or lifestyle change in the individual (that is, host factor modification); l product design and/or environmental modification (agent and/or environmental factor modification); l legislation and regulation (leading to agent, host, or environmental factor modification). l

As with all injury prevention initiatives, passive preventive measures (such as the latter two strategies) are generally more effective than active preventive strategies, which require continuing action and compliance on the part of the individual. Nonetheless, education is important. Education can promote awareness of risk and encourage actions or measures that can prevent burns from occurring or reduce the severity of burn injuries (such as the application of cool water to a burn). Many burn prevention programs combine both active and passive strategies. For example, a community-based burn prevention program in Harstad, Norway used a mix of strategies that included education, stove safeguards, and lowered hot tap water temperature settings to reduce the burn injury rate by 51.5% (Ytterstad et al., 1998). Burn prevention strategies can be classified as primary, secondary, or tertiary. Primary prevention refers to interventions aimed at reducing the likelihood of a burn occurring; secondary prevention refers to the early management of burn injury to minimize adverse outcomes, and tertiary prevention refers to postacute care and rehabilitation aimed at reducing long-term sequelae from burn injury. William Haddon Jr. combined the concept of risk factors (agent-host-environment) with the idea of primary, secondary, and tertiary prevention to create what has become known as the Haddon matrix. Initially developed to explore traffic injuries, it has become a tool for identifying potential interventions for many different types of injuries. Table 2 gives an example of the Haddon matrix applied to the prevention of residential fire-related injury in children. The horizontal axis of the matrix addresses the risk factors for residential fires, while the vertical axis identifies the period of time in which an intervention may be implemented relative to the fire event; the individual cells within the matrix identify potential actions, and together they provide a comprehensive list of strategies for preventing or reducing residential fire-related injury in children.

Burns and Scalds Table 2

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Interventions to prevent residential fire-related injury in children: Haddon’s matrix Host

Agent

Environment

Pre-event

Child and parent education on fire safety

Fire-safe cigarettes heater designs that avoid tipping over child-proof containers for storage of flammable fluids

Event

Teach children to stop-drop-roll to smother flames on clothes

Fire-retardant children’s clothing (nightwear)

Post-event

Teach children and parents first aid for burns

Heater with automatic shut-off switch to shutdown if tipped over

Building codes addressing structural adaptations and use of less pyrogenic material Access to safe heating and lighting options (subsidies for electricity) Ban the private use of fireworks Install functional smoke alarms Install sprinkler systems Fire exit options Availability of burn treatment and rehabilitation

Adapted from McClure, R., Stevenson, M., McEvoy, S. (Eds.), 2004. The Scientific Basis of Injury Prevention and Control. IP Communications, East Hawthorn, with permission from IP Communications Pty Ltd.

Primary Prevention A number of landmarks in burn prevention have been identified in a review by Liao and Rossignol (2000). These have contributed to a reduction in burn mortality and morbidity in developed countries. Some of these are presented below, but readers are referred to the original article for further details and other strategies.

Prevention of Hot Tap Water Burns in Domestic Settings

Following the identification of hot tap water as a significant cause of burns, Feldman et al. (1977) found that water heaters were preset at the factory to deliver water at temperatures that could cause full-thickness burns within seconds. They argued that such burns could be prevented passively, by limiting household water temperatures to less than 52  C (125  F). Since then, educational campaigns to inform the public about safer water temperatures have been successful. Many jurisdictions have also adopted legislation that mandates lower hot tap water temperatures, and this has been associated with declining admission rates for scald injuries from this source.

Prevention of Fire-Related Injury from Residential Fires through Installation of Smoke Alarms

Central to the prevention of residential fire-related deaths is the prevention of smoke inhalation and asphyxia. For the majority of victims of residential fires, this is the cause of death, rather than burns. Smoke alarms are a means of providing early warning of fire. Research shows that smoke alarm ownership is associated with a decreased risk of fire-related death, especially for fires involving young children (Runyan et al., 1992). Interventions to promote smoke alarm ownership have shown modest beneficial effects. For example, community trials providing free smoke alarms appear to have been successful in reaching high-risk homes and in decreasing fire-related injuries, although the quality of the evidence is limited (DiGuiseppi and Higgins, 2003). Legislation also appears effective, with evidence supporting an increase in the proportion of homes with working alarms following the introduction of laws requiring homes to be fitted with smoke alarms.

Prevention of Clothing Ignition Burns

Burns from the ignition of clothing are often very severe, and are associated with high mortality rates. Girls are more frequently affected than boys, and this has been attributed to the loose and flowing nature of their clothing, which is more likely to both ignite and burn, than closely fitted clothes. Epidemiological studies, such as the study by McLoughlin et al. (1977) have identified children’s sleepwear as a significant risk factor for clothing ignition fires. A number of countries have subsequently passed legislation requiring the use of fabrics with low flammability potential in children’s sleepwear, which has resulted in a fall in the number of burn admissions due to sleepwear ignition. Some countries, such as Australia, have also instituted labeling on children’s clothes to indicate potential flammability, and mandated closer fitting styles in children’s sleepwear.

Prevention of Firework-Related Burns

Many countries celebrate special days with fireworks. Unfortunately, when used without the necessary caution or supervision, fireworks have been a source of significant injury, including burn injuries. As a result, many jurisdictions have restricted the sale and manufacture of fireworks through legislation. For example, in the United States, the federal government prohibits the sale of the most hazardous fireworks to the public. Some states, however, have further restricted sales with even greater benefit. Professionally managed and controlled public displays of fireworks have been implemented as a safer alternative to private use.

Reduction in Cigarettes as an Ignition Source

Fire-safe cigarettes, also known as reduced ignition propensity cigarettes, have a reduced likelihood to burn when left unattended. Smoking has consistently been identified as a leading cause of residential and total fire deaths, thus the introduction of fire-safe cigarettes promises to be another landmark in burn prevention. Some jurisdictions in the United States have announced the adoption of a fire safety standard for cigarettes; in 2005, Canada became the first country to implement a cigarette fire-safety standard, nationwide. Other countries are considering similar action (Coalition for Fire-Safe Cigarettes, 2015).

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Because the risk factors are often different for low- and middle-income countries, compared with high-income countries, measures found to be successful in high-income countries may not be directly transferable to low- and middle-income countries. For example, reducing the temperature at which hot tap water is delivered to prevent scald injuries in high-income countries would not be effective in places where households do not have hot running water (Forjuoh, 2006); similarly, while legislation may be easy to create, it will be of limited effectiveness if there are insufficient resources to enforce it (Liao and Rossignol, 2000). Therefore, burn prevention efforts need to be tailored to specific risk factors and settings. Burn prevention recommendations for low- and middle-income countries include a blend of active and passive measures, with particular attention to the kitchen, which is the setting for most burns (Forjuoh, 2006). Few studies in low- and middle-income countries have evaluated the effectiveness of burn prevention interventions and more research in these settings is required. Proposed potential primary prevention strategies reported in the literature include (Forjuoh, 2006): l

l l l l l l l

interventions to improve socioeconomic status such as education, better housing (including separating cooking areas from living areas), and the provision of basic amenities such as water; the regulation and safer design of products such as kerosene stoves and lamps; correct storage of flammable substances; the provision of a bucket of sand in the kitchen; use of flame-resistant materials in clothing; wearing close-fitting clothes while cooking; the provision of adequate child supervision, especially for children with impairments; parental education about burn prevention and burn first aid.

Secondary Prevention Research supports the immediate application of cool water to a burn as an effective secondary intervention strategy. For example, a study undertaken by Nguyen et al. (2002) in Vietnam indicated that early cooling prevents a significant percentage of superficial burns from progressing to deep burns, reducing the probability that skin grafting will be required, and reducing the other risks associated with deep burns that may be fatal. The authors conclude that public health programs promoting immediate cooling of burns with cool water are at least as important in determining outcome as subsequent medical and surgical treatment.

Tertiary Prevention Advances in burn care treatment in developed countries have markedly improved survival rates for burn patients. Over the past five decades, the burn size associated with 50% mortality has increased from 40% to 80% of total body surface area. Improved outcomes can be attributed to therapeutic developments, which include vigorous fluid resuscitation, early burn wound excision, advances in critical

care and nutrition, control of infection, and the development of specialized, multidisciplinary burn centers (Saffle, 1998). Burn survivors may suffer significant long-term physical and psychological sequelae. For example, scarring can lead to considerable disfigurement and loss of function. Rehabilitation is commenced early following injury and may continue for many years after discharge from hospital. It addresses both the physical and psychological problems that arise as a consequence of burn injury. Rehabilitation aims to assist individuals to achieve their optimal level of function (physical, mental, social, and vocational), thus supporting their reintegration into the community.

Intentional Burn Injuries Most burns are reported as unintentional; however, intentional burn injuries do occur. Intentional burn injuries include cases of self-inflicted burns and burns caused by assault or maltreatment. Cases of deliberate self-burning have been classified into three broad groups (Laloe, 2004): Those with psychiatric illness, those with personal reasons such as interpersonal problems and marital disharmony, and those who are politically motivated. Maltreatment by burning is recognized in children and the elderly. While the prevalence in the elderly is unknown, Greenbaum et al. (2006) report recent estimates in children that range from 9% to 18% of pediatric burn admissions (depending on whether injuries resulting from neglect are included with intentional injury). Homicidal bride burning (or dowry deaths) in India is increasingly being recognized as a major public health problem (Sharma et al., 2002). While its true extent is unknown, it may account for some of the difference in burn risk between males and females in the region.

See also: Injury Epidemiology; Occupational Injuries and Work Place Violence; Road Traffic Injuries.

References Barss, P., Smith, G.S., Baker, S., Mohan, D., 1998. Injury Prevention: An International Perspective. Epidemiology, Surveillance and Policy. Oxford University Press, New York. Brigham, P.A., McLoughlin, E., 1996. Burn incidence and medical care use in the United States: estimates, trends, and data sources. J. Burn Care Rehabil. 17 (2), 95–107. Coalition for Fire-Safe Cigarettes, 2015. The Coalition for Fire-Safe Cigarettes has worked to save lives and prevent injuries and devastation from cigarette-ignited fires. http://www.firesafecigarettes.org (accessed October 2007). DiGuiseppi, C., Higgins, J.P.T., 2003. Interventions for promoting smoke alarm ownership and function (Cochrane review). Cochrane Database Syst. Rev. 2007. Feldman, K., Schaller, R., Feldman, J., McMillon, M., 1977. Tap water scalds in children. Pediatrics 62, 1–7. Finkelstein, E.A., Corso, P.S., Miller, T.R., 2006. Incidence and Economic Burden of Injuries in the United States. Oxford University Press, New York. Forjuoh, S.N., 2006. Burns in low- and middle-income countries: a review of available literature on descriptive epidemiology, risk factors, treatment, and prevention. Burns 32, 529–537. Greenbaum, A.R., Horton, J.B., Williams, C.J., Shah, M., Dunn, K.W., 2006. Burn injuries inflicted on children or the elderly: a framework for clinical and forensic assessment. Plastic Reconstr. Surg. 118, 46e.

Burns and Scalds Laloe, V., 2004. Patterns of deliberate self-burning in various parts of the world. A review. Burns 30, 207–215. Latarjet, J., 1995. A simple guide to burn treatment. Burns 21, 221–225. Liao, C.C., Rossignol, A., 2000. Landmarks in burns prevention. Burns 26, 422–434. McClure, R., Stevenson, M., McEvoy, S. (Eds.), 2004. The Scientific Basis of Injury Prevention and Control. IP Communications, East Hawthorn. McLoughlin, E., Clarke, N., Stahl, K., Crawford, J., 1977. One pediatric burn unit’s experience with sleepwear related injuries. Pediatrics 60, 406–409. Nguyen, N.L., Gun, R.T., Sparnon, A.L., Ryan, P., 2002. The importance of immediate cooling – a case series of childhood burns in Vietnam. Burns 28, 173–176. Peden, M., McGee, K., Sharma, G., 2002. The Injury Chart Book: A Graphical Overview of the Global Burden of Injuries. World Health Organization, Geneva, Switzerland. Runyan, C.W., Bangdiwala, S.I., Linzer, M.A., Sacks, J.J., Butts, J., 1992. Risk factors for fatal residential fires. N. Engl. J. Med. 327, 859–863. Saffle, J.R., 1998. Predicting outcomes of burns. N. Engl. J. Med. 338, 387–388. Sharma, B.R., Harish, D., Sharma, V., Vij, K., 2002. Kitchen accident vis-a-vis dowry deaths. Burns 28, 250–253. Ytterstad, B., Smith, G., Coggan, C., 1998. Harstad injury prevention study: prevention of burns in young children by community based intervention. Inj. Prev. 4, 176–180.

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Further Reading Berger, L.R., Mohan, D., 1996. Injury Control. A Global View. Oxford University Press, Delhi, India. Christoffel, T., Gallagher, S.S., 2006. Injury Prevention and Public Health, second ed. Jones and Bartlett, Sudbury, UK. Harborview Injury Prevention and Research Center. Burns. http://depts.washington. edu/hiprc/about/topics/burns.html (accessed October 2007). Hettiaratchy, S., Dziewulski, P., 2004. ABC of burns. Introduction. Br. Med. J. 328, 1366–1368. Katcher, M.L., 1998. Tap water scald prevention: it’s time for a worldwide effort. Inj. Prev. 4, 167–169. McLoughlin, E., 1995a. A simple guide to burn epidemiology. Burns 21, 217–220. McLoughlin, E., 1995b. A simple guide to burn prevention. Burns 21, 226–229. Rivara, F., 2000. Burns: the importance of prevention. Inj. Prev. 6, 242–244. Rivara, F., Grossman, D., Cummings, P., 1997. Injury prevention. N. Engl. J. Med. 337, 613–618. Van Baar, M.E., Essink-Bot, M.L., Oen, I.M.M.H., Dokter, J., Boxma, H., Van Beek, E.F., 2006. Functional outcome after burns: a review. Burns 32, 1–9.

C Cadmium Anthony Fristachi, Battelle Memorial Institute, Columbus, OH, USA Harlal Choudhury, National Center for Environmental Assessment, Cincinnati, OH, USA Ó 2017 Elsevier Inc. All rights reserved.

Cadmium (Cd), a naturally occurring element, is often found in nature combined with other elements such as oxygen, chlorine, or sulfur in the form of complex oxides, sulfides, and carbonates in zinc (Zn), lead (Pb), and copper (Cu) ores. Cd is not regarded as essential to human life (unlike other metals such as Cu), and excess exposure to Cd may result in adverse health effects to humans. Cd compounds, which do not have any recognizable taste or odor, are often found in, or attached to, small particles present in air. Most Cd used in the United States (U.S.) is extracted as a byproduct during the processing of other metals such as Zn, Pb, or Cu. Cd has many uses in industry and consumer products, such as in batteries, pigments, metal coatings, plastics, and some metal alloys. This article addresses human exposure to Cd, the exposure pathways for Cd in the human body, and the potential health effects of such exposures. The article also presents a discussion of the public health impacts of Cd exposure and the mitigation of risks from exposure.

Sources of Exposure to Cadmium Fish, plants, and animals can be exposed to Cd through air, water, or food. Soils and rocks contain varying amounts of Cd; approximately 30 000 tons of Cd are released to the environment each year, with roughly half from the weathering of rocks into rivers and then to the oceans (Thorton, 1992). Anthropogenic sources of Cd from mining activities and burning of fossil fuels and household waste, such as NiCd batteries, are responsible for 4000–13 000 tons released per year (Hutton, 1983). Forest fires and volcanoes also discharge Cd to the air; atmospheric transport of Cd attached to small particulate matter contributes to deposition in remote regions, such as the Arctic, where there are few local Cd sources (Nriagu, 1990). A lack of infrastructure to properly dispose of electronic equipment and batteries, as well as open burning of waste products containing Cd, could contribute as an important source in some developing countries (Nriagu, 1990). Cd present in water may bind to soil, remain in water, or be taken up by plants (Muntau and Baudo, 1992). Fertilizers often contain Cd that can enter the soil when applied to crops. Cd can also enter the soil or water from spills or leaks at hazardous waste sites. Cd metal does not breakdown in the environment, but it can change into different forms. Most forms

316

of Cd have long environmental half-lives and may persist in media for long periods.

Pathways of Human Cadmium Exposure Cd can enter the human body through consumption of food and water and by inhalation of particles in the air or cigarette smoke. For ingestion route exposures, diet is a major Cd exposure pathway in most human populations worldwide. Drinking water, though, is a much less significant source of Cd in the United States. Cd that is not absorbed into the body from food or water leaves the body slowly in urine and in feces. Most of the Cd that enters the body distributes to the kidney and liver and can remain there for many years. The human body can change most Cd into a form that is not harmful; however, too much Cd can overload the capacity of the liver and kidneys to transform Cd. Virtually no Cd enters the human body through skin. The biological half-life of Cd in humans is lengthy; Cd can remain in the human body 13–47 years. Both Cd tissue concentration and total body burden tend to increase in concentration with age (Hammons et al., 1978).

Ingestion Average Cd levels in U.S. foods range from 2 to 40 parts of Cd per billion parts of food (2–40 ppb). The lowest levels are found in fruits and beverages; the highest levels are found in leafy vegetables and potatoes. The level of Cd in most drinking water supplies is less than 1 ppb, which is well below the drinking water standard of 50 ppb. Levels in drinking water, however, may vary greatly depending on local conditions. The average level of Cd in unpolluted soil is about 250 ppb. At hazardous waste sites, Cd has been measured in soil at 4 ppm and in water at 6 ppm. At the 2005 meeting of the Joint FAO/WHO Expert Committee of Food Additives, data on Cd levels in seven commodity groups reported from around the world to the Global Environmental Monitoring System (GEMS) was analyzed (WHO, 2005). The evaluation included rice, oysters, other mollusks, wheat, stem/root vegetables, leafy vegetables, other vegetables, and potatoes. Total intakes from regional diets in the GEMS database ranged at 2.8–4.2 mg kg
1 body weight per day (mg kg
1 day); this is roughly 3–4 times the Provisional Tolerable Weekly Intake of 1 mg kg
1 day. The

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Cadmium Third National Report on Human Exposure to Environmental Chemicals conducted by estimates that the mean lifetime Cd exposure to adults in the United States from food only is estimated to be approximately 0.14 mg kg
1 day.

Inhalation Air levels of Cd in major U.S. cities range from less than 1– 40 ng per cubic meter (ng m
3), although levels greater than 40 ng m
3 may occur in urban areas with high levels of air pollution from the burning of fossil fuels. Inhalation exposures from smoking cigarettes are a more serious health concern than Cd in food. Smokers may be exposed to roughly twice the daily intake of Cd compared with nonsmokers. Uptake of Cd via the inhalation route in humans can be considerable (i.e., 10–50%), with as much as 60% transferred to the GI tract through mucociliary clearance. Mucociliary clearance refers to the mechanical elimination of foreign substances from the respiratory tract through ciliary function and airway surface fluid secretion. Assuming that a cigarette contains from 1 to 2 mg of Cd (WHO, 1992), there are 20 cigarettes in a pack and the upper bound of inhaled Cd absorption is 0.5: inhaled Cd equals 20 mg Cd per pack (2 mg Cd/cig $ 0.5 $ 20 cig/pack) multiplied by 0.6 transfer to GI tract translates that smokers may take in an additional 12 mg of Cd into their body per day from each pack of cigarettes smoked. Aside from smokers, individuals living near hazardous waste sites or factories that release Cd into the air have the potential for increased exposure to Cd in air. However, numerous state and federal regulations control the amount of Cd that can be released into the air from waste sites and incinerators. In the United States, Cd is regulated by the Environmental Protection Agency (EPA) and some states under the Clean Water Act’s National Pollutant Discharge Elimination System and General Pretreatment Regulations. EPA offices overseeing regulations and guidelines applicable to Cd include the Offices of Air Quality Planning and Standards; of Drinking Water; of Toxic Substances; of Solid Waste; of Pesticide Programs; and of Emergency and Remedial Response. The general population and people living near hazardous waste sites may be exposed to Cd in contaminated food, dust, or water from unregulated releases or accidental releases. Approximately 512 000 workers in the United States may be exposed to Cd in air from smelting and refining of metals or from the air in factories that make Cd products such as batteries, coatings, or plastics (OSHA, 2004). Workers can also be exposed when soldering or welding metal that contains Cd. The Occupational Safety and Health Administration (OSHA) sets two 8-h time-weighted average permissible exposure limits (TWA PEL) of 5 and 1 mg-Cd m
3-air to protect workers and ensure that occupational levels of Cd in the air are considerably below levels thought to result in harmful effects (OSHA, 2004).

Human Health Effects of Cd General Health Effects Studies by Friberg et al. (1986) and Cleveland and Draggan (2007) have established that excess Cd exposure produces

317

adverse health effects on human beings. Though Cd accumulates in the liver and kidneys, it can also be deposited in other organs and tissues, depending on its chemical form (inorganic or free). A determinant of Cd toxicity is the constitutive and inducible nature of the protein metallothionein (MT), which exists as three isoforms in humans. MT is ubiquitous in animals and has a high binding capacity for Cd and other divalent metals such as zinc (Zn) and copper (Cu). MT plays an important role in the human placenta by serving as a partial barrier to Cd transfer to the fetus. The mammary glands may also serve as a partial barrier. Iron (Fe) deficiency plays an important role in Cd absorption. Studies on both rodents (Cleveland and Draggan, 2007) and humans have conclusively shown that Cu deficiency results in increased Cd absorption. A Cd–MT complex is formed in the liver but may be released to the blood (e.g., hepatic damage) and transported to the kidney, thus potentially causing nephrotoxicity. Cd–MT complexation, however, is considered a protective mechanism against hepatoand nephrotoxicity. Renal damage is believed to occur when Cd dissociates from MT during proteolysis.

Cancer The EPA has classified Cd as a probable human carcinogen based on sufficient evidence of carcinogenicity in rats and mice by inhalation and intramuscular and subcutaneous injection (EPA, 1992). Increased risk of lung and prostate cancer has been linked to occupational exposure to Cd. Many of the reported studies did not control for confounding factors, such as smoking, alcohol intake, and co-exposure to other metals such as nickel (Ni) and arsenic (As). Occupational studies reported in countries other than the United States have found some increases in lung cancer but no clear relationship between level and duration of Cd exposure and increased risk of lung cancer (see ATSDR in the Relevant Websites section). The exposed workers in the cohorts study were from an English Zn-Pb-Cd smelter, from 17 different manufacturing or processing facilities involving Cd in England, from a nickel-Cd battery plant in Sweden, and from a nickel-Cd battery plant in England. These data, however, suggest a lower relative risk in the groups exposed to Cd in the absence of As and Ni. Human evidence also exists for Cd-induced carcinogenesis in the prostate, kidney, pancreas, liver, and other organs. In rodents, Cd has been associated with tumor induction by various routes at various sites concordant with sites in humans. Testicular tumors in rats, however, are thought to arise from early toxic lesions as opposed to a specific carcinogenic effect. Studies in worker populations in Europe exposed to Cd indicated an elevation of prostrate cancer, but subsequent investigations found either no increases in prostate cancer or increases that were not statistically significant (ATSDR, 2004). However, any positive correlation between Cd and prostate cancer may be partially masked by the relatively high incidence of prostate cancer in the general population and the low numbers of prostate cancer deaths in the cohorts studied. In particular, studies based on mortality incidence may not be sufficiently sensitive because increased screening for prostate cancer in exposed populations could lead to increased survival.

318

Cadmium

No exposure–response relationship between cumulative exposure to Cd and lung cancer was found in the most recent follow-up of the cohort of 869 Swedish battery workers exposed to Cd oxide. A series of studies conducted (ATSDR, 2004) on a cohort at an American smelter in Colorado that had been used for both As and Cd reported an increase in lung cancer deaths related to cumulative Cd exposure. None of these studies have eliminated the possibility of either As or smoking as confounders, both of which are strongly associated with lung cancer mortality.

Non-cancer Health Effects Ingestion of Cd by the oral route is not an immediate threat because high doses are irritating enough to induce vomiting. The only known fatalities are reported to be associated with intentional ingestion of high doses of Cd. In contrast, inhalation exposure to high doses of Cd can be particularly dangerous because early symptoms are often as mild as those associated with low-levels of exposure, thus possibly prolonging the period of exposure until a harmful event or a fatal dose is observed. The critical effect following chronic exposure of humans to Cd was found to be proteinuria resulting from damage to the proximal tubule cells of the kidney. The progression of Cd-induced nephropathy in humans is as follows: Cd–MT in blood is filtered at the glomerulus into the urine. Essentially all of the filtered Cd–MT is reabsorbed by pinocytosis into proximal tubule cells in the renal cortex and MT is catabolized by lysosomes, releasing the free Cdþ2. Free Cd then stimulates the production of MT in proximal tubule cells, and the Cd–MT remains in the cells; although the free Cd ion is toxic to these cells, intracellular Cd–MT apparently is not. During chronic exposure, Cd accumulates in the kidneys, which may eventually account for more than one-third of the body burden of Cd. When the level of Cd in the renal cortex exceeds the critical concentration, there is a rapid increase in the level of unbound Cd in proximal tubule cells. Unbound Cd nonspecifically binds to other intracellular ligands, including metalloenzymes. Although the toxicological mechanism of action of unbound Cd on proximal tubule cells is not known, it may initially involve Cd displacement of Zn from metalloenzymes involved in cellular metabolism. In addition, Cd may destabilize proximal tubule cell membranes, resulting in decreased resorption of filtered substances and increased urinary excretion of low-molecular-weight proteins, amino acids, glucose, and calcium. Destruction of proximal tubule cells releases intracellular components including enzymes and MT into the filtrate; increased urinary excretion of these substances are biomarkers of proximal tubule damage. Chronic exposure of humans to Cd in the workplace or environment has resulted in debilitating bone changes, including osteoporosis, osteomalacia, and spontaneous bone fractures (Kazantzis, 1979). Cd may cause these effects through a direct action on bone, or the effects may be secondary to Cd-induced alteration of renal metabolism of vitamin D and decreased tubular resorption of calcium, both leading to loss of calcium and phosphate from bone. Cd could also be shown to be associated with occurrences of Itai-Itai disease, in which

patients show a wide range of symptoms such as: low grade of bone mineralization, high rate of fractures, increased rate of osteoporosis, and intense bone-associated pain (Jarup et al., 1998). Oral exposure to Cd has produced neurological effects in animals characterized by changes in behavior, neurotransmitter levels, and histological effects in the brain. The mechanism of action for Cd neurotoxicity may be a suppression of neurotransmitter release, possibly by a Cd-induced decrease in the influx of calcium into the nerve terminal following an action potential. However, overall the data are inadequate to assess whether Cd is likely to cause neurological effects in humans at exposures near those causing renal effects. Oral exposure of animals to Cd has resulted in decreases in hemoglobin levels and hematocrit in some studies, but not in others (ATSDR, 2004); a similar situation exists for data regarding the effects of Cd on the hematological system in humans. A possible mechanism for this effect of Cd is the inhibition of Fe absorption. The inconsistency in the results observed in different studies may be related to iron content in the diets. In addition, exposure of animals to Cd has been shown to result in respiratory, cardiovascular, gastrointestinal, hepatic, developmental, and reproductive (i.e., testicular) effects. However, many of these toxic effects were induced in animals by using routes of exposure and/or exposure levels and experimental conditions not relevant to human environmental exposure scenarios. In addition, some of these effects are observed in animals but not in humans. Thus, these effects may not be sensitive endpoints of Cd toxicity in humans. The EPA reference dose (RfD) for the critical effect of significant proteinuria from chronic oral exposure from water is 5  10
4 mg kg
1 day (EPA, 1992). The Rfd for human studies involving chronic exposures from food is 1  10
3 mg kg
1 day (EPA, 1992).

Public Health Implications Cd is a cumulative toxicant for which the human exposure conditions of most concern are long-term exposure to inhaled Cd in cigarette smoke and elevated Cd levels in the diet. For populations living in close proximity to hazardous waste sites, increased dietary consumption could occur from Cd-contaminated dust on food or hands, from garden vegetables or fruit grown in Cd-contaminated soil, and from Cd-contaminated water used for drinking or garden irrigation. Fugitive dust emissions from Cd-contaminated soil could expose such populations by the inhalation route. Currently there is insufficient information to assess potential absorption or toxicity of Cd from the dermal route of exposure. Advances in analytical chemistry have allowed for the measurement of Cd in blood and urine, giving public health-care providers the ability to determine whether people have been exposed to higher levels of Cd than those found in the general population. These biomarker data also will help scientists plan and conduct research about Cd exposure and health effects.

Cadmium

See also: Carcinogens, Environmental; Environmental Health: Overview; Environmental Protection Laws; Hazardous Wastes; Human Exposure Science; Human Health Risk Assessment; Occupational Health: Overview.

References ATSDR, 2004. Interaction Profile for Arsenic, Cadmium, Chromium, and Lead. Agency or Toxic Substances and Disease Registry. U.S. Department of Health and Human Services, Atlanta, Georgia. Cleveland, C.J., Draggan, S., 2007. Health effects of cadmium. In: Cleveland, C.J. (Ed.), Encyclopedia of Earth, revised ed., Environmental Information Coalition. National Council for Science and the Environment, Washington, DC. Environmental Protection Agency (EPA), 1992. Integrated Risk Information System (IRIS): Cadmium. U.S. EPA, Office of Research and Development, Washington, DC (CASRN 7440–43–9). Friberg, L., Elinder, C.G., Kjellstrom, T., et al. (Eds.), 1986. Cadmium and Health: A Toxicological and Epidemiological Appraisal. Effects and Response, vol. 12. CRC Press, Boca Raton, FL. Hammons, A.S., Huff, J.E., Braunstein, H.M., et al., 1978. Reviews of the Environmental Effects of Pollutants: IV, Cadmium. U.S. EPA, Washington, DC, p. 251. Rep. 600/1–78–026. Hutton, M., 1983. Sources of cadmium in the environment. Ecotoxicol. Environ. Saf. 7 (1), 9–24. Jarup, L., Alfven, T., Persson, B., Toss, G., Elinder, C.G., 1998. Cadmium may be a risk factor for osteoporosis. Occup. Environ. Med. 55 (7), 435–439.

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Kazantzis, G., 1979. Renal tubular dysfunction and abnormalities of calcium metabolism in cadmium workers. Environ. Health Perspect. 28, 155–159. Muntau, H., Baudo, R., 1992. Sources of cadmium, its distribution and turnover in the freshwater environment. IARC Sci. Publ. 118, 133–148. Nriagu, J.O., 1990. Global metal pollution: poisoning the biosphere? Environment 1990, 6–11. Occupational Safety and Health Administration (OSHA), 2004. Cadmium. OSHA Publication, 3136–06R. http://www.osha.gov/Publications/osha3136.pdf (accessed December 2007). Thorton, I., 1992. Sources and pathways of cadmium in the environment. IARC Sci. Publ. 118, 149–162. U.S. Centers for Disease Control and Prevention (CDC), 2005. Third National Report on Human Exposure to Environmental Chemicals. http://www.cdc.gov/exposurereport/ pdf/thirdreport.pdf (accessed December 2007). World Health Organization (WHO), 1992. Environmental Health Criteria 134 – Cadmium International Programme on Chemical Safety (IPCs) Monograph. WHO, Geneva, Switzerland. World Health Organization (WHO), 2005. Joint FAO/WHO Nutrient Risk Assessment Workshop: A Model for Establishing Upper Levels of Intake for Nutrients and Related Substances. www.who.int/entity/ipcs/features/en/ (accessed December 2007).

Relevant Websites http://www.atsdr.cdc.gov/toxprofiles/tp5.pdf – The Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profile for Cadmium. http://www.atsdr.cdc.gov/interactionprofiles/IP-metals1/ip04.pdf – ATSDR Interaction Profile for Arsenic, Cadmium, Chromium, and Lead.

Canada, Health System of GP Marchildon, University of Regina, Regina, SK, Canada Ó 2017 Elsevier Inc. All rights reserved.

Introduction Canada is a high-income country that enjoys one of the world’s highest Human Development Index rankings. The burden of disease is among the lowest in the world even though Canada’s ranking, based on health-adjusted life expectancy (HALE), slipped from second place in 1990 to fifth position by 2010 (Murray et al., 2013). The Canadian health system reflects the inherent complexity and diversity of a country covering the second largest landmass in the world (Figure 1). In addition to its original Aboriginal inhabitants and official language communities of French and English, the population is made up of immigrants, many recent, from virtually every part of the globe. Most live in large urban centers that hug the southern

Figure 1

320

border with the United States but vibrant communities, some predating European colonization, are sprinkled throughout the 10 provinces in the south and three territories in the far north. Canada is a constitutional monarchy based on a parliamentary system in the British tradition and, similar to Australia, it is a federation with two constitutionally recognized orders of government. The federal government is responsible for certain aspects of health and pharmaceutical regulation and safety, data collection, biomedical, clinical and other research funding, and some health services and coverage for designated First Nation and Inuit populations. The second order of government consists of 10 provincial governments mainly responsible for a broad range of health programs and services including

Atlas of Canada. Source: Atlas of Canada, Natural Resources Canada.

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Canada, Health System of the provision of universal coverage for medically necessary hospital and physician services known as Medicare in Canada. In most provinces, health services are organized and delivered by public bodies known as regional health authorities that have been legislatively delegated to provide hospital, long-term and community care as well as improve population health within defined geographical areas.

While provincial governments play a dominant and direct role in the financing and administering of health care, they have a more arm’s-length role in the delivery of many public health-care services. Most physicians, for example, are responsible for their own private practices and clinics, and receive their remuneration through a fee schedule negotiated between these governments and the provincial medical associations. Most of the health professions are self-regulated under provincial government laws that set out a general framework under which the professions operate. Many health facilities, including nursing homes and other long-term care institutions, home care and community care organizations, medical laboratories, and diagnostic clinics are privately owned and administered. The majority are community-based not-for-profit organizations but some are private for-profit enterprises conducted on a commercial basis. Figure 3 illustrates the extent to which services are delivered privately in the Canadian system even when such services are publicly funded and administered (Figure 4). Until recently, almost all hospitals in Canada were owned and administered at the local level by municipalities or private not-for-profit corporations, including religious-based organizations. However, some (but not all) of these hospitals have recently been subsumed by new public arm’s-length organizations known as regional health authorities (RHAs), which were established by the provinces beginning in the late 1980s.

Political and Administrative Organization The provinces and northern territories of Canada cover a land area of about 10 million km2. Under the constitution of Canada, the provinces have the primary jurisdiction over health care. As a consequence, provincial governments are mainly responsible for the financing and administering of public health care in Canada. To enforce and uphold the Canada Health Act, the federal government makes cash transfers to the provinces, portions of which it can deduct from the transfers to provinces if they permit or encourage facilities or physicians to charge user fees for medically necessary and/or required services or breach the five broad principles of public administration, comprehensiveness, universality, portability, and accessibility as defined in the Canada Health Act (Figure 2).

Canadian Constitution

Provincial and Territorial Governments

Regional Health Authorities

Mental Health and Public Health Providers

Transfer payments

Ministers and Ministries of Health

Home Care and Long-term Care Providers

FederalProvincialTerritorial Conferences & Committees

Statistics Canada

Federal Government

Canadian Institutes for Health Research

Minister of Health

Canada Health Act, 1984

Hospital and Medical Services Providers

Health Canada

Public Health Agency of Canada

Patented Medicine Prices Review Board

Provincial and Territorial Prescription Drug Programs

Canadian Agency for Drugs and Technologies in Health (1989)

Canadian Institute for Health Information (1994)

Health Council of Canada (2003–2013)

Canadian Blood Services (1996)

Figure 2

Political organization of the Canadian health-care system.

321

Canada Health Infoway (2001)

Canadian Patient Safety Institute (2003)

322

Canada, Health System of

Funding

Administration Universal, singlepayer provincial systems. Private self-regulating professions subject to provincial legislative framework

Delivery

Public Canada Health Act services (hospital and physician services plus) and public health services

Public taxation

Mixed goods and service, including most prescription drugs, home care, and institutional care services

Public taxation, private insurance, and out-ofpocket payments

Public services that are generally welfare-based and targeted, private services regulated in the public interest by governments

Private professional, private not-forprofit and forprofit, and public arm’slength facilities and organizations

Private goods and services including most dental and vision care as well as overthe-counter drugs and alternative medicines

Private insurance and out-of-pocket payments including full payments, copayments, and deductibles

Private ownership and control; private professions, some self-regulating with public regulation of food, drugs, and natural health products

Private providers and private forprofit facilities and organizations

Private professional, private not-forprofit, privatefor-profit, and public arm’slength facilities and organizations

Figure 3 Matrix of funding, administration, and delivery. Reproduced from Marchildon, G.P., 2005. Health systems in transition: Canada. World Health Organization on behalf of the European Observatory on Health Systems and Policies, Brussels, p. 120.

This change, commonly referred to as regionalization in Canada (see Table 1), involved the provincial governments carving up their respective territories into geographic regions and then creating RHAs to administer the delivery of a continuum of health services, from hospitals and nursing Private health insurance 12.8%

Other 2%

Out of pocket 14.7%

Taxation 70.5%

Figure 4 Revenue sources for total health expenditures in Health Canada (2003). Reproduced from Canadian Institute for Health Information (CIHI), 2005 National Health Expenditure Trends, 1975–2005. Canadian Institute for Health Information, Ottawa.

homes to home care and public health to the population resident in these regions. As arm’s-length public organizations established under provincial law, RHAs have a mandate to meet the health needs of the populations within their boundaries as both purchasers and providers of services. The type and extent of services purchased from independent facilities or professionals vary considerably among RHAs and among provinces. As can be seen in Table 1, the number of RHAs varies considerably with two provinces having RHAs that cover the entire provincial population and two territories in which regionalization was never established. Since RHAs are delegated authorities with a law-making or regulatory capacity, provincial governments regulate health facilities and organizations. However, health-care organizations, including independent hospitals and long-term care facilities as well as RHAs are accredited on a voluntary basis through Accreditation Canada, a membership-based non-governmental body. Most health professions, including physicians and nurses, are self-regulating based on provincial and territorial framework laws. Six provincial governments have established health quality councils to work with health providers and health organizations (including RHAs) to improve quality and safety. However, no provincial quality council has been given the mandate to regulate quality or set enforceable standards.

Canada, Health System of Table 1

323

Population (in thousands) and regionalization in Canadian provinces and territories, 2013

Province or Territory

Total population

% of total population in Canada

Year regionalization first established

British Columbia Alberta Saskatchewan Manitoba Ontario Québec New Brunswick Nova Scotia Prince Edward Island Newfoundland and Labrador Yukon Northwest Territories Nunavut

4582.0 4025.1 1108.3 1265.0 13 538.0 8153.3 756.1 940.8 145.2 526.7 36.7 43.5 35.6

13.0 11.4 3.2 3.6 38.5 23.2 2.2 2.7 0.4 1.5 0.1 0.1 0.1

1997 1994 1992 1997 2005 1989 1996 1992 1993 1994

Although the provincial governments are responsible for administering most publicly funded health care in Canada, the federal government nonetheless plays a critical role in health care beyond upholding the broad principles and conditions under the Canada Health Act. These other activities include: funding health research; collecting health data through Statistics Canada; financing and administering health services for First Nations people and Inuit, inmates of federal penitentiaries, war veterans, and active members of the Canadian armed forces; as well as regulating the pharmaceutical and natural health products industries. In 2000, the federal government replaced the Medical Research Council with the Canadian Institutes of Health Research (CIHR), which in turn, is made up of 13 funding bodies supporting research on Aboriginal peoples’ health, aging, cancer, circulatory and respiratory disease, gender, genetics, health services and policy, human development, children and youth, infection and immunity, metabolism and diabetes, neurosciences including mental health and addiction, and population and public health. Through CIHR funding of both investigator-driven as well as more government-driven strategic research, the federal government’s original objective was to make Canada one of the top five health research nations in the world.

Intergovernmental Collaboration in Health Regulation, Planning, and Policy Due to the decentralized nature of the Canadian federation, federal, provincial and territorial governments rely on intergovernmental collaboration to administer, deliver, and reconfigure public health care. At the apex of this collaboration is the Conference of Federal-Provincial-Territorial Ministers of Health as well as a mirror committee of deputy ministers of health (O’Reilly, 2001). In addition to this committee structure, intergovernmental organizations with specific health-care mandates and varying degrees of independence from their sponsoring governments have been established in recent years. These organizations are shown at the base of Figure 2.

1997

Number of RHAs 5 1 13 5 14 18 2 8 1 4 0 8 0

The federal government regulates the safety of food and pharmaceutical products through Health Canada and the Food and Drugs Act, and the prices of patented pharmaceutical products through the Patented Medicine Prices Review Board. In 2004, the federal government, through the Natural Health Products Directorate in Health Canada, began regulating and approving traditional herb products, vitamins and mineral supplements, and homeopathic preparations. Since the provincial governments operate their own prescription drug programs, most of which are categorical programs targeting seniors and the poor, they in turn attempt to control cost by limiting the number and type of pharmaceuticals placed on provincial formularies. Some provinces have instituted reference-based pricing policies, in which only the lower-cost therapeutic alternative is subsidized in full by the provincial drug plan. To manage the jurisdictional and policy overlaps in pharmaceutical regulation, the federal and provincial governments work through an intergovernmental body known as the Canadian Agency for Drugs and Technologies in Health (CADTH). Conducting clinical- and cost-effectiveness studies under a Common Drug Review, CADTH makes formulary listing recommendations to all provincial governments with the exception of Quebec. Through the Canadian Optimal Medication Prescribing and Utilization Service, CADTH promotes evidence-based best practices in pharmaceutical prescribing and use. Finally, CADTH conducts a major health technology assessment program for a broad range of prescription drugs, medical devices, and other similar health technologies to assist all jurisdictions in decisions concerning the purchase of new health technologies on the basis of both clinical and cost-effectiveness. The Canadian Institute for Health Information (CIHI) was established in 1994 to coordinate the gathering and dissemination of health data previously done by jurisdictions in isolation of each other. CIHI’s core functions include identifying national health indicators, coordinating the development and maintenance of national information standards, developing and managing health databases and registries, as well as conducting and disseminating basic research and analysis. In its work, CIHI cooperates closely with Statistics Canada, a federal

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government agency which enjoys an international reputation for the gathering and dissemination of population health data. Since the late 1990s, Canadian governments have collaborated in the establishment of a number of new intergovernmental health organizations. These include Canadian Blood Services, which was set up by the provinces and territories in response to a major ‘tainted blood’ controversy surrounding the safety of the country’s blood supply as then managed by the Canadian Red Cross. Established in 2001, Canada Health Infoway emerged out of the desire of federal, provincial, and territorial ministers of health to accelerate the development of electronic health records in all jurisdictions. In 2003, the Health Council of Canada was created to provide both an assessment of progress in priority areas of health reform, as identified by the prime minister and the premiers of the provinces and territories, as well as make recommendations for future health reform on a national basis. Beginning its work in 2005, the Canadian Patient Safety Institute was established to provide systematic evidence on medical errors and initiate change to improve patient safety throughout Canada.

Health-Care Expenditures and Financing Approximately 70% of health expenditures are financed through public taxation while a further 30% are financed out of pocket or through private health insurance mainly in the form of employment benefit packages. Every provincial and territorial government provides universal coverage for medically necessary hospital and physician services. These 13 governments act as single payers in ensuring that their respective residents receive such services free at the point of service. This universal coverage is portable for all Canadians. Provincial governments are responsible for raising roughly 80% of the revenues for their own health expenditures. The remaining 20% comes from the federal government through the Canada Health Transfer which is used to encourage compliance with the five principles of the Canada Health Act and discourage provincial governments from allowing user fees for medically necessary hospital and physician services. Provincial tax revenues come from a number of sources including individual income taxes, consumptions taxes and corporation taxes. In those provinces such as Alberta that have abundant natural resources, resource royalties (taxes) and fees form a significant source of revenue. Consistent with being a tax-based Beveridge-style national health system (and unlike social health insurance systems), the Canadian health system, there is limited pooling of funds in the Canadian system. However, there is a type of pooling through cash transfers from the federal government which collects taxes at the national level, to the provincial governments, and from the provincial governments (which pool federal cash transfers with own-source revenues) to regional health authorities or other health-care organizations which have no autonomous powers of taxation.

Health Human Resources Government spending on the health workforce has climbed steadily since the turn of the century causing higher than

average inflation (CIHI 2011). Medical, nursing and other health profession faculties have expanded their university seats to produce more graduates, even while an increasing number of foreign-education doctors and nurses have moved to Canada. What has generally been perceived as a health human resource shortage since the mid-1990s may yet become a surplus over the next few years. With the exception of physicians, most health professionals and workers are employees of health-care organizations and are remunerated through salary and wage income. The majority of health workers, including nurses, are members of public sector unions with remuneration and working conditions negotiated through collective bargaining. Almost all physician remuneration is paid through fee-for-service or alternative payment agreements negotiated with provincial governments.

Delivery and Reform of Health Services All provincial and territorial governments have public health programs. They also conduct health surveillance and manage epidemic response. While the Public Health Agency of Canada develops and manages programs supporting public health programs at the provincial, regional and local community levels, the stewardship for most day-to-day public health activities and supporting infrastructure remains with the provincial and territorial governments. Most primary care is provided by GPs and family physicians, with family medicine recently recognized as a specialization by the Royal College of Physicians and Surgeons of Canada. Although mandated through policy and practice rather than law, GPs/family physicians act as gatekeepers, deciding whether patients should obtain diagnostic tests, prescription drugs or be referred to medical specialists. Provincial ministries have renewed efforts to reform primary care in the last decade. Many of these reforms focus on moving from the traditional physician-only practice to interprofessional primary teams capable of providing a broader range of primary health care. Almost all acute care is provided in public or private non-profit hospitals although specialized ambulatory and advanced diagnostic services are sometimes provided in private-for-profit clinics, particularly in larger urban centers. Most hospitals have an emergency department that is fed by independent emergency medical service units providing first response care to patients while being transported to the hospital. Due to the scattered nature of remote communities without secondary and tertiary care, provincial and territorial governments provide air-based medical evacuation, a major expenditure item for the most northern jurisdictions (Marchildon and Torgerson, 2013). Long-term care services, including supportive home and community care, are not classified as insured services requiring universal access under the five national criteria set out in the Canada Health Act. As a consequence, public policies, subsidies, programs and regulatory regimes for long-term care vary considerably among the provinces and territories. Facility-based long-term care (LTC) ranges from residential care with some assisted living services to chronic care facilities (originally known as nursing homes) with 24-h a day nursing supervision. Most residential care is privately funded whereas

Canada, Health System of high-acuity LTC is heavily supported by provincial and territorial governments (Canadian Healthcare Association, 2009). Until the 1960s, the locus of most mental health care was in large, provincially run psychiatric hospitals which in turn had evolved out of the nineteenth-century asylum and the twentieth-century mental hospital. With the introduction of pharmaceutical therapies and a greater focus on reintegration into the community, mental health conditions have since been mainly treated on an outpatient basis or, in the case of severe episodes, in the psychiatric wards of hospitals. GPs provide the majority of primary mental health care in part because medical care is an insured service with first dollar coverage whereas psychological services are provided largely on a private basis. Almost all dental care is delivered by independent practitioners and 95% of these services are paid privately. Dental services are paid for through private health insurance – provided mainly through employment-based benefit plans – or out-of-pocket. As a consequence of access being largely based on income, outcomes are highly inequitable. For historical reasons, the federal government finances a host of health service programs targeting Aboriginal Canadians, in particular eligible First Nation and Inuit citizens. These services include health promotion, disease prevention and public health programs as well as coverage for medical transportation, dental services and prescription drug therapies. Despite these targeted efforts, the gap in health disparity between these Aboriginal citizens and the majority society remains large. Since the 1990s, there have been a series of health funding transfer agreements between the federal government and First Nation governments – largely based on reserves in rural and remote regions of Canada. At the same time, there has been an Aboriginal health movement advocating for a more uniquely Aboriginal approach to health and health care (Marchildon, 2013).

Public Health Public health can be defined as the science and art of promoting health, preventing disease, and prolonging life through policies and programs that focus on the population as a whole. The implicit contrast is with health-care policies, the main focus of which is on treating already ill or injured individuals. Today, public health in Canada is generally identified with six discrete functions: (1) disease and injury control at the population level, (2) health protection at the population level, (3) emergency preparedness and response, (4) surveillance, (5) population health assessment, and (6) health promotion. Before the introduction of universal hospital insurance in the 1950s, and universal physician care insurance in the 1960s – together referred to as Medicare – public health programs and services, at least those concerned with infectious disease control and public health and safety, constituted the main health-care responsibilities of all governments in Canada. This was reflected in the names of the departments that emerged in the early twentieth century – almost all were officially designated as departments of public health. At the same time, however, the work of such departments was largely

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limited to treating and preventing infectious diseases on a population basis as well as recording vital statistics such as births and deaths. With the introduction of Medicare, the responsibilities of departments and ministers of public health were greatly expanded. At the same time, the provincial departments of health, as they were renamed, increasingly assumed the public health responsibilities of cash-strapped and tax-poor municipalities. Only larger urban centers in Canada were able to provide their inhabitants with public health services including infectious disease control and the administration and enforcement of health and safety standards. The definition of public health, and along with it the role of government, did not change or expand fundamentally until the emergence of the determinants of health approach in the 1970s and 1980s, and the introduction of regionalization in most provinces in the 1990s. Although health scholars and program decision makers were aware of the impact of living standards, education, employment, and healthy lifestyles on health outcomes, as well as the elimination of financial barriers to Medicare for all necessary treatment and the marginal influence of illness care on the ultimate health of a population, it took considerable time for the full policy implications of this basic insight to be systematically examined. In 1974, Marc Lalonde, the federal minister of the Department of National Health and Welfare, released a working report entitled A New Perspective on the Health of Canadians (Lalonde, 1974). Although it attracted little media attention at the time, the four-quadrant health field concept at the center of the Lalonde report would prove to be exceptionally influential not only in Canada but throughout the world, in large part because of its emphasis on the impact of lifestyle and environmental factors as major determinants of health alongside the long-emphasized factors of human biology and health care. The Lalonde report was the product of a group of policy thinkers in the Long Range Health Planning Branch of the federal department of health. For its 8-year existence, the branch operated more like a think tank than a bureaucratic unit within government (McKay, 2000). The reasoning behind the Lalonde Report was subsequently used to support the federal government’s decision to loosen the conditions on transfer funding in 1977 and to reduce the rate of growth of such transfers by the early 1980s. At the same time, a new Health Promotion Directorate within the federal Department funded and supervised cost-shared projects with citizen groups to pilot the new approach to health determinants. Although the projects at the local, regional, and national level initially focused on encouraging lifestyle changes, they eventually targeted larger societal and structural changes. This work had a profound impact on Health and Welfare Canada’s Framework for Health Promotion as well as the major contributions of Canada to the World Health Organization’s first international conference on health promotion and the release of the Ottawa Charter for Health Promotion, both of which appeared in 1986 (Epp, 1986; Boyce, 2002). Despite these advances, Canada’s more traditional system of public health remained highly fragmented, poorly coordinated, and poorly funded by federal, provincial, and local governments. As a consequence, it did not fare well when faced with its first major crisis of the twenty-first century.

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In 2003, Canadians were caught by surprise with a major outbreak of severe acute respiratory syndrome, or SARS. By August of that year, there were 400 probable and suspect SARS cases in Canada, as well as 44 deaths in the greater Toronto area. Health-care workers were among the most vulnerable and 3 of the 100 SARS-infected health-care workers ultimately died. As the hardest-hit country outside of the Asian continent, Canada became the focus of international attention, with the World Health Organization recommending against nonessential travel to Toronto for almost a month during the worst part of the crisis. As a consequence of the problems of coordination and communication associated with the public health response by the city of Toronto and the governments of Ontario and Canada, Health Canada established a National Advisory Committee on SARS and Public Health chaired by Dr David Naylor of the University of Toronto. The mandate of the Naylor Committee went beyond recommendations on how to organize responses to infectious diseases crises in the future to providing directional recommendations on the future of public health in Canada. Influenced by the coordinating function of the Centers for Disease Control and Prevention (CDC) in the United States, the Naylor Committee recommended the establishment of a national public health agency in Canada (Health Canada, 2003). The federal government established the Public Health Agency of Canada (PHAC) in 2004. Although created as a government department separate from Health Canada, PHAC reports directly to the federal Minister of Health and is headed up by a Chief Public Health Officer. Although cities, provincial governments, and RHAs have long had chief public health officers, this was the first national officer for the country as a whole.

Health Status and Health System Outcomes Similar to many other high-income countries, Canada has experienced major increases in life expectancy. While both men and women have enjoyed a decline in the mortality rate, the adult male rate declined by almost 43% between 1980 and 2005. Heart disease and cancer (malignant neoplasms) have alternated as the main cause of death. Among the cancers, lung cancer is the most prevalent killer. Ischaemic heart disease remains the most important cardiovascular contributor to death (Marchildon, 2013). As the Lalonde Report points out, many if not most of the factors influencing health are outside the health-care system. Lifestyle and environmental factors both play a significant role in shaping an individual’s diet as well as risky behaviors in terms of alcohol, tobacco, and other drug consumption. Tobacco consumption has fallen by almost 50% since the early 1980s, a result in part of aggressive anti-tobacco initiatives by the federal and provincial governments and fundamental changes in attitudes and lifestyle behaviors by Canadians. Though not as dramatic, alcohol consumption has also fallen over the same period, again in part the result of attitudinal and behavioral changes. However, Canadians have been increasing their intake of calories, apparently the

result of greater reliance on prepared foods from both supermarkets and restaurants, which tend to have higher fat content. As a consequence, the rate of obesity has also gradually climbed, particularly among children and teenagers (CIHI, 2004).

Conclusion and Assessment Canada’s relatively high ranking in terms of health status is due to a number of factors including relatively low disparities in socioeconomic status and access to health care. When compared to the United States, in particular, both factors – socioeconomic status as measured by income, education, and occupation, and access based on medical rather than income – combine to produce better health outcomes (Lasser et al., 2006). However, the poor health status associated with the majority of Canada’s Aboriginal peoples, many of whom are economically, geographically, and socially marginalized, has nonetheless resulted in an enormous health disparity within the Canadian population (Adelson, 2005). In terms of health-care organization, Canada is in the mid-range of OECD countries in terms of the extent to which its system is publicly financed and administered. During the early to mid-1990s, access to, and the quality of, some health services were impaired as a result of government budget cutbacks. As a consequence, public confidence in the system was eroded although most Canadians remained committed to the solidarity principles underlying Medicare (Romanow, 2002). Since the late 1990s, both federal and provincial governments have been reinvesting in public health care in an effort to improve quality and reduce waiting time. This public reinvestment in health care has triggered concerns about the fiscal sustainability of Medicare. In reality, most of the cost drivers appear to be in the mixed and private categories of health services rather than Medicare services. In particular, the growth of private and public prescription drug plans has been in excess of double the rate in growth of hospital and physician expenditures. Despite this, most media and think tank commentators continue to focus on Medicare, occasionally suggesting alternatives to the current single-payer model of administration. These arguments were given considerable political support in a recent Supreme Court of Canada judgment. In the now famous Chaoulli case, the court concluded that the Quebec government’s prohibition on private insurance for Medicare services violated the province’s Charter of Rights in a situation in which a patient waits an unreasonable amount of time for elective surgery. While the decision is not likely to lead to private, multipayer insurance for Medicare services, it has fueled the ongoing debate concerning the appropriate divide between the public and the private sector in financing, administration, and delivery of health care in Canada.

See also: Health Systems of Mexico, Central America and the Caribbean; Health Systems: United States, Health System of the; United Kingdom, Health System of.

Canada, Health System of

References Adelson, N., 2005. The embodiment of inequity: health disparities in aboriginal Canada. Can. J. Public Health 96, S45–S61. Boyce, W.F., 2002. Influence of health promotion bureaucracy on community participation: a Canadian case study. Health Promot. Int. 17 (1), 61–68. Canadian Healthcare Association, 2009. Home Care in Canada: From the Margins to the Mainstream. Canadian Healthcare Association, Ottawa, Canada. Canadian Institute for Health Information (CIHI), 2004. Overweight and Obesity in Canada: A Population Health Perspective. Canadian Institute for Health Information, Ottawa, Canada. Canadian Institute for Health Information (CIHI), 2011. National Health Expenditure Trends, 1975–2011. Canadian Institute for Health Information, Ottawa, Canada. Epp, J., 1986. Achieving Health for All: A Framework for Health Promotion. Health and Welfare Canada, Ottawa, Canada. Health Canada, 2003. Learning from SARS: Renewal of Public Health in Canada. Health Canada, Ottawa, Canada. Lalonde, M., 1974. A New Perspective on the Health of Canadians: A Working Document. Department of Health and Welfare, Ottawa, Canada. Lasser, K.E., Himmelstein, D.U., Woolhander, S., 2006. Access to care, health status, and health disparities in the United States and Canada: results of a cross-national population-based survey. Am. J. Public Health 96, 1300–1307. Marchildon, G.P., 2013. Health Systems in Transition: Canada. World Health Organization on Behalf of the European Observatory on Health Systems and Policies, Copenhagen, Denmark.

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McKay, L., 2000. Making the Lalonde Report: Background Paper. Canadian Policy Research Networks, Ottawa, Canada. Murray, C.J.L., Richards, M.A., Newton, J.M., et al., 2013. UK health performance: findings of the Global Burden of Disease Study. Lancet 381, 997–1021. O’Reilly, P., 2001. The federal/provincial/territorial health conference system. In: Adams, D. (Ed.), Federalism, Democracy and Health Policy in Canada. McGill-Queen’s University Press, Montreal and Kingston, pp. 107–129. Romanow, R., 2002. Building on Values: The Future of Health Care in Canada. Commission on the Future of Health Care in Canada, Saskatoon, Saskatchewan.

Further Reading Canadian Institute for Health Information (CIHI), 2013. National Health Expenditure Trends, 1975–2013. Canadian Institute for Health Information, Ottawa, Canada. Jonas, W.B., Levin, J.S. (Eds.), 1999. Essentials of Complementary and Alternative Medicine. Lippincott, Williams & Wilkins, Philadelphia, PA. Ostry, A., 2006. Change and Continuity in Canada’s Health Care System. CHA Press, Ottawa, Canada. Organisation for Economic Co-operation and Development (OECD), 2005. OECD Health Data 2005: A Comparative Analysis of 30 Countries, fifth ed. Organisation for Economic Co-operation and Development, Paris, France.

Cancer and Senescence Koji Itahana, The University of North Carolina, Chapel Hill, NC, USA Goberdhan P Dimri, Northwestern University, Evanston, IL, USA Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 1, pp. 391–395, Ó 2008, Elsevier Inc.

Increased Risk of Cancer Development with Aging The adult human body consists of approximately 60 trillion cells. The rate of proliferation and growth of this vast number of cells are under strict regulation and are highly coordinated. However, in rare cases, a few cells in a particular organ escape this tight regulation of growth, start uncoordinated proliferation, acquire invasive and metastatic properties, and become cancerous. The incidence of cancer rises exponentially with age in humans (Ries et al., 2006). As shown in Figure 1, until age 35, the incidence of cancer is 0.2% in the general population. This incidence rises to about 1.5% at ages 50–60. The maximum incidence of cancer, which is close to 5%, occurs between ages 70 and 80. Therefore, cancer tends to develop after 50 years of age, which is halfway from the 100th year, the maximum lifespan of humans. In addition, women tend to have twice the incidence of cancer at age 30–50 than men, although this trend reverses after age 50. After age 85, there tends to be a slight decline in the incidence of cancer. The genetic basis of this increased incidence of cancer with age is unclear. Recent progress in aging and cancer research suggests that errors accumulated in DNA during each round of replication, together with several other genetic and epigenetic factors, are involved in the increased risk of cancer with advanced age. In addition to genetic factors such as the accumulation of mutations in DNA, epigenetic factors, such as methylation of DNA and acetylation or deacetylation of histones, which do not affect DNA sequence per se, but change the expression of

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Figure 1 Age-specific SEER (Surveillance Epidemiology and End Results) incidence rates by sex for all cancer sites. These data are from SEER 17 Registries for 2000–2003 and do no include American Indians/Alaska Natives cases for the 2003 diagnosis year. The statistics are from malignant cases only and rates are expressed as cases per 100 000. Blue squares, male; green diamonds, female; red circles, male and female. The figure is reproduced from the SEER website, http:// seer.cancer.gov/, of the National Cancer Institute, Bethesda, MD.

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genes, also contribute to various diseases, including cancer (reviewed in Jones and Laird, 1999). Other factors that may contribute to the age-dependent increase in cancer incidence are DNA repair defects (reviewed in Lombard et al., 2005), impaired mitochondrial function (reviewed in Taylor and Turnbull, 2005), and the decrease in immune surveillance (reviewed in Burns and Leventhal, 2000). Here we focus on the role of an altered cellular phenotype, known as cellular senescence, which is associated with aging in culture and in vivo.

Cellular Senescence and Accumulation of Senescent Cells in Aging Tissues Normal human cells irreversibly arrest growth with a large and flat cell morphology after a limited number of cell divisions. This process is termed cellular senescence and was first described by Hayflick and colleagues in cultured human fibroblasts (Hayflick and Moorhead, 1961). Since eukaryotic cells have linear chromosomes, each chromosome shortens from the ends, or telomeres, during every round of cell division due to the biochemistry of DNA replication. It is thought that senescence in culture may also reflect an aging process in vivo (reviewed in Itahana et al., 2004). It is generally accepted that human fibroblasts and other types of cells senesce because they eventually acquire one or more short dysfunctional telomeres. In addition to telomeric signals, recent evidence suggests that cells also undergo senescence in response to acute signals that are potentially oncogenic. These signals include inappropriate activation or expression of oncogenes, strong mitogenic signals, direct DNA damage, and chromatin remodeling agents (Figure 2) (reviewed in Campisi, 1996; Dimri, 2005). Senescence induction by these nontelomeric signals may be much more important in age-related diseases such as cancer. Using senescence-associated b-gal (SA-b-gal) as a biomarker to detect senescent cells (Dimri et al., 1995), it has been shown that at least in some tissues, senescent cells accumulate in the human body with advanced age (Itahana et al., 2004). For example, senescent cells accumulate in aging human skin, primate retina, and liver. Senescent cells have also been detected at sites of age-related pathology, such as benign hyperplastic prostate and atherosclerotic lesions. If senescent cells do accumulate in vivo, the natural question is what is the cell’s role in vivo? In the late 1990s, based on theory of evolutionary antagonistic pleiotropy, Campisi proposed a hypothesis of senescence being a double-edged sword (Campisi, 1996). The theory of evolutionary antagonistic pleiotropy states that genes and processes that are beneficial to an organism early in life are detrimental later in life (Kirkwood and Austad, 2000). When this theory is applied to senescence, Campisi proposed that senescence, by virtue of its tumor suppressor nature, must be beneficial to us early on in life but actually may be bad in later life by contributing to an age-dependent increase in cancer

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Nonsenescent cell DNA damage signals (X-ray, H2O2, etc.) Telomeric signals

Non-telomeric signals

Oncogenic/mitogenic signals (RAS, RAF, E2F1, etc.) Chromatin remodeling agents (inhibitors of histone deacetylases and DNA methyltransferases, etc.) Undefined stress signals

Senescent cell

Figure 2 Various types of human cells undergo senescence in response to telomeric and non-telomeric signals. Telomeric signals such as telomere shortening and uncapping of telomere ends trigger replicative senescence while non-telomeric signals such as DNA damaging agents (e.g., X-rays, g-radiation and H2O2), oncogenic/mitogenic signaling (e.g., RAS, RAF, BRAF, and E2F1), epigenetic factors (e.g., polycombs, HDACs, HMTs and other chromatin remodeling agents), and undefined stress signals induce premature senescence. Both phenotypes (replicative senescence and premature senescence) resemble very closely and exhibit an overlapping pattern of gene expression. Telomeric and non-telomeric signals induce senescence via upregulation of p53 transcriptional activity, which results in upregulation of p21 and other growth inhibitors. Independent of p53, non-telomeric signals also induce p16, which blocks kinase activity of CDKs and maintains pRb in its growth-inhibitory form (under-phosphorylated). The black filled circle inside the non-senescent cell represents an active DNA synthesis in such cell as measured by 3H-thymidine labeling, while in this assay, senescent cell does not incorporate 3H-thymidine into DNA.

incidence (Campisi, 1996; Campisi, 2005). As discussed below, there is accumulating evidence to support this hypothesis.

Possible Contribution of Senescence to Oncogenesis Elegant studies from Campisi’s laboratory have shown that, at least in some cases, the accumulation of senescent cells provides a pro-oncogenic signal (Campisi, 2005). It has been found that compared to nonsenescent cells, senescent cells secrete a high level of matrix metalloproteinases, growth factors, and inflammatory cytokines (Campisi, 2005). The inappropriate expression of these factors can influence oncogenesis in multiple ways, most notably by altering the stromal environment, making it such that cancer cells can thrive and prosper in it. Indeed, it was shown that senescent fibroblasts stimulate proliferation of premalignant epithelial cells in culture and facilitate tumorigenic conversion of preneoplastic epithelial cells in a mouse model (Krtolica et al., 2001). Recently, it was shown that senescent fibroblasts upregulate vascular endothelial growth factor (VEGF) expression and secretion (Coppe et al., 2006). The secreted VEGF by senescent fibroblasts was shown to increase invasiveness of human umbilical vascular endothelial cells in culture and cause increased vascularization of tumors in vivo (Coppe et al., 2006). Recently, senescent prostate fibroblasts were also shown to enhance proliferation of neoplastic prostate epithelial cells through paracrine mechanisms (Bavik et al., 2006). The detailed characterization of other secretory molecules responsible for pro-oncogenic activities of senescent fibroblasts

remains to be investigated. It is also important to note that most of these studies employed fibroblasts only; at present, not much is known about the pro-oncogenic contribution of other senescent cell types. Moreover, at present, direct evidence showing the accumulation of senescent cells in the vicinity of a malignant tumor is lacking. Nonetheless, it seems reasonable to assume that the accumulation of senescent cells in aged tissues could facilitate cancer development by creating a matrix environment that is more conduit to cancer progression.

Senescence Acts as an Initial Barrier to Cancer Development On the bright side, senescence has been convincingly shown to be a tumor suppressor mechanism and an initial barrier to cancer development. It is very well established that cellular senescence is regulated by tumor suppressor pathways (Dimri, 2005). In particular, functional pRb (retinoblastoma tumor suppressor protein) and p53 pathways are required for the genesis and maintenance of the senescent phenotype (Dimri, 2005). Inactivation of these tumor suppressors results in the bypass of senescence and propensity to cell immortalization. Due to essentially irreversible growth arrest characteristics and the requirement for p53 and pRb functions, cellular senescence is considered a potent tumor suppressor mechanism. The importance of cellular senescence in cancer is underscored by the fact that the first step in creating an in vitro model of human cancer involves the abrogation of cellular senescence (reviewed in Boehm and Hahn, 2005). These studies show that

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a combination of SV40 large T, small t, hTERT (human telomerase catalytic subunit), and H-RAS is able to transform a variety of normal human cell types such as fibroblasts, embryonic kidney cells, mammary epithelial cells, ovarian epithelial cells, and endothelial cells (Boehm and Hahn, 2005). Recent published reports from various laboratories clearly show that cellular senescence is an important anticancer defense and acts as an initial barrier to cancer development in vivo. It was found that the expression of BRAF oncoprotein, activated H-RAS, or inactivation of the tumor suppressor PTEN induces an acute senescence response in vivo, and, as a result, tumor progression is blocked at a very early stage (Braig et al., 2005; Chen et al., 2005; Collado et al., 2005; Michaloglou et al., 2005). Tumor progression was facilitated only by additional mutations that caused bypass of senescence. Accordingly, malignant tumors that eventually arose in these systems were largely devoid of biomarkers of senescence including SA-b-gal. In the Michaloglou et al. study, it was found that the benign nevi in human patients, which express the oncogenic form of BRAF, by and large are made of senescent melanocytes, as these cells express markers of senescence such as SA-b-gal and p16 tumor suppressor. Patients with malignant melanomas showed no presence of senescent cells. In the transgenic model of lung cancer progression by K-Ras, it was shown that premalignant tumors but not malignant tumors contained senescent cells (Collado et al., 2005). In another study, oncogene-induced senescence (OIS) was shown as an initial barrier in lymphoma development in the Eu-N-Ras transgenic mouse model (Braig et al., 2005). Finally, Chen et al. showed that PTEN inactivation per se leads to the induction of premature senescence in vitro and in vivo, which is p53-dependent. It was also shown that early-stage benign human prostate cancer samples but not late-stage prostate cancer samples contained senescent cells (Chen et al., 2005). Collectively, these studies suggest that senescence induction, in particular OIS, acts as an initial barrier to cancer progression in vivo. Although it is yet to be shown, it is very likely that senescence induction in response to other potential oncogenic signals such as DNA damage, mitogenic signals and chromatin remodeling signals, and telomere attrition also act as an antioncogenic response.

Senescence in Cancer Treatment A number of in vitro studies have demonstrated that chemotherapeutic drugs act in part by inducing premature senescence (Roninson, 2003). In addition, recent studies provide compelling evidence that senescence can also be induced in vivo by chemotherapeutic drugs (Roberson et al., 2005; Schmitt et al., 2002; te Poele et al., 2002). In a mouse model, Schmitt et al. showed that a chemotherapy drug CTX (cyclophosphamide) is able to engage a senescence program when apoptosis is inhibited by Bcl2 overexpression. In another study, te Poele et al. stained newly sectioned archival breast tumors from patients who had undergone chemotherapy regimens for senescence markers. It was found that the normal tissues adjacent to the tumors were devoid of SA-b-gal and p16 protein, while 15 out of 36 (41%) tumors stained positive for the SA-b-gal marker and had high expression of p16 (te Poele et al., 2002). Similarly, induction of premature senescence by

chemotherapy treatment of human lung cancer was also recently demonstrated (Roberson et al., 2005). Thus, chemotherapeutic drugs can induce a senescence-like stage in vivo, implying that these drugs may work via induction of a senescence-like stage. Another important regulator of senescence is telomerase and its target telomeres. More than 90% of tumors contain readily detectable telomerase activity; in principle, telomerase can be targeted to cause telomere shortening and induce apoptosis or senescence in precancerous and tumor cells (Shay and Wright, 2002). Indeed, several telomerase inhibitors are known to induce senescence and/or apoptosis in tumor cells (Dimri, 2005). Thus, senescence induction by chemotherapeutics clearly contributes to the antioncogenic activity of these compounds.

Concluding Remarks The relationship between aging and cancer is well recognized; however, the underlying mechanisms are not fully understood. As discussed here, senescence is a common thread that connects cancer and aging. Senescence can act both ways: it can protect an organism from cancer or it can facilitate cancer development, depending on when and where it occurs. Although the latter role of senescence may be more significant during aging, it is also possible that the failure of cells to undergo senescence due to defects in senescence checkpoints contributes to late life cancers. It is conceivable that, due to genetic and epigenetic factors, in some cells, senescence checkpoints are compromised, and that these cells, when challenged with potential oncogenic signals, fail to invoke a senescence response and undergo oncogenesis. On the other hand, as discussed earlier, the presence of senescent cells could be detrimental, when present in the vicinity of cells that are halfway from being fully malignant. It is important to note that although senescent cells do accumulate with age, the fraction of senescent cells is always minor when compared to the vast overall number of nonsenescent cells in various organs, even in the aged tissues. Nobody can predict how many senescent cells are needed to facilitate cancer development. On the other hand, it is predictable that if senescence checkpoints are compromised, there is a good chance that the cells will become cancerous. In other words, senescence may be guilty of aiding and abetting cancer unknowingly in some cases, but by and large, it protects us from developing cancer. In summary, a better understanding of the facts is just what the jury needs to convict or acquit this fascinating phenotype, when it comes to one of the most frightening diseases of our time, cancer.

See also: Cancer Epidemiology; Cancer: Global Burden, Trends, and Projections; Cancer Mortality.

References Bavik, C., Coleman, I., Dean, J.P., Knudsen, B., Plymate, S., Nelson, P.S., 2006. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res. 66, 794–802.

Cancer and Senescence Boehm, J.S., Hahn, W.C., 2005. Understanding transformation: progress and gaps. Curr. Opin. Genet. Dev. 15, 13–17. Braig, M., Lee, S., Loddenkemper, C., et al., 2005. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665. Burns, E.A., Leventhal, E.A., 2000. Aging, immunity, and cancer. Cancer Control 7, 513–522. Campisi, J., 1996. Replicative senescence: an old lives’ tale? Cell 84, 497–500. Campisi, J., 2005. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120 (4), 513–522. Chen, Z., Trotman, L.C., Shaffer, D., et al., 2005. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730. Collado, M., Gil, J., Efeyan, A., et al., 2005. Tumour biology: senescence in premalignant tumours. Nature 436, 642. Coppe, J.P., Kauser, K., Campisi, J., Beausejour, C.M., 2006. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J. Biol. Chem. 281, 29568–29574. Dimri, G.P., 2005. What has senescence got to do with cancer? Cancer Cell 7 (6), 505–512. Dimri, G.P., Lee, X., Basile, G., et al., 1995. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. U.S.A. 92, 9363–9367. Hayflick, L., Moorhead, P.S., 1961. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621. Itahana, K., Campisi, J., Dimri, G.P., 2004. Mechanisms of cellular senescence in human and mouse cells. Biogerontology 5, 1–10. Jones, P.A., Laird, P.W., 1999. Cancer epigenetics comes of age. Nat. Genet. 21, 163–167. Kirkwood, T.B., Austad, S.N., 2000. Why do we age? Nature 408, 233–238. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P.Y., Campisi, J., 2001. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl. Acad. Sci. U.S.A. 98, 12072–12077. Lombard, D.B., Chua, K.F., Mostoslavsky, R., et al., 2005. DNA repair, genome stability, and aging. Cell 120, 497–512. Michaloglou, C., Vredeveld, L.C., Soengas, M.S., et al., 2005. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724.

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te Poele, R.H., Okorokov, A.L., Jardine, L., Cummings, J., Joel, S.P., 2002. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 62, 1876–1883. Ries, L.A.G., Harkins, D., Krapcho, M., et al. (Eds.), 2006. SEER Cancer Statistics Review, 1975–2003. National Cancer Institute, Bethesda, MD. Roberson, R.S., Kussick, S.J., Vallieres, E., Chen, S.Y., Wu, D.Y., 2005. Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res. 65, 2795–2803. Roninson, I.B., 2003. Tumor cell senescence in cancer treatment. Cancer Res. 63, 2705–2715. Schmitt, C.A., Fridman, J.S., Yang, M., et al., 2002. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346. Shay, J.W., Wright, W.E., 2002. Telomerase: a target for cancer therapeutics. Cancer Cell 2, 257–265. Taylor, R.W., Turnbull, D.M., 2005. Mitochondrial DNA mutations in human disease. Nat. Rev. Genet. 6, 389–402.

Further Reading Fossel, M.B., 2004. Cells, Aging, and Human Disease. Oxford University Press, New York. Weinberg, R.A., 1998. One Renegade Cell – How Cancer Begins. Weidenfeld and Nicolson, London.

Relevant Websites http://www.seer.cancer.gov – National Cancer Institute, SEER. http://www.nature.com/nature/focus/senescence/index.html – Nature Web Focus: Senescence: Cells, Ageing and Cancer.

Cancer Economics Thomas N Chirikos, University of South Florida, Tampa, FL, USA Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 1, pp. 408–415, Ó 2008, Elsevier Inc.

Cancer economics may be defined as a nascent field of applied research focusing on the resource implications of all forms of malignant disease. The field has been forged by the rapid growth in cancer incidence and prevalence worldwide, by continuing technological advances in detection and treatment of the disease, and reimbursement and pricing issues facing virtually all medical care financing systems. Empirical methods dominate work in the field, with hypotheses generated typically by simple economic precepts and tested with secondary data such as administrative claims records. As a result, the nature and scope of cancer economics vary over time and place, and the growth of its cumulative knowledge base is both slow and uneven. Any attempt to delineate the field will perforce be time-dependent, restricted in scope, and limited in the depth of coverage. The aim of this article is to present key features of the field as it has developed in the English language literature in the more advanced economies of North America, Western Europe, and Australia over the past decade, 1995– 2005. These limitations in focus make the task at hand more manageable, while still providing a meaningful basis for describing the central characteristics of this emerging field.

Conceptual Overview A fundamental premise of economics is that resources are always scarce relative to the wants they may satisfy, so they must be used as efficiently as possible. Economists have developed an elaborate theory that posits that scarce resources will be used most efficiently under the conditions prevailing in well-functioning market systems. Market allocations to cancer detection, treatment, and research, however, may not yield fully efficient outcomes because cancer markets are thought to function imperfectly, if they exist at all. Public policy actions targeting cancer markets are then needed to shift, arrange, and/ or attract resources to ensure better outcomes. Cancer economics contributes policy-relevant knowledge to decision makers charged with the responsibility of designing and evaluating these policies. In recent years, these contributions have focused mostly on the opportunity costs of cancer, that is, the value of resources given up (foregone) for alternative uses when they are committed to fight cancer in various ways. Opportunity costs of cancer have been investigated at two levels: (1) the full costs to patients, their families, and society in detecting and treating the disease itself and (2) the opportunity costs of alternative interventions for detecting, diagnosing, and treating cancer to patients, payers, and society. The most visible costs of the disease are the amounts spent on all cancer-related health-care services – conventionally referred to as the direct costs of cancer. Direct costs are computed as Siciqi, where q represents service units, c represents mean cos t, and i indexes all relevant services used in detecting and treating cancer during a given period. The ci in the cancer field are invariably observed amounts paid to health-care

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providers, which differ by how the payer group is defined. The literature often takes the limited perspective of thirdparty payers, so the costs are valued only for reimbursable services (inpatient hospital care, physician services, skilled nursing, and the like) and the types of providers covered by the insurance plan. From a broader societal perspective, the costs incurred by patients and their families (deductibles and coinsurance payments, expenditures for special diets, durable medical equipment, outpatient drugs, etc.) are also included in the tally. In either case, the key research question is what determines the level and distribution of direct costs. This question has assumed increasing policy significance because of the widespread assumption that cancer costs are bloated by inefficiencies in the delivery system. These inefficiencies stem from demand distortions introduced by extensive insurance coverage and imperfect rate-setting policies, among others; they also stem from the high degree of uncertainty surrounding the effectiveness of cancer treatment and the corresponding wide variation in what is considered best-practice care. Opportunity costs of the disease are also incurred even if cancer is never detected or treated, and these costs add cumulatively to overall direct costs when it is. Individuals with undetected disease, as well as treated survivors, may experience periods when they are unable to fulfill major role responsibilities and, regrettably, they may die prematurely. The time away from major responsibilities such as market work or home making can be valued (by human capital methods) as the lost market earnings of workers and the replacement value of home-making services. When they refer to cancer patients or survivors themselves, these losses are called morbidity or disability costs. They are typically calculated for n prevalent cases as SnwnTn, where T represents time away from work and w average earnings loss per time unit. Family or household members may also lose time away from market work to assist cancer patients and/or provide valuable in–home services to those patients that substitute for formal health-care services. The imputed value of household-produced care is often referred to as the informal costs of cancer, and they are estimated in a way analogous to morbidity costs. For decedents, economists compute the number of years an individual might be expected to live with and without cancer, and then use the difference to gauge how many years the cancer death was premature. The stream of foregone income (market earnings) over these lost years is then estimated and discounted back to its present value, which adjusts for the fact that income received sooner is valued more highly than income received later. These computations are called mortality costs. Because morbidity, disability, informal, and mortality costs are not valued directly in the market, they are referred to as the indirect costs of the disease. Research has focused mostly on the determinants and distribution of the morbidity and informal components of indirect costs. Opportunity costs at the level of interventions are the central focus of cost-effectiveness analyses (CEAs) of

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Cancer Economics alternative means of detecting and treating cancer, such as alternative types of surgery, chemotherapy regimens, screening and diagnostic tests, supportive care protocols, and so forth. CEAs appraise the extent to which the incremental difference in costs (C) between any substitutable pair of interventions (a and b) is commensurate with the incremental change in outcomes (E) that each yields, that is, (Ca
Cb)/(Ea
Eb). (We refer hereafter to this as the incremental cost-effectiveness ratio or ICER.) Estimated ICERs typically encompass elements of the opportunity costs of the disease: Direct costs of care figure prominently in the cost numerator term and effectiveness denominators use many of the same disease parameters as indirect cost estimates. However they are measured, ICERs are ultimately judged in terms of the commensurability between extra costs and outcome gains. (How commensurability is judged depends on the metric of the denominator term, a matter taken up below.) The issue of commensurability creates tension between economic and clinical decision processes. The clinicians’ decision rule is, above all, do no harm. In contrast, economists believe that even an intervention that does a small amount of good can be economically inefficient if it can do this good only at incommensurately higher costs. This conclusion depends crucially on whether the perspective of the analysis is society at large, a payer group, or an individual patient. For expository purposes, applied research on the opportunity costs of cancer may be divided three ways: aggregate studies of the economic burden of cancer; microlevel studies of direct and indirect costs of cancer, and cancer-related CEAs. The next three sections discuss each of these aspects of the field in turn.

Aggregate Estimates of the Economic Burden of Cancer The sum of total direct, morbidity, and mortality costs in a given year is referred to as the economic burden of cancer in that year. In any given country and point in time, aggregate burden estimates provide a convenient, though imprecise, measure of the size and structural characteristics of the cancer economy. The United States, for instance, now routinely produces estimates of these costs, cross classified by the most common cancers and by type of provider. The total economic burden for 2005 was put at $US214 billion, up from an estimated $US72 billion (current dollars) in 1985 (American Cancer Society (ACS), 2006; Brown, 1990). When general and medical care inflationary trends are taken into account, the 1985 value is roughly equivalent to 152 billion in 2005 constant U.S. dollars. (Note: unless otherwise indicated, all cost figures reported in this article have been adjusted by the author to year 2005 U.S. dollars; see Tables 1 and 3). The present discounted value of mortality losses is the largest component, accounting for about 56% of the total in 2005, whereas direct costs accounted for slightly more than 35%, and indirect morbidity costs the remaining 9%. Direct costs differed substantially by type of cancer and provider. For example, more than half of total direct costs in 2005 was accounted for by the four most prevalent cancers: lung, breast, colorectal, and prostate; and roughly 90% of total direct costs was accounted for by hospital and physician services. Over the period 1985–2005, constant dollar aggregate costs rose at an annual rate of approximately 1.7% per annum, though the indirect and direct components increased at different rates,

Table 1 Proportional differences in treatment costs by stage at diagnosis and treatment phase, selected cancer sites and patient populations in the United States

Site/population stage at diagnosis Colorectal, Medicare  65c Stage 1 Stage 2 Stage 3 Stage 4 Lung, Medicare  65d Local Regional Distant Female breast, Medicare  65d Local Regional Distant Female breast, HMO, all agese Local Regional Distant a

a

Reference cost b (US $ 2005) 25 300

38 950

16 900

24 600

Reference cost by phase (%) Initial

Continuing (per year)

Final

100.0 127.5 141.9 135.9

25.7 26.3 31.7 49.7

143.7 141.3 154.5 156.9

100.0 100.4 88.4

20.7 21.5 26.3

70.7 67.7 71.9

100.0 116.6 141.8

35.3 38.5 54.9

125.0 137.5 140.4

100.0 123.0 102.9

29.5 36.0 54.4

133.2 124.5 119.6

Excludes in situ and unstaged cases. Note: colorectal stage data use post-1985 AJCC categories; all others use pre-1985 AJCC categories. Reference costs are reported costs for the initial treatment phase of cases diagnosed with local or stage 1 disease, each adjusted for inflation to year 2005 U.S. dollars by means of the Medical Care component of the U.S. Consumer Price Index. c Brown et al. (1999). d Riley et al. (1995). e Fireman et al. (1997). b

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roughly 2.2% and 1.1% per year, respectively. While direct costs grew at approximately twice the rate of annual new cancer cases, they grew at the same general pace as all health-care spending in the United States over the same period. The percentage of total spending accounted for by cancer, therefore, is roughly the same now (4.7%) as it was 20 (and, indeed, 40) years ago (Brown et al., 2001). Countless methodological problems mar aggregate burden estimates. To illustrate, estimates of direct and indirect morbidity costs are usually based on annual cancer prevalence data, whereas mortality costs are, by definition, incidence-based. The admixture tends to gauge only shortterm, as opposed to lifetime, effects of a cancer diagnosis, especially morbidity/disability consequences. Human capital accounting probably overstates indirect costs relative to newer methods, for example, the friction cost approach. Top-down procedures used to allocate health-care utilization to cancer on the basis of principal diagnostic codes often omit significant interactions between cancer and major comorbidities. The policy uses of these aggregate burden estimates have also been questioned. There is a line of economic reasoning that interprets them as the present value of annual economic yields realized in perpetuity of investments that (hypothetically) prevent all cancers this year. This interpretation assumes, among many other assumptions, causeindependence in the disease data, which overstates economic benefits relative to those that might be yielded in a competing risk framework. The aggregate figures thus tend to be presented without much theoretical justification, and they are used simply as guidelines for research investments and as background data for budget deliberations in the legislative process. Methodological differences also render international comparisons of aggregate cancer burdens difficult, if not impossible, to make. For example, computed real changes in total direct and indirect costs over the period 1986–98 in Canada grew at an annual rate of 0.9% per year, or only about one-half that of the United States (Health Canada, author’s calculations). However, the policy relevance of this comparison is quite limited, because the methods used to compute indirect costs, among others, differ significantly between the two nations. As a result, international comparisons are often just restricted to direct cancer costs. But even these estimates differ widely, not only because of variations in medical practice patterns, but also because of the methods used to allocate national health expenditures to disease categories and to differences in the items, for example, patient co-payments, included in the expenditure data. Polder et al. (2005) recently demonstrated that the published percentages of total health expenditures attributable to cancer in Australia, Canada, Germany, the Netherlands, United Kingdom, and Sweden are much higher than they are in the United States, averaging 6.1% (SD ¼ 1.5) across the six nations versus the 4.7% in the United States. But when adjustments are made that account for the differences in methodology, the mean of the six nations is 4.5% (SD ¼ 0.5), or 0.2 percentage points lower than in the United States. Of course, absolute cost differentials are much greater, because the United States spent in 2005 about 15% of its GDP on the health sector, whereas the six countries just mentioned averaged only 9.5% (SD ¼ 1.5) of GDP.

Microlevel Studies of Direct Cancer Costs Given the methodological limitations of aggregate estimates, attention has shifted recently to microlevel studies of direct costs, in some cases to build economic burden estimates from the bottom up rather than top down and, simultaneously, to shift from prevalence to incidence-based estimates of the cumulative costs of cancer episodes. Microlevel studies have also been designed to advance our understanding of cost drivers for reimbursement and cost containment purposes. Although there is increasing interest in payments to medical care providers beyond those covered by third-party insurance, especially out-of-pocket spending by cancer patients themselves, most microlevel studies take a payer perspective. This focus is not surprising because these studies have been based on newly generated administrative claims data sets. One such data set, constructed by researchers at the U.S. National Cancer Institute, links cancer registry cases in 11 surveillance epidemiology and end results (SEER) regions to Medicare claims records at the individual patient/beneficiary level. In contrast to prevalence-based studies, these linked data permit samples of patients with confirmed cancer diagnoses to be followed analytically over the entire course of the disease episode. Direct costs (program reimbursements) can be cumulated over the disease episode, both in total and for various subcategories built up from available diagnosis and provider service codes. These cost profiles only encompass the set of services reimbursable under the insurance plan. (Medicare coverage excludes, for instance, nursing home care and, until quite recently, outpatient drugs.) A methodological limitation of most linked data sets such as SEER-Medicare is that cost profiles are often truncated or censored, on the right-side for patients still alive at the end of the observation period, and sometimes also on the left for individuals who may have been diagnosed before they became Medicareeligible. Incomplete cost profiles have led researchers to divide the cancer episode into various phases or treatmentrelated periods. The most common set of phases is threefold: the initial 6-month period following cancer diagnosis, the 6month period immediately prior to death for decedents, and the annual costs between the initial phase and death for decedents or the end of the observation period for survivors. Differing numbers of patients thus contribute complete data for computing cumulative cost totals for each treatment phase. With the aid of projected annual survival probabilities, these phase-specific estimates can then be assembled serially to compute the lifetime costs of the cancer in question. Linked registry/claims data at the level of individual beneficiaries can also be used to analyze the myriad factors that shape the cost distributions of cancer care. Common points of departure in such analyses are differentials in costs across the stages at which various malignancies are diagnosed, as well as across the phases of treatment. The general expectation is that treatment costs of virtually all cancers rise systematically with the stage at which the cancer is diagnosed. With respect to the phase of treatment, the expectation is that costs will be higher in the initial and terminal phases of treatment, but lower in between. Table 1 sets out stage- and phase-related data as percentages of initial phase, early stage cumulative cost amounts for three common malignancies in the United States;

Cancer Economics two different results are presented for female breast cancer to illustrate the potential confounding effects of age and type of provider. Costs of the initial treatment phase do generally differ by stage, though late-stage disease often costs less if physicians choose not to treat aggressively. Note that the longer stream of follow-up costs that attend longer periods of survivorship may offset lower initial treatment costs. Stage at diagnosis, of course, is only one of a large number of variables that help explain cost variations across patients. Unless these other explanatory variables are also included in the analysis, measured effects of stage are probably overstated. Other significant predictors include the sociodemographic characteristics of patients, especially age and income status, and medical comorbidities. In some U.S. studies, the economic characteristics of providers such as the supply of specialist physicians and the volume of procedures at specific hospitals, are also significant predictors. Yet the predictors included in multivariate statistical models of cancer treatment costs do not ordinarily account fully for the dispersion (variance) in cumulative cost distributions, even those for the most common cancers. Statistical noise in cost data suggests the presence of economic inefficiencies. Second-generation studies are needed to explain a greater fraction of the variance in costs across subgroups of cancer patients, as well as pinpoint areas of likely inefficiency requiring policy action. These studies will require additional and better-measured covariates, as well as more robust multivariate statistical techniques, for dealing with the complexities of cancer cost data.

Table 2

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Microlevel Studies of Indirect Costs These microlevel studies focus mainly on morbidity/disability effects on the economic fortunes of individuals diagnosed and treated for malignant disease; many also focus on informal costs, the economic impact of that cancer on family or household members. Table 2 lists some basic hypotheses tested in recent studies (most, but not all, conducted in the United States) as a means of summarizing a disparate, though growing, literature on indirect/informal costs. Many studies test hypotheses about the work activity of cancer survivors. An earlier literature on this topic probed simply whether individuals treated for various cancers returned to market work after treatment, if working before diagnosis. The more recent literature examines a broader set of questions, including whether survivors work progressively fewer hours and/or earn less per hour worked so as to experience diminutions in economic welfare the longer they survive their cancer. There is convincing evidence that cancer survivors do reduce their own work effort after diagnosis and initial treatment, though this evidence refers to only several of the most common cancers and has been based mostly on small convenience samples. These short-term effects are easy to understand, given the rigor of many cancer treatments, especially chemotherapy. Longer-run changes are more challenging to explain. Evidence of residual functional impairment is often implicated, for example, the impaired use of arms and shoulders of women developing lymphedema after axillary surgery for breast cancer. Yet there is also evidence that family income

Examples of hypotheses tested in recent studies of indirect and informal costs of cancer

Target population

Hypotheses a

Patients/survivors:

H0: Patients undergoing treatment for cancer have the same rates of short-term work absence and/or short-term disability as matched controls H1: Over a 5-year follow up period, prostate and bladder cancer survivors earn less per week than age-sex-adjusted average workers H0: Long-term survivors of breast cancer experience the same changes in market earnings, annual hours of market work and/or hourly wage rates in the 5-year period post-diagnosis as those experienced by an age- and workmatched set of controls without a history of cancer H0: Women with breast cancer have the same probability of labor force participation 1–2 and 3 or more years postdiagnosis as women with no history of the disease, controlling for other predictors of labor force participation H0: Married working women with breast cancer work the same number of hours per week as married working women without a history of the disease, controlling for other work predictors H0: Cancer survivors identified in a national sample survey have the same likelihood of: working, reporting inability to work for health reasons, and/or number of days lost-from-work as a nationally representative sample of population controls, irrespective of type of cancer or time from diagnosis H1: There is a systematic time path of when cancer survivors who were engaged in market work at the time of diagnosis leave market work, i.e., right after treatment, after 1-year post-diagnosis, after 2 years, etc. H0: Health insurance coverage of the spouse of married women with cancer influences the probability of labor force participation of those women to the same degree as women without a history of the disease, controlling for other participation predictors H1: Informal family costs of caring for a cancer patient differ by cancer, by number of activities of daily living, by living arrangements, by type of treatment, and/or by elapsed time since treatment H0: Caregivers of cancer patients have the same rates of short-term work absence and/or wage losses as matched caregiver controls H0: Informal family costs of breast cancer survivors do not differ from those of non-survivors H0: Households of breast cancer survivors experience the same changes in market earnings, household income, and household assets over the 5-year period post-diagnosis as households of an age- and work-matched set of controls without a history of cancer

Families of patients/survivors:

a

Some studies included multiple hypotheses. Null forms of hypotheses are labeled H0, all others are labeled H1.

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and availability of pensions predict work reductions, suggesting that preferences for more leisure also play a role in the economic behavior of long-term survivors. Whether cancer shifts these preferences warrants further study. Whatever the impact on the survivor herself, research suggests that the economic behavior of household members also changes when an individual is diagnosed and treated for cancer. In the immediate period of treatment, family members change their work schedules in order to accommodate the cancer patient. A more important issue from an economic perspective is what happens over the longer run. On the one hand, there is fragmentary evidence that household members change their own commitment to market work in the aftermath of a family member’s cancer treatment, though the direction of this change is ambiguous. Some individuals work less, perhaps as a means of sharing the additional leisure time sought by the cancer patient herself, whereas others engage in more market work to compensate for the losses to family income by reduced work effort of the patient. On the other hand, family members may spend more time producing informal care and home services, both in caring for the patient and substituting for the patient’s historical role in running the household. Second-generation studies should focus on the growing policy importance of indirect cancer costs. Rising prevalence rates are one reason; the advent of novel therapies are another. Consider, for example, that targeted therapies based on recent advances in genomics and molecular biology are expected to have high direct costs, in part because the number of patients that can benefit from any one of them is expected to be small. Yet if these therapies lessen side effects and/or shift some therapy away from highly invasive procedures performed in formal settings, there may be highly significant, compensatory effects on indirect costs. Cancer economists should be preparing now to analyze the net effect of the shift from provider to patients and families on the costs of these new therapies.

Cancer-Related Cost-Effectiveness Analyses Cost–effectiveness analysis (CEA) is used in the cancer field in virtually the same way it is used elsewhere. The boundaries of this part of the field thus overlap with cognate areas such as pharmacoeconomics. Yet cancer-related CEAs warrant discussion here because they rely algebraically on direct and indirect cost estimates in ICER numerator terms, and many ICER denominators are disease-specific. With respect to denominators, some studies use cancerspecific process measures, for example, the number of mammographies performed or the number of polyps detected in breast or colon cancer screening interventions, which permit within-class comparisons of cost per process unit. These comparisons, however, are conditioned on the assumption that the entire class of interventions itself is cost-effective, often a doubtful assumption. Thus, many studies use more broadly conceived denominator terms, the two most common being changes in life years (LYs) and quality-adjusted life years (QALYs). LY denominators gauge changes in life expectancy, and thus can be compared across an extensive set of lifesaving health interventions. QALY denominators may be described as composite measures that reflect functional

capacities or quality of life during, as well as the length of, cancer survivorship. Although LYs are only disease-specific to the extent that changes in cancer deaths are translated into differences in life expectancy, many cancer-related QALYs are constructed in terms of health states unique to cancer treatment. Some illustrations from a recent review by Earle et al. (2000) include recurrence of disease, adverse events attending therapy, advanced cancer but responding to hormonal therapy, partial impotence from prostate cancer surgery, and terminal metastatic breast cancer, among others. These health states are then assigned preference or utility weights by various means to reflect their relative value. (Utilities here have the same conceptual meaning as those described in economic textbooks; their role in calculating QALYs explains why studies using these denominators are now referred to as cost–utility analysis.) In cancer-related analyses, utility weights have been elicited mostly from oncology specialists and cancer patients. QALY denominators admit to comparisons across a broad range of health-saving interventions. There are two primary analytic frameworks within which incremental cost per LY or cost per QALY ratios have been estimated. One is the modeling approach, which relies on decision-analytic (or equivalent) techniques to project under conditions of uncertainty differences in disease outcomes and the cumulative use of cancer-related services of synthetic cohorts undergoing a specific intervention versus, say, standard care. The expected values of the temporal outcome and cost streams are then used to construct the ICER for the intervention. Parameter estimates needed to estimate the model such as likelihood of death or probability of recurrence at each time point are retrieved from literature reviews, meta-analyses of clinical trial results, and so forth. Since the true values of many parameters are unknown, modeling studies typically conduct sensitivity analyses based on small changes in the values of critical parameters, either alone or in combination, to assess their impact on the estimated ICER. Since the gold standard for determining the true effect of an intervention is a randomized control trial, the second framework is thus a cancer clinical trial that adds cost endpoints. Perhaps surprisingly, there has been continuing controversy about the desirability of adding CEAs to trials. One reason is that trial CEAs may not generalize well. Trials enroll comparatively homogeneous, but not always representative, patient populations, whereas CEAs attempt to gauge the costs and outcomes that obtain in the community at large. Another is that the cost of conducting a trial increases substantially because sample size and the length of the observation period for cost endpoints are much greater than clinical endpoints. When CEAs are just tacked on to trials, questions of statistical power and heavily censored cost endpoints arise. Finally, cost comparisons run into problems in international trials enrolling patients across national borders because of variations in practice patterns, as well as in relative and absolute price differences across nations. Although they are often combined, the recent cancer-related CEA literature nonetheless divides naturally between trialbased and modeling efforts. CEA studies built into trials tend to focus on cancer therapies, especially new drugs or drug combinations, and they are usually conducted from a payer perspective. Although straightforward, these CEAs often yield divergent results, especially across time and place. Nonetheless,

Cancer Economics this class of CEAs has found a ready group of decision makers interested in using the results for reimbursement and pricing policies, practice guideline development, and other actions influencing how scarce cancer resources are allocated. The development of institutional decision mechanisms has fostered this use. The creation of NICE (National Institute for Health and Clinical Excellence) in the United Kingdom and the threshold levels of cost per QALY that they have set to appraise new medical technologies is a case in point. Modeling-related CEAs tend to appraise ICERs from a societal as well as payer viewpoint. They often compare a given intervention to no intervention and/or assess whether an intervention thought to be economically efficient when targeting a particular population subgroup is also cost-effective when targeting another subgroup. Cancer-related CEA studies of adjuvant therapy are cases in point. They have focused on the economic implications of adding adjuvant therapy to the treatment regimens of patients who have typically not received it, such as older patients or those with less severe disease. A related area of interest in modeling studies is cancer screening interventions. Table 3 summarizes some recent findings of screening CEAs testing age limits in breast cancer, different detection methods in colorectal cancer, and the use of expensive CT scanning to detect lung cancer. As might be expected, there are wide variations in these results, particularly for screening at different ages or by means of an expensive technology for which there are yet no trial data determining actual efficacy. The differences

Table 3

often stem from analytic assumptions about the discount, attrition, and/or recurrence rates, among others; they also stem from how uncertainty is treated in the model. Yet the results are useful in showing the range of potential opportunity costs of such screening, thereby providing a point of reference for conducting screening trials. These results, however, illustrate a more fundamental limitation of CEAs that is not always appreciated by cancer specialists. These results can only be interpreted in relative or ordinal terms and few, if any, computed CEA ratios can ever be completely ruled out. To be sure, the maintained hypothesis is that viable ICERs do not exceed some rule of thumb or cut point – $50 000 per QALY is one. From the viewpoint of economic theory, however, this cut point is completely arbitrary, so caution must be exercised when using it to judge the commensurability of costs and outcomes. Furthermore, in theory, all CEA results are rank-ordered from low to high, and interventions are then funded seriatim until the overall budget is exhausted. This rank-ordering should encompass all interventions with identical denominator terms, not necessarily just cancer interventions. More important is the fact that the budget is determined exogenously by the political or payer authorities. There is nothing in cost-effectiveness analyses that provides guidance to the determination of the overall amount of resources to be allocated to the cancer sector. In contrast, cost–benefit analysis, wherein both numerator and denominator terms are measured in monetary units, can be

Selected cancer screening cost/effectiveness results ICER by typea (US $ 2005)b

Cancer, program alternatives, and study perspective Breast cancer Biennial mammography screening. Dutch societal perspectivec Screen all women 50 years of age versus only women 50–69 years of age Screen all women 50 years of age versus only women 50–75 years of age Biennial mammography screening. US societal perspectived Screen women age 50–79 versus only women age 50–70 Screen all women 50 versus only women age 50–70 Colorectal cancer Annual fecal occult blood test (FBOT) versus no screen. U.S. payer perspectivee Flexible sigmoidoscopy every 5 years versus no screen. U.S. payer perspectivee Colonoscopy every 10 years versus no screen. U.S. payer perspectivee Lung cancer Screen with low-dose, helical CT scan; 5-year screening round versus no screening U.S. payer perspectivef Screen with low-dose, helical CT scan, 5-year screening versus no screening, male smokers ages 60–64. Australian payer perspectiveg Screen with low-dose, helical CT scan, 20-year annual screening versus no screening, U.S. societal perspectiveh Screen current smokers Screen former smokers a

Cost/LY

Cost/QALY

– –

28 100 120 300

101 700 187 675

– –

14 700 24 600 18 750

– – –

60 000

–

48 400

88 750

– –

137 800 275 250

ICER, Incremental cost-effectiveness ratio; C/LY, cost per life-year saved; C/QALY, cost per quality-adjusted life-year saved. Costs reported in other national currencies were first converted to U.S. dollars for the reported year by means of the OCED GDP Purchasing Power Parity index; they were then adjusted to constant 2005 dollars by means of the Medical Care component of the CPI. c Boer et al. (1995). d Mandelblatt et al. (2005). e Pignone et al. (2002). These are the means of the ratios of five studies considered by the U.S. Preventive Services Task Force. f Chirikos et al. (2002). g Manser et al. (2004). h Mahadevia et al. (2003). b

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used, at least in principle, to determine the optimal budget for cancer interventions by equalizing the rate of return across all competing interventions. Similarly, willingness to pay or contingent valuation methods may also provide usable economic results for decisions about the cancer budget. There is growing sentiment in the field that cost–benefit analysis should be used more extensively, despite ethical concerns arising from the need to value life in monetary terms.

See also: Cancer Epidemiology; Cancer: Global Burden, Trends, and Projections; Decision Analytic Modeling; Determinants of National Health Expenditure; Global Burden of Disease; International Classification Systems for Health; Measurement and Modeling of Health-Related Quality of Life; Measurement and Valuation of Health for Economic Evaluation.

References American Cancer Society (ACS), 2006. Cancer Facts and Figures. ACS, Atlanta, GA. Boer, R., de Koning, H.J., van Oortmarssen, G.J., et al., 1995. In search of the best upper age limit for breast cancer screening. Eur. J. Cancer 31A, 2040–2043. Brown, M.L., 1990. The national economic burden of cancer: an update. J. Natl. Cancer Inst. 82, 1811–1814. Brown, M.L., Riley, G.F., Potosky, A.L., et al., 1999. Obtaining long-term disease specific costs of care, application to Medicare enrollees diagnosed with colorectal cancer. Med. Care 37, 1249–1259. Brown, M.L., Lipscomb, J., Snyder, C., 2001. The burden of illness of cancer: economic cost and quality of life. Annu. Rev. Public Health 22, 91–113. Chirikos, T.N., Hazelton, T., Tockman, M., et al., 2002. Screening for lung cancer with CT: a preliminary cost-effectiveness analysis. Chest 121, 1507–1514. Earle, C.C., Chapman, R.H., Baker, C.S., et al., 2000. Systematic overview of costutility assessments in oncology. J. Clin. Oncol. 18, 3302–3317. Fireman, B.H., Quesenberry, C.P., Somkin, C.P., et al., 1997. Cost of care for cancer in a health maintenance organization. Health Care Financ. Rev. 18, 51–76. Health Canada, 1998. Economic Burden of Illness in Canada. Policy Research Division, Population and Public Health Branch. Health Canada, Ottawa, Canada. Mahadevia, P.J., Fleisher, L.A., Frick, K.D., et al., 2003. Lung cancer screening with helical computed tomography in older adult smokers, a decision and costeffectiveness analysis. J. Am. Med. Assoc. 289, 313–322. Mandelblatt, J.S., Schechter, C.B., Yabroff, K.R., et al., 2005. Toward optimal screening strategies for older women, costs, benefits, and harms of breast cancer screening by age, biology, and health status. J. Gen. Intern. Med. 20, 487–496. Manser, R., Dalton, A., Carter, R., et al., 2004. Cost-effectiveness analysis of screening for lung cancer with low dose spiral CT (computed tomography) in the Australian setting. Lung Cancer 48, 171–185.

Pignone, M., Saha, S., Hoerger, T., et al., 2002. Cost-effectiveness analysis of colorectal cancer screening: a systematic review for the U.S. preventive services task force. Ann. Intern. Med. 137, 96–104. Polder, J.J., Meerding, W.J., Bonneux, L., et al., 2005. A cross-national perspective on cost of illness: a comparison of studies from The Netherlands, Australia, Canada, Germany, United Kingdom, and Sweden. Eur. J. Health Econ. 6, 223–232. Riley, G.F., Potosky, A.L., Lubitz, J.D., et al., 1995. Medicare payments from diagnosis to death for elderly cancer patients by stage of diagnosis. Med. Care 33, 828–841.

Further Reading Brown, M.L., Riley, G.F., Schussler, N., et al., 2002. Estimating health care costs related to cancer treatment from SEER-Medicare data. Med. Care 40 (Suppl.), IV104–IV-117. Etizioni, R., Riley, G.F., Ramsey, S.D., et al., 2002. Measuring costs, administrative claims data, clinical trials, and beyond. Med. Care 40 (suppl), III-63–III-72. Frew, E., Wolstenholme, J.L., Whynes, D.K., 2001. Willingness-to-pay for colorectal cancer screening. Eur. J. Cancer 37, 1746–1751. Fryback, D.G., Craig, B.M., 2004. Measuring economic outcomes of cancer. J. Natl. Cancer Inst. Monogr. 33, 134–141. Hayman, J.A., Langa, K.M., Kabeto, M.U., et al., 2001. Estimating the cost of informal care giving for elderly patients with cancer. J. Clin. Oncol. 19, 3219–3225. Howard, D.H., 2005. Life expectancy and the value of early detection. J. Health Econ. 24, 891–906. Krahn, M.D., Mahoney, J.E., Eckman, M.H., et al., 1999. Screening for prostate cancer, a decision analytic view. J. Am. Med. Assoc. 272, 773–780. Koopmanschap, M.A., Touw, K.C., Rutten, F.F.H., 2001. Analysis of costs and costeffectiveness in multinational trials. Health Policy 58, 175–186. Oliva, J., Lobo, F., Lopez-Bastida, J., et al., 2005. Indirect costs of cervical and breast cancers in Spain. Eur. J. Health Econ. 6, 309–313. Penberthy, L., Retchin, S.M., McDonald, M.K., et al., 1999. Predictors of Medicare costs in elderly beneficiaries with breast, colorectal, lung, or prostate cancer. Health Care Manag. Rev. 2, 149–160. Steiner, J.F., Cavender, T.A., Main, D.S., et al., 2004. Assessing the impact of cancer on work outcomes, what are the research needs? Cancer 101, 1703–1711. Yabroff, K.R., Warren, J.L., Knopf, K., et al., 2005. Estimating patient time costs associated with colorectal cancer care. Med. Care 43, 640–648.

Relevant Websites http://www.cancer.org/ – American Cancer Institute (last accessed 19.06.16.). http://www.healthservices.cancer.gov/seermedicare – National Cancer Institute, SEERMedicare Linked Database (last accessed 19.06.16.). http://www.oecd.org/statsportal/ – Organisation for Economic Co-operation and Development (last accessed 19.06.16.). http://www.who.int/en/ – World Health Organization (last accessed 19.06.16.).

Cancer Epidemiology Petra A Wark, London School of Hygiene and Tropical Medicine, London, UK Julian Peto, London School of Hygiene and Tropical Medicine, London, UK; and Institute of Cancer Research, Sutton, UK Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 1, pp. 419–423, Ó 2008, Elsevier Inc.

Cancer Distribution Worldwide

Effect of Cancer Screening on Incidence and Mortality

Cancer is a major public health problem throughout the world, causing more than a quarter of all deaths in many countries. Cancer accounted for approximately 7 million deaths worldwide in 2002, 1 in 8 of all deaths. In the same year, 11 million people were diagnosed with cancer and nearly 25 million people diagnosed with cancer over the previous 3 years were still alive (Parkin et al., 2005). The absolute number of people diagnosed with cancer is increasing steadily because of continuing increases in life expectancy and world population, and it has been estimated that there will be 15 million new cases per year by 2020. Lung (1.4 million cases), breast (1.2 million cases), and colorectal (1 million cases) cancer are the most commonly diagnosed cancers, whereas lung cancer (1.2 million cancer deaths), stomach cancer (700 000 deaths), and liver cancer (600 000 deaths) are the most common causes of cancer death (Parkin et al., 2005). Numbers of new cancer cases (incidence) and deaths (mortality) in 2002 are presented in Figure 1 for developed and developing countries. The ratio of mortality to incidence reflects the fatality rate of the cancer. Pancreas and liver cancer, for instance, have similar incidence and mortality because their prognosis is poor. Breast cancer has a relatively good prognosis, so mortality is much lower than incidence, particularly in developed countries. Many types of cancer vary in incidence by more than one order of magnitude between different populations, and every type is rare in some part of the world (Doll and Peto, 1981). The convergence toward local cancer rates seen among immigrants (Figure 2) excludes a genetic explanation of these differences. By the 1960s, cancer epidemiologists had therefore concluded that most cancers are in principle preventable and many could be avoided by a suitable choice of lifestyle and environment. Many specific causes of cancer are now known, the most important being smoking, obesity, and a few cancer-causing (oncogenic) viruses, but a large proportion of global variation for common cancers such as breast, prostate, colon, and rectum remains unexplained. Age-specific cancer incidence and mortality rates have fallen for some cancer sites, while other cancers have become more common, reflecting changes in relevant exposures, diagnosis, treatment, and screening. Increases in cigarette smoking since the 1950s caused large increases in death rates for smoking-related cancers, but overall mortality from cancers not caused by smoking has generally decreased or remained stable in most Western countries (Peto et al., 2006).

Cancer screening programs can reduce mortality by early detection of the disease and hence earlier treatment, but for some cancers the benefit may be too small to justify the costs. Well-organized cervical screening prevents the majority of cervical cancers by detecting and treating premalignant disease, but for breast and prostate cancers mortality is reduced while cancer incidence is increased by screening, because early cancers are detected that would never have become symptomatic. Widespread prostate specific antigen (PSA) testing from around 1986 onward has caused an enormous increase in the incidence of prostate cancer in the United States, followed a few years later by smaller increases in other countries, but has had only a small effect on mortality. Population screening for colorectal cancer has recently been introduced in some Western countries, but its long-term impact on mortality and morbidity in a population setting will not be known for many years. Studies on the benefits of lung cancer screening are ongoing. Some screening programs are targeted at individuals at high risk, particularly people with a strong family history of the disease.

International Encyclopedia of Public Health, 2nd edition, Volume 1

Environmental and Lifestyle Causes of Cancer Carcinogenic Effects of Tobacco The most important discovery in the history of cancer epidemiology is the carcinogenic (cancer-causing) effect of tobacco. Lung cancer incidence increases rapidly among continuing smokers, but remains roughly constant in ex-smokers. The risk is therefore greatest in those who begin to smoke when young and continue throughout life. Secondhand, or environmental, tobacco smoking is also carcinogenic, but it is hard to quantify the magnitude of the risk. The large increase in male cigarette smoking in most developed countries that occurred during the first half of the twentieth century caused an unprecedented epidemic in the lung cancer rate several decades later. A reduction in tar levels in cigarettes combined with decreases in smoking has subsequently reduced the lung cancer rate in many developed countries. Women in most Western countries began smoking later than men and fewer have stopped, so their lung cancer rates are either still increasing or falling less rapidly. For many years, the carcinogenic effects of tobacco were thought to be restricted largely to the lung, pancreas, bladder, and kidney, and (synergistically with alcohol) the larynx, mouth, pharynx (except nasopharynx), and esophagus. More recent evidence indicates that stomach, liver, cervix, myeloid leukemia, and probably colorectal cancer are also increased

http://dx.doi.org/10.1016/B978-0-12-803678-5.00048-5

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Developed 482

Lung

481

424 196

Stomach 353

Colon/rectum

423 405

129

316 196

160

118

513

Prostate

91

130

165 366 344

74 71 58 50

Liver Esophagus 175

Bladder

52 65

Oral cavity

256 210

22

83

39 58 28 71 71 87 40 41 20 41 27

Larynx Pancreas Kidney etc. Other pharynx Brain, nervous system

700

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500

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200

111

58

101 79 92 59 82 50 54 48 42 22 65 48 67 48

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Incidence Mortality

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97

Corpus uteri Liver Esophagus Leukemia

62 29 36 38 16 15 55 38

Non-Hodgkin lymphoma

34

65 68

Pancreas

26 8

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44

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33 25

Kidney etc.

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234 214

84

136

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195 161

Ovary etc.

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Lung

500

221

Cervix uteri Stomach

400

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190 312

Colon/rectum

300

Female

636

700

99

56

70 46

Leukemia Non-Hodgkin lymphoma

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Developing

Male

7

21

63 62

108

147 143 130 110

75 59 58 38 43 40 72 38 60 17 26 14

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Incidence Mortality

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Figure 1 Estimated numbers of new cancer cases (incidence) and deaths (mortality) in 2002. Data shown in thousands for developing and developed countries by cancer site and sex. Reproduced from Parkin, D.M., Bray, F., Ferlay, J., Pisani, P., 2005. Global cancer statistics, 2002. CA Cancer J. Clin. 55, 74–108.

by smoking. This makes smoking the most important known risk factor for cancer. The relative importance of different smoking-related diseases varies widely between populations, as smoking usually multiplies the background rate due to other factors. In China, where liver cancer is common, smoking causes more premature deaths from liver cancer than from heart disease, while in the United States liver cancer is rare even in smokers (Figure 3).

The Effects of Diet and Overweight Nutritional epidemiology is notoriously complex owing to the variety of foods and their many constituents and to

intercorrelations and temporal changes in their patterns of use. Cancer risks in old age may also depend as much on diet in early life as on current habits. Most dietary factors do not show a strong and consistent enough effect to establish them unequivocally as important carcinogens or anticarcinogens. Exceptions are drinking alcohol, consumption of various foods contaminated with aflatoxin, and a few local customs (such as feeding Chinese-style salted fish to infants, which causes nasopharyngeal cancer). Extensive research during the past two decades has shown that rates for various cancers correlate fairly consistently with certain aspects of diet, but opinions still differ on the strength of the evidence. In the 1980s, nutritional epidemiology focused

Cancer Epidemiology

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15

Cumulate rate by age 75 (%)

Osaka 1970−70 Osaka 1988−92

Hawaiian Japanese 1988−92 Hawaiian Caucasian 1968−72 Hawaiian Caucasian 1988−92

10

5

0 Prostate

Colon (M)

Stomach (M)

Breast (F)

Cancer type Figure 2 Cancer rates in migrants become similar to those in the local population. Cancer rates in 1990 among Japanese migrants to Hawaii, and around 1970 and 1990 in Japan (Osaka) and in Hawaiian Caucasians. Local rates for prostate, colon, and breast cancer increased over time (due partly to increased completeness of diagnosis and registration, particularly for prostate cancer in Hawaiian Caucasians) and stomach cancer decreased; but the effects of migration were larger.

China Liver cancer 11%

Lung cancer 18%

Stomach cancer 9% Esophageal cancer 8% TB 5%

Other cancer 4% Heart disease 9%

Other respiratory 27%

Stroke 9%

USA Other respiratory 12% Stroke 5%

Heart disease 36%

Stomach cancer + liver + TB 1% Lung cancer 39%

Esophageal cancer 2% Other cancer 5%

Figure 3 Deaths below age 70 in 1990 caused by smoking in China and the United States. Other cancers are mouth, pharynx, larynx, bladder, and pancreas. Data on China are derived from Liu, B.Q., Peto, R., Chen, Z.M., et al., 1998. Emerging tobacco hazards in China: 1. Retrospective proportional mortality study of one million deaths. Br. Med. J. 317, 1411–1422, and data on the United States are derived from Peto, R., Lopez, D., Boreham, J., et al., 1994. Mortality from Tobacco in Developed Countries, 1950–2000. Oxford University Press, Oxford, UK.

mainly on meat, fat, and total energy intake as potential risk factors, and on dietary fiber, fruits, and vegetables, vitamins A, C, and E, and b-carotene as protective factors. More recent research has concentrated on red and processed meat as risk

factors, and on folate and other B vitamins, vitamin D and calcium, selenium and specific non-nutrient components of fruits, vegetables, and whole grains (e.g., phytoestrogens and isothiocyanates present in cruciferous vegetables) as protective factors. The overall evidence that fats are hazardous and fruits and vegetables are protective seems less convincing than initially thought, and more specific compounds and mechanisms are being investigated. Fat is classified according to its source (animal or vegetable fat) and its different subtypes (e.g., saturated fat). A high intake of n-3 fatty acids, derived from fatty fish, may prove to be beneficial. The evidence on diet and cancer has been systematically reviewed and summarized by the World Cancer Research Fund/American Institute for Cancer Research (2007). Dietary supplements may not have the same effects as the foods that contain them, and some may even be harmful. For example, b-carotene appeared to be associated with reduced risk of cancer in observational studies, but 12 years of treatment in a large randomized trial showed no benefit, and in two shorter trials the lung cancer risk was higher in those who received b-carotene supplements (Greenwald et al., 2007). Aspirin probably reduces colorectal cancer incidence but may take a decade or more to do so. Most reports conclude that about one-third of cancer deaths might be avoidable by dietary change. However, dietary recommendations differ, and Doll and Peto (2005) concluded that only cancers due to obesity are definitely avoidable. Radical changes in national dietary habits would not be easy to achieve even if there were a consensus on which foods are relevant. There is now a consensus that cancer is commoner in those who are overweight. The evidence on weight is strongest for postmenopausal breast cancer and cancers of the endometrium, gallbladder, and kidney, but several other sites contribute to the observed overall cancer risk. A large prospective cohort of nonsmokers in America, where obesity is particularly common, provides the strongest evidence on the

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association between body mass index (BMI; weight divided by the square of height) and cancer mortality (Calle et al., 1999). The authors did not calculate an attributable fraction, but if the observed excess mortality reflects a direct effect their data suggest that approximately 10% of all cancer deaths among American nonsmokers (7% in men and 12% in women) would be avoided if no one’s BMI exceeded 25 kg m 2. It is, however, not clear how much the risk can be reduced by weight reduction in those who are already overweight. Mortality from nonmalignant diseases is increased in those who are either too thin or too fat. Since obesity is an increasing problem in Western societies, the number of weight-related cancers will inevitably increase in the years to come.

Reproductive and Hormonal Factors The effects of reproductive factors on breast and ovarian cancer have long been assumed to reflect underlying hormonal processes, and this is confirmed by the effects of both endogenous and exogenous hormones. Breast cancer incidence is transiently increased by pregnancy and while estrogens are administered as oral contraceptives or hormone replacement therapy (HRT), and is permanently lowered by late menarche, early menopause, early first childbirth, and high parity. Endometrial cancer incidence is also transiently increased by HRT. Combined estrogen and progestin HRT has a larger effect than estrogen alone for breast cancer, but a smaller effect for endometrial cancer. Ovarian cancer incidence declines with increasing parity, and both endometrial and ovarian cancers are less common in oral contraceptive users. Both oral contraceptives and HRT appear to reduce colorectal cancer incidence. The Western diet is associated both with earlier age at menarche and with postmenopausal obesity, which increases endogenous estrogen production. Breast cancer incidence is much higher in most Western countries than in many developing countries, and this is partly (and

Table 1

perhaps largely) accounted for by these dietary effects combined with later first childbirth, lower parity and shorter breastfeeding. The development of cancers of the testis and prostate may also depend on hormonal effects, but apart from the increased risk in an undescended testis, no behavioral or reproductive correlate is strongly predictive of these diseases.

Viruses, Bacteria, and Parasites Important discoveries of the past 30 years in cancer epidemiology relate to the carcinogenic effects of infectious agents. Recent estimates of the global cancer burden caused by specific viruses, bacteria, and parasites (Parkin, 2006) imply that about 20% of all cancers worldwide are caused by known infections (Table 1). Helicobacter pylori, a chronic gastric bacterial infection that can cause gastric ulcers, is a major factor in the development of stomach cancer, accounting for an estimated 63% of all stomach cancers and 5.5% of all cancers world-wide. The evidence is particularly strong for noncardiac gastric cancers, which comprise more than 80% of gastric cancers. Helicobacter pylori is common in developed and developing countries, and more than half of all stomach cancers might be prevented if H. pylori could be eradicated. More than 100 human papillomaviruses (HPVs) have been identified, and DNA from a subgroup of sexually transmitted HPVs that includes HPV16, HPV18, and HPV45 is detectable in virtually all cervical cancers world-wide. These and other HPVs are also found in other anogenital cancers, and in some cancers of the mouth and pharynx. HPV vaccines are now available, but their long-term effect on overall cervical cancer incidence remains to be established. At present, the high cost of HPV vaccines precludes their widespread use in developing countries that lack the resources for organized cervical screening, where their potential impact is greatest. Their effect in countries that already have effective screening is unclear.

Carcinogenic infectious agents and the percentage of the global cancer burden they account for Percentages caused by organism

Agent

Organism

Cancer

Helicobacter pylori Human papillomaviruses (HPV)

Bacterium Virus

Hepatitis B and C virus (HBV, HCV) Epstein–Barr virus (EBV)

Virus Virus

Human immunodeficiency virus/Herpes virus 8 (HIV/HHV8) Schistosomes Human T-cell lymphotropic virus I (HTLV-1) Liver flukes Total

Virus

Stomach Cervix Other anogenital Mouth, pharynx Liver Nasopharynx Hodgkin lymphoma Burkitt’s lymphoma Kaposi sarcoma Non-Hodgkin lymphoma Bladder Leukemia Liver

Parasite Virus Parasite

% of this cancer

% of global cancer burden

63 100 56 4 85 98 46 82 100 12 3.0 1.1 0.4 –

5.5 4.5 0.5 0.1 4.9 0.7 0.3 0.1 0.6 0.3 0.1 0.03 0.02 17.8

Adapted from Parkin, D.M., 2006. The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer 118, 3030–3044.

Cancer Epidemiology They are only effective against specific HPV types, so they will not prevent all cervical cancers; they are unlikely to be effective in women who have already been infected; and vaccinated women may be less likely to participate in cervical screening, which is known to be very effective. The contribution of hepatitis B virus (HBV) to liver cancer in high-incidence regions has long been recognized, and the hepatitis C virus (HCV) is similarly carcinogenic. Hepatitis B infection is common in developing countries, and together with hepatitis C it accounts for 85% of all liver cancers worldwide (Parkin, 2006). The incidence of several virally induced cancers is further increased by specific cofactors such as salted fish (nasopharynx), smoking (liver and cervix), aflatoxin (liver), and malaria (the major cofactor with EBV for Burkitt’s lymphoma in Africa). There is also strong epidemiological evidence for an infective etiology in childhood leukemia, but no specific pathogen has been implicated. Therapeutic immunosuppression causes a marked increase in the incidence of non-melanoma skin cancer and some virally induced cancers. The discovery that many other epithelial cancers are also increased by immunosuppression (Buell et al., 2005) suggests that unidentified viruses may be important in these cancers as well. The alternative is the longstanding but equally speculative theory that many nonviral cancers are normally kept in check by the immune system.

Occupational and Environmental Carcinogens Roughly a dozen specific occupational exposures and several complex mixtures, particularly the combustion products of coal, have caused high risks of certain cancers (predominantly lung cancer) in heavily exposed workers. Exposure levels for many industrial hazards have been progressively reduced in many Western countries since the 1930s, and by the late 1970s it was assumed, probably correctly, that the occupational exposure levels then current would contribute a very small proportion of future cancer incidence. But uncontrolled asbestos use had been widespread in the construction industry in Western countries from the 1950s to the mid-1970s, when public concern led to a rapid reduction. The resulting epidemic of mesothelioma in building and other workers born after 1940 did not become apparent until the 1990s because of the long latency of the disease. Incidence rates are still rising, and asbestos exposure prior to 1980 may eventually cause 250 000 mesotheliomas and a similar number of lung cancers in Western Europe. Chrysotile (white asbestos) causes a much lower mesothelioma risk than other types, but all forms of asbestos cause cancer. This tragic episode was largely avoidable, as the carcinogenic effects of asbestos were known by 1960; but it illustrates the major weakness of epidemiology as an early warning system. The increase in cancer incidence caused by increased exposure to a carcinogen might not be detectable for several decades, and laboratory testing must remain the first line of defense against potentially dangerous new agents, particularly those affecting endocrine or paracrine signaling that could be biologically active at very low levels. Epidemiological studies of markers such as DNA adducts in the lung or chromosomal aberrations in lymphocytes might

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also provide early warning of a potential hazard. But such direct or indirect measures of mutagenic or transforming potency have never detected an important carcinogen and even today cannot provide quantitative estimates of risk. Epidemiological data on human cancer rates still provide the only reliable evidence that the cancer risks caused by long-established activities such as working in an oil refinery or living near a high-voltage power line are not large. There is as yet little evidence of a link between mobile phone use and cancer risk, but it may be too early for an effect to be detected. Apart from melanoma and other (usually nonfatal) skin cancers due to excessive exposure to sunlight, the only substantial and widespread cancer risk known to be caused by an avoidable environmental factor in developed countries is the further increase in lung cancer among smokers caused by indoor radon escaping from the ground or from building materials, although both indoor and outdoor air pollution from fossil fuels may also contribute to the risk in smokers. The risk to nonsmokers is relatively trivial in developed countries, but burning fossil fuels indoors without adequate ventilation certainly contributes to the high lung cancer rates, even in nonsmokers, seen in parts of China.

Genetic and Molecular Epidemiology of Cancer An inherited mutation that predisposes carriers to cancer often involves a gene that is mutated or deleted during the transformation of a normal cell to cancer in people who have not inherited a defective gene. Some of these genes affect metabolism of carcinogens, but many are involved in normal cellular mechanisms such as detection and repair of DNA damage, control of the cell cycle, or apoptosis (programmed cell death). They have been discovered in many ways, notably by laboratory studies of such pathways, linkage in families with cancer syndromes such as hereditary retinoblastoma, DNA sequence homology with oncogenic viruses, and recently by direct comparison of normal and tumor DNA, which is now being done systematically throughout the genome for a few cancers.

Polymorphisms in Candidate Genes There have been many studies comparing the prevalence in cancer patients and unaffected controls of differences in DNA sequence in genes involved in the metabolism of external or endogenous mutagens or in the production or processing of sex hormones or their analogs. A few polymorphisms in such genes seem to alter the risk substantially, such as the N-acetyltransferase 2 (NAT2) variant underlying the slow acetylator phenotype, which increases the risk of bladder cancer, particularly in workers heavily exposed to certain aromatic amines. But systematic meta-analysis reveals little or no effect for most such single polymorphisms, and the pooled data for the minority that are statistically significant usually suggest carrier:noncarrier risk ratios of less than two, and often much less. There have been various reports of statistically significant gene–environment interactions, such as a much larger lung cancer risk due to passive smoking in women with glutathione S-transferase m1 (GSTM1) deficiency, or an increased breast cancer risk due to smoking in postmenopausal women that

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was confined to NAT2 slow acetylators. In these examples, however, the estimates of the risk in susceptibles (although not their lower confidence limits) were inconsistent with the much lower overall effect of passive smoking on lung cancer or of smoking on breast cancer (which is nil) in larger studies. Many apparently significant gene–gene or gene– exposure interactions will arise by chance, but some will be real. The reported interaction between a polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene and dietary folate in colorectal cancer is a biologically plausible mechanism with epidemiological support.

Familial Risks for Common Cancers Hereditary cancer syndromes caused by an inactivating mutation in a single crucial gene such as hereditary breast cancer (BRCA1 or BRCA2), polyposis coli (APC), Li-Fraumeni syndrome (TP53), and familial retinoblastoma (RB1) are very rare, and most familial cancers seem to be the result of a spectrum of genetic risk in the population, varying continuously from very low to very high, because of the combined effects of dozens or even hundreds of low-penetrance variants in different genes, each with a very small effect. The people at highest risk are those who happen to inherit a large number of such variants. This has been studied most extensively for breast cancer. The high risk in patients’ identical twins indicates that susceptible women contribute a high proportion, and perhaps even the majority, of overall breast cancer incidence. This must be due mainly to low-penetrance genes, as only about 2% of all cases are attributable to inactivating mutations in BRCA1 or BRCA2. Such polygenic susceptibility conferring a site-specific lifetime risk the order of 30–50% in those at highest risk may underlie many cancers. The effects of such variants in combination with each other and with environmental risk factors could be substantial, but their total contribution to cancer incidence will not be known until data on risk factors and extensive genotyping are available for very large numbers of patients and controls. Recent studies have focused on inactivating mutations or polymorphisms in genes involved in cellular mechanisms of cancer development rather than carcinogen metabolism. This is now a major area of research, and several low-penetrance genes have already been discovered. Inactivating mutations in several genes that interact with BRCA1 or BRCA2 (ATM, CHEK2, BRIP1, PALB2) increase the breast cancer risk by approximately twofold, and some polymorphisms in such genes also confer a moderately increased cancer risk. An example is the I1307K single nucleotide polymorphism (SNP) in the APC gene, which is carried by about 1 in 20 Ashkenazi Jews and almost doubles their colon cancer risk.

Genomewide Studies Complete genetic information on cancer patients and healthy controls will ultimately require sequencing of the whole genome in many thousands of individuals. This is not yet feasible, but a million known SNPs throughout the genome can now be analyzed simultaneously, and very-large-scale studies involving protein and RNA expression profiles or DNA methylation at specific sites are also being carried out.

Genomewide SNP studies have identified common haplotypes (ancient DNA sequences that may be carried by 10% or more of the population) associated with prostate, colorectal, and breast cancer risk. These associations sometimes identify a specific gene, but some are in noncoding regions, and their significance is not yet understood. An SNP that is commoner in cancer patients may cause the specific alteration in a protein that produces the increased cancer risk, but most merely identify a region containing an unknown susceptibility locus, and discovering the relevant sequence variant and its effects may require extensive further research.

Mechanisms of Carcinogenesis Age-incidence patterns for non-hormone-dependent carcinomas, and the effects of timing and dose level of various agents alone and in combination (particularly smoking, alcohol, ionizing radiation, and some occupational carcinogens), are parsimoniously explained by the multistage model of carcinogenesis. This was developed many years before the identification of any of the hypothesized sequence of heritable events in human carcinogenesis and has led to several important conclusions, notably the epidemiological and experimental evidence that somatic aging processes per se play little or no role in carcinogenesis (Figure 4). The incidence rate of cancer is presumably proportional both to the rate of the final rate-limiting step in carcinogenesis and to the number of premalignant cells that have undergone all but this final step. The rapid increase in the lung cancer incidence rate among continuing smokers ceases when they stop smoking, the rate remaining roughly constant for many years in ex-smokers. The fact that the rate does not fall abruptly when smoking stops indicates that the mysterious final event that triggers the clonal expansion of a fully malignant bronchial cell is unaffected by smoking, suggesting a mechanism involving signaling rather than mutagenesis. Such data are still generating new mechanistic hypotheses.

The Future of Cancer Epidemiology Over the next decade, cancer epidemiologists will be increasingly preoccupied with genetically susceptible subgroups. Comparison of the DNA in cancerous and normal cells from the same patient may lead directly to the identification of most of the genes that are commonly mutated in carcinogenesis. Candidate genes are also being identified on the basis of structural homologies from the human genome sequence. Extensive sequence or SNP comparisons between affected relatives and between cancer patients and controls may define combinations of polymorphisms or inherited defects in such genes that identify a few percent of the population whose average lifetime risk may be as high as 50% for a particular cancer. An alternative possibility is that many susceptibility genes will be discovered by studying phenotypic characteristics such as mammographic density or chromosomal instability that correlate with cancer risk. Assays for defective DNA repair correlate consistently with substantially increased susceptibility, and chromosomal

Cancer Epidemiology

Age at first exposure (years) 15–24 25–34 35+ 10

0

45 55 10 25 35 Years since beginning exposure

100

Cumulative skin tumor risk (%)

Cumulative mesothelioma risk (%)

20

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50 Age at first exposure (weeks) 10 25 40 55 0 40 50 60 70 80 90 100 Weeks since beginning exposure

Figure 4 Age has no effect on susceptibility to some carcinogens. Left panel, cumulative mesothelioma risk in US insulation workers. Right panel, cumulative skin tumor risk in mice treated weekly with benzo(a)pyrene. Mesothelioma rates in humans and skin tumor rates in mice depend on time since first carcinogenic exposure but not on age, suggesting an initiating effect of these carcinogens. Lung cancer incidence in smokers depends on duration of smoking but not on age, and stops increasing when smoking stops, indicating both early- and late-stage effects. Radiation-induced cancer incidence increases with age at exposure above age 20, suggesting predominantly late-stage effects.

aberrations predict increased cancer risk irrespective of carcinogenic exposure. Once they are identified, susceptible people might benefit disproportionately from screening or prophylaxis, while those at low risk would be reassured. But there will also be penalties. A different susceptible minority will be identified for each disease, and a high proportion of the population may eventually suffer the consequences of being classed as genetically susceptible to some major risk. The hazards of screening for cancer susceptibility are illustrated by the widespread introduction of testing for prostate-specific antigen in the United States, which has reduced prostate cancer mortality only marginally but has led to a sharp increase in recorded incidence and considerable postoperative psychosexual and physical morbidity. Striking gene–environment interactions may be discovered, but most causes of cancer are likely to increase the risk by a smaller amount but a similar factor in those who are less susceptible. If smokers are less likely to stop smoking on discovering that their lifetime lung cancer risk is only 10%, the population death rate might even be increased by such knowledge. Advances in genetic and molecular understanding will increasingly enable epidemiologists to quantify the relationships between risk factors and specific events in carcinogenesis. Direct monitoring of changes in the genes that underlie carcinogenesis or their products is likely to provide sensitive and specific measures that can be correlated both with cancer incidence and with exposure to carcinogenic agents or activities. Characteristic mutations in DNA from subclinical cancers or their precursor lesions can already be quantified, and serum levels of hormones such as estrogen and prolactin, or growth factors such as insulin-like growth factor-I, as well as chromosomal damage itself, are predictive of increased risk for certain cancers. The effects of some carcinogens are seen mainly in histological subtypes of cancer. For example, smoking increases

the risk for squamous cell cervical cancer, but not for the adenomatous type. Such research is now extended through the identification of subtypes of cancer that develop through different pathways by analysis of their patterns of gene alterations or protein expression. The most significant developments in cancer epidemiology may result from discoveries in virology and tumor immunology. The speculation that unidentified viruses (perhaps including some animal viruses) are associated with many human cancers is consistent with the large increase in overall cancer rates seen in immunosuppressed patients (Buell et al., 2005). The difficulty is that an unknown virus might mimic the epidemiological effects of dietary or genetic mechanisms. Thus, for example, the migrant patterns for prostate cancer (Figure 2) might be due partly to an endemic infection, as they are for stomach cancer. Viruses usually act synergistically with other carcinogens and therefore provide alternative approaches to risk reduction. The crucial issue is which of the increased cancer risks in immunosuppressed patients reflect an unknown viraletiology and which reflect immunosurveillance targeted at nonviral tumor markers. Some cancers may well be preventable by vaccination with tumor-specific antigens or by some less specific immunostimulation.

Current Priorities in Cancer Prevention The large differences in the pattern of cancer incidence between developed and developing countries (Figure 1) imply different priorities for prevention, but at an individual level the most important difference is between smokers and nonsmokers, particularly in developed countries. Table 2 shows approximate percentages of future cancer deaths in the United States that would be avoided by successively removing the effects of

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Table 2 Approximate percentages of future cancer deaths among smokers and nonsmokers in the United States that would be prevented by successive elimination of smoking, known infections, alcohol, sun exposure, current levels of workplace and air pollution, lack of exercise, and obesity Deaths (%) after removing preceding causes Cause

Current smokers

Nonsmokers

Smoking Known infections Alcohol Sunlighta Air pollution Occupation Lack of exercise Diet Overweight (BMI > 25 kg m 2) Other dietary factorsb Presently unavoidable

60 2 0.4 ? 0.4 0.4 0.4

– 5 1 ? 1 1 1

4 4–12? About a quarter

10 10–30? At least half

a

Sunlight is the main source of vitamin D and hence may prevent more deaths from other cancers than it causes through melanoma and other skin cancers. The effects of specific dietary factors in people of normal weight are still uncertain.

b

smoking, known infections, alcohol, current occupational and environmental pollution, inactivity, and obesity. Whether sunlight increases or reduces overall cancer mortality is not yet established. The additional effect of specific dietary recommendations such as those of the American panel (American Institute for Cancer Research/World Cancer Research Fund, 1997) is much more speculative. Avoidance of overweight and prevention or treatment of oncogenic infections are the most important aims for nonsmokers; but it is absurd for smokers in the West to worry about anything except stopping smoking. Tobacco causes one-third of all cancer deaths in developed countries. About one in five of cancers worldwide are caused by known infectious agents. HBV alone causes almost as many cancers as smoking in China, and can be prevented by vaccination. HPV vaccines may eventually prevent almost all cervical cancers, and if the prevalence of H. pylori can be reduced, many stomach cancers would be avoided. The belated elimination of asbestos by many Western countries will eventually prevent the great majority of mesotheliomas and many lung cancers. Various cancer screening tests are partially effective, and cervical screening is very effective.

Acknowledgments This article is based on an earlier review (Peto, J., 2001. Cancer epidemiology in the last century and the next decade. Nature 411, 390–395), which includes references to original work. We are grateful to Cancer Research UK for support.

See also: Clinical Epidemiology; Disease Prevention: An Overview; Environmental and Occupational Epidemiology; Genetic Epidemiology.

References American Institute for Cancer Research/World Cancer Research Fund, 2007. Food, Nutrition and the Prevention of Cancer: A Global Perspective. American Institute for Cancer Research/World Cancer Research Fund, Washington, DC. Buell, J.F., Gross, T.G., Woodle, E.S., 2005. Malignancy after transplantation. Transplantation 80, S254–S264. Calle, E.E., Thun, M.J., Petrelli, J.M., Rodriguez, C., Heath, C.W., 1999. Body-mass index and mortality in a prospective cohort of US adults. N. Engl. J. Med. 341, 1097–1105. Doll, R., Peto, R., 1981. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Natl. Cancer Instit. 66, 1191–1308. Doll, R., Peto, R., 2005. Epidemiology of cancer. In: Warrell, D.A., Cox, T., Firth, J., Benz Jr., E.J. (Eds.), Oxford Textbook of Medicine, fourth ed. Oxford University Press, Oxford, UK, pp. 193–218. Greenwald, P., Anderson, D., Nelson, S.A., Taylor, P.R., 2007. Clinical trials of vitamin and mineral supplements for cancer prevention. Am. J. Clin. Nutr. 85, 314S–317S. Liu, B.Q., Peto, R., Chen, Z.M., et al., 1998. Emerging tobacco hazards in China: 1. Retrospective proportional mortality study of one million deaths. Br. Med. J. 317, 1411–1422. Parkin, D.M., Bray, F., Ferlay, J., Pisani, P., 2005. Global cancer statistics, 2002. CA Cancer J. Clin. 55, 74–108. Parkin, D.M., 2006. The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer 118, 3030–3044. Peto, R., Lopez, D., Boreham, J., et al., 1994. Mortality from Tobacco in Developed Countries, 1950–2000. Oxford University Press, Oxford, UK. Peto, R., Watt, J., Boreham, J., 2006. Deaths from Smoking. International Union Against Cancer (UICC), Geneva, Switzerland.

Further Reading Adami, H.-O., Hunter, D.J., Trichopoulos, D., 2002. Textbook of Cancer Epidemiology. Oxford University Press, Oxford, UK. Buffler, P.E., 1997. Mechanisms of Carcinogenesis: Contributions of Molecular Epidemiology. International Agency for Research on Cancer, Lyon, France. Dos Santos Silva, I., 1999. Cancer Epidemiology: Principles and Methods, second ed. International Agency for Research on Cancer, Lyon, France. Peto, J., Carbone, M. (Eds.), 2004. Cancer Epidemiology. Oncogene, vol. 23, pp. 6327–6540. Schottenfeld, D., Fraumeni, J.F., 2006. Cancer Epidemiology and Prevention, third ed. Oxford University Press, New York. Stewart, B.W., Kleihues, P., 2003. World Cancer Report. IARC Press, Lyon, France.

Relevant Websites http://www.cancer.org – American Cancer Society (last accessed 12.04.16.). http://www.cancer.gov/ – American National Cancer Institute (last accessed 12.04.16.). http://www.cancerresearchuk.org/ – Cancer Research UK (last accessed 12.04.16.). http://www.deathsfromsmoking.net/ – Deaths from Smoking. Estimates of the Number of Deaths Caused by Smoking, for Each of 40 Developed Countries (and Five Groupings of Countries) (last accessed 12.04.16.). http://www-dep.iarc.fr/ – International Agency for Research Cancer, Which Includes Worldwide Cancer Incidence and Mortality Data (last accessed 12.04.16.).

Cancer: Global Burden, Trends, and Projections Freddie Bray and Kevin D Shield, Section of Cancer Surveillance, International Agency for Research on Cancer, Lyon, France Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Freddie Bray, volume 1, pp. 424–451, Ó 2008, Elsevier Inc.

Nomenclature AFCRN African Cancer Registry Network ASR Age-standardized rate CI5 Cancer Incidence in Five Continents HDI Human Development Index

IARC International Agency for Research on Cancer PSA Prostate-specific antigen TURP Transurethral resection of the prostate WHO World Health Organization

Glossary Cancer Incidence in Five Continents (CI5) A serial publication (currently in its tenth iteration) of high-quality cancer incidence data from cancer registries. Case fatality (cancer) The probability of dying from cancer within a given period of time after diagnosis (1 – survival rate). GLOBOCAN A global cancer database that provides data for 184 countries on cancer incidence, mortality, and prevalence for 27 cancer sites by age and sex. Incidence rate (cancer) The frequency of occurrence of new cases of cancer in a defined population for a given period of time. The numerator is the number of new cancer cases and the denominator is the person-time at risk from which the cases in the numerator arose.

Introduction Cancer is a leading cause of death and disability globally (Lozano et al., 2013; World Health Organization, 2016; Soerjomataram et al., 2012; Ferlay et al., 2015), the scale and profile of which can be linked to the Human Development Index (HDI) (Bray et al., 2012). Population growth (Torre et al., 2015), population aging (particularly in developing societies) (Lutz et al., 2008; Lloyd-Sherlock et al., 2012), changes in lifestyle behaviors that increase the risk of cancer (such as smoking, obesity, alcohol consumption), and reproductive changes among women (including a decrease in parity and an increase in the age at first birth) (McCormack and Boffetta, 2011) have led, and will continue to lead, to an increase in the magnitude of the cancer burden at all geographical levels (Bray et al., 2015). The current cancer burden is not uniform however, and nor will be the expected future increase in this burden (Bray, 2016). Therefore, an understanding of how cancer incidence, mortality, and prevalence are measured, together with robust statistics on the variations in the historical and current cancer burdens as well as predictions of future cancer burdens, is critical for cancer prevention, early detection, and the development of risk reduction programs. This article aims to summarize (1) the methodology used to collect information on global cancer incidence, mortality,

International Encyclopedia of Public Health, 2nd edition, Volume 1

Mortality rate The number of deaths in a population from a given cause over a given period of time. Prevalence (cancer) The number of people alive as of a given date who have been diagnosed with cancer (complete or lifetime prevalence), or who have been diagnosed with cancer within a given number of previous years (partial prevalence). This measure reflects both incidence and prognosis. Survival (cancer) The time that elapsed between the diagnosis of and death from cancer. Survival (cancer) proportion The percentage of people who are alive after a given period of time after having been diagnosed with cancer.

and prevalence as well as how to estimate these statistics where data are sparse or nonexistent; (2) global variations in cancer incidence, mortality, and prevalence; (3) trends in cancer incidence and mortality based on high-quality data from worldwide cancer registries; and (4) the expected changes in the global profile of cancer by 2030 due to anticipated changes in population age structures and to population growth.

Routine Measures of Cancer Burden Various measures are used to quantify the cancer burden at the local, national, regional, and global levels (Ferlay et al., 2015), with numerous data sources available to enable quantification of this burden. These measures include cancer incidence (the number of new cancer cases over a given period of time), cancer prevalence (the number of people living with cancer over a given period of time), and cancer mortality (the number of cancer deaths over a given period of time).

Incidence Differences in the incidence of various cancers over a given period of time are useful in providing clues as to the

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underlying etiology of cancer incidence. These differences are also useful in providing data on cancer occurrences and transitions (Ferlay et al., 2015) for the purposes of assessing and controlling the impact of cancer in the community through planning, evaluating, and prioritizing resources for primary prevention where the aim is to reduce cancer incidence by means of changes in cultural and personal patterns of behavior (Weir et al., 2003). Data on the incidence of new cancer cases are collected by population-based (regional or national) cancer registries which classify such information in a defined population. The comparability, completeness, and accuracy of these data are essential for making reliable inferences regarding geographical and temporal variations in incidence rates. Cancer Incidence in Five Continents (CI5) (see Relevant Websites), published by the International Agency for Research on Cancer (IARC) and the International Association of Cancer Registries, is considered to be the most comprehensive and accurate source of cancer incidence data and only includes data from high-quality population-based cancer registries. Specifically, CI5, which was first published in 1966 (Doll et al., 1966), is now in its tenth volume (Forman et al., 2013), containing information from 290 cancer registries in 68 countries about cancers diagnosed from 2003–07. Additionally, the CI5plus database compiles comparable incidence rates across time, allowing for the analysis of rate trends in cancer incidence.

Mortality Cancer mortality (for a given cancer) is a key measure of the cancer’s impact and is determined based on both cancer incidence and fatality (1 – survival rate). As data on cancer mortality are dependent upon cancer survival, in countries with a high HDI, where both treatment and cancer management have markedly improved (De Angelis et al., 2014), trends in incidence and mortality can be divergent. Data on mortality are collected through vital registration systems, where, typically, a medical practitioner certifies the occurrence and cause of death (Mathers et al., 2005); however, in many resource-poor areas of the world, data on occurrence and cause of mortality are often collected through verbal autopsies (Mathers et al., 2005; Dikshit et al., 2012). The International Classification of Diseases (ICD) provides a standardized system of nomenclature and coding for mortality data, as well as a suggested format for death certificates (World Health Organization, 2007). The quality of mortality data, in general, is affected by both the degree of detail and the quality of the information, namely, the accuracy of the recorded cause of death, the completeness of registration, and the population coverage of the databases; indeed, mortality data are more comprehensively available than are incidence data. Data on cancer mortality are also available from the cancer mortality database of the World Health Organization (WHO) and held at IARC, which contains national cancer mortality data from 120 countries, covering, in many cases, extended periods of time (International Agency for Research on Cancer, 2016); however, these data are typically from more developed

countries, with the quality of the data varying in its completeness and coverage.

Prevalence Cancer prevalence is a combined measure of cancer incidence and fatality, knowledge of which assists in the quantification and development of the strategies needed for treating and supporting cancer patients (Bray et al., 2013). As such, data on cancer prevalence are estimated based on cancer incidence and fatality data; where such data are not available or are incomplete, they are based on mathematical modeling (Bray et al., 2013). However, unlike the measures of incidence and mortality, there is no universal definition of prevalence. Total (or complete) prevalence indicates the number of people in a defined population who are alive and have a previous diagnosis of cancer. Limited-duration (or partial) prevalence is estimated based on the number of people who are alive in a population and who have a previous diagnosis of cancer and is based also on the number of years since diagnosis, i.e., initial cancer treatment (within 1 year), clinical follow-up (2–3 years), and possible cure (4–5 years).

Trends in Incidence and Mortality Investigations of cancer trends have important applications in epidemiological research and in planning and evaluating cancer prevention strategies. Analyses of how rates of different cancers are changing in different populations over time can provide clues to the underlying determinants and serve as aids in formulating, implementing, or further developing population-based preventative strategies. Genetic factors have only a minor impact on time trends of cancer in the absence of large migration influxes and exoduses within the population under study. Issues concerning data quality and other detectable artifacts in interpreting time trends have been comprehensively addressed (Saxen, 1982; Muir et al., 1993), and cancerspecific artifacts and their likely effects on time trends are reasonably well understood. The efforts of cancer registries in standardizing procedures and data definitions have been important in providing consistently high-quality cancer incidence data and ensuring comparability of these data over time. Global trends in the five most common cancers are presented herein as age-standardized rates (ASR) using data compiled in successive volumes of the CI5. While these figures can only provide a broad overview of trends, references are made to trends in cancer mortality (where the trends diverge from incidence), in the age-specific rates by calendar period or birth cohort (where the age-adjusted trends are partially misleading), and according to subsite or histological groups (where they differ from the overall trend).

Data Synthesis: Global Estimates of Cancer Burden National cancer incidence, mortality, and prevalence data are available for a minority of countries, so estimation procedures are necessary to obtain a comprehensive global picture of cancer. The GLOBOCAN 2012, which used multiple data

Cancer: Global Burden, Trends, and Projections

Figure 1

Map depicting sources of incidence data and methods of estimation worldwide for GLOBOCAN.

sources, provides data for 184 countries by sex and age on cancer incidence, mortality, and prevalence (based on cancer survival) for 27 major cancer sites (Ferlay et al., 2015). The available sources and methods used to derive the GLOBOCAN 2012 by country estimates are summarized in Figure 1 (incidence) and Figure 2 (mortality). The preferable data for the compilation of cancer statistics are high-quality and high-coverage cancer incidence, mortality, and survival data sets for a given country. Incidence rates for a country are obtained wherever possible from cancer registries, and national mortality data are obtained from the WHO’s cancer mortality database. Adjustments are

Figure 2

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made where underreporting of mortality is suspected, and deaths recorded as due to uterine cancer are reallocated to the specific sites of the cervix or corpus uteri (Ferlay et al., 2015). When incidence data are unavailable or inaccurate, such data may be estimated by applying a registry-based incidence:mortality ratio to national mortality data; however, this ratio is dependent on country-level factors, as large survival differences exist between countries (Sankaranarayanan et al., 2010; De Angelis et al., 2014). Lastly, global prevalence is estimated by combining the estimated incidence data with corresponding estimates of survival (Pisani et al., 2002).

Map depicting sources of mortality data and methods of estimation worldwide for GLOBOCAN.

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Data from GLOBOCAN 2012 are provided as numbers, crude and age-adjusted rates, including ASRs based on population weights using the world standard (Doll et al., 1966). While the crude rates can be important as measures of the cancer ‘load,’ for planning purposes, the use of ASRs allows for differing population age structures between countries and regions. Data on cancer incidence, mortality, and prevalence are also provided in GLOBOCAN 2012 according to 21 geographical regions. Furthermore, countries can also be grouped according to their HDI, a summary measure of the average achievement in three dimensions of human development: (1) a long and healthy life, (2) knowledge (i.e., educational achievement), and (3) a decent standard of living (i.e., gross national income per capita, adjusted for purchase power parity) (Anand, 1994).

Global Cancer Burden in 2012 Excluding nonmelanoma skin cancers, 14.1 million people were diagnosed with cancer in 2012, 8.2 million people died of cancer, and 32.5 million people were living with cancer (5-year prevalence) (see Table 1). The five leading contributors to cancer incidence in terms of all new cancer cases were lung cancer (13.0%), breast cancer (11.9%), colorectal cancer (9.7%) prostate cancer (7.8%), and stomach cancer (6.8%); these cancers contributed almost 50% of all new cancers in

Table 1

2012. Indeed, over one-half of the total cancer mortality burden in 2012 was caused by four of the five above-noted leading contributors to cancer incidence. Lung cancer was the most common cause of cancer mortality, responsible for close to one in every five cancer deaths (19.4%), followed by liver (9.1%), stomach (8.8%), colorectal (8.5%), and breast cancer (6.4%). Lastly, the top five cancers within the 5-year prevalence category (taking into account both incidence and prognosis) contributed more than 50% of total cancer prevalence: breast cancer accounted for close to one in every five cancer cases (19.2%), followed by cancers of the prostate (11.9%), colorectum (10.9%), lung (5.8%), and cervix (4.8%). Men had a higher cancer incidence (7.4 vs. 6.7 million new cancer cases among men and women, respectively) and a higher cancer mortality (4.7 vs. 3.5 million cancer deaths of men and women, respectively) in 2012, whereas women had a higher 5-year prevalence of cancer (15.3 vs. 17.2 million among men and women, respectively). The distribution and frequency of the different cancer types varied also by sex (see Figure 3). In women, breast and colorectal cancer ranked first and second for both new cancer cases and 5-year cancer prevalence, while breast and lung cancer ranked first and second for cancer deaths. For men, lung and prostate cancer ranked first and second for new cancer cases, lung and liver cancer ranked first and second for cancer mortality, and prostate and colorectal cancer ranked first and second for 5-year cancer prevalence.

Estimated new cancer cases, deaths, and 5-year prevalence by cancer site in 2012

Cancer site (ICD-10 code)

Incident cases

%

Deaths

%

5-year prevalence

%

Lip, oral cavity (C00–08) Nasopharynx (C11) Other pharynx (C09, 10, C12–14) Esophagus (C15) Stomach (C16) Colorectal (C18–21) Liver (C22) Gallbladder (C23, 24) Pancreas (C25) Larynx (C32) Lung (C33, 34) Melanoma of skin (C43) Kaposi sarcoma (C46) Breast (C50) Cervix uteri (C53) Corpus uteri (C54) Ovary (C56) Prostate (C61) Testis (C62) Kidney (C64–66) Bladder (C67) Brain, nervous system (C70–72) Thyroid (C73) Hodgkin lymphoma (C81) Non-Hodgkin lymphoma (C82–85, C96) Multiple myeloma (C88, C90) Leukemia (C91–95) All cancers excluding nonmelanoma skin cancer (C00–97 excluding C44)

300 000 87 000 142 000 456 000 952 000 1 361 000 782 000 178 000 338 000 157 000 1 825 000 232 000 44 000 1 671 000 528 000 320 000 239 000 1 095 000 55 000 338 000 430 000 256 000 298 000 66 000 386 000 114 000 352 000 14 068 000

2.1 0.6 1.0 3.2 6.8 9.7 5.6 1.3 2.4 1.1 13.0 1.7 0.3 11.9 3.8 2.3 1.7 7.8 0.4 2.4 3.1 1.8 2.1 0.5 2.7 0.8 2.5 100.0

145 000 51 000 96 000 400 000 723 000 694 000 746 000 143 000 330 000 83 000 1 590 000 55 000 27 000 522 000 266 000 76 000 152 000 307 000 10 000 143 000 165 000 189 000 40 000 25 000 200 000 80 000 265 000 8 202 000

1.8 0.6 1.2 4.9 8.8 8.5 9.1 1.7 4.0 1.0 19.4 0.7 0.3 6.4 3.2 0.9 1.9 3.7 0.1 1.7 2.0 2.3 0.5 0.3 2.4 1.0 3.2 100.0

702 000 229 000 310 000 464 000 1 538 000 3 544 000 633 000 206 000 212 000 442 000 1 893 000 870 000 80 000 6 232 000 1 547 000 1 217 000 587 000 3 858 000 215 000 907 000 1 320 000 343 000 1 206 000 189 000 833 000 229 000 501 000 32 455 000

2.2 0.7 1.0 1.4 4.7 10.9 2.0 0.6 0.7 1.4 5.8 2.7 0.2 19.2 4.8 3.7 1.8 11.9 0.7 2.8 4.1 1.1 3.7 0.6 2.6 0.7 1.5 100.0

Data source: Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F., 2015. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386.

Cancer: Global Burden, Trends, and Projections

Figure 3

351

Cancer burden in 2012 among men and women.

Cancer incidence, prevalence, and mortality also varied greatly by geographic region and human development level, the latter measured by four-level HDI aggregate of countries (see Table 2). The largest number of new cancer cases occurred in countries indexed with very high HDI levels (40.9% of all cases), followed by countries indexed as medium (37.2%), high (15.1%), and low (6.7%) HDI. Conversely, the largest number of cancer deaths occurred in countries with medium HDI scores (contributing 44.6% of all cancer deaths), followed by very high HDI (31.8%), high HDI (15.2%), and low HDI (8.4%) countries. Adjusting for population size and age structure, a clear increase in the ASRs of cancer incidence can be observed between low HDI countries (with 112.8 cases per 100 000 people) compared to very high HDI countries (with 278.1 cases per 100 000 people). The ASRs for mortality, although lower for low HDI countries (86.7 cancer deaths per 100 000 people) were relatively similar for countries with medium, high and, very high HDI scores (100.8, 102.3, and 105.5 cancer deaths per 100 000 people, respectively). The observed increase in cancer incidence rates as HDI increases is partially

attributable to population growth and aging (see cancer projections section). The relative contribution of different cancer sites to the burden also varied between HDI regions (Figures 4 and 5). For example, in very high HDI countries, breast, prostate, lung, colorectal, and stomach cancers were the largest contributors to the overall incidence, while in low HDI countries, the corresponding five cancers were breast, cervix, liver, prostate, and esophagus. The mortality in terms of leading sites was similar in very high HDI countries, although cancer of the prostate was displaced by pancreas within the top five cancers, while the very same five cancers contributed to the mortality burden in low HDI countries as was seen for incidence. In 2012, the cancer burden was greatest in eastern Asia (including China), where approximately 3 in 10 of the new cancer cases (4.1 million new cancer cases) and 2.8 million cancer deaths occurred. After adjusting for population size and structure, the ASRs showed a large geographical variation in the number of new cancer cases and cancer deaths. Specifically, the ASRs for new cancer cases were highest in Australia/ New Zealand, northern America, and western Europe, while

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Table 2

Estimated new cancer cases and deaths by geographical region and Human Development Index (HDI) designation in 2012 Incidence

World region

ASR

Casesa

World Low HDI Medium HDI High HDI Very high HDI Africa Eastern Middle Northern Southern Western Latin America and Caribbean Caribbean Central America South America Northern America Asia Eastern Southeastern South-central Western Europe Central and eastern Northern Southern Western Oceania Melanesia Micronesiab Polynesiab Australia/New Zealand

182.0 112.8 144.2 180.2 278.1 123.4 137.8 100.8 129.7 177.5 95.4 177.0 185.4 133.6 190.6 315.6 152.2 186.0 138.2 100.1 168.3 253.6 216.1 277.4 253.6 292.1 298.4 164.7 171.4 200.7 318.5

14 068 000 943 000 5 232 000 2 126 000 5 759 000 847 000 287 000 74 000 221 000 83 000 182 000 1 096 000 91 000 198 000 808 000 1 786 000 6 763 000 4 145 000 786 000 1 514 000 318 000 3 420 000 1 037 000 526 000 769 000 1 088 000 155 000 10 000 800 1 200 143 000

Mortality % of global cancers 100.0 6.7 37.2 15.1 40.9 6.0 2.0 0.5 1.6 0.6 1.3 7.8 0.6 1.4 5.7 12.7 48.1 29.5 5.6 10.8 2.3 24.3 7.4 3.7 5.5 7.7 1.1 0.1 0.0 0.0 1.0

ASR

Casesa

102.4 86.7 100.8 102.3 105.3 89.9 106.5 81.3 86.8 112.5 71.6 94.9 102.0 73.7 101.2 105.5 100.1 117.7 94.8 69.3 103.0 113.1 123.4 108.2 105.2 105.0 102.5 116.4 79.7 108.1 97.6

8 202 000 690 000 3 657 000 1 244 000 2 607 000 591 000 208 000 57 000 143 000 51 000 131 000 603 000 53 000 111 000 440 000 692 000 4 500 000 2 758 000 529 000 1 023 000 189 000 1 756 000 638 000 245 000 390 000 483 000 60 000 7 000 400 700 52 000

% of global cancers 100.0 8.4 44.6 15.2 31.8 7.2 2.5 0.7 1.7 0.6 1.6 7.4 0.6 1.4 5.4 8.4 54.9 33.6 6.4 12.5 2.3 21.4 7.8 3.0 4.8 5.9 0.7 0.1 0.0 0.0 0.6

Most common cancer (% of regional cancers) Lung Breast Lung Breast Breast Breast Cervix uteri Cervix uteri Breast Breast Breast Prostate Prostate Breast Breast Prostate Lung Lung Breast Breast Breast Breast Colorectum Prostate Colorectum Prostate Prostate Breast Lung Prostate Prostate

13.0 15.6 16.4 13.2 13.0 15.8 15.9 15.6 17.9 12.4 21.8 13.9 20.6 12.6 14.3 14.6 15.5 19.2 13.7 14.8 13.4 13.4 13.5 15.5 13.7 14.9 16.8 13.7 19.7 18.4 17.6

Most common death (% of regional cancers) Lung Breast Lung Lung Lung Breast Cervix uteri Cervix uteri Liver Lung Liver Lung Lung Stomach Lung Lung Lung Lung Lung Breast Lung Lung Lung Lung Lung Lung Lung Cervix uteri Lung Lung Lung

19.4 10.8 21.4 15.7 22.2 10.7 13.5 13.9 13.0 13.0 16.9 12.4 16.7 10.4 12.8 27.1 20.8 25.8 17.7 10.2 18.1 20.1 19.1 21.4 20.4 20.7 17.8 10.3 38.2 22.7 19.0

a

Rounded to the nearest 1000. rounded to the nearest 100. ASR, age-standardized rate. Data source: Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F., 2015. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386.

b

the ASRs for new cancer cases were lowest in central and middle Africa, and south-central Asia. The highest ASRs for cancer deaths were observed for central and eastern Europe, eastern Asia, and southern Africa. The overall risk in different regions reflected the additive contribution of different forms of cancer. In northern Africa, although incidence and mortality rates were low, cancers associated with infections were more common relative to other types of cancer (De Martel et al., 2012). In contrast, in southern Africa, where incidence rates were elevated relative to other regions in continent, there were high rates of a prostate, cervical, breast, lung, and colorectal cancer.

Incidence of and Mortality Trends for the Five Most Common Cancers Lung Cancer

For decades, lung cancer has ranked as the most important neoplasm in terms of both incidence and mortality (Parkin et al., 1999; Torre et al., 2015, Murray and Lopez, 1997).

Indeed, in 2012, lung cancer ranked as the leading contributor to cancer incidence, with over 1.8 million new lung cancer cases diagnosed annually, accounting for more than one in eight of all new cancer cases. Lung cancer was also the leading form of cancer mortality, with 1.6 million cancer deaths, or almost one in five of all cancer deaths. There was a clear association between lung cancer and human development, with the ASRs for new cancer cases and cancer deaths being 5.9 and 4.9 times higher in very high HDI countries when compared to low HDI countries, respectively. Geographically, lung cancer incidence ranked first in few geographical regions; however, lung cancer was the largest contributor to new cancer cases in eastern Asia, the region which experienced the highest overall incidence in 2012. In contrast, lung cancer was the largest contributor to cancer mortality in the majority of geographical regions. At the country level, the highest ASRs of new lung cancer cases and deaths were observed in Hungary and Serbia (see Figure 6). Temporal studies of smoking and the resulting lung cancer incidence and mortality have played an important part in

Cancer: Global Burden, Trends, and Projections

353

Lung Breast Colorectum Prostate Stomach Liver Cervix uteri Esophagus Bladder Non-Hodgkin lymphoma Leukemia Pancreas Kidney Corpus uteri Lip, oral cavity Thyroid Brain, nervous system Ovary Melanoma of skin Gallbladder Larynx Other pharynx Multiple myeloma Nasopharynx Hodgkin lymphoma Testis Kaposi sarcoma 0

2

4

6

8

10

12

14

16

18

Cancer cases (100 000)

Figure 4

Low

Medium

High

Very high

New cancer cases in 2012 for 27 different cancer sites and by Human Development Index (HDI) designation.

determining the role of smoking as the primary cause of the disease (Proctor, 2012). The contrasting trends observed in different parts of the world largely reflect the changing profile of tobacco use – the number of cigarettes smoked, the duration of the habit, and the composition of the tobacco – within different populations over time. Among men, overall lung cancer ASRs in many high and very high HDI countries – in Europe, northern America, and Australia – peaked between 1980 and 2000 and subsequently declined, although there is a distinct variability between countries in terms of the magnitude of the ASRs and the year of peak incidence (Figure 7). Additionally, previous research observed a dramatic increase in ASRs among men in many eastern European countries (Brennan and Bray, 2002). In the low and medium HDI countries, ASRs tend to be reasonably stable or decreasing; however, there is a consistent and large variation in lung cancer risk (e.g., ASRs in Uganda are more than 10 times lower than ASRs in the Philippines). The global profile of female lung cancer trends is some what different. ASRs are steadily increasing with time in most high and very high HDI countries, an observation that reflects historic increases in smoking by women (Thun et al., 2012); however, in some Western populations – including the United States and Denmark, where a long-established decrease in the prevalence of smoking among women has been observed – plateaus and recent declines can be seen in lung cancer rates. The proportion of lung cancer cases due to smoking ranges from greater than 80% of cases in the United States (US

Department of Health and Human Services, 2014) and France (Ribassin-Majed and Hill, 2015) to 61% of cases in Asia (pooled analysis of cohorts) (Zheng et al., 2014). In countries with low-to-medium smoking prevalence, smoking and smoking-related mortality due to causes which include lung cancer are currently rather low but likely to increase (Thun et al., 2012). For example, based on the projected increases in lung cancer and other tobacco-related diseases, an increased burden from tobacco-related cancers and other diseases, as observed in very high HDIs, may be expected, in the absence of intervention, in many countries in Asia, Africa, and South America (Peto et al., 1999). Since the 1950s, trends in lung cancer incidence and mortality are correlated with birth cohorts, namely incidence rates in a given birth cohort can be related to the smoking habits of the same generation (Holford et al., 2014). The ‘smoking epidemic’ (i.e., the increase in smoking rates and the subsequent increase in smoking-related mortality) produced changes in ASRs which were first observed within younger age groups, leading to increasingly higher overall ASRs as these generations reached the older age groups where lung cancer was most common (Jemal et al., 2003; Bray and Weiderpass, 2010; Islami et al., 2015). There are intriguing differences in time trends by the histological type of lung cancer (Devesa et al., 2005; Govindan et al., 2006; Lortet-Tieulent et al., 2014). Squamous cell carcinoma incidence rates among men have declined in North America

354

Cancer: Global Burden, Trends, and Projections

Lung Liver Stomach Colorectum Breast Esophagus Pancreas Prostate Cervix uteri Leukemia Non-Hodgkin lymphoma Brain, nervous system Bladder Ovary Lip, oral cavity Kidney Gallbladder Other pharynx Larynx Multiple myeloma Corpus uteri Melanoma of skin Nasopharynx Thyroid Kaposi sarcoma Hodgkin lymphoma Testis 0

2

4

6

8

10

12

14

16

Cancer deaths (100 000)

Figure 5

Low

Medium

High

Very high

Cancer deaths in 2012 for 27 different cancer sites and by Human Development Index (HDI) designation.

and in some European countries, whereas among women they have generally increased (Devesa et al., 2005). In contrast, lung adenocarcinoma rates have increased in both sexes in many areas of the world (Devesa et al., 2005). Such observations are probably explained by shifts in cigarette composition toward low-tar, low-nicotine, and filtered cigarettes (Wynder and Muscat, 1995).

Breast Cancer

Among women, breast cancer is the leading contributor to both new cancer cases and to cancer deaths globally, with 1.7 million new cases and 0.5 million deaths in 2012. Thus, among women, close to approximately one in four new cancer cases and one in seven cancer deaths are caused by breast cancer. Furthermore, when considering cancers among both sexes, breast cancer is the second most frequently diagnosed cancer and the fifth most common cause of cancer death. The ASRs for new breast cancer incidence in very high HDI countries are 2.5 times those of low HDI countries; however, no difference in breast cancer mortality rates was observed by HDI level. Breast cancer incidence and mortality ASRs deviated by geographical region. The ASRs for new breast cancer cases were higher in northern America, western Europe, and northern Europe, while the ASRs for breast cancer deaths were higher in western Africa, Melanesia (a subregion of Oceania), and northern Africa (Figure 8). This was exemplified at the country level where the highest ASRs for new breast cancer cases were

observed in Belgium, Denmark, and the Netherlands, respectively, while the highest ASRs for breast cancer deaths were observed in Fiji, Bahamas, and Nigeria. The ASRs for new breast cancer cases among women have increased in many countries in the last few decades, regardless of HDI level (see Figure 9). For breast cancer deaths, however, increases in ASRs for breast cancer deaths are observed for countries indexed at low-to-medium HDI levels, while in countries with high and very high HDI scores, both increases (e.g., Japan and Colombia) and decreases (e.g., Australia, Denmark, France, and the United States) have been observed. Furthermore, increases in breast cancer death ASRs were observed in many European countries from the 1950s to 1980s, particularly in eastern and southern Europe, followed by a plateau and subsequent decline (observed for both younger and older women) (Althuis et al., 2005; Bray et al., 2004). A similar trend for breast cancer has been observed also in the United States (among people who identify as both white and black) and Canada. However, breast cancer mortality has increased in several eastern European countries, including the Russian Federation, Estonia, and Hungary (Bray et al., 2004). These temporal patterns in European and North American countries are complex and are likely due to numerous and interactive risk factors (Soerjomataram et al., 2008, World Cancer Research Fund International and American Institute for Cancer Research, 2011), to the introduction of screening (Harding et al., 2015; Independent UK Panel on Breast Cancer

Cancer: Global Burden, Trends, and Projections

Figure 6

355

Age-standardized (world) rates of lung cancer, by country in 2012.

Screening, 2012), and to improved therapies and the establishment of therapeutic guidelines (Webb et al., 2004). The observed screening-related increases in incidence seen in the 1980s in some countries were attributable, in part, to the implementation of screening programs; however, in several Nordic countries, and in England, Wales, and the Netherlands, incidence rates had been rising before the introduction of national screening programs in the mid- to late-1980s (Botha et al., 2003). Furthermore, screening-related increases in incidence have not been observed in all countries following their implementation of screening programs. In addition, despite an international consensus that there is sufficient evidence for the efficacy of mammography screening of 50- to 69-year-old women in reducing breast cancer mortality (International Agency for Research on Cancer, 2002), quantification of screening’s contribution to the observed decline in mortality has been problematic. While some of the overall reduction in breast cancer mortality has been attributed directly to screening via prediction models, the observed declines (e.g., a 25% reduction

in mortality by 2000 in the United Kingdom and United States (Peto et al., 2000)) began in 1986, before screening was introduced. Indeed, some recent decreases in mortality are also seen in several countries without national screening programs, although these trends tend to be confined mainly to younger age groups (Bray et al., 2004). Some of the greatest increases in breast cancer mortality have been observed in non-Western countries, whose populations have historically been at relatively low risk for breast cancer (Bray et al., 2004). For instance, breast cancer rates in Japan of both incidence and mortality have been increasing fairly rapidly (Figure 9), an observation which is consistent with the reported increasing risk among successive generations of women (Wakai et al., 1995). The reported increases in mortality are often attributed to childbearing, dietary habits, and exposure to exogenous estrogen, resulting in a movement toward a distribution closer in profile to that of women of the very high HDI countries in Europe and North America. Again in Japan, decreasing age at menarche, increasing age at

356

Figure 7

Cancer: Global Burden, Trends, and Projections

Low/medium HDI

High/very high HDI

Low/medium HDI

High/very high HDI

Trends in age-standardized (world) rates of lung cancer, by Human Development Index (HDI).

Cancer: Global Burden, Trends, and Projections

Figure 8

357

Age-standardized (world) rates of female breast cancer, by country in 2012.

menopause, decreasing fertility, increasing age at first birth, and increases in both height and weight have been noted as factors contributing to an increased risk of breast cancer (Wakai et al., 1995; World Cancer Research Fund International and American Institute for Cancer Research, 2011).

Colorectal Cancer

There were 1.3 million new colorectal cancer cases and 0.7 million colorectal cancer deaths in 2012. A similar number of men and women were affected, with colorectal cancer accounting for almost 1 in 10 cancer cases diagnosed and for approximately 1 in 12 cancer deaths. Due to the large difference between colorectal cancer incidence and mortality, colorectal cancer was the third most prevalent cancer globally. Colorectal cancer was strongly correlated with HDI, with colorectal cancer constituting 12.1% and 12.5% of all new cancer cases and cancer deaths, respectively, in very high HDI countries; however, in contrast, colorectal cancer constituted 4.2% and 5.3% of all new cancer cases and cancer deaths, respectively, in low HDI

countries. The burden of colorectal cancer also showed a large geographical variation, with higher ASRs for new colorectal cancer cases in Australia/New Zealand, western Europe, and southern Europe; the ASRs for colorectal cancer deaths were higher in central and eastern Europe, northern Europe, and southern Europe (Figure 10). At the country level, the Republic of Korea, Slovakia, and Hungary experienced the highest ASRs for new cancer cases, while Hungary, Croatia, and Slovakia experienced the highest ASRs for cancer deaths. While there are some important differences in the epidemiological characteristics of colon cancer compared to rectal cancer, Figure 11 depicts the sex-specific trends for colon cancer and rectum cancer combined, thus avoiding the recognized problems of varying subsite allocations of cancers found at the rectosigmoid junction. The most notable features of global trends are the rather rapid increases in male and female ASRs in countries formerly at low risk. With respect to the most recent 10-year period, there are three general groupings of countries based on the temporal

358

Cancer: Global Burden, Trends, and Projections

Low/medium HDI

Figure 9

High/very high HDI

Trends in age-standardized (world) rates of female breast cancer, by Human Development Index (HDI).

pattern of new colorectal cancer cases and colorectal cancer deaths (Arnold et al., 2016). Firstly, several eastern European countries, and also populations in Latin America and Asia (including Philippines, China, and Colombia), have had increasing incidence and mortality trends. Secondly, several European countries, as well as Canada and Singapore, have experienced an increase in the ASRs for new colorectal cancer cases and a decline in the ASRs for colorectal cancer deaths. Thirdly, for countries with the highest HDI, such as Australia, Iceland, New Zealand, and Japan, decreases in both the ASRs for new colorectal cancer cases and for colorectal cancer deaths have been observed. Declines in mortality may be a consequence of changes in incidence, a result of progress in therapy, and a result of the effects of improved early detection; however, the pattern in the United States is probably due to more widespread screening, resulting in stage-specific shifts in incidence and a subsequent increase in survival (Troisi et al., 1999). In high-risk Western countries, there has been a notable shift in the subsite distribution within the colorectum, with increases in the incidence of proximal (ascending colon) compared to distal (descending and sigmoid colon) cancers (Thörn et al., 1998; Troisi et al., 1999). In low-risk populations, such as Singapore, the reverse subsite distribution has been

reported (Huang et al., 1999), while the trend in rates of proximal and distal cancers was similar in Shanghai to that found in high-risk Western countries (Ji et al., 1998). For rectal cancers, the countries with the most rapid increases in incidence are Japan and countries in eastern Europe. In the United States, there has been a decline in incidence and mortality for several decades among white and black females and among white men, although an increase in rectal cancer is apparent in black males (Troisi et al., 1999). The risk factors that could explain the geographical and temporal variations in colorectal cancer are likely numerous and interactive. The observed declines in distal cancer incidence in some Western populations may be the result of increased detection and treatment of premalignant polyps; however, overall screening of at-risk groups remains low (Meissner et al., 2006). Where colorectal cancer incidence rates are increasing, as is the case in Asia and eastern Europe, a Westernization of lifestyle may be responsible, in part, particularly as a result of the adoption of a more Westernized diet.

Prostate Cancer

An estimated 1.1 million new cases of prostate cancer and 0.3 million prostate cancer deaths occurred worldwide in 2012

Cancer: Global Burden, Trends, and Projections

Figure 10

359

Age-standardized (world) rates of colorectal cancer, by country in 2012.

(Table 2), making prostate cancer the fourth and seventh most frequent cancer globally in terms of new cancer cases and deaths. The incidence of prostate cancer varies with HDI, with high and very high HDI countries having ASRs 1.5 times higher than low and medium HDI countries. Geographically, the ASRs for incidence were notably elevated in central and eastern Europe and in northern Europe, while the ASRs for prostate cancer deaths were elevated in Melanesia (a subregion of Oceania) and in central and eastern Europe (Figure 12). The magnitude of such variations in incidence reflects the high prevalence of prostate-specific antigen (PSA) testing in some Western countries – as a means to detect latent cancers in asymptomatic individuals – rather than real differences in risk (Draisma et al., 2003). In this respect, mortality rates may be a better guide to true geographical differences than are incidence rates. For example, the ASR for new prostate cancer cases in the United States was 4.7 times that of China in 2012. At the country level, Martinique, France, Norway,

and Trinidad and Tobago had the highest rates of new prostate cancer cases, while Trinidad and Tobago, Guyana, and Barbados had the highest rates of prostate cancer deaths. The ASRs for new prostate cancer cases have increased in many countries regardless of their HDI. In several low-risk countries, including China, Thailand, and Japan, an increase in prostate cancer incidence over the past 20 years parallels the growth of breast and colorectal cancer incidence in those countries (Figure 13). However, for countries with higher ASRs such as the United States, ASRs for new prostate cancer cases have stabilized. In many very high HDI countries, the ASRs for prostate cancer deaths increased from 1980 to a peak in approximately 1995, after which time they decreased. For countries with a high HDI, such as Russia and Bulgaria, the ASRs for prostate cancer deaths did not peak in 1995, and further increases in mortality have been observed (Center et al., 2012). The large increases in prostate cancer incidence in high-risk countries, as illustrated in Figure 13, can be attributed

360

Cancer: Global Burden, Trends, and Projections

Figure 11

Low/medium HDI

High/very high HDI

Low/medium HDI

High/very high HDI

Trends in age-standardized (world) rates of colorectal cancer, by Human Development Index (HDI).

Cancer: Global Burden, Trends, and Projections

Figure 12

361

Age-standardized (world) rates of prostate breast cancer, by country in 2012.

primarily to increased detection following transurethral resection of the prostate (TURP), and, due to the use of PSA testing (Potosky et al., 1990, 1995). In the United States, incidence rates increased slowly up to the 1980s (Figure 13), probably due to a genuine increase in risk, coupled with an increased diagnosis of latent, asymptomatic cancers in prostatectomy specimens due to the increasing use of TURP (Potosky et al., 1990). Beginning in 1986, and accelerating after 1988, there was a rapid increase in incidence, coinciding with the introduction of PSA testing, allowing the detection of preclinical (asymptomatic) disease (Potosky et al., 1995). With the introduction of PSA screening, and the dramatic surge of incidence it precipitated, there was an increase in the rate of mortality, but this latter increase was much less marked than the change in incidence (Figure 13). In the United States (since 1992 in white men, and since 1994 in black men), mortality rates have decreased. The contribution that PSA screening and/or improved treatments have made to the slow, steady decline in mortality continues to be the subject of

much debate (Gavin et al., 2004). The increased mortality observed from the 1970s into the 1990s is probably partly due to misclassification of the cause of death among the large number of men who were diagnosed with latent prostate cancer in the late 1980s and early 1990s (Feuer et al., 1999). The later decline in mortality may be attributable, in part, to a reversal of this effect, as it seems unlikely that screening was entirely responsible for the initial decrease in prostate cancer mortality observed in 1992 (Center et al., 2012). Similar mortality trends have been reported in Australia, Canada, the United Kingdom, France, and the Netherlands, although, in general, they are less pronounced, or occurred later, than in the United States (Center et al., 2012). In some of the countries concerned (Canada, Australia), there has been considerable screening activity, but this is not the case in other countries where falling prostate cancer mortality rates are just as marked (France, Germany, Italy, and the United Kingdom) (Oliver et al., 2001). The rapid growth in prostate cancer incidence observed in some low-risk countries may be the result, in part, of greater

362

Cancer: Global Burden, Trends, and Projections

Figure 13

Trends in age-standardized (world) rates of prostate breast cancer, by Human Development Index (HDI).

awareness of the disease and of the diagnosis of small and latent cancers. Although it remains likely that there have been genuine increases in risk in many countries related to the aforementioned Westernization of lifestyles, mortality rate increases in these populations are also large and are of a similar magnitude to the observed increases in incidence (Center et al., 2012).

Stomach Cancer

Stomach cancer has historically ranked as one of the most frequently diagnosed cancers worldwide (Jemal et al., 2011; Parkin et al., 1984; Torre et al., 2015), and, according to 2012 estimates, the disease ranked fifth (1.0 million new cases). Furthermore, stomach cancer ranks as the third most common cause of mortality from cancer, with 0.7 million deaths occurring worldwide in 2012 (Table 2). The majority of stomach cancer cases and deaths affected men, with roughly twice the number of the new stomach cancer cases and deaths occurring in men compared to women. Incidence and mortality rates were highest in eastern Asia; however, these rates were also elevated in central and eastern Europe and South America (Figure 14). Furthermore, at the country level, the Republic of Korea, Mongolia, and Japan had the highest incidence of

new stomach cancer cases, and Mongolia, Guatemala, and Tajikistan had the highest rates of stomach cancer deaths. Declines in the ASRs for new stomach cancer cases and for stomach cancer deaths have been observed in most populations worldwide, a trend which has been observed for both men and women (Figure 15). This relative decline has been greatest for countries with lower ASRs for new stomach cancer cases when compared to countries with higher ASRs, such as Japan, China, Korea, Columbia, Ecuador, Ukraine, and Russia (Bertuccio et al., 2009). The reason for this decline in the ASRs in incidence and mortality is not fully understood. The temporal profile is consistent with improved food preservation techniques and better nutrition, particularly the invention of refrigeration for the transport and storage of food, making obsolete salting, smoking, and pickling. There is also evidence that, at least in countries with a higher HDI, there has been a progressive decline in Helicobacter pylori infection rates between successive birth cohorts, likely as a result of continual changes within the childhood environment (Kobayashi et al., 2004). Some studies have reported that the declines in gastric cancer are dependent on histology as they are restricted to intestinal-type adenocarcinoma, with stable incidence trends observed for the diffuse-type carcinomas (Liu et al., 2004; Wu

Cancer: Global Burden, Trends, and Projections

Figure 14

363

Age-standardized (World) rates of stomach breast cancer, by country in 2012.

et al., 2009); however, this pattern may not be universal (Ekström et al., 2000). There has been particular interest in the distinct trends of stomach cancer by site, with rates of cancer of the gastric cardia increasing in several populations (Powell et al., 2002), and concomitant increases in the prevalence of Barrett’s esophagus and adenocarcinoma of the lower third of the esophagus. It is possible, therefore, that much of the increase in gastric cardia cancer incidence represents misclassification of cancers at the gastroesophageal junction (Ekström et al., 1999).

Predicting Cancer Incidence in 2030 It is expected that future cancer burden will continue to increase over time due to changes in population risk, population growth, and aging (Bray et al., 2015). As such, the prediction of the number of new cancer cases and cancer deaths is a necessary tool for advocating and implementing cancer prevention strategies, early detection protocols, and risk reduction

programs, as well as for determining future resource allocation. Commonly, these predictions are determined by extrapolating recent trends, while accounting for anticipated population changes; however, historical patterns are not always a sound basis for future projections. Indeed, for several cancer sites, trends differ depending on the region of the world being considered, and these trends can change direction even on a short-term basis, as has been observed for lung cancer in the last decade. Irrespective of changing risks, population growth and aging are large determinants of future burden, and foreseeable demographic changes are projected to substantially increase the magnitude of global cancer incidence in the coming decades. The GLOBOCAN model predicts the cancer burden in 2030 by applying 2012 sex- and age-specific cancer incidence rates to population projections. In the absence of changing risk or intervention, it is projected that by 2030 there will be 21.6 million new cases of cancer worldwide per year, an approximate 53.9% increase from 2012 (Figure 16). The

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Figure 15

Trends in age-standardized (World) rates of stomach breast cancer, by Human Development Index (HDI).

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Figure 16

Cancer Incidence Projected to 2030, by age and Human Development Index (HDI).

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greatest relative increase in cancer cases in transitioning countries will occur among the elderly (defined herein as 65 years of age or older): a 76.9% increase is projected from the 6.7 million cases in 2012 to 11.8 million by 2030. Given the projected large increase in the burden of cancer over the next decades, there is a need to provide for an older and disproportionately larger number of people who will be diagnosed with cancer within the developing and developed regions, and (although not modeled) a need to increase the capacity to reduce and nullify expected risk factor increases, such as expected increases in tobacco smoking in lower-HDI countries. This latter consideration is a particularly important strategy to combat the burden of cancer in the vast populations living in Asia, Africa, and South America, where the destructive effects of tobacco to health are beginning to be realized.

Other Considerations Other Cancer Burden Measures Cancer survival and survival proportions are also important in assessing the cancer burden in a given country, as they are partial measures of the success of early detection programs used to screen for cancer (i.e., the stage at which tumors are diagnosed and treated) (Independent UK Panel on Breast Cancer Screening, 2012; Shaukat et al., 2013; Gakidou et al., 2008), as well as of the quality and coverage of cancer treatment resources in a country. Analyses of available survival estimates from countries in Africa, Asia, and Central America (Sankaranarayanan et al., 2010), as well as from Europe (De Angelis et al., 2014), indicate that there are geographical, cancer-specific, and temporal differences in cancer survival. Increases in cancer survival, in settings where medium-level and high-level resources exist, have brought to light the relevance of changes in quality of life due to cancer-related sequelae (Van De Poll-Franse et al., 2011; Soerjomataram et al., 2012). These changes are typically measured in years lived with disability (YLD), a measure of both the magnitude of the disability experienced and the duration of this disability. YLD can be combined with data on years of life lost due to premature mortality, to estimate the disability-adjusted life years (DALYs) lost, a measure of both cancer mortality and disability experienced by long-term survivors (Murray, 1994) (see Soerjomataram et al., 2012 for global estimates of cancer DALYs lost).

Limitations in Incidence, Mortality, and Prevalence Data There are several limitations to the cancer registry incidence data. Firstly, changes in registration practices, accuracy of case ascertainment, likelihood of diagnosis of cancer, which definition of malignancy is employed, and which classification system is used (such as the revision of the ICD) can artificially impact the reported incidence rate(s) (Muir et al., 1993). Additionally, cancer incidence reporting (especially in instances such as prostate cancer) is impacted by issues of overdiagnosis (as indicated by a rise in the incidence of early stage cancer (indolent cases) without a decrease in the incidence of later stage cancer) and, consequently, patients are susceptible to overtreatment (Esserman et al., 2013). Furthermore, with

respect to CI5 data, there remains low coverage of highquality data in certain world regions. In North America, 99% of the population is covered by cancer registries included in the CI5, while only 7%, 5%, and 2% of the populations in the South American, Asian, and African regions, respectively, are covered by the cancer registries included in the CI5. The Global Initiative for Cancer Registry Development (GICR, see Relevant Websites), a partnership of funding and technical organizations led by IARC, is bringing about the needed improvement in the quantity and quality of cancer incidence through investment in PBCR. There are also several limitations to the cancer mortality data. Firstly, consistent usage of the coding systems for cause of death reporting, such as the ICD, is known to vary considerably both between countries and over time, making comparisons difficult (Janssen and Kunst, 2004). Secondly, the detail and accuracy of mortality coding is an issue with data collected through population-based cancer registries, especially with respect to the elderly and people with advanced diseases where cause of death classification is susceptible to miscoding (Schaffar et al., 2013). Data on the prevalence of cancer is limited through the requirement of both cancer registration and vital data linkage for multiple years, with long-term partial prevalence typically requiring data on cancer incidence and mortality over a long period of time. Furthermore, the utility of prevalence is limited for some cancer cases, such as where there has been a previous diagnosis of female breast cancer or prostate cancer where the risk of death remains higher than for the general population beyond 4–5 years (i.e., possible cure) from their initial treatment (Brenner and Hakulinen, 2002).

Summary Globally, cancer is a leading cause of death, with the burden expected to increase in the future. However, the burden of cancer is not uniform. Geographical and HDI-based variations are evident when one examines the distribution of common cancers outlined in this article. Furthermore, trends in incidence and mortality differ by geographical region and HDI, indicating the complex diversity of cancer as well as future cancer transitions that will see the incidence and mortality of certain (Westernization-related) cancers to increase and corresponding rates of a number of (infectionorientated) cancers to decrease. Many countries lack both formal cancer registries and the interoperability of health information systems to capture data on cancer incidence, mortality, and prevalence. Furthermore, for countries and regions where such data are available, there are often problems with data accuracy and whether they are representational (Ferlay et al., 2015). Thus, there is a need for surveillance systems to collect accurate data on cancer incidence, mortality, and prevalence (as part of populationbased systems collecting data on the occurrence of all cancers and on all-cause deaths), as well as to determine the risk factors for various cancers. These data are critical for cancer prevention and early detection and for the establishment of risk reduction programs (Glaser et al., 2005). The GICR as a collaboration of international partners working with

Cancer: Global Burden, Trends, and Projections governments to ensure cancer registries becomes a cornerstone of cancer control; the focus is to strengthen cancer registration in the very countries in transition where surveillance is limited and for which an increasingly high proportion of the global cancer burden will be observed, as documented here.

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Further Reading Bray, F., Soerjomataram, I., November 01, 2015. The changing global burden of cancer: transitions in human development and implications for cancer prevention and control. In: Gelband, H., Jha, P., Sankaranarayanan, R., Horton,, S. (Eds.), Cancer: Disease Control Priorities, third ed., vol. 3. The International Bank for Reconstruction and Development/The World Bank, Washington, DC. Chapter 2. PubMed PMID: 26913347.

Relevant Websites http://www.afcrn.org/ – African Cancer Registry Network (AFCRN) (last accessed 06.07.16.). http://www.ci5.iarc.fr – Cancer Incidence in Five Continents (CI5) (last accessed 06.07.16.). http://www.encr.com.fr/ – European Network of Cancer Registries (ENCR) (last accessed 06.07.16.). http://www.gicr.iarc.fr – Global Initiative for Cancer Registry Development (GICR) (last accessed 06.07.16.). http://www.gco.iarc.fr – IARC’s Cancer Surveillance Website. The Global Cancer Observatory Includes “Cancer Today” (Data on Cancer Incidence, Cancer Mortality), “Cancer Over Time” (Data on Changes in Cancer Incidence and Mortality Rates Over Time), “Cancer Tomorrow” (Data on Projected Cancer Incidence and Mortality), and “Cancer Causes” (Data on Cancer Incidence and Mortality Attributable to Various Risk Factors) (last accessed 06.07.16.). http://www.iacr.com.fr/ – International Association of Cancer Registries (IACR) (last accessed 06.07.16.).

Cancer Mortality Anette Hjarta˚ker, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway Elisabete Weiderpass, The Cancer Registry of Norway, Oslo, Norway; Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway; Karolinska Institutet, Stockholm, Sweden; and Genetic Epidemiology Group, Folkhälsan Research Center, University of Helsinki, Helsinki, Finland Freddie Bray, International Agency for Research on Cancer, Lyon, France Ó 2017 Elsevier Inc. All rights reserved.

Introduction Cancer is the most frequent cause of death worldwide, ranking above both coronary heart disease and stroke. 8.2 million people died from cancer in the year 2012, representing nearly 15% of deaths from all causes worldwide (WHO, 2014a), and at premature ages (30–69 years) the 4.2 million cancer deaths represent over 30% of the 13.8 million non-communicable disease deaths globally. The proportion of all annual deaths attributed to cancer varies considerably between and within world regions. Age-adjusted (world standard) mortality rates of cancer in men of around 126 per 100 000 are about 50% higher than those observed for women (83 per 100 000) (Ferlay et al., 2013). Overall rates are slightly higher in more developed areas: 138.0 and 120.1 per 100 000 for men in more and less developed countries, respectively, compared with 86.2 and 79.8 per 100 000 for women, respectively, although the difference is narrowing. The global map of overall cancer mortality by sex in Figure 1(a) and 1(b) illustrates the variability between and within world areas, with elevated rates observed in both sexes in certain countries in each continent. Lung cancer is the most common cause of death from cancer, accounting for close to one in fifth (19.4%) of all deaths due to cancer. Liver cancer is in second place (9.1%), followed by stomach cancer (8.8%). There are some differences in the five leading causes of cancer mortality between sexes: In men, deaths from cancers of the lung, liver, stomach, colorectal, and prostate are the most frequent, while in women, breast, lung, colorectal, cervix, and stomach cancer dominate. These cancers also represent some of the most frequent forms of cancer in terms of incidence globally (Ferlay et al., 2013), although the specific ranking is somewhat different given variations in prognosis associated with these tumors. In this article we discuss the characteristics of cancer mortality, the primary data sources, and the availability and quality of data between countries and over time, and ensuing difficulties with interpretation. We also provide geographical descriptions of cancer mortality patterns by sex, and focus on lung, liver and stomach cancer, the three major causes of death from cancer globally. The article concludes with an assessment of the application of mortality trends as an indicator of progress in reducing the cancer burden.

Characteristics of Cancer Mortality Definition Cancer mortality is commonly expressed either as the number of cancer deaths occurring, or as a mortality rate, i.e., the number of cancer deaths per 100 000 persons per year. Cancer

International Encyclopedia of Public Health, 2nd edition, Volume 1

mortality provides a measure of the impact of cancer in a given population. National mortality data derive from vital registration systems, where usually a medical practitioner certifies the fact and cause of death. The International Classification of Diseases (ICD) provides a uniform system of nomenclature and coding and a recommended format for the death certificate. Cancer mortality is the product of the incidence and the case fatality rate of a given cancer. Death rates estimate the average risk to the population of dying from a specific cancer, whereas the case fatality rate, the inverse of survival, represents the proportion of individuals with the specific cancer that will die from it within a specified time.

Relation to Incidence and Survival Although cancer registration systems are developing globally, cancer incidence data tend to still be available in fewer populations and for shorter time periods than cancer mortality data, particularly in low and/or middle income countries. Mortality data are therefore sometimes used as a practical surrogate for incidence, although mortality patterns do not always reflect well those of incidence given the former’s dependence on both incidence as well as case fatality. Declines in case fatality may thus result in substantial and misleading variability in the temporal trends of the incidence and mortality rates, particularly for cancers associated with reasonable survival and where improvements in prognosis have been observed over several decades. Mortality is better suited as a proxy for the incidence of cancers associated with rather poor and stable survival proportions (e.g., lung, pancreatic cancer). Historically there have also been concerns regarding incidence. In their landmark study of environmental causes of cancer in the United States, published in 1981, Doll and Peto utilized mortality rather than incidence, citing that the latter was a more complex statistic to interpret (Doll and Peto, 1981). They were concerned about two factors: first, and in addition to the artifacts associated with changing efficiency of the registration process, they considered the effects of changing practice in classification of cancers associated with different rates of fatality and the spread of screening tools that detect cases earlier as having had a large impact on the record incidence of many cancer types. Second, they noted that incidence, while of great value, did not remove the need for mortality data, necessary – in combination with incidence – to detect improvements in therapy, and partly to verify the validity of incidence trends. While Doll and Peto’s circumvention of the available incidence data drew some criticism (Clemmesen and Nielsen, 1982; Devesa et al., 1984) and can perhaps be seen in the context of the availability and quality of registry data at that time, there has long been consensus that the combined description of trends in incidence, mortality, and

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Figure 1 (a) Estimated age-adjusted cancer mortality rates (world standard) per 100 000 (men). All-sites but non-melanoma skin cancer. (b) Estimated age-adjusted cancer mortality rates (world standard) per 100 000 (women). All-sites but non-melanoma skin cancer. GLOBOCAN 2012, with permission.

Cancer Mortality survival often serves to confirm and clarify understanding of the underlying biological and epidemiological processes, as well as restate the relative strengths and weaknesses of each measure in interpretation. However, mortality rates are often used as indicators of disease outcome, for instance in determining the beneficial effects of a specific treatment regimen at the population level or a screening intervention for those cancers in which a precursor lesion is not the target of the intervention, e.g., breast cancer.

Sources of Data, Availability, and Estimation Mortality data are commonly available from national statistics offices by year of death, 5-year age group, and sex. Given their more comprehensive availability, temporal analyses of cancer mortality tend to be more common than those of incidence in the medical and epidemiological literature, despite the caveats already mentioned. The national data are combined in the World Health Organization (WHO) mortality databank, which contains data series going back in time for around 90 countries. Country-specific estimates worldwide are available (presently for 2012) from IARC’s GLOBOCAN database (see Relevant Websites).

The WHO Mortality Database The WHO mortality database is an updated database of cause-specific national mortality of around 90 countries, predominantly in developed areas. The mortality data were previously published in the World Health Statistics Annual, but are now available on WHO’s website, with online tables and figures available from the International Agency for Research on Cancer (IARC) website containing data for some countries from the 1950s through to 2012. The WHO data are based on deaths registered in national vital registration systems, with underlying causes of death coded using ICD9 and ICD10. The numbers of registered deaths are coded by cause, sex, and age for each country and year. A discussion of the availability and quality of death registration data, assessed by timeliness, completeness and coverage of registration, and proportion of deaths assigned to ill-defined causes for national mortality data in general, is available from the Bulletin of the World Health Organization (Mathers et al., 2005; see Relevant Websites).

GLOBOCAN 2012 The IARC compiles the GLOBOCAN database, a database that in addition to cancer mortality data also provides data on cancer incidence and prevalence (Ferlay et al., 2013). The data are presented by sex for 184 countries worldwide for 27 cancer sites and for all cancers but non-melanoma skin cancer. GLOBOCAN currently presents cancer mortality estimates by country for the year 2012. Several data sources and methods have been utilized to provide these estimates depending on the availability of data, the level of detail, and its accuracy. National mortality data have been applied wherever available. If the data were known to be an underestimate of the likely number of deaths, it has

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been corrected for in the published data. If no national mortality data were available, local or regional data were used for the entire country. Finally, for countries with no mortality data or data considered of poor quality, the estimates are based on incidence and country- or region-specific survival. Where cancer data were neither available nationally nor regionally, mortality was estimated from the average of selected neighboring countries within the same regions. Since cancer data are always collected and compiled sometime after the events to which they relate, the most recent statistics are only available several years after the end of the corresponding year of death. Where possible, the cancer deaths were estimated in GLOBOCAN 2012 from rates projected to 2012 (69 countries) or the most recent rates applied to 2012 population (in 27 further countries). As the sources of data are continuously improving in quality and extent, and the methods re-evaluated, one should be careful when comparing GLOBOCAN 2012 estimates with worldwide estimates published in prior years. The estimates are not strictly comparable, and observed differences may in part be a result of changes in methodology. Particular caution is needed in utilizing the cancer-specific mortality statistics generated in Africa where data were available from only four countries, of which two were of medium quality (Mauritius and Reunion) and two of low quality (in Egypt and the Republic of South Africa) (Mathers et al., 2005).

Data Quality Mortality statistics are produced according to the underlying cause of death, although this may not equate with the presence of a particular tumor. Comprehensive mortality statistics require that diagnostic data are available on decedents, which are transferred in a logical, standardized fashion to death certificates, which are then accurately and consistently coded, compiled, and analyzed. Death registrations require that the correct diagnosis is written on the death certificate and further that this diagnosis is then certified as the underlying cause of death. Many studies have investigated the accuracy of death certificate diagnoses in vital statistics data, comparing cause of death entered on the death certificate with a reference diagnosis derived from autopsy reports, detailed clinical records, or cancer registry data. Such studies have shown that the level of accuracy of the stated cause of death declined as the precision in the diagnosis increased; although the total number of deaths from cancer of all types may only be slightly underestimated, the corresponding distribution by site of cancer may be associated with more substantial errors. A tendency to overregister nonspecific diagnoses instead of the correct location (e.g., large intestine instead of rectum) has been noted, and the accuracy tends to be lower in those dying at older ages. Illustrative examples include a study by Grulich et al. (1995) on cancer trends in England and Wales 1970–90 in the 75–84 year age group. They found that the rise in all-cancer mortality in the elderly was in part due to increasing lung cancer mortality, but data artifacts were responsible for much of the increase in the other commonly specified cancers (Grulich et al., 1995). Another well-known study by

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Percy et al. (1981) compared death certificates mentioning cancer as the underlying cause of death for almost 50 000 incidence cases, contrasting detection rates (proportion of death certificates conveying the same diagnosis as that made in life) and confirmation rates (proportion of cancer deaths for which the underlying cause was confirmed by hospital diagnosis) (Percy et al., 1981). Overreporting on death certificates was indicated when the detection rate was high relative to the confirmation rate, as was the case for neoplasms of the larynx and colon, and unspecified cancers of the uterus. Conversely, underreporting was observed (confirmation high relative to detection rates) for cancers of the cervix and corpus uteri, and rectal cancers. For melanoma and breast cancer, death certification was deemed more or less correct. There may also be quite marked differences between countries in the allocation of ICD codes to death certificate diagnoses (Percy and Dolman, 1978). As well as erroneous death certification, mortality data are affected by changes in coding practice.

Variation in Cancer Mortality by Cancer Site, Sex, and Population The estimated 8.2 million people dying from cancer in 2012 translates to approximately one in seven deaths worldwide, irrespective of cause. Overall, the age-adjusted mortality rate of cancer (world standard) is higher in men: 126 per 100 000 compared to 83 per 100 000 for women. Rates vary greatly between world regions and countries, particularly among men, as shown in Figure 1. Male all-cancer mortality rates among Western African men are about 2.5 times lower than those for men in Central and Eastern Europe (69 and 173 per 100 000, respectively). For women, the highest rates are found in Melanesia and Eastern Africa, and the lowest in Central America and South-Central Asia (range 119 to 65 per 100 000) (Ferlay et al., 2013). Cancer mortality rates in men in Armenia are the highest in the world (210 per 100 000). The cumulative lifetime mortality of 22.5 indicates that every fourth to fifth Armenian man dies of cancer in the absence of competing causes of death. Men in Hungary, Kazakhstan and Mongolia also have cancer mortality rates above 200 per 100 000, and cumulative mortalities above 20. Such high mortality rates in Armenia and Hungary and to some degree Kazakhstan largely reflect smoking patterns and the high frequency of lung cancer death, whereas in Mongolia, liver cancer mortality rates are particularly high (Ferlay et al., 2013). For women, there is a geographically clustering of high cancer mortality rates in Eastern Africa. The highest all-cancer mortality rates are found in Zimbabwe (147 per 100 000), where there are elevated rates of mortality from cervical cancer and Kaposi sarcoma. The cumulative mortality for women in Zimbabwe is 15.5. The second and third-highest rates among women are observed in Malawi (138 per 100 000) and in Kenya (133 per 100 000), respectively, which also have high mortality rates of cervical cancer (Ferlay et al., 2013). For men, lung cancer, liver cancer and stomach cancer are the most common causes of death from cancer, followed by colorectal and prostate cancer (Figure 2(a)). For most cancer forms,

mortality rates are higher for men than for women, and for all cancers combined, worldwide rates in men are nearly 30% higher than those observed in women. Age-adjusted mortality rates are 50% higher for men than for women. For women, breast cancer is the main cause of death from cancer, accounting for almost 15% of all female cancer deaths worldwide (Figure 2(b)). More than half a million women die of breast cancer every year; two-thirds in less developed parts of the world. The age-adjusted death rate from breast cancer ranges from 28.4 to 26.3 per 100 000 in Fiji and Bahamas, respectively, to 5.0 or below per 100 000 in Guatemala, Swaziland, The Gambia and Mongolia. The second to fifth most common causes of death from cancer in women worldwide are neoplasms of the lung, colorectum, cervix, and stomach. Figure 2(a) and 2(b) present global numbers of cancer deaths for the most common cancer sites for men and women, respectively, as well as percentage distribution. While crude mortality rates in the more developed regions of the world are two to three times as high as those of the less-developed countries, the age adjusted mortality rates differ considerably less (109 and 98 per 100 000, respectively). In terms of absolute numbers almost 70% of all cancer deaths in 2012 occurred in Africa, Asia and Central and South America (WHO, 2014b). Figure 3 presents global numbers of cancer incident and deaths for the most common cancer sites for both sexes combined partitioned into more developed and less developed regions. Lung cancer is the most frequent cause of death from cancer worldwide in both sexes combined, as it is when global cancer incidence is considered. Liver and stomach cancer rank second and third, respectively. In developing countries, these cancers predominate, although colorectal cancer and esophageal cancer are also important causes of cancer death. Lung cancer is also the most frequent cause of cancer death in more developed countries followed by death from colorectal and breast cancer.

Lung Cancer Lung cancer is the most common cause of death from cancer worldwide, with nearly 1.6 million deaths in 2012 (Ferlay et al., 2013). Approximately 60% of the lung cancer deaths occur in less developed areas of the world. The highest age-adjusted mortality rates for males are found in Hungary (66.6 per 100 000), Armenia (65.6), and FYR Macedonia (63.5), whereas in women the highest figures are found in Denmark (28.4 per 100 000), Hungary (26.6), and Canada (25.1). As can be seen in Figure 4, the rates are considerably higher in developed than in developing countries, particularly for women. Overall, the age-adjusted mortality rate for lung cancer is nearly three times higher in men than in women (30.0 and 11.1 per 100 000, respectively). Maps describing the geographical variation in lung cancer mortality rates for men and women are given in Figure 5(a) and 5(b), respectively. Survival following a lung cancer diagnosis is poor. The geographical and temporal variations in mortality rates therefore tend to be a good indicator of overall incidence, largely reflecting population-level changes in smoking patterns, with mortality rates by age related primarily to year of birth. Smoking prevalence has either leveled off or declined in recent

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Figure 2 (a) Worldwide number of cancer deaths and percentage distribution (men). (b) Worldwide number of cancer deaths and percentage distribution (women). GLOBOCAN 2012, with permission.

decades in some developed countries, particularly among men (e.g., United States, United Kingdom, and Japan), where birth cohort-specific mortality is related to the smoking habits of the same generation; and those countries where smoking was first established were also the first to observe a decline in smoking prevalence among males, followed, in the same generations of men, by a decline in risk (Lortet-Tieulent et al., 2013). In most other countries, there is a continuing rise in rates. In women, the tobacco habit has generally been adopted quite recently or not at all (Zatonski et al., 2012). Thus, the most common picture in Western populations is of rising rates (Lortet-Tieulent et al., 2013), while in many developing countries (where female smoking generally remains rare), lung cancer rates remain very low. However, tobacco consumption is rising in the populations within the developing world (Palipudi et al., 2012; Teo et al., 2013), and a marked increase in lung cancer mortality can therefore be anticipated in many of the highly populated regions of Africa and Asia (Ferlay et al., 2013).

Liver Cancer Liver cancer is a highly fatal neoplasm, with 5-year survival estimated at around 5% (Spangenberg et al., 2006). Nearly

746 000 people were estimated to have died of the disease in 2012, making it the second most common cause of death from cancer worldwide (Ferlay et al., 2013). A large proportion of these deaths can be attributed to chronic infection with hepatitis B (Parkin, 2006), and the mortality largely follows the distribution of this infection agent (Figures 6 and 7). Hepatitis C infection and consumption of foods contaminated by aflatoxin are also important risk factors (WHO, 2014c). Liver cancer mortality is particularly high in Mongolia, with age-adjusted mortality rates of 89.3 and 54.1 per 100 000 for men and women, respectively (Ferlay et al., 2013). High mortality rates for men are also seen in Vietnam (39.1) and in Egypt (37.0), and for women in Guatemala (15.0) and in the Gambia (14.2). Lowest liver mortality rates are seen in South Central Asia for men (3.6) and in Micronesia for women (1.6). The age-adjusted liver cancer mortality is generally higher in developing than in developed countries. More than 80% of all liver cancer deaths occur in the less developed parts of the world. Liver cancer mortality rates are considerably higher in men than women (Figure 8(a) and 8(b)), with global age-adjusted liver cancer mortality rate among men is more than 2.5 times higher: 14.3 and 5.1 per 100 000, respectively.

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Figure 3 Worldwide incidence and mortality of cancer (sexes combined). More developed and less developed regions of the world. GLOBOCAN 2012, with permission.

Consideration of the temporal variation of cancer mortality is particularly problematical for liver cancer. Mortality data may be unreliable because of the variable inclusion of metastatic liver cancers. There also have been changes in the ICD rubric in successive classifications, with the ICD code for liver cancer including gallbladder neoplasms in the seventh revision, only cancers of the liver and intrahepatic bile ducts specified as primary in the eighth revision, and including tumors that are unspecified (either primary or secondary) in the ninth revision.

Stomach Cancer Stomach cancer is the third most common cause of death from cancer. GLOBOCAN 2012 estimates the number of stomach cancer deaths to be around 107 000 and 362 000 for men in developed and less developed countries, respectively. There were 68 000 deaths caused by stomach cancer in women in developed countries, compared to more than 186 000 in

women in less developed areas. The global age-adjusted mortality rate for stomach cancer is 12.7 per 100 000 for men and 5.7 per 100 000 for women (Ferlay et al., 2013). As can be seen in Figure 9, the age-adjusted mortality rate varies greatly across different regions of the world. The large variation in stomach cancer mortality rates worldwide may be exemplified by the figure of 24.0 per 100 000 estimated for Eastern Asian men compared with the 2.8 per 100 000 seen in men in Northern America. Stomach cancer was formerly the leading site of cancer deaths worldwide, but during the last several decades there has been a uniformly declining trend in stomach cancer mortality in most countries worldwide. This trend is probably due to a declining incidence of Helicobacter pylori infections in many populations along with increased use and availability of refrigeration leading to better nutrition and a lesser need for salt and salt-preserved foods, alongside a higher relative consumption of fresh fruit and vegetables.

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Figure 4 (a) Age-adjusted lung cancer mortality rates (world standard) (men). World and different regions. (b) Age-adjusted lung cancer mortality rates (world standard) (women). World and different regions. GLOBOCAN 2012, with permission.

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Lung cancer 34.9+ 22.9-34.9 10.7-22.9 3.9-10.7 2 points independently predicted about 5-fold higher risk of stroke at 90 days.

Risk Factors A number of stroke risk factors have been identified and commonly described as well documented and less well documented, modifiable and nonmodifiable. The major established risk factors for stroke that can be addressed therapeutically are

Key features of modern stroke incidence and prevalence research

The overall age-standardized incidence of stroke in people aged 55 years and older ranges from 4.2 to 11.7 per 1000 person-years. The proportion of ischemic stroke ranges from 67% to 81%; intracerebral hemorrhage, 7–20%; and subarachnoid hemorrhage, 1–7%. The risk of ischemic stroke (including ischemic stroke subtypes) and intracerebral hemorrhage and the proportion of intracerebral hemorrhage in non-white populations is about two times greater than that in white populations Two-thirds of stroke-related deaths occur in developing countries and there is some evidence that, at least in developed countries, acute cerebrovascular events (stroke and transient ischemic attack) are becoming more common events than acute coronary events (myocardial infarction and unstable angina) Stroke incidence, prevalence, stroke-subtype structure, 1-month case fatality, and mortality rates show modest geographical variations, with the exception of Ukraine, Russia, and Japan, where incidence rates are highest, and Italy and the UK, where prevalence rates are highest The average age of patients affected by stroke is 70 years in men and 75 years in women, but it is substantially younger in non-white populations and developing countries. In developed countries, more than half of all strokes occur in people over 75 years of age. Approximately 25% of all strokes occur in people younger than 65 years, and 5% in people younger than 45 years The age-standardized prevalence rate of stroke in people aged 65 years and older ranges from 5% to 7% and is tending to increase due to the aging of the population and improved survival; therefore, the overall burden of stroke is likely to continue to increase In developed countries, overall case fatality within 1 month of stroke onset is approximately 23% and is higher for intracerebral hemorrhage (42%) and subarachnoid hemorrhage (32%) than for ischemic stroke (16%). Early stroke-related case fatality in developing countries is substantially greater than that in developed countries Overall, there is a trend toward stabilizing or decreasing stroke incidence in some developed countries, but there is suggestive evidence that incidence of stroke is increasing in developing countries Modified from Feigin, V.L., Lawes, C.M., Bennett, D.A., Anderson, C.S., 2003. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol. 2 (1), 43–53.

Cerebrovascular Disease elevated blood pressure, cardiac disease, TIA, asymptomatic carotid stenosis, cigarette smoking, and diabetes mellitus. Less well-documented but also potentially controllable risk factors include low socioeconomic status, unhealthy diet/ nutrition, alcohol abuse (especially binge drinking; the overall relationship between alcohol consumption and stroke is J-shaped), obesity, diabetes mellitus, physical inactivity, some blood disorders and lipid abnormalities, migraine with aura, hormone replacement therapy, oral contraceptives, drug abuse, inflammatory processes, and low personal and environmental temperature. Although some risk factors are similar for various stroke pathological types and subtypes (e.g., elevated blood pressure, cigarette smoking), some are more specific for particular types of stroke (e.g., unruptured intracranial aneurysms for SAH, atrial fibrillation for cardioembolic stroke). Nonmodifiable but well-documented risk factors for stroke are increasing age (almost doubling for each successive decade), sex (men are at greater risk of stroke than women until the age of 65 years but women are at greater risk of stroke than men at older age). Some studies suggest that a parental history of stroke and genetic predisposition are also important risk factors for stroke. Current evidence suggests that stroke and vascular risk factors have similar relative effects across the world, with modest interaction with ethnicity and nation (Feigin and Carter, 2004; Pearce et al., 2004). Asia offers a widely heterogeneous ethnic distribution and data on interethnic differences in the Asian stroke population are limited. In a recent study of Singaporean stroke patients (mixture of multiple ethnic groups, the Singaporean population may be considered a representative sample of patients of ‘Asian’ origin), we did not find any differences in in-hospital mortality and functional independence at discharge among various ethnic groups. This interesting phenomenon was observed despite the differences in risk factors and in stroke subtypes (Sharma et al., 2012). At least two-thirds of strokes are explained by identifiable risk factors and there is suggestive evidence that at least 80% of strokes can be prevented (Wald and Law, 2003). The modern approach to stroke prevention includes a combination of population-based (control of risk factors on the population level) and individual-based or high-risk strategies. The high-risk strategy includes identification and management of individuals with high risk of stroke or even preclinical individuals with high risk of developing some stroke risk factors (e.g., subjects with increased left atrial volume). Current American Heart Association Guidelines for primary prevention of cardiovascular disease and stroke recommend risk factor screening in adults to begin at age 20 years, with blood pressure, body mass index, waist circumference, and pulse (to screen for atrial fibrillation) to be recorded at least every 2 years; and fasting serum lipoprotein profile (or total and high-density lipoprotein cholesterol if fasting is unavailable) and fasting blood glucose measured according to person’s risk for hyperlipidemia and diabetes, respectively (at least every 5 years if no risk factors are present, and every 2 years if risk factors are present). For all adults 40 years of age and older or people with two or more risk factors (e.g., smoking, elevated blood pressure, total/LDL cholesterol, ECG documented left ventricular hypertrophy, or diabetes), the absolute risk of developing coronary heart disease and stroke can be calculated. Prediction charts have also been developed for selecting people with an

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increased risk of cardiovascular disease (stroke, TIA, coronary heart disease, congestive heart failure, or peripheral vascular disease) (Figure 8). Control of risk factors should be aimed to lower the absolute risk of developing coronary heart disease and stroke as much as possible. A stepwise implementation of evidence-based interventions with comprehensive and integrated action at the country level have recently been suggested by the WHO as the major means to the worldwide prevention and control of chronic diseases including stroke.

Stroke Outcomes Clinical outcomes in stroke have often been classified into survival (death), impairment (signs and symptoms of the underlying pathology), disability (limitation in functional activities), handicap (disadvantage to the individual resulting from impairment and disability), and quality of life (patient’s general well-being resulting from physical, psychological, and social aspects of life that may be affected by changes in health states). The recent International Classification of Functioning (ICF), Disability and Health (World Health Organization, 2001) describes outcomes in terms of body functioning, activities (related to tasks and actions by an individual) and participation (involvement in a life situation), and environment. According to the ICF, functioning and disability are viewed as a complex interaction between the health condition of the individual and the contextual factors of the environment as well as personal factors. The picture produced by this combination of factors and dimensions is of ‘the person in his or her world.’ The classification treats these dimensions as interactive and dynamic rather than linear or static. It allows for an assessment of the degree of disability, although it is not a measurement instrument. It is applicable to all people, whatever their health condition. The language of the ICF is neutral as to etiology, placing the emphasis on function rather than condition or disease. It also is carefully designed to be relevant across cultures as well as age groups and genders, making it highly appropriate for heterogeneous populations. The ICF is currently considered as the standard measure of outcomes and has been shown to have reasonably good psychometric and administrative properties in the area of stroke rehabilitation and research. Accurate information on short-term and long-term stroke outcomes is important to the patients, their families, and health-care providers for setting up appropriate goals and expectations and developing appropriate management options (e.g., discharge plan, interventions).

Survival On average, about one-quarter of stroke patients die within the 1st month after stroke onset, one-third within the first 6–12 months, and one-half within the first 2 years after stroke, with the average case fatality of 5% between years 1 and 10 and about 2% between years 10 and 21 after stroke, with older patients having the worse prognosis. Based on these and other similar population-based studies, cumulative case-fatalities have been estimated at 40–60% at 5 years, approximately 80% at 10 years, 90% at 15 years, and 93% at 21 years. Stroke patients have nearly twice the mortality rates of the general population.

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Risk level Benefit (1) Benefit (2) 5 year cardiovascular Cardiovascular events Number needed to treat for 5 years to risk (nonfatal and fatal) prevented per 100 treated for 5 years* prevent 1 event* Very high High Moderate Mild

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¼2 to classify ‘obesity.’ BMI-for-age Z-scores < 2 and energy expenditure), while many factors affect people’s eating and PA. The factors are more complex for children than for adults due to many differences between them. Many factors have contributed to the increase in prevalence of obesity in children. In short, these factors include: unhealthy eating, lack of PA, increased sedentary behaviors especially screen time, short sleep duration, parenting and family factors, school factors, social norms, community food, and PA environments (Lobstein et al., 2004; Reilly et al., 2005; World Health Organization, 2015). During recent years, researchers and key related public health organizations including the WHO and U.S. Institute of Medicine (IOM) have argued that the increase in childhood obesity results from many changes in society, in particular, due to social and economic development and policies in the areas of agriculture, transport, urban planning, the environment, food processing, distribution and marketing, and education. These factors have contributed to unhealthy eating, lack of PA, and increasing sedentary behaviors in children, which result in excessive weight gain (World Health Organization, 2015; Institute of Medicine, 2012). According to the WHO, the global increases in childhood overweight and obesity are attributable to a number of factors including mainly a global shift in diet toward increased intake of energy-dense foods that are high in fat and sugars but low in other healthy micronutrients and the trend toward decreased PA levels due to the increasingly sedentary nature of recreation activities, changing modes of transportation, and urbanization (World Health Organization, 2015).

Genetic Factors and Gene–Environment Interactions A large body of evidence including studies on twins, siblings, nuclear families, and extended pedigrees has shown the heritability of obesity including measures on BMI and body fat – especially twin studies (Cecil et al., 2012; Manco and Dallapiccola, 2012; Min et al., 2013). Advances in genotyping technologies have raised hope and expectations that genetic testing will pave the way to personalized medicine and that complex traits such as obesity will be prevented even before birth (Manco and Dallapiccola, 2012). For example, our recent systematic review and meta-regression analysis examined the BMI heritability (BMI-H) and the differences in BMI-H by population characteristics, such as sex, age, time period of observation, and average BMI, as well as by broad national level social–environmental factors (Min et al., 2013). Based on findings from 32 twin studies from various countries worldwide, we found BMI-H ranged about 30–90%; and the heterogeneity of BMI-H was significantly attributable to differences in study subjects’ age, time period of study, average BMI, and economic development levels of the study populations. The fact that not all children become obese given the shifts in people’s eating and PA patterns under the influence of the ‘obesogenic’ environments indicates the presence of susceptibility and resistance, and the importance of the effect of the interaction between genetic and environmental factors on

childhood obesity development. Pediatric obesity is a complex phenotype and is modulated by unique gene–environment interactions that occur in early periods of the life. Susceptibility could be mediated through a failure of appetite regulation leading to increased energy intake or via diminished energy expenditure. A recent review suggests that susceptibility to childhood obesity involving specific allelic variants of certain genes is mediated primarily through food consumption (appetite regulation) rather than through a decrease in PA (Cecil et al., 2012). Twin studies implicate weak satiety and enhanced food responsiveness as factors determining an increase in BMI. Single gene mutations, for example, in the leptin receptor gene, that lead to extreme obesity appear to operate through appetite regulating mechanisms and overconsumption. Investigations of robustly characterized common gene variants of fat mass and obesity associated (FTO), peroxisome proliferator–activated receptor (PPARG) and melanocortin 4 receptor (MC4R) which contribute to variance in BMI also influence the variance in appetite factors.

Risk Factors during Early Life Stages Experiences during early life stages can have many important, long-term impacts on later health. According to the ‘Developmental Origins of Health and Disease (DOHaD) theory,’ a poor start to life is associated with an increased risk of a number of disorders, especially noncommunicable diseases, throughout the life course. These diseases include obesity, cardiovascular disease, type 2 diabetes, osteoporosis, some forms of cancer, and some other diseases. Many studies have been conducted to examine the effects of factors during early life stages on childhood obesity risks, which include pre- and post-natal factors such as gestational weight gain (GWG) and feeding practice during infancy. Research suggests that overweight/obese women’s offspring tend to have higher birth weights and more body fat, and have increased risks of obesity later in life (Symonds et al., 2013). A recent meta-analysis of findings from 12 cohort studies reported that the risk of childhood overweight/obesity was significantly associated with excessive GWG. The combined OR of excessive GWG and childhood overweight/obesity was 1.33 (95% CI: 1.18–1.50). The association is robust. Adjustment for maternal BMI, investigation area, child age, research type, and omission of any single study had little effect on the pooled estimate (Tie et al., 2014). The mother–child association for childhood obesity may be partly related to the increased risk of gestational diabetes (Frias and Grove, 2012; Symonds et al., 2013).

Birth Weight Research has reported a nonlinear relationship between birth weight (BW) and obesity risks in children and adults. For example, a recent review (Yu et al., 2011) examined the association between BW and obesity risk: 20 studies for the metaanalysis and the other 13 articles for systematical review. Both approaches showed consistent results: high BW (>4000 g) (vs BW  4000 g) was associated with increased risk of obesity (OR ¼ 2.07; 95% confidence interval [CI], 1.91–2.24). Low BW (30% of calories from fat), and more than 91% eat too much saturated fat (i.e., >10% of calories from saturated fat). Although dietary fat is suggested as a risk factor for weight gain and obesity, total calories have not been controlled in most of studies. Thus, it is not ascertained whether the association is due to fat per se or the fact that there are more calories per gram of fat than protein or carbohydrate. In addition, studies have shown inconsistent findings for the influence of low glycemic load diets on obesity (Mirza et al., 2013; Spieth et al., 2000). The few existing clinical trials for weight control in children have reported mixed results for

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whether a low fat or low glycemic load diet is superior to other dietary strategies (Demol et al., 2009; Mirza et al., 2013).

Vegetable and Fruit Consumption Increased vegetable and fruit consumption can help reduce the intake of dietary fat and calories because they are naturally low in fat and energy density compared with other foods (Rolland-Cachera et al., 1997). Adequate consumption of vegetable and fruit is important for good health (U.S. Department of Agriculture and U.S. Department of Health and Human Services, 2000). Americans older than 2 years are urged to eat three to five servings of vegetables and two to four servings of fruits each day (U.S. Department of Health and Human Services and U.S. Department of Agriculture, 2005). But studies show that American children and adolescents’ vegetable and fruit consumption is very low compared with the recommendations (Centers for Disease Control and Prevention, n.d.; Krebs-Smith et al., 1996; Pesa and Turner, 2001). Only one in five American children eats five servings of vegetable and fruit a day, 51% eat less than one serving of fruit a day, and 29% eat less than one serving of vegetables a day that are not fried. Children and adolescents eat, on average, only 3.6 servings of vegetable and fruit a day, and fried potatoes account for a large proportion of the vegetables eaten. Despite a wide belief that adequate vegetable and fruit consumption helps reduce obesity risk, the protective effect has not been well supported by intervention trials (Wang et al., 2015).

Portion Size Increases in standard portion sizes have occurred across a range of foods eaten inside and outside the home. Studies suggest that while very young children have a precise innate control of appetite and are able to match intake to energy needs, this biological mechanism can be overridden by environmental and social factors in older children (French et al., 2001).

Sugar Sweetened Beverages Increasing research including intervention trials indicate that the consumption of SSBs and the fructose they contain increases obesity risks and has contributed to the rising epidemic of childhood obesity. Meta-analyses suggest that consumption of SSBs is related to the risk of obesity as well as diabetes, the metabolic syndrome, and cardiovascular disease in children and adults (Bray and Popkin, 2013). Randomized, controlled trials in children and adults lasting from 6 months to 2 years have shown that lowering the intake of SSBs reduced weight gain (Bray and Popkin, 2013). However, after reviewing seven prospective studies, Pérez-Morales et al. (2013) concluded that although the trend of the studies indicates an association between SSB intake before 6 years of age and increased weight, BMI, or waist circumference later in childhood, to date, the results were inconsistent, and the two studies with the higher number of children showed a positive association.

Short Sleep Duration The evidence is growing and is strong regarding the influence of sleep duration on obesity risks. Systematic reviews and

meta-analyses including ours based on cohort studies have reported association between short sleep duration and obesity risks in children (Chen et al., 2008; Fatima et al., 2015). Recently, Fatima et al. (2015) have reviewed 22 longitudinal studies, with subjects from diverse backgrounds, and reported an inverse association between sleep duration and BMI. Their meta-analysis of 11 longitudinal studies, comprising 24,821 participants, showed that children who slept for short duration doubled their risk of being overweight/obese than those with long duration (OR ¼ 2.15; 95% CI, 1.64–2.81).

Screen Time and Social Media Screen time is a major source of inactivity among children in many countries, and in the recent decade the sources for increased screen time are shifting from television viewing to the use of other devices including smart phones and ipads. Previously well documented evidences including intervention trials have linked television viewing time and obesity risks in children, and showed that reducing television viewing time will help reduce children’s risk of developing obesity (Robinson, 1999). It is likely that the increasing use and influence of social media in children’s life have affected their eating and PA, and thus could affect their weight. A recent longitudinal study observed a positive association between screen time and changes in the BMI at the upper tail of the BMI distribution among U.S. adolescents (Mitchell et al., 2013). However, only few recent studies have examined the impact of overall screen time and the impact of social media on obesity risks in children.

Health Consequences of Childhood Obesity Increasing evidence suggests that childhood obesity has a number of immediate, intermediate, and long-term health consequences. Several comprehensive reviews have examined this topic (e.g., Lostein et al., 2004; Must and Anderson, 2003; Must and Strauss, 1999; Power et al., 1997; Vivier and Timpkins, 2008; World Health Organization, 2000). These health consequences of obesity include cardiovascular risk factors, type 2 diabetes, menstrual abnormalities, sleepdisordered breathing, psychosocial consequences and quality of life (QOL), orthopedic complications, pulmonary complications and breathing disorders, and other conditions (e.g., neurological problems Dietz, 1998; see Table 3). Childhood obesity also has long-term effects on morbidity and mortality (Lostein et al., 2004; Must et al., 1992; Must and Strauss, 1999; Rossner, 1998). However, most of our current knowledge is accumulated from small, unrepresentative, short-term, hospital-based studies. More research is needed to help narrow the gaps in the literature.

Immediate and Intermediate Health Consequences Cardiovascular Risk Factors Dyslipidemia

Increased total serum cholesterol, high normal to mildly elevated low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels and decreased levels of high-density lipoprotein

Child Obesity and Health Table 3

Health consequences of childhood and adolescent obesity

Categories/systems

Conditions/diseases

Immediate and intermediate consequences Cardiovascular Hypertension, dyslipidemia Endocrine Insulin resistance/impaired glucose tolerance, type 2 diabetes, menstrual abnormalities, polycystic ovary syndrome Gastroenterological Cholelithiasis, liver steatosis, gastroesophageal reflux Neurological Idiopathic intracranial hypertension (e.g., pseudotumor cerebri) Orthopedic Slipped capital epiphyses, Blount’s disease (tibia vara), flat feet, ankle sprains Pulmonary Asthma, sleep disorders, Pickwickian syndrome Long-term consequences Persistence Obese children are likely to remain obese as adults (tracking) Morbidity Coronary heart disease, diabetes, atherosclerosis, hip fracture, some types of cancer Mortality All-cause, disease-specific mortality (e.g., coronary heart disease

(HDL) cholesterol are correlated with obesity in children (Kwiterovich, 2008). For example, data from the Bogalusa Heart Study show that overweight during adolescence predicted a 2.4-fold increase in the prevalence of high total cholesterol (>240 mg dl1), a threefold increase in high LDL (>160 mg dl1), and an eightfold increase in low HDL (25) was associated with a 1.5-fold increased risk for all-cause death and 2.5-fold increased risk for coronary heart disease mortality (Hoffmans et al., 1988). Studies also suggest that BMI in adolescence may have lasting implications for risk of cancer mortality in later life (Okasha et al., 2002). Finally, a higher mortality risk for all causes of death, especially atherosclerotic cerebrovascular disease and colorectal cancer, was demonstrated in males but not in females who were overweight during high school years (Maffeis and Tatò, 2001).

The Influence of Obesity on Young People’s Psychosocial Development and Well-Being A growing number of studies, predominately based on crosssectional data collected from school-age youths, have examined the association between obesity and young people’s psychosocial development and well-being, although few are cohort studies based on nationally representative data. In general, most of these studies indicate an adverse impact of obesity. Reilly et al. (2003) reviewed five high quality studies and concluded that obese children are more likely to experience psychological or psychiatric problems than nonobese children. Compared to boys, girls are at higher risk of developing psychological morbidity, which increases with age. The Institute of Medicine also recognized that youth is at risk for serious psychosocial burdens related to obesity (Institute of Medicine, 2005).

Obesity and Self-Esteem The relationship between self-esteem and obesity, in particular among school-age children, has received a lot of attention (e.g., Bosch et al., 2004; French et al., 1995; Friedlander et al., 2003; Hesketh et al., 2004; Strauss, 2000; Willows et al., 2013). During recent years, a growing number of studies confirm a negative impact of obesity on self-esteem in young people, although the findings from different studies vary, in part because of differences in study designs, study samples, and the assessment of study variables. In an early comprehensive review, French et al. (1995) analyzed findings from 35 studies on the relationship between self-esteem and obesity in children and adolescents. Thirteen of the 25 (52%) cross-sectional studies clearly showed lower self-esteem in obese adolescents and children. Six of eight (75%) treatment studies showed that weight loss treatment programs appear to improve selfesteem, although it is unclear whether increases in self-esteem might enhance weight loss. A recent cross-sectional study in Canadian children from grades four to six showed that the

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psychosocial correlates of obesity are important for both sexes, especially girls (Willows et al., 2013). Many of the studies reviewed suffered from some methodological weakness such as small and select samples and lack of appropriate comparison groups. Stronger studies have been published since then. A recent prospective cohort study followed a random sample of 1157 Australian children, who were 5–10 years old at baseline, for more than two years. Overweight/obese children had lower median self-esteem scores than non-overweight children at both time points, especially at follow-up. On the other hand, non-overweight children with low baseline self-esteem were twice as likely to develop overweight/obesity (p < 0.05; Hesketh et al., 2004). Another 4-year follow-up study conducted among 1520 U.S. children aged 9–10 at baseline has shown a strong impact of obesity on self-esteem (Strauss, 2000). Over the 4-year period, obese Hispanic females and obese white females showed significantly decreased levels of global selfesteem compared with nonobese Hispanic females and nonobese white females, respectively. Mild decreases in self-esteem were also observed in obese boys compared with nonobese boys. As a result, by 13–14 years of age, significantly lower levels of self-esteem were observed in obese boys, obese Hispanic girls, and obese white girls compared with their nonobese counterparts. Decreasing levels of self-esteem in obese children were associated with significantly increased rates of sadness, loneliness, and nervousness compared with obese children whose self-esteem increased or remained unchanged. In addition, obese children with decreasing levels of selfesteem over the 4-year period were more likely to engage in high-risk behavior such as smoking or consuming alcohol.

Obesity and Quality of Life Several recent studies have examined the relationship between obesity and QOL in young people. The Health of Young Victorians Study in Australia, with data collected from 1456 children aged 9–12, shows that QOL scores in physical and social functioning were lower in obese children than in non-overweight children (p < 0.001; Williams et al., 2005). In a U.S. study, based on cross-sectional data collected in the 1996 Add Health Study – a nationally representative sample of adolescents in grades 7 to 12 during the 1994–95 school year (N ¼ 4743) – Swallen et al. (2005) studied the association between obesity and QOL. Health-related QOL was assessed in four dimensions: general health (self-reported general health), physical health (absence or presence of functional limitations and illness symptoms), emotional health, and a school- and social-functioning scale. The researchers found a statistically significant relationship between BMI and poor total QOL score, general health, and physical health, although not psychosocial outcomes. Adolescents who were overweight or obese had significantly worse self-reported health (OR ¼ 2–5) and were also twice as likely to have a functional limitation. This study also found considerable differences between blacks and whites. In other words, although there was a strong reverse association between obesity and functional limitations in whites, this relationship was not observed among blacks. Similar findings have been reported in several smaller studies (e.g., Friedlander et al., 2003; Schwimmer et al., 2003). A recent meta-analysis of the association between

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BMI and overall, physical, and psychosocial health–related quality of life (HRQoL) in children and adolescents included 11 studies with 13,210 study participants (UI-Haq et al., 2013). It showed that although parents overestimate the impact of obesity on the HRQoL of their children, obese children and adolescents have significantly reduced overall, physical, and psychosocial HRQoL; their overall score was reduced by 10.6 points (95% CI, 14.0–7.2; p < 0.001).

Prevention of Childhood Obesity A large number of studies have been conducted regarding children obesity prevention and treatment, while the majority are conducted in high-income countries and very limited is known about the other countries. Nevertheless, lessons learned in high-income countries are useful for middle- and low-income countries. The growing obesity problem is societal and thus it demands a population-based multisectoral, multidisciplinary, and culturally relevant approach (World Health Organization, 2015). Unlike most adults, children do not have much power to choose the environment in which they live and the food they eat. Furthermore, they have a limited ability to understand the long-term consequences of their behaviors. Therefore, special attention and efforts are needed to help them develop desirable lifelong habits for preventing obesity. We and others have reviewed various interventions conducted in countries worldwide to determine what programs are successful and what more research is needed for childhood obesity prevention (Lobstein et al., 2015; van Hoek et al., 2014; Wang et al., 2013, 2015). A large number of studies have been conducted to study childhood obesity prevention, and mixed results are reported (Wang et al., 2013, 2015). Nevertheless, adequate evidences have been accumulated supporting that interventions, especially school-based programs, could be effective in preventing childhood obesity. Meanwhile, even if some of the interventions cannot reduce obesity, they may still result in other beneficial changes in other health outcomes such as lowered blood pressure and improved blood lipid profile as shown by our recent systematical reviews and metaanalyses (Bleich et al., 2013; Cai et al., 2014a,b; Showell et al., 2013; Wang et al., 2015). According to the WHO and other recommendations (World Health Organization, 2015; Lobstein et al., 2004), children are recommended to do the following to prevent obesity: (1) increase consumption of fruit and vegetables, legumes, whole grains, and nuts; (2) limit energy intake from total fats and shift fat consumption away from saturated fats to unsaturated fats; (3) limit the intake of high energy density food such as fried food, sugars, as well as SSBs; and (4) be physically active and reduce sedentary behaviors such as to accumulate at least 60 min of moderate-to vigorous–intensity activity each day and limit their screen time.

Conclusions Childhood and adolescence are two critical periods for the development of obesity since obese children are twice as likely as nonobese children to become obese adults. Childhood

obesity has many immediate, intermediate, and long-term negative consequences on health in addition to the many immediate effects it has on children’s psychosocial development. Multiple factors at individual, family, school, society, and global levels affect children’s energy-balance related behaviors, and have contributed to the increases in childhood obesity worldwide. Because childhood and adolescence are the most important times for one to form lifelong dietary habits, lifestyles, and health beliefs, the development of effective programs and policies for the prevention and management of obesity in children and adolescents should be a priority in order to combat the growing global obesity epidemic. Population-based health promotion approaches should emphasize moderate amounts of activity, gradual and sustainable lifestyle modifications, and the flexibility to vary choices according to personal preference and life circumstances in order to encourage more people to adopt regular PA and healthy eating in their daily lives. School-based interventions for youth are particularly promising. This is not only because almost all young people between the ages of 6 and 18 attend school but also because of the potential impact of the behaviors formed during these years on one’s lifelong habits.

Acknowledgment Part of this work was supported by research grants from the U.S. National Institute of Health (#1R01 DK63383, 1R01HD064685-01A1, 1 U54 HD070725).

See also: Obesity/Overweight: Health Consequences; Overweight and Obesity: Prevention and Weight Management.

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Manco, M., Dallapiccola, B., 2012. Genetics of pediatric obesity. Pediatrics 130 (1), 123–133. Mast, M., Langnäse, K., Labitzke, K., Bruse, U., Preuss, U., Müller, M.J., 2002. Use of BMI as a measure of overweight and obesity in a field study on 5-7 year old children. Eur. J. Nutr. 41 (2), 61–67. McDowell, M.A., et al., 1994. Energy and Macronutrient Intakes of Persons Ages 2 Months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988–91. Advance Data from Vital and Health Statistics; no. 255. National Center for Health Statistics, Hyattsville, MD. Min, J., Chiu, D.T., Wang, Y., 2013. Variation in the heritability of body mass index based on diverse twin studies: a systematic review. Obes. Rev. 14 (11), 871–882. Mirza, N.M., Palmer, M.G., Sinclair, K.B., et al., 2013. Effects of a low glycemic load or a low-fat dietary intervention on body weight in obese Hispanic American children and adolescents: a randomized controlled trial. Am. J. Clin. Nutr. 97 (2), 276–285. Mitchell, J.A., Rodriguez, D., Schmitz, K.H., Audrain-McGovern, J., 2013. Greater screen time is associated with adolescent obesity: a longitudinal study of the BMI distribution from Ages 14 to 18. Obes. (Silver Spring) 21 (3), 572–575. Mokhlesi, B., Kryger, M.H., Grunstein, R.R., 2008. Assessment and management of patients with obesity hypoventilation syndrome. Proc. Am. Thorac. Soc. 5 (2), 218–225. Must, A., Anderson, S.E., 2003. Effects of obesity on morbidity in children and adolescents. Nutr. Clin. Care 6 (1), 4–12. Must, A., Strauss, R.S., 1999. Risks and consequences of childhood and adolescent obesity. Int. J. Obes. Relat. Metab. Disord. 23 (Suppl. 2), S2–S11. Must, A., Dallal, G.E., Dietz, W.H., 1991. Reference data for obesity: 85th and 95th percentiles of body mass index (wt/ht2) and triceps skinfold thickness. Am. J. Clin. Nutr. 53, 839–846. Must, A., Jacques, P.F., Dallal, G.E., Bajema, C.J., Dietz, W.H., 1992. Long- term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935. N. Engl. J. Med. 327 (19), 1350–1355. von Mutius, E., Schwartz, J., Neas, L.M., Dockery, D., Weiss, S.T., 2001. Relation of body mass index to asthma and atopy in children: the National Health and Nutrition Examination Study III. Thorax 56, 835–838. Ng, M., Fleming, B.S., Bobinson, M., et al., 2014. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384 (9945), 766–781. de Onis, M., Onyango, A.W., Borghi, E., Siyam, A., Nishida, C., Siekmann, J., 2007. Development of a WHO growth reference for school-aged children and adolescents. Bull. World Health Organ. 85, 660–667. de Onis, M., Blossner, M., Borghi, E., 2010. Global prevalence and trends of overweight and obesity among preschool children. Am. J. Clin. Nutr. 92, 1257–1264. Ogden, C.L., Carroll, M.D., Kit, B.K., Flegal, K.M., 2014. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA 311 (8), 806–814. Okasha, M., McCarron, P., McEwen, J., Smith, G.D., 2002. Body mass index in young adulthood and cancer mortality: a retrospective cohort study. J. Epidemiol. Community Health 56, 780–784. Papadimitriou, A., 2015. Timing of adiposity rebound and prevalence of obesity. J. Pediatr. 167 (2), 498. Papoutsakis, C., Priftis, K.N., Drakouli, M., et al., 2013. Childhood overweight/obesity and asthma: is there a link? A systematic review of recent epidemiologic evidence. J. Acad. Nutr. Diet. 113 (1), 77–105. Parsons, T.J., Power, C., Logan, S., Summerbell, C.D., 1999. Childhood predictors of adult obesity: a systematic review. Int. J. Obes. Relat. Metab. Disord. 23 (Suppl. 8), S1–S107. Pereira, M.A., Kartashov, A.I., Ebbeling, C.B., et al., 2005. Fast-food habits, weight gain, and insulin resistance (the CARDIA study): 15-year prospective analysis. Lancet 365 (9453), 36–42. Pérez-Morales, E., Bacardí-Gascón, M., Jiménez-Cruz, A., Jan–Feb 2013. Sugarsweetened beverage intake before 6 years of age and weight or BMI status among older children; systematic review of prospective studies. Nutr. Hosp. 28 (1), 47–51. Pesa, J.A., Turner, L.W., 2001. Fruit and vegetable intake and weight-control behaviors among US youth. Am. J. Health Behav. 25, 3–9. Piper, A.J., 2011. Obesity hypoventilation syndrome–the big and the breathless. Sleep. Med. Rev. 15 (2), 79–89. Poskitt, E.M., 1995. Defining childhood obesity: the relative body mass index (BMI). European Childhood Obesity Group. Acta Paediatr. 84, 961–963. Power, C., Lake, J.K., Cole, T.J., 1997. Measurement and long-term health risks of child and adolescent fatness. Int. J. Obes. Relat. Metab. Disord. 21, 507–526. Reilly, J.J., Methven, E., McDowell, Z.C., Hacking, B., Alexander, D., Stewart, L., Kelnar, C.J., 2003. Health consequences of obesity. Arch. Dis. Child. 88 (9), 748–752.

Reilly, J.J., Armstrong, J., Dorosty, A.R., Emmett, P.M., Ness, A., Rogers, I., Steer, C., Sherriff, A., Avon Longitudinal Study of Parents and Children Study Team, 2005. Early life risk factors for obesity in childhood: cohort study. BMJ 330 (7504), 1357. Robinson, T.N., 1999. Reducing children’s television viewing to prevent obesity: a randomized controlled trial. J. Am. Med. Assoc. 282, 1561–1567. Rolland-Cachera, M.F., Cole, T.J., Sempe, M., et al., 1991. Body mass index variations: centiles from birth to 87 years. Eur. J. Clin. Nutr. 45, 13–21. Rolland-Cachera, M.F., Deheeger, M., Bellisle, F., 1997. Nutrient balance and body composition. Reprod. Nutr. Dev. 37, 727–734. Rossner, S., 1998. Childhood obesity and adulthood consequences. Acta Paediatr. 87, 1–5. Rowell, H.A., Evans, B.J., Quarry-Horn, J.L., Kerrigan, J.R., 2002. Type 2 diabetes mellitus in adolescents. Adolesc. Med. 13, 1–12. Schellong, K., Schulz, S., Harder, T., Plagemann, A., 2012. Birth Weight and LongTerm Overweight Risk: systematic review and a meta-analysis including 643,902 persons from 66 studies and 26 countries globally. PLoS One 7 (10), e47776. Schwimmer, J.B., Burwinkle, T.M., Varni, J.W., 2003. Health-related quality of life of severely obese children and adolescents. J. Am. Med. Assoc. 289 (14), 1813–1819. Scott, E.C., Johnston, F.E., 1982. Critical fat, menarche, and the maintenance of menstrual cycles: a critical review. J. Adolesc. Health Care 2, 249–260. Serdula, M.K., Ivery, D., Coates, R.J., Freedman, D.S., Williamson, D.F., Byers, T., 1993. Do obese children become obese adults? A review of the literature. Prev. Med. 22, 167–177. Showell, N.N., Fawole, O., Segal, J., Wilson, R.F., Cheskin, L.J., Bleich, S.N., Wu, Y., Lau, B., Wang, Y., 2013. A systematic review of home-based childhood obesity prevention studies. Pediatrics 132 (1), e193–e200. Silverstein, J.H., Rosenbloom, A.L., 2001. Type 2 diabetes in children. Curr. Diabetes Rep. 1, 19–27. Singh, A.S., Mulder, C., Twisk, J.W., van Mechelen, W., Chinapaw, M.J., 2008. Tracking of childhood overweight into adulthood: a systematic review of the literature. Obes. Rev. 9 (5), 474–488. Spieth, L.E., Harnish, J.D., Lenders, C.M., et al., 2000. A low-glycemic index diet in the treatment of pediatric obesity. Arch. Pediatr. Adolesc. Med. 154 (9), 947–951. Srinivasan, S.R., Bao, W., Wattigney, W.A., Berenson, G.S., 1996. Adolescent overweight is associated with adult overweight and related multiple cardiovascular risk factors: the Bogalusa Heart Study. Metabolism 45, 235–240. Steinberger, J., Moorehead, C., Katch, V., et al., 1995. Relationship between insulin resistance and abnormal lipid profile in obese adolescents. J. Pediatr. 126 (5 Pt 1), 690–695. Strauss, R.S., 2000. Childhood obesity and self-esteem. Pediatrics 105 (1), e15. Swallen, K.C., Reither, E.N., Haas, S.A., Meier, A.M., 2005. Overweight, obesity, and health-related quality of life among adolescents: the National Longitudinal Study of Adolescent Health. Pediatrics 115 (2), 340–347. Symonds, M.E., Mendez, M.A., Meltzer, H.M., Koletzko, B., Godfrey, K., Forsyth, S., van der Beek, E.M., 2013. Early life nutritional programming of obesity: motherchild cohort studies. Ann. Nutr. Metab. 62 (2), 137–145. Tie, H.T., Xia, Y.Y., Zeng, Y.S., Zhang, Y., Dai, C.L., Guo, J.J., Zhao, Y., 2014. Risk of childhood overweight or obesity associated with excessive weight gain during pregnancy: a meta-analysis. Arch. Gynecol. Obstet. 289 (2), 247–257. Tremblay, M.S., Katzmarzyk, P.T., Willms, J.D., 2002. Temporal trends in overweight and obesity in Canada, 1981–1996. Int. J. Obes. Relat. Metab. Disord. 26 (4), 538–543. Trusell, J., 1980. Statistical flaws in evidence for the Frisch hypothesis that fatness triggers menarche. Human Biol. 52, 711–720 (An International Record of Research). Tsaoussoglou, M., Bixler, E.O., Calhoun, S., Chrousos, G.P., Sauder, K., Vgontzas, A.N., 2010. Sleep-disordered breathing in obese children is associated with prevalent excessive daytime sleepiness, inflammation, and metabolic abnormalities. J. Clin. Endocrinol. Metab. 95 (1), 143–150. U.S. Department of Agriculture and U.S. Department of Health and Human Services, 2000. Nutrition and Your Health: Dietary Guidelines for Americans, fifth ed. Washington, DC. U.S. Department of Health and Human Services and U.S. Department of Agriculture, January, 2005. Dietary Guidelines for Americans, sixth ed. U.S. Government Printing Office, Washington, DC. Ul-Haq, Z., Mackay, D.F., Fenwick, E., Pell, J.P., 2013. Meta-analysis of the association between body mass index and health-related quality of life among children and adolescents, assessed using the pediatric quality of life inventory index. J. Pediatr. 162 (2), 280–286.

Child Obesity and Health Van Lenthe, F.J., Kemper, C.G., van Mechelen, W., 1996. Rapid maturation in adolescence results in greater obesity in adulthood: the Amsterdam Growth and Health Study. Am. J. Clin. Nutr. 64, 18–24. Vivier, P., Timpkins, C., 2008. Health consequences of obesity in children and adolescents. Chapter handbook of childhood and adolescent obesity. Part Ser. Issues Clin. Child Psychol. 11–24. Wabitsch, M., Moss, A., Kromeyer-Hauschild, K., January 31, 2014. Unexpected plateauing of childhood obesity rates in developed countries. BMC Med. 12, 17. Wagner, I.V., Sabin, M.A., Pfäffle, R.W., 2012. Effects of obesity on human sexual development. Nat. Rev. Endocrinol. 8 (4), 246–254. Wang, Y., Beydoun, M.A., 2007. The obesity epidemic in the United Statesdgender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol. Rev. 29, 6–28. Wang, Y., Lobstein, T., 2006. Global trends in childhood obesity. Int. J. Pediatr. Obes. 1, 11–25. Wang, Y., Baker, J.L., Hill, J.O., Dietz, W.H., 2012. Controversies regarding reported trends: has the obesity epidemic leveled off in the United States? Adv. Nutr. 3 (5), 751–752. Wang, Y., Wu, Y., Wilson, R.F., Bleich, S., Cheskin, L., Weston, C., Showell, N., Fawole, O., Lau, B., Segal, J., 2013. Childhood Obesity Prevention Programs: Comparative Effectiveness Review and Meta-Analysis [Internet]. Agency for Healthcare Research and Quality (US), Rockville (MD). Report No.: 13-EHC081-EF. AHRQ Comparative Effectiveness Reviews. Wang, Y., Cai, L., Wu, Y., Wilson, R.F., Weston, C., Fawole, O., Bleich, S.N., Cheskin, L.J., Showell, N.N., Lau, B.D., Chiu, D.T., Zhang, A., Segal, J., 2015. What childhood obesity prevention programmes work? A systematic review and meta-analysis. Obes. Rev. 16 (7), 547–565. Wang, Y., 2002. Is obesity associated with early sexual maturation? A comparison of the association in American boys versus girls. Pediatrics 110, 903–910. Wang, Y., 2004. Epidemiology of childhood obesity: methodological aspects and guidelines: what is new? Int. J. Obes. Relat. Metab. Disord. 28 (Suppl. 3), S21–S28. Whitaker, R.C., Pepe, M.S., Wright, J.A., Seidel, K.D., Dietz, W.H., 1998. Early adiposity rebound and the risk of adult obesity. Pediatrics 101, E5. Williams, J., Wake, M., Hesketh, K., Maher, E., Waters, E., 2005. Health-related quality of life of overweight and obese children. J. Am. Med. Assoc. 293 (1), 70–76. Willms, J.D., Tremblay, M.S., Katzmarzyk, P.T., 2003. Geographic and demographic variation in the prevalence of overweight Canadian children. Obes. Res. 11 (5), 668–673. Willows, N.D., Ridley, D., Raine, K.D., Maximova, K., 2013. High adiposity is associated cross-sectionally with low self-concept and body size dissatisfaction among indigenous Cree schoolchildren in Canada. BMC Pediatr. 13 (1), 118. World Health Organization Expert Committee, 1995. Physical Status, the Use and Interpretation of Anthropometry. Technical Report Series No. 854. World Health Organization, Geneva, Switzerland. World Health Organization, 2000. Obesity: Preventing and Managing the Global Epidemic: Report of a WHO Consultation. Technical Report Series, No. 894. World Health Organization, Geneva, Switzerland. World Health Organization, 2006. WHO Child Growth Standards: Length/Height-forAge, Weight-for-Age, Weight-for-Length, Weight-for-Height and Body Mass Indexfor-Age: Methods and Development. WHO, Geneva. World Health Organization, 2015. Global Strategy on Diet, Physical Activity and Health. http://www.who.int/dietphysicalactivity/en/ (assessed 18.11.15.). Yu, Z.B., Han, S.P., Zhu, G.Z., et al., 2011. Birth weight and subsequent risk of obesity: a systematic review and meta-analysis. Obes. Rev. 12 (7), 525–542.

Further Reading Adams, L.B., 1997. An overview of adolescent eating behavior barriers to implementing dietary guidelines. Ann. N.Y. Acad. Sci. 817, 36–48. Archenti, A., Pasqualinotto, L., 2008. Childhood obesity: the epidemic of the third millenium. Acta Biomed. 79 (2), 151–155. Ball, G.D., McCargar, L.J., 2003. Childhood obesity in Canada: a review of prevalence estimates and risk factors for cardiovascular diseases and type 2 diabetes. Can. J. Appl. Physiol. 28, 117–140.

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Baur, L.A., 2009. Tackling the epidemic of childhood obesity. CMAJ 180 (7), 701–702. Birch, L.L., Davison, K.K., 2001. Family environmental factors influencing the developing behavioral controls of food intake and childhood overweight. Pediatr. Clin. N. Am. 2001 (48), 893–907. Birch, L.L., Fisher, J.O., 1998. Development of eating behaviors among children and adolescents. Pediatrics 101, 539–549. Blundell, J.E., Macdiarmid, J.I., 1997. Passive overconsumption. Fat intake and shortterm energy balance. Ann. N.Y. Acad. Sci. 827, 392–407. Brophy, S., Cooksey, R., Gravenor, M.B., Mistry, R., Thomas, N., Lyons, R.A., Williams, R., 2009. Risk factors for childhood obesity at age 5: analysis of the millennium cohort study. BMC Public Health 9, 467. Catalano, P.M., Farrell, K., Thomas, A., Huston-Presley, L., Mencin, P., de Mouzon, S.H., Amini, S.B., 2009. Perinatal risk factors for childhood obesity and metabolic dysregulation. Am. J. Clin. Nutr. 90 (5), 1303–1313. Dietz, W.H., Gortmaker, S.L., 2001. Preventing obesity in children and adolescents. Annu. Rev. Public Health 22, 337–353. Dietz, W.H., Robinson, T.N., 1998. Use of the body mass index (BMI) as a measure of overweight in children and adolescents. J. Pediatr. 132, 191–193. Dreeben, O., 2001. Health status of African Americans. J. Health Soc. Policy 14, 1–17. Ellis, K.J., Bell, S.J., Chertow, G.M., et al., 1999. Bioelectrical impedance methods in clinical research: a follow-up to the NIH Technology Assessment Conference. Nutrition 15, 874–880. Heymsfield, S.B., Wang, Z., Baumgartner, R.N., Ross, R., 1997. Human body composition: advances in models and methods. Annu. Rev. Nutr. 17, 527–558. Huus, K., Ludvigsson, J.F., Enskar, K., Ludvigsson, J., 2007. Risk factors in childhood obesity-findings from the All Babies In Southeast Sweden (ABIS) cohort. Acta Paediatr. 96 (9), 1321–1325. Koletzko, B., Broekaert, I., Demmelmair, H., Franke, J., Hannibal, I., Oberle, D., Scchiess, S., Baumann, B.T., Verwied-Jorky, S., 2005. Protein intake in the first year of life: a risk factor for later obesity? The E.U. childhood obesity project. Adv. Exp. Med. Biol. 569, 69–79. Li, Y.P., Yang, X.G., Zhai, F.Y., Piao, J.H., Zhao, W.H., Zhang, J., Ma, G.S., 2005. Disease risks of childhood obesity in China. Biomed. Environ. Sci. 18 (6), 401–410. MacPhee, M., 2008. Global childhood obesity: how to curb an epidemic. J. Pediatr. Nurs. 23 (1), 1–4. Mayer-Davis, E.J., Rifas-Shiman, S.L., Zhou, L., Hu, F.B., Colditz, G.A., Gilman, M.W., 2006. Breast-feeding and risk for childhood obesity: does maternal diabetes or obesity status matter? Diabetes Care 29 (10), 2231–2237. McCrindle, B.W., 2006. Will childhood obesity lead to an epidemic of premature cardiovascular disease? Evid. Based Cardiovasc. Med. 10 (2), 71–74. Must, A., 1996. Morbidity and mortality associated with elevated body weight in children and adolescents. Am. J. Clin. Nutr. 63 (3 Suppl.), 445S–447S. Pietrobelli, A., Wang, Z., Heymsfield, S.B., 1998. Techniques used in measuring human body composition. Curr. Opin. Clin. Nutr. Metab. Care 1, 439–448. Rana, A.R., Michalsky, M.P., Teich, S., Groner, J.I., Caniano, D.A., Schuster, D.P., 2009. Childhood obesity: a risk factor for injuries observed at a level-1 trauma center. J. Pediatr. Surg. 44 (8), 1601–1605. Rees, A., Thomas, N., Knox, G., Williams, R., 2009. Cross sectional study of childhood obesity and prevalence of risk factors for cardiovascular disease and diabetes in children aged 11–13. BMC Public Health 9, 86. Reilly, J.J., 2005. Descriptive epidemiology and health consequences of childhood obesity. Best. Pract. Res. Clin. Endocrinol. Metab. 19 (3), 327–341. Rugholm, S., Baker, J.L., Olsen, L.W., Schack-Nielsen, L., Bua, J., Sorensen, T.I., 2005. Stability of the association between birth weight and childhood overweight during the development of the obesity epidemic. Obes. Res. 13 (12), 2187–2194. Semiz, S., Ozgoren, E., Sabir, N., Semiz, E., 2008. Body fat distribution in childhood obesity: association with metabolic risk factors. Indian Pediatr. 45 (6), 457–462. Tounian, P., 2007. Consequences in adulthood of childhood obesity. Arch. Pediatr. 14 (6), 718–720. Wang, F., Veugelers, P.J., 2008. Self-esteem and cognitive development in the era of the childhood obesity epidemic. Obes. Rev. 9 (6), 615–623. Wang, Y., Chen, X., Klag, M.J., Caballero, B., 2006. Epidemic of childhood obesity: implications for kidney disease. Adv. Chronic Kidney Dis. 13 (4), 336–351. Weiss, R., Kaufman, F.R., 2008. Metabolic complications of childhood obesity: identifying and mitigating the risk. Diabetes Care 31 (Suppl. 2), S310–S316. Zhang, Q., Wang, Y., 2004. Trends in the association between obesity and socioeconomic status in U.S. adults: 1971 to 2000. Obes. Res. 12 (10), 1622–1632.

Child Rights Jeffrey Goldhagen, University of Florida, Jacksonville, FL, USA Gerison Lansdown, International Consultant on Children’s Rights, London, UK Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 1, pp. 605–612, Ó 2008, Elsevier Inc.

The relevance and importance of children’s rights to the global health and well-being of children and families cannot be overstated. In developed countries, changes in the demography of children, socioeconomic and political movements, and globalization are establishing a new ecology of childhood and child health. As a result, social and environmental determinants of health have replaced the historical causes of childhood morbidity – for example, infectious diseases and nutritional deficiencies – as the critical contemporary health issues challenging children (Spencer, 2003; Wood, 2003). In developing countries, excess childhood morbidity and mortality remain rooted in mutable social and environmental determinants (Black et al., 2003; Jones et al., 2003). Despite the worldwide annual expenditure of trillions of dollars for health care and public health, great disparities remain within and between wealthy and low-income countries. A rights-based approach to health will be necessary to ensure child health equity, overcome these disparities and achieve optimal health for children. The history of public and child health is a chronicle of the relationship between health and human rights, equity, and social justice (Markel and Golden, 2005). However, globalization has changed the balance of power and loci of decision making for public policies related to the human condition (Huynen et al., 2005). This and other societal transitions demand a new context for conceptualizing the health and well-being of children and childhood. They demand a shift in the roles and functions of public and children’s health professionals if these disciplines are to remain viable and relevant to the health and well-being of children and families. The application of a rights-based approach to health provides such a conceptual framework (Mann et al., 1999), as well as tangible strategies and skills that can be applied by public and child health professionals to the delivery of the core functions of public health, health services, child advocacy and the generation and implementation of relevant and effective public policy (Institute of Medicine, 1988). This article provides insight and understanding of the relevance and importance of the principles of human rights and the UN Convention on the Rights of the Child to the health and well-being of children (UNICEF, 2005). In so doing, it attempts to increase understanding of the relevance of the application of children’s rights to the core functions of public health, and to encourage a commitment by public and child health professionals to the development of an advocacy role in respect of children’s rights. The United Nations Convention on the Rights of the Child (the Convention) is discussed in detail as the foundation and framework for the integration of children’s rights into the practice of public and child health (UNICEF, 2005).

The UN Convention on the Rights of the Child The UN Convention on the Rights of the Child is an international human rights treaty that introduces the concept of

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children as subjects of rights with the same inherent value as adults. It was drafted over a 10-year period by a working group established by the UN General Assembly, who adopted it in 1989, and is among the eight current UN human rights treaties (United Nations, n.d.; Table 1). The Convention promotes a philosophy of respect for children. While acknowledging that children are entitled to special protection and care, the Convention also insists that they are entitled to participate, in accordance with their age and competence, in the protection of their own rights. The Convention challenges the traditional perception of children as mere recipients of adult protection, and requires their acceptance by society as social actors with rights to be listened to and taken seriously. This challenge has significant implications for the ways adults relate to children. The importance of the Convention is derived from the legal and ethical precedent it establishes for children. It is the first and only legal document to assert a full array of rights that are inherently due to children. It is the world’s only universally accepted human rights document. (The United States is the only country to have signed but not ratified the document.) It is the strongest foundation we have as communities, professionals, parents, advocates, educators, etc., to support our individual and societal efforts on behalf of children. The Convention recognizes that children are vulnerable and includes a range of protection rights that are specific to children; for example, the concept of best interests, obligations associated with alternative care, and adoption. However, its key significance is that it also acknowledges them as actors and subjects of rights in its inclusion of civil and political rights. In other words, it introduces the obligation to balance protection and participation. It introduces the concept of participation precisely because children lack the automatic autonomy to exercise rights on their own behalf. The Convention deals comprehensively with the critical contemporary determinants affecting children’s health. Traditionally, most laws in the North have been framed primarily in terms of child protection – protecting children from Table 1

United Nations Human Rights Documents

International Covenant on Civil and Political Rights (1966) International Covenant on Social, Economic and Cultural Rights (1966) International Convention on the Elimination of All Forms of Racial Discrimination (1966) Convention on the Elimination of All Forms of Discrimination against Women (1979) Convention against Torture, and Other Cruel, Inhuman and Degrading Treatment (1984) Convention on the Rights of the Child (1989) International Convention on the Protection of the Rights of All Migrant Workers and Members of Their Families (1990) International Convention on the Rights of Persons with Disabilities (in progress)

International Encyclopedia of Public Health, 2nd edition, Volume 1

http://dx.doi.org/10.1016/B978-0-12-803678-5.00062-X

Child Rights exploitation and abuse; ensuring their best interests in family issues, educational programs, health systems, and so forth; and protecting the legal entitlements that are extended to them. Legal systems have promulgated a large patchwork of laws to protect children but relatively few that define their fundamental rights and establish measures to protect them. Laws that protect rights are fundamentally different from those that extend privileges that can and often are revoked by executive or legislative actions. The Convention establishes the legal basis for extending human rights to children. It establishes a concrete foundation for child advocacy and defines the social systems that are required to protect children’s rights. The Convention contains some 40 ‘articles’ that can be broadly categorized as the following: l

l

l

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Social rights: The right to life and optimal survival and development, to the best possible health and access to health care, to education, to play, to family life unless not in the child’s best interests, to alternative care when children are unable to be in the custody of parents, to family reunification, to promotion of the fullest possible social inclusion for disabled children, to support for parents so that they can protect their children’s rights. Economic rights: The right to an adequate standard of living for proper development, to benefit from social security, to protection from economic exploitation. Cultural rights: The right to respect for language, culture, and religion, to abolition of traditional practices likely to be prejudicial to the child’s health. Protective rights: The right to promotion of the child’s best interests, to protection from physical and sexual abuse and exploitation, armed conflict, from harmful drugs, illegal sale and trafficking, abuse and neglect, to rehabilitative care following neglect, and so forth. Civil and political rights: The right to be heard and taken seriously, to freedom from discrimination in the exercise of rights on any grounds, to freedom of religion, association and expression, to privacy, to information, to respect for physical and personal integrity and freedom from all forms of violence, torture or other cruel, inhuman or degrading treatment, to respect for due process in the law, recognition of the importance of treating the child with respect within the criminal justice system and respect for the right not to be detained arbitrarily.

Although all rights defined in the Convention are indivisible and apply to all children, four key principles must be considered when implementing all other rights. Article 2 – the right to nondiscrimination. All rights in the Convention apply to all children without discrimination on any grounds. Governments must take measures to ensure that all the rights in the Convention apply without discrimination to all children within the jurisdiction of the state. This means both direct and indirect discrimination. l Article 3 – the duty to promote the best interests of the child. Article 3 places an obligation on public and private social welfare institutions, courts of law, administrative authorities or legislative bodies, etcetera, that in all actions affecting children, the best interests of the child must be a primary consideration. l

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Article 6 – the right to survival and development. Article 6 stresses the right of every child to life and optimal survival and development. This right imposes obligations to create environments in which children’s development can flourish. It means that the lives of all children must be equally protected, irrespective of disability, gender, ethnicity, or any other factors. l Article 12 – the right to be listened to and taken seriously. Article 12 provides that all children have the right to express their views on all matters of concern to them and to have those views taken seriously in accordance with their age and maturity. Children are entitled as a right to be consulted when decisions that affect them are being made, either as individuals or as a body. Respecting the rights of children is an important mechanism through which children can contribute toward their own health and protection. Adults can make better-informed decisions if they first listen to children. Only if children are listened to by adults can they challenge abuses or neglect of their rights. l

Translating Children’s Rights into Improved Health Outcomes A review of the articles of the Convention will clarify how the rights defined by them relate to the practice of public and children’s health. It provides a framework and mechanism for fulfilling the World Health Organization’s definition of health, a “state of complete physical, mental and social well-being and not merely the absence of disease or infirmity,” by establishing the responsibility of governments, institutions, and families to ensure children’s rights are respected (World Health Organization, n.d.). With respect to public and child health professionals: The rights afforded to children for survival, development, and health care (Articles 6 and 24), education (Articles 28 and 29), and a standard of living adequate for physical, mental, and social development (Articles 26 and 27) establish an expanded set of obligations for the generation of public policy and child advocacy. l The definition of an explicit set of rights for the vulnerable child – orphaned, adopted, refugee, disabled, and abused children (Articles 20 through 23, 37) – including responsibility for rehabilitative care (Article 39), expand the required breadth and expertise of public and child health systems in the context of their public health assurance role. l The rights of protection from maltreatment and neglect (Article 19) and from all forms of exploitation, including child labor, drug abuse, sexual exploitation, abduction, and in the juvenile justice system (Articles 32 through 36, and 40), confirm and extend the public and child health practitioner’s role in ensuring the child’s physical and social well-being. l The child’s rights, within the context of their competencies and family, to form and express an opinion, associate with peers, enjoy freedom of thought and conscience, maintain privacy, and have access to appropriate information (Articles 12 through 17) contribute to an evolving child image of great relevance to public and child health professionals. l

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The rights of children to be free from all forms of discrimination (Article 2), to a name, nationality, and identity (Articles 7 and 8), and to enjoy and practice their own culture and religion relate to the challenges to serve children in diverse communities. l The obligation of all parties at all times to act in the best interest of the child (Article 3) and to provide families with the support and assistance they require to fulfill their parental responsibilities, including access to child care services for working parents (Article 18), define a set of standards to guide and support child advocates. l With respect to families, the Convention establishes the obligation of governments to respect the rights and duties of parents to raise their children and to provide the resources necessary for families to fulfill these responsibilities (Articles 2, 5, 7, 8, 9, 10, 11, and 18). l

The rights defined in the Convention are indivisible and universal. There is no hierarchy of importance. Together they create a holistic framework of rights that, if fully respected, would promote the health, welfare, development, and active participation of all children. It is not possible, for example, to tackle violence and sexual exploitation against children without also addressing the violation or neglect of rights that expose children to violence – poverty, lack of access to education, discrimination, racism, prejudice and xenophobia, and failure to listen directly to and take seriously children’s accounts of their lives. Similarly, children’s right to optimal health and development cannot be fulfilled without a commitment to simultaneously address their right to an adequate standard of living, decent housing, and protection from violence at home and in institutions, economic exploitation, exposure to harmful work environments, and so forth. Given the impact of behavior on health, it is not possible to ensure children contribute to their own health without providing them access to information to enable them to make informed choices and protect themselves.

Obligations of Governments that Ratify the Convention All governments, except the United States, have ratified the Convention, a process of making a formal commitment under international law to implement its principles and standards. Three obligations are established with ratification: To implement rights without discrimination for all children. To make the Convention and the rights contained in it known to both children and adults. l To report regularly to the UN Committee on the Rights of the Child.

their health and well-being, forced into bonded labor, to die of preventable disease, and to be denied a voice in matters of concern to them (UNICEF, 2005). However, neglect and abuse of children’s rights is not just a problem in the developing world. In many developed countries, immigrants and refugees are routinely denied equal rights, children continue to be subjected to physical violence and sexual abuse, significant numbers of children live in poverty, children are homeless, and there is vulnerability to widespread drug misuse. Realization of the rights contained in the Convention is a goal toward which much progress has been made during its relatively short life-span. Since its adoption by the UN General Assembly in 1989, the Convention has already achieved a great deal for children. At the international level, for example, there is a far greater awareness of and commitment to end exploitive child labor, sexual abuse and exploitation of children, discrimination against the girl child and disabled children, and the use of children as soldiers. l At the national level, many governments have begun to analyze and improve their legislation to bring it in line with the Convention’s rights, establish independent children’s rights commissioners or ombudsmen (European Network of Children’s Ombudsmen, n.d.), raise public awareness of children’s rights, develop programs designed to promote the best interests of children, end all forms of violence against children, and divert extra resources to fulfill obligations to children. l At the national, regional, and local levels, many countries have implemented measures to ensure children have the opportunity to express their views and have them taken seriously, and have executed strategies to tackle discrimination, improve child protection, and encourage breast-feeding (Lansdown, 2001, 2005). l

Although sanctions cannot be brought against governments that violate children’s rights, the Committee on the Rights of the Child, the international body established under the terms of the Convention to monitor governments’ progress in fulfilling their obligations to children, engages countries and communities in constructive dialogue about the relevance of human rights to health. This continuing dialogue is a tool and catalyst for change and has resulted in an increasing awareness and understanding about the nature of children’s rights and the ways in which they are violated. It is a slow process but one that has continued to achieve real change for children.

l l

The principles of children’s rights contained in the Convention do not require ratification for implementation, nor is ratification a guarantee that governments will cease to violate, abuse, or neglect children’s rights. In many countries that have ratified the Convention, children continue to be discriminated against, forced into armed conflict, sexually exploited, denied education, exposed to violence, denied access to health care, exposed to living and working conditions detrimental to

Is the Convention Anti-family or Anti-parent? Concerns have been expressed in many countries that by emphasizing the rights of children the Convention is anti-family and undermines parental authority. These concerns are based on a fundamental misunderstanding of the Convention. The preamble, as well as many of the Convention’s articles, emphasize that growing up within a caring family environment is crucial to children’s healthy development. The Convention requires that societies provide families the capacity to extend the rights it contains to their children as a prerequisite for fulfilling children’s rights.

Child Rights Article 5 recognizes parents’ rights and duties to provide direction and guidance to children. l Article 9 stresses the right of children not to be separated from their parents unless necessary for their best interests. l Article 18 stresses the obligations of governments to provide support to parents in order to help them fulfill their role of promoting and protecting their children’s rights. l

However, the Convention does imply changes to the traditional way in which children have often been viewed within the family. It requires that they are listened to and their views taken seriously, increased recognition is given to their ability to make decisions for themselves as they grow older, l parents consider children’s best interests when making decisions that affect them, and l recognition is given to the fact that children’s interests will not always coincide with those of their parents. l l

The Convention encourages a culture of respect for children within families as well as in society. But this does not undermine or diminish the role of parents. Rights allow children to take part in decisions that affect them, not to take over. They place a responsibility on parents to provide proper care and protection through listening and valuing children’s opinions. Parental respect for children is likely to encourage children’s respect for their parents.

Implementing a Rights-Based Approach to Children’s Rights The application of children’s rights to health has critical implications to the core functions of public health. Assurance of the functionality of the health, social, and educational systems that are required to attain optimal child health will need to include a rights-based context framed by the articles of the Convention. Assessment functions, including indicators and surveillance strategies, will similarly need to be expanded to include rights-based indicators that reflect proximal social, civil and political, economic, cultural, and environmental determinants of health (Equity Gauge, n.d.; Hillemeier et al., 2003). Finally, the core policy function of public health will need to be retooled to include a human rights, equity, and social justice framework (Rodriguez-Garcia and Akhter, 2000). This will require a new approach and parlance to the generation and implementation of public policy, as well as education of the public health and clinical medicine workforce. Figures 1 and 2 present a series of schematics of a health system model that will facilitate the visualization of a rights-based approach to public health. Figure 1 presents the model as a continuum of elements in a system that links proximal determinants of health with morbidities, surveillance indicators, interventions, and outcomes. Using obesity and type 2 diabetes as

Determinants

Figure 1

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Health systems framework.

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an example, in a traditional biomedical approach to health (Figure 2(a)), biomedical determinants (calories, genetics) present as morbidities (obesity, diabetes), which we measure through surveillance systems as outcomes; for example, rates and disparities of obesity, chronic illnesses, hospitalizations, and deaths. In this biomedical paradigm, our advocacy priorities are primarily clinical interventions that respond to the indicators we measure and that reflect our system’s predominant construct of health and illness; for example, access to health care, improved and expanded pharmacological interventions, expanded treatment modalities, and diet manipulation. These biomedical interventions receive priority and funding. Not surprisingly, poor health outcomes and disparities continue to mount. In an equity (rights) model of health (Figure 2(b)), child health morbidities result from proximal social, political, civil, economic, cultural, and environmental determinants. The recently coined term ‘Millennial Morbidities’ is used in this model to encompass children’s health issues that are rooted in these determinants (Palfrey et al., 2005). Surveillance systems and indicators are not formulated as biomedical measures, but rather in terms of measurements of rights, social justice, and social capital. Advocacy interventions are equity-based, extend beyond the clinical interface, and result in interventions that relate to the proximal determinants of health outcomes and disparities. Figure 2(c) again uses childhood obesity and type 2 diabetes to illustrate the utility of using the equity (rights) approach to a common and mounting public health issue affecting children.

Challenges to Implementing Children’s Rights and the Convention Public and child health professionals will experience many challenges in their efforts to advance a rights-based approach to children’s health. The primary barriers impeding respect for children’s rights fall into four broad areas: Tradition and attitudes Children’s invisibility l Economic constraints l Lack of democratic traditions. l l

Understanding and responding to these challenges is crucial to the successful implementation of a rights-based approach to health.

Tradition and Attitudes There is widespread resistance to changing cultural traditions that have long affected attitudes and behaviors toward children; for example, early marriage of girls, harsh forms of physical punishment, female genital mutilation, expectations of

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Morbidity

Calories genetics

Obesity diabetes

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Morbidity

Social Political Civil Economic Cultural Environmental

Millennial Morbidities

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Determinants

Morbidity

Welfare reform

Obesity

Urban development

Diabetes

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Rates and disparities • Diagnoses • Hospitalizations • Amputations • Deaths

Surveillance indicators

Clinical Community Policy Screening Diet Exercise Surgery

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Human rights Social justice Social capital

Surveillance indicators

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Article 3. Best interests • Advertising • School meals

Restrict advertising fast food

Segregation

Article 17. Access to information

Tax incentives for super markets

Globalization

Article 27. Adequate standard of living •Food security • Geographic access to quality food • Food costs

Price monitoring to prevent noncompetitive pricing

Media marketing policies

Schools required to provide nutritional meals

Public support for parks and recreational facilities Media deregulation

Article 31. Leisure, recreation • Access to recreational resources • Time for recreation

Expanded use of schools

Article 32. Child labor

Urban development policies

Article 24. Health care

Limiting child labor

Figure 2 (a) Health systems framework: biomedical model, (b) Health systems framework: equity model, (c) Health systems framework: equity (rights) approach.

respect for authority, and failure to take children’s views seriously. Although the Convention includes clear recognition of the importance of respecting children’s culture and the right of parents to exercise direction and guidance to children, this must be done in a manner that is consistent with children’s rights. Adult, institutional, and societal behaviors toward children that threaten or violate their rights, even if they result from traditional practices, are prejudicial and undermine children’s opportunities for optimal health and development. For many children, rights are denied by discriminatory attitudes – denial of the right to education

for girls, social isolation and segregation of disabled children, violence and hostility toward ethnic minority and immigrant groups, and so on. The Convention’s demand that adults listen to children is perhaps the most fundamental challenge to traditional attitudes. Its central tenet is that without listening to children, adults cannot protect them or enable them to protect themselves. Children who are silenced cannot act to bring an end to the abuse of their rights. Nor can they provide information to help socially responsible adults provide them proper protection.

Child Rights Invisibility of Children Children’s rights are often breached or neglected simply because politicians and policymakers fail to give consideration to children when they make decisions that affect them. Subsequently, their rights, needs, and interests are not given sufficient priority. This barrier to respecting children’s rights results from their invisibility or powerlessness in public arenas, as compared with more powerful influences on government agendas. For example, children’s rights to the best possible health will rarely be considered in the context of urban development or zoning for industrial development, despite the potential impact of the environment on children and their relative vulnerability. Construction of new roads may increase children’s exposure to pollution and accidents and reduce their opportunities for safe play. Tobacco and alcohol companies seeking to promote their product often have a greater influence on governments than those seeking to protect children. Children’s lack of access to those in power and to the media, combined with their lack of voting rights, renders them vulnerable to being ignored by those in power. Subsequently, their rights and interests can be and are often neglected. Children need public and child health advocates who can help them articulate their concerns to those in power.

Economic Constraints In many countries there are overwhelming economic constraints that limit governmental capacity for implementation of children’s rights, particularly economic and social rights. There are difficulties, for example, in implementing universal access to health care and primary education, or in providing an adequate standard of living for all children. The Convention states that these rights must be implemented to the maximum extent of available resources. It recognizes that implementation will be necessarily incremental. All governments, however poor, make choices about priorities. For example, in India, Pakistan, and many African countries, expenditures on military hardware are greater than on primary health care. Haiti, Ethiopia, Mali, and Niger enroll less than 50% of children in primary school. However, in other countries with per capita GNPs below $500 – for example, Bangladesh, Malawi, and Vietnam – rates of school enrollment of over 80% have been achieved. Zimbabwe, with a per capita GNP of $480, achieves a rate of 90% compared with Guinea, which has the same GNP but enrolls less than 60%. Even the poorest economies can make a significant contribution toward the implementation of social and economic rights for children (UNICEF, 2005).

Lack of Democratic Traditions In undemocratic countries, or in newly emerging democracies, there is likely to be a weaker culture of respect for human rights for all people, including children. Mechanisms through which democratic rights are exercised and strengthened – elections, the media, the courts, pressure groups, trade unions, ombudsmen, or human rights commissions, for example – are less developed or accessible to individuals. However, even in democratic countries, some children have very limited access to these processes. In undemocratic or newly democratic countries, there may be little opportunity for children’s rights to be articulated or represented.

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Summary Ensuring the rights of children is a necessary strategy to achieve their optimal health and well-being. A rights-based approach to child health is consistent with and reflects the history of public and child health. The UN Convention on the Rights of the Child provides a framework and mechanism to support the work of public and child health professionals. The Convention defines the full range of children’s needs and provides a practical approach for addressing these needs in an integrated and holistic way by fulfilling children’s rights. l It poses a challenge to traditional approaches to children, which have viewed them as incompetent, passive objects of adult protective care, and acknowledges children as both capable of and entitled to active participation in decisions that affect their lives. l It is legally binding on all countries that have ratified it. Governments are required under international law to take all necessary measures to implement its provisions. It provides a universal set of standards against which to measure and improve the treatment of children. l Although there are no formal sanctions that can be brought against governments for failing to comply with its provisions, the process of reporting to the UN Committee on the Rights of the Child is an invaluable mechanism for monitoring how a government is complying. It provides an opportunity for all those involved in children’s health and well-being to work together to improve standards. l

A rationale for public and child health professionals to apply children’s rights to child health can be structured from the following four principles. All children have needs. The UN Convention on the Rights of the Child establishes international recognition that children have a right to have these needs met. l The Convention provides a comprehensive framework of rights that will facilitate a holistic approach to promoting the well-being of children. l Children’s health and development is best promoted by responding to all of their needs. Respect for all the rights embodied in the Convention will help achieve this goal. l The Convention is legally binding and imposes obligations on governments to respect children’s rights. l

In one comprehensive document, the UN Convention on the Rights of the Child defines the prerequisites for the health and well-being of children, and the obligations of individuals, parents, communities, and governments to meet children’s needs by fulfilling their rights. Implementation of a rights-based approach to the core functions of public and child health that uses the framework of children’s rights contained in the Convention would herald a fundamental change in the status of children in all societies in the world and help ensure their optimal health and development.

See also: Child Labor; Child Soldiers; Child Witness to Violence; Global Health Law: International Law and Public Health Policy; Politics, and Public Health Policy Reform; Racism and Health;

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Social Gradients and Child Health; Social Science Contributions to Public Health: Overview.

References Black, R., Morris, S., Bryce, J., 2003. Where and why are 10 million children dying every year? Lancet 361, 2226–2233. Equity Gauge: Concepts, Principles, and Guidelines, n.d. http://www.gega.org.za (accessed November 2007). European Network of Ombudsmen for Children, n.d. http://www2.ombudsnet.org/ (accessed November 2007). Hillemeier, M., Lynch, J., Harper, S., Casper, M., 2003. Measurement issues in social determinants. Health Serv. Res. 38, 1645–1718. Huynen, M., Martens, P., Hilderink, H., 2005. The health impacts of globalization: a conceptual framework. Global. Health 1. http://www.globalizationandhealth.com/ content/1/1/14 (accessed November 2007). Institute of Medicine, 1988. The Future of Public Health. Institute of Medicine, Washington, DC. Jones, G., Steketee, R., Black, R., Bhutta, Z., Morris, S., 2003. How many child deaths can we prevent this year? Lancet 362, 65–71. Lansdown, G., 2001. Children’s Participation in Democratic Decision-Making. UNICEF Innocenti Research Centre, Florence. Lansdown, G., 2005. The Evolving Capacities of the Children. UNICEF Innocenti Research Centre, Florence. Mann, J., Gruskin, S., Grodin, M., Annas, G., 1999. Health and Human Rights: A Reader. Routledge, London. Markel, H., Golden, J., 2005. Success and missed opportunities in protecting our children’s health: critical junctures in the history of children’s health policy in the United States. Pediatrics 115 (4 Pt 2), 1129–1133. Palfrey, J., Tonniges, T., Green, M., Richmond, J., 2005. Addressing the millennial morbidity: the context of community pediatrics. Pediatrics 115 (4), 1121–1123. Rodriguez-Garcia, R., Akhter, M., 2000. Human rights: the foundation of public health practice. Am. J. Public Health 90, 693–694.

Spencer, N., 2003. Social, economic and political determinants of child health. Pediatrics 112 (3), 704–706. UNICEF, 2005. State of the World’s Children. Oxford University Press, Oxford, UK. United Nations, n.d. United Nations Convention on the Rights of the Child. http://www. unicef.org/crc/ (accessed November 2007). United Nations, n.d. United Nations Human Rights Documents. http://www.unhchr.ch/ data.htm (accessed November 2007). Wood, D., 2003. Effect of child and family poverty on child health in the United States. Pediatrics 112, 707–711. World Health Organization, n.d. http://www.who.int/en/ (accessed November 2007).

Further Reading Hodgkin, R., Newell, P., 2002. Implementation Handbook on the Convention on the Rights of the Child. UNICEF, New York. Hofrichter, R., 2003. Health and Social Justice. Jossey-Bass, San Francisco, CA.

Relevant Websites http://www.childfriendlycities.org/home.html – Child Friendly Cities. www.uvic.ca/iicrd/proj_credi.html – Child Rights Education for Professionals (CRED-PRO). www.crin.org – Children’s Rights Information Network. http://www2.ombudsnet.org – European Network of Ombudsmen for Children. http://www.paho.org/english/dd/ikm/eq-list.htm – PAHO, Equity, Health and Human Development. http://www.savethechildren.org – Save the Children. http://www.unicef-icdc.org – UNICEF. http://www.unicef.org/crc/ – United Nations Convention on the Rights of the Child. http://www.unhchr.ch/data.htm – United Nations Human Rights Documents. http://www.unicef.org/specialsession/wffc/ – World Fit for Children. http://www.who.int/en/ – World Health Organization.

Child Soldiers John Pearn, Australian Defence Force and Royal Children’s Hospital, Brisbane, QLD, Australia Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 1, pp. 612–616, Ó 2008, Elsevier Inc.

Child soldiers comprise a new class of combatants distinct from those of immature years who have, since the times of ancient Greece, served in uniform as an adjunct to former armies and navies. The child soldier of today is enmeshed in a triad of anarchic civil war, light-weight weaponry, and drug or alcohol addiction. One profile of the child soldier of today is a rag-clad, drug-addicted 10- to 18-year-old male carrying an automatic weapon and bonded to a group of other compunctionless combatants led by an older teenager. He lives and kills with impunity and in the absence of identifiable conventions of war or other ethical principles. He acts without the constraints of any regimental tradition. Child soldiers are a unique phenomenon first encountered in the later decades of the twentieth century. Public health and medicine have traditionally focused on those killed or wounded in battle or on the care of civilians caught in the crossfire of violent political conflict and its aftermath. Since the 1970s, interest has also developed on the identification and care of the psychiatrically scarred among the ranks of both victors and vanquished. Although not traditionally counted among the battle casualties of war, children today are indeed numbered among the victims of each of these categories. However, today’s disciplines of public health and medicine also include study of the plight of child soldiers. The existence of these victims, analogous to those stricken by occupational or industrial disease and morbidity, is due to social forces. And like the plight of other vulnerable populations, the predicament of child soldiers may be understood and addressed by public health approaches: Identification of risks, examination of patterns of injury and death, and engagement in effective, concerted prevention, intervention, and advocacy efforts. There is nothing new about warfare. There has, however, since the establishment of the Red Cross in 1864 and the St. Petersburg Convention of 1869, been an evolution of the international Laws of War in an attempt to alleviate the horrors of war. This has achieved much in the context of international warfare, particularly in conflicts between first-world nations. Less has been achieved in the context of civil wars where the genocide experienced in such places as Bosnia (1991) and Rwanda (1994) has again demonstrated that there is indeed a thin veneer of civilization in contemporary humankind when civil wars erupt. In spite of the ethic of the Geneva Conventions and the influence of the International Red Cross, the Pershing (1921) and Ottawa (1997) Conventions, children and adolescents remain unprotected in many regions of the world where they exist both as perpetrators and victims of combat violence. Children, and particularly orphan children, who are born into and survive in communities that are all but destroyed by civil war, grow and develop both as unprotected victims on the one hand and are subject to recruitment as child soldiers on the other. In both instances, they are not subject to either of the two principal moderating, even humanizing, sanctions of (1) family traditions and (2) civilized, societal mores.

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Scholars estimate that there are 300 000 child soldiers in the world today, and they have been involved in over two dozen of the world’s armed conflicts since the start of the twenty-first century. These combatants fall into two classes. The first class includes those adolescents who are still voluntarily or semi-voluntarily recruited into the ranks of combatants in armies that subscribe to international codes and principles such as the Geneva Conventions or more generic concepts of the Laws of War. In the past, such children and adolescents have been a proud and important part of the military forces of many nations. The second class of child soldiers, and the focus of this article, differs from the former group in that there is no formal institutional socialization of such child soldiers. Rather, they may become socialized informally by an ethos that has superficial parallels with urban civilian gangs. The social dynamics of bonded groups of child soldiers, however, differ from those of such urban criminal gangs in at least one very important respect. Criminal gangs remain subject to the sanction of law enforcement and exist within otherwise relatively stable societies. By contrast, child soldiers in their formal or informally bonded groups, do not operate in environments where violent behavior is held in check by the rule of law, law enforcement, or other mechanisms of formal or informal social control. This absence of social controls means that these combatants engage routinely in wanton atrocities and hideously violent acts without remorse or constraint. Consequently, child soldiers often behave to satisfy the dictates of primal gratification rather than to serve as military agents of the State or of organized rebel movements engaged in more traditional forms of warfare or insurgency. The tragic syndrome of the typical contemporary child soldier involves a boy between the ages of 8 and 16 years, bonded into an armed group of peers. He is almost always an orphan, drug- or alcohol-addicted, amoral, merciless and dangerous, illiterate, and armed with an automatic or semiautomatic weapon and a knife. These combatants rape, steal, and pillage without compunction or remorse. Their targets are never strategic or tactical, but idiosyncratic and personal. The attacks by child soldiers tend to be opportunistic and targets may be male or female, young or old, civilian or uniformed. The modus operandi of killing is often brutal, even mutilatory.

Historical Comparisons In the preliterate past, adolescent boys after initiation have always taken part in intertribal conflicts as fighting combatants, serving alongside their adult relatives. In recorded history, children have formed part of traditional armies since the fourth century BC. Some of the best recorded examples relate to the boys of ancient Sparta. Such youths were taught the socially desirable virtues of courage, discipline, self-sufficiency, and resilience, often in the context of extreme training that was demanded of all, irrespective of age, who undertook military

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service. Unquestionably, many such youths were exploited sexually. Although they were in most cases voluntarily recruited, the term voluntary had little meaning in the absence of child rights and in a context where social pressures and expectations compelled participation. Armies and navies of the past have always recruited young adolescents. Hospital Apprentice Fitzgibbon, of the Bengal Medical Department, received the Victoria Cross for his action at North Taku Fort, in China, on August 21, 1860, when he was 15 years of age. Boy Cornwell of the Royal Navy received the award of the Victoria Cross posthumously, for his action at the Battle of Jutland when he was 16 years of age. Both these examples were of child soldiers who were already military veterans in their early teenage years. Many boys under the age of 16 years joined the American Revolutionary (Patriot) Army in 1776. In this context of the use of young adolescents as members of traditional armies, many nations have lauded the underage enlistment of teenagers. The untruthful overstating of age, by which young adolescents could go to war, is today usually regarded with paternalistic admiration. The most recent use of this type of formal child soldier was seen in the Iran–Iraq War of 1982–83. In some campaigns in that conflict, young children were used in the vanguard of assaulting troops in the belief that this might deter tactical artillery counter-bombardments. There has been a progressive evolution among civilized nations and combatant States to forbid the use of young teenagers in combat. The 1998, Statute of the International Criminal Court defined the conscription or enlistment of children under 15 years of age into armed forces for their use in combat as a war crime.

Child Soldiers of the Twenty-First Century Child soldiers often exist when a society has broken down and anarchy pervades. Under such circumstances, authority is exerted by brute force or its threat. In the twenty-first century, such occurs almost exclusively in civil war contexts or in protracted border disputes between developing nations. Child soldiering imposes extreme stress. This, in turn, has three profound consequences. The first of these is that the desocialization and dehumanization of a young adolescent’s mind become self-perpetuating. The thrill and rush of physical combat, of using powerful weapons, and of domination and sexual conquest intoxicate. Secondly, the lost childhood of such victims means that schooling and rehabilitation are very difficult to institute. This has been very evident in the African experience as the educational rehabilitation of former child soldiers has proven extremely difficult there once the normal window of childhood has closed. Thirdly, many who work with children and adolescents who were child soldiers find high rates of posttraumatic stress disorder (PTSD) among them. Though published work on the long-term mental health and developmental sequelae is lacking, many anticipate that rehabilitation of those once engaged as child soldiers will be difficult if not impossible to achieve. The responses of young adolescents to violence and disaster cause profound changes in their attitudes toward life and their

future. Traumatized adolescents may be especially likely to engage in risky behaviors. Often, in the prerecruitment phase when a child or young adolescent has already lost parents, siblings, and extended family members, he is particularly vulnerable to enmeshment as a child soldier in societies engaged in long-term political or military conflict. The situation may be compounded by the fact that when parents or other close relatives are lost in massacres, land mine or bomb blasts, or in epidemics, normal rituals of grief and closure do not occur. In the aftermath of conflict, burials and memorialization are a luxury of those civilian societies where the Laws of War still apply. Young adolescents enmeshed in civil wars are constantly exposed to threats to their own life. This engenders perhaps the highest risk of psychiatric morbidity. Those who are themselves injured by violence or disaster are at highest risk. Exposure to dead bodies and mutilated victims increases the potential for adverse psychiatric sequelae. Of the many different types of stressors, the most powerful predictor of PTSD is direct experience and engagement in physical violence. Children and young adolescents as soldiers and the perpetrators of violence are often simply continuing in the chronological sequence of their entire lifetime experience, themselves having been traumatized as preschool children. Preschool children exposed to violent trauma, even in the civilian sphere, sometimes re-enact their trauma in their play and storytelling. Moreover, exposure to violence may alter developmental trajectories and cause other problems with behavior, cognition, emotional status, and social skills. Thus, the milieu in which child soldiers operate represents a high-risk setting for children already damaged by exposure to violence and in which they might have unfortunate and unchecked opportunities to execute violent acts of revenge and aggression ordinarily restricted to play and fantasy. Violent behavior by male adolescents is highly correlated with prior violent acclimation, even in otherwise stable, civilian, developed nations where violence is eschewed. In a United States study from Yale, it was shown that there exists a very high correlation between prior violent victimization and later perpetration of physical assault. Adolescent males in particular are likely to re-enact their own experiences of violent victimization by perpetrating similar forms of violence on others. There are no quantitative research reports about violence exposure among child soldiers. Methodological challenges rule the day. Almost all child soldiers are illiterate, the contexts they exist within are extremely volatile and dangerous, and the social destruction of civil wars where they thrive make defining and obtaining representative samples difficult if not impossible. However, journalistic accounts, reports of nongovernmental organizations and first person narratives like Ismael Beah’s A Long Way Home: Memoirs of a Boy Soldier (2007) grant important insights into this emerging problem.

Aftermath and Rehabilitation Child soldiers have almost never been to school and almost all are illiterate. The harm and disabilities from this denial of

Child Soldiers a basic human right have lifelong consequences. For example, in the context of the 2001 war in Afghanistan, the Wall Street Journal reported that “A key issue is what to do with thousands of young men who have, over two decades of conflict in Afghanistan, learned little more than how to pull a trigger” (p. A14). Some adolescents exposed to violent trauma respond by developing a perspective and outlook that life will be short and that a fragile, shortened future marked by suffering and vulnerability is their inevitable lot. Under such circumstances, they often spiral downward into a maelstrom of hedonism and hopelessness. Many children enmeshed in war develop fear-conditioned responses to early experiences of violence. As adolescents they may regress or engage in aggressive behavior throughout their lives. While many normal adults without traumatic histories of exposure to violence have flashbacks triggered by the smell of certain foods or plants, these hippocampus-mediated responses are often pleasurable. However, for survivors exposed to violence or war during childhood, their olfactory triggers are the stench of burning flesh, bloody wounds, or explosives. Some postulate that flashbacks induced in these ways result from neuronal short circuits of the rhinencephalon – the atavistic remnants of the highly developed smell memories of lower animals. But whatever the mechanisms, experiences of war and violence can make their mark extremely early in life, indelibly, and even prior to consciousness. In this way, many communities embroiled in long-term violent political conflict may produce children who have been affected by war long before they become weapon-carrying combatants themselves. For example, research into the aftermath of the Bosnia–Croatia conflict of 1995 showed that the average birthweight and nutritional indices of breastfed infants were reduced during periods of continued immediate combat threat. Of sinister import is that children chronically exposed to the injury and death of war may carry a unique and dangerous datum reference point into their adult lives: That violence is the fundamental relationship that characterizes human interaction. Perhaps this is why studies of child survivors of the Spanish Civil War of 1936, the Nazi Holocaust, and the London Blitz have revealed that they grow up to be adults more inured than their unexposed peers to the horrors of violence. One of the most important tasks of normal childhood is the development of conscience, that is, the acquisition of a sense of higher-order morality and ethics. Among child soldiers, the development of this sense of right and wrong is either never attained or is lost in the absence of normal influences of family and society.

Advocacy Children are sometimes injured or killed in war by its direct effects: Blast, bomb, missile, burns, or gas. Larger numbers suffer or die from exposure to the elements or from disease and starvation. Just like other calamities – earthquakes, famine, cyclones, and epidemic pestilence – war is another type of

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social catastrophe that destroys families, communities, and societies. Just as in these other disasters, the problem of child soldiers can be ameliorated by approaches common to public health and preventive medicine. Advocacy can make a difference here as well. The humanitarian work of nongovernmental organizations (NGOs) does much to rehabilitate child soldiers. Some term these efforts demobilization, disarmament, and reintegration programs (DDR). However, one of the great challenges of these efforts is that surviving child soldiers often return to brittle, depleted, post-conflict societies. The survivors may be hard to identify and the road to recovery is long and difficult. These realities elevate the importance of prevention, a task which requires vigorous national and international advocacy. International advocacy has done much to protect the plight of civilians (the third Geneva Convention), to achieve considerable reduction in the use of chemical warfare (the Pershing Convention of 1921), and to offer partial protection to future generations by the Ottawa Convention (1997) by which an increasing number of nations have become signatories to the banning of the manufacture and international sale of antipersonnel land mines. The 1972 Biological and Toxin Weapons Convention banned the development of biological weapons for offensive purposes. Although it was violated by several nations, its spirit is implicitly accepted by all governments today. Professor John Steinburner, Professor of Public Policy at the University of Maryland, has described it as “arguably among the most significant universal rules of human civilization,” (Steinburner, 2006: p. 20). To this pantheon of conventions has been added one of great significance. This is the convention to ban child soldiers. The International Criminal Court by its 1998 Statute (also known as the Rome Statute) bans the conscription and enlistment of children aged under 15 years into armed forces for use in combat and other military activities such as scouting, spying, sabotage, and use as couriers and decoys or at checkpoints. In addition, the ILO Worst Forms of Child Labor Convention 182, enacted in 2000, commits states which ratify it to take measures to prohibit and eliminate the “worst forms of child labor,” which include use in armed conflict. Moreover, the recruitment and use of any person under age 15 years in armed conflict is prohibited by Article 38 of the Convention on the Rights of the Child (the Optional Protocol of the CRC enacted in 2002 raised the minimum age of use in armed conflict to 18 years). Like all such international conventions and rules, there will continue to be violations. Nevertheless, the legal infrastructure to prevent child soldiers now in place is a global standard against which interventions can be evaluated and toward which advocacy can be directed. Ongoing national and international advocacy to prevent, ban, and rehabilitate child soldiers has become a critical global humanitarian and public health goal and is the way forward.

See also: Child Rights; Child Witness to Violence; Ethnic Conflict and Public Health; Torture and Public Health.

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References Newman, S., 2001. Will Afghans give up their weapons? Many carry Kalashnikofs after years of civil war. Wall Street J. Int. 228, A14. Steinburner, J., 2006. In the name of defence. New Sci. 192, 20.

Further Reading Bodman, F., 1941. War conditions and the mental health of the child. Br. Med. J. 12, 468–488. Chimienti, G., Nasr, J.A., Khalifeh, I., 1989. Children’s reactions to war-related stress. Soc. Psychiatry Psychiatr. Epidemiol. 24, 282–287.

McWhirter, L., 1983. Northern Ireland: growing up with the ‘troubles’. In: Goldstein, A.P., Segall, M.H. (Eds.), Aggression in Global Perspective. Permagon Press, New York, pp. 367–400. Pearn, J.H., 1996. War zone paediatrics in Rwanda. J. Paediatr. Child Health 32, 290–295. Pearn, J.H., 2003. Children and war. J. Paediatr. Child Health 39, 166–172. Schaller, J.G., Nightingale, E.O., 1992. Children and childhoods. Hidden casualties of war and civil unrest. J. Am. Med. Assoc. 268, 642–644.

Child Witness to Violence Caroline Kistin and Megan H Bair-Merritt, Boston University School of Medicine, Boston, MA, USA Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Marilyn Augustyn, Barry Zuckerman, volume 1, pp. 616–620, Ó 2008, Elsevier Inc.

Introduction Children’s exposure to violence is a pervasive challenge in the world today. Exposure to violence may include seeing or hearing violent interpersonal events, direct involvement such as trying to prevent a violent encounter or to call for outside help, or experiencing the visible or emotional consequences of such encounters. Data from the United Nations Secretary-General’s Study on Violence against Children estimate that up to 275 million of the world’s children are exposed to violence in their homes (Unicef, 2006). In the United States, Finkelhor et al. (2015), with support from the US Department of Justice’s Office of Juvenile Justice and Delinquency Prevention, recently demonstrated the pervasiveness of children’s exposure to violence by conducting a national survey; the authors reported that more than 60% of US children were exposed to some form of violence in the past year. This article will discuss the impact on children of exposure to interpersonal violence, with particular focus on children’s exposure to intimate partner violence (IPV). Our review takes on the following questions: How common is childhood exposure to violence? How do children make sense of the violence around them? What are the health and developmental implications of exposure? And, what evidence-based programs exist to prevent or treat children’s violence exposure?

Epidemiology Statistical estimates of the rates of violence exposure among children abound and differ vastly. Many hypothesize these differing rates are due to varied methods of data collection, different definitions of types of violence, and both over- and underreporting. Rates of childhood exposure to IPV have been particularly difficult to quantify. For example, the US National Family Violence Survey (NFVS) sampled 6000 households by telephone interviews (Gelles and Straus, 1988). This survey indicated that 116 per 1000 women reported experiencing some form of physical or verbal aggression by an intimate partner in 1 year, and 44 per 1000 women reported that they had engaged in some form of physical or verbal aggression toward their male partners in that year. Thirty-four per thousand women surveyed reported that they had experienced severe violence at the hands of their intimate male partners. Although the NFVS did not gather data on child exposure to IPV, survey results have been used to estimate the prevalence of child exposure to be at least 3.3 million annually (Carlson, 1984). In 1995 and 1996, the National Institute of Justice and the Centers for Disease Control and Prevention (CDC) cosponsored the National Violence Against Women Survey (Tjaden and Thoennes, 1998). A sample of 8000 men and 8000 women

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was drawn from random-digit telephone dialing to households in all 50 states and the District of Columbia. Findings indicated that in the United States
1.5 million women and 834 700 men are raped and/or physically assaulted by an intimate partner annually. But what about the children? One recent nationally representative, random-digit dialing survey conducted in the United States estimated that over 15 million children live in homes with IPV. Seven million of these children live in homes with severe violence, such as a one parent beating another parent up or one parent using a knife or gun against the other parent (McDonald et al., 2006). One major multicity research effort in the United States sponsored by the National Institute of Justice, the Spousal Assault Replication Program (SARP), was designed to address some of the limitations of other data sources by providing data obtained by law enforcement officers on children exposed to family violence (Fantuzzo et al., 1997). Findings revealed that, in all five cities studied, children were present in the households of the IPV group at more than twice the rate they were present in comparable households in the general population. Furthermore, children aged 5 and under were more likely than older children to be exposed to multiple incidents of IPV over a 6-month periodand to parental substance abuse. Other well-known risk factors, such as poverty, status as a single-parent household headed by a female, and a primary caregiver with a low educational level, were also more likely to be present in the homes in which IPV occurred. Overall, these data suggest that those children who are most dependent on their caregivers are most vulnerable to witnessing serious IPV and are additionally threatened by a host of other developmental risk factors. These co-occurring risk factors also complicate efforts to identify the unique developmental consequences of exposure to family violence. Perhaps the most comprehensive and up-to-date assessment of children’s exposure to violence in their communities is Finkelhor’s Childhood Exposure to Violence survey. Unlike other national surveys focused on children’s exposure to violence, the researchers spoke directly to children over 10 years of age rather than restricting discussions to only a parent or primary caregiver. Finkelhor reported that over 60% of US children were exposed to some form of violence in the past year. In addition, many children were exposed to violence on multiple occasions, with over 30% reporting multiple victimizations (Finkelhor et al., 2015). Older children and adolescents had the highest risk of past year and lifetime violence exposure, with children aged 12–19 years being more than twice as likely as the general population to be victims of crimes (Finkelhor et al., 2015). However, younger children also face significant exposure to violent episodes. In a survey at a pediatric clinic in Boston, MA, parents indicated that 10% of the children under the age of 6 years reported witnessing a shooting or a stabbing (Taylor et al., 1994).

http://dx.doi.org/10.1016/B978-0-12-803678-5.00064-3

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Developmental and Health Effects of Children’s Violence Exposure Recent developments in neuroscience, immunology, and endocrinology have furthered our understanding of the impact of violence exposure on the developing body and brain. Specifically, when children are exposed to a violent event, the initial response is commonly (and appropriately) fear. The physiological correlate of ‘feeling afraid’ is mounting of the fight or flight response, which includes increasing heart rate and blood pressure, and eventual release of cortisol. While this stress response is adaptive in the short term, humans were not meant to chronically mount the stress response (Johnson et al., 2013). Repeated activation of the stress response system – without the buffer of a safe and nurturing primary caregiver – has been called toxic stress and leads to increased allostatic load, or wear and tear on the bodies’ developing brain and other organ systems (Johnson et al., 2013). This physiological response – and general perception of the world as an unsafe place – can have significant impact on children’s development and on their emotional and physical health. Notably, however, it is important to recognize that exposure to violence may differ in its impact on and meaning for individual children; this differential impact stems from differences in the violence exposure (e.g., type, severity, frequency), the child (e.g., temperament, age, sex), and family (e.g., presence of supportive relationships). For example, witnessing threats to one’s own mother and receiving threats to one’s own physical safety from a caregiver may extract a different and more serious toll on a child’s emotional stability than exposure to community violence outside the home (Wade et al., 2016). Some literature suggests that exposure during sensitive developmental windows – the first 1000 days of life and adolescence – may lead to particularly significant adverse health impact (Carpenter and Stacks, 2009; Cisler et al., 2012). Considering impact on development, a preschooler who has witnessed IPV may be anxious about his mother’s safety and so may have trouble separating from the mother at the start of the day, experience difficulty with other transitions, or may be unable to engage in typical imaginary play because of his concerns, or because literally the survival parts of the brain are more well developed than the parts of the brain that deal with emotional regulation and executive function. Exposure to violence may not only stall the developmental trajectory but may also lead to behavioral regression. A child who was toilet-trained may begin to have ‘accidents’ in which he wets or soils his clothes. In addition, for very young children who are developing primary attachments to their caregivers, these fundamental relationships may be challenged by the caregivers’ inability to be ‘available’ for the child because of their own fears and concerns for physical safety. Several types of emotional health outcomes have been tracked. The first of these is future externalizing problems (aggressive behavior and conduct problems). The studies are mixed. Some show no link between IPV and child aggression, conduct disorders, and other externalizing problems (Jouriles et al., 1987; Wolfe et al., 1995). Others demonstrate a link between domestic violence and increased aggression (Holden and Ritchie, 1991; McCloskey et al., 1995; Graham-Berman and Levondosky, 1998).

One longitudinal study in Chicago among a sample of 245 African-American and Latino boys and their caregivers from economically disadvantaged inner-city neighborhoods in Chicago showed that exposure to community violence was related to increases in aggressive behavior and depression over a 1-year period even after controlling for previous status (Gorman-Smith and Tolan, 1998). Similarly, Miller found that in a cohort of 6- to 10-year-old urban American boys (N ¼ 97) at familial risk for antisocial behavior 15 months later boys reported high rates of lifetime exposure to community violence. In families with low conflict, higher levels of witnessed violence predicted increases in antisocial behavior over time (Miller et al., 1999). The literature also shows a link between witnessing community violence and IPV and internalizing problems such as depression and anxiety. The link between childhood exposure to violent physical aggression between parents and internalizing problems has been a robust finding in multiple studies (Davies et al., 2006; Gordis et al., 2001). However, GormanSmith and Tolan (1998) found that exposure to community violence is also related to anxiety and depression, and Schwab-Stone et al. (1995) found that exposure to violence predicted depressed/anxious mood among 6th-, 8th-, and 10th-graders. Finally, a growing literature supports that exposure to violence in general, and IPV specifically, increases risk of multiple physical health conditions over the life course. In 2012, the American Academy of Pediatrics cited the evidencebased ecobiodevelopmental (EBD) framework to highlight the significant ongoing interaction between adversity in the social environment – such as violence exposure, and one’s biology; they emphasized that this interaction profoundly affects lifelong health (Garner and Shonkoff, 2012; Shonkoff et al., 2012). For example, a robust (and growing) body of work demonstrates the link between asthma incidence and morbidity and childhood exposure to violence (Subramanian et al., 2007). Using data from the Behavioral Risk Factor Surveillance System administered in 10 US States, Breiding found that maternal lifetime history of IPV was associated with 61% higher odds of child asthma (measured by maternal report) (Breiding and Ziembroski, 2011). Suglia documented an 80% increased odds of a maternally reported diagnosis of asthma for children of mothers experiencing IPV (Suglia et al., 2009). Additional literature supports increased risk of obesity, particularly for girls, who are IPV exposed compared to their nonexposed peers (Boynton-Jarrett et al., 2010). Indeed, the highly cited Adverse Childhood Experiences (ACE) papers document that exposure to violence during childhood including exposure to a battered mother and personal history of physical, sexual, or emotional abuse increases risk for a host of adult health outcomes including, but not limited to, smoking, alcohol abuse, sexually transmitted diseases, and overall morbidity and mortality (Felitti et al., 1998). The ACE study results found not only high prevalence of ACEs (over 2/3 of insured adults had experienced at least one ACE), but also indicated that a consistent, graded relationship existed between the number of ACEs and poor adult health outcomes such that the more ACEs a person had the greater their risk of risk-taking behaviors and poor physical health in adulthood (Felitti et al., 1998).

Child Witness to Violence

Prevention and Treatment The CDC has identified the prevention of violence, including child witness to IPV and other forms of violence, as an important public health priority. There are different approaches that have been shown to be effective for primary prevention (preventing the occurrence of violence in the first place), secondary prevention (reducing the harmful impact of violence exposure once it has already occurred), and tertiary prevention or treatment (helping children and families who are symptomatic or significantly affected by exposure to violence).

Primary Prevention Many adults first experience violent intimate relationships in the adolescent years (Kann et al., 2014; Finkelhor et al., 2015). Several primary prevention initiatives for IPV, therefore, focus on promoting healthy teen dating relationships (Foshee et al., 2005; Cornelius and Resseguie, 2007). The ‘Safe Dates’ program, for example, is a school-based curriculum for middle and high-school students that has been shown to decrease the risk of physical, sexual, and psychological partner violence with a sustained intervention effect 4 years following intervention delivery (Foshee et al., 2005). In many communities, schools play an active role in developing additional primary violence prevention programs, and several such school-based approaches have shown promise. One program, Responding in Peaceful and Positive Ways (RIPP), is a 6th-grade universal violence prevention program studied among classes of 6th-graders at three urban middle schools serving predominantly African-American youth. Compared to students randomized to the control group, RIPP participants had fewer disciplinary violations for violent offenses and in-school suspensions at posttest compared with the control group. The reduction in suspensions was maintained at 12month follow-up for boys but not for girls (Farrell et al., 2001). Additional social emotional learning primary prevention programs, such as the Seattle Social Development Project (Hawkins et al., 1992), the Positive Action Program (Flay et al., 2001), and Second Step (Espelage et al., 2013) incorporate individual, school, and family components. Although the specific elements and foci of these programs may differ from program to program, all build on earlier research demonstrating multiple, interdependent, and mutually reinforcing pathways to healthy development (McCord et al., 2001; Leaf and Keys, 2005).

Secondary Prevention When a child has witnessed violence, the most important first step is to assess and ensure the ongoing safety of the child and any other affected (nonoffending) family members. Depending on the nature of the traumatic exposure, this may require placement in a shelter and connection to legal services and other community resources. Even children who do not seem to exhibit posttraumatic symptoms may benefit from close follow-up with their primary care physician for monitoring of well-being and support of caregivers. The United States Preventive Services Task Force (USPSTF) currently recommends IPV screening for all women of childbearing age (B rating) with referral to services as indicated

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(Moyer, 2013). While the USPSTF recommendation does not discuss whether or how to assess child witness to violence, a positive screen should be considered a high risk for child exposure.

Tertiary Prevention/Treatment For children who witness violence and exhibit posttraumatic symptoms, there are a number of evidence-based treatments. Child–parent psychotherapy (CPP) is a dyadic relationshipbased treatment that has demonstrated efficacy in decreasing behavior problems and symptoms of posttraumatic stress disorder among both children and their mothers in a culturally diverse, low-income group of preschoolers exposed to marital violence when they were compared with a control group receiving a combination of case management and individual psychotherapy (Lieberman et al., 2005; Ghosh Ippen et al., 2011). Additional programs recommended by the National Child Traumatic Stress Network include Trauma-Focused Cognitive Behavioral Therapy (Weiner et al., 2009; Cohen et al., 2011) and Structured Psychotherapy for Adolescents Responding to Chronic Stress (Habib et al., 2013).

Advocacy Beyond treatment of individual cases, it is critically important that we begin examining societal trends and cultural norms around violence and violence exposure (including mediarelated violence). To truly prevent children’s exposure to violence, societies must reduce tolerance for violence in all sectors. In addition, child-serving systems (e.g., health and education) that are traditionally in silos should work together such that all families have access to supportive services to ensure basic needs are met and that evidence-based, cross-system treatments are available to families who have experienced violence. In the next decade, advocates must move from a reactive strategy to an upstream and proactive one in which prevention and education are the hallmarks. The World Health Organization recommends a comprehensive approach to preventing violence that includes individual-level components, such as investing in parenting and early child education programs that support parents and families, as well as community- and society-level components, including sustainable economic opportunities, comprehensive drug and alcohol dependence treatment programs, and policies and programs that promote gender equality and women’s rights in the home, schools, and work place.

See also: Children and Adolescents, Measuring the Quality of Life of; Media and Health; Sexual Violence; Young People and Violence.

References Boynton-Jarrett, R., Fargnoli, J., Suglia, S., Zuckerman, B., Wright, R., 2010. Association between maternal intimate partner violence and incident obesity in preschool-aged children: results from the Fragile Families and Child Well-being Study. Arch. Pediatr. Adolesc. Med. 164, 540–546. Breiding, M., Ziembroski, J., 2011. The relationship between intimate partner violence and children’s asthma in 10 US states/territories. Pediatr. Allergy Immunol. 22, e95–e100.

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Carlson, B., 1984. Children’s observations of interparental violence. In: Roberts, A.R. (Ed.), Battered Women and Their Families. Springer, New York, pp. 147–167. Carpenter, G., Stacks, A., 2009. Developmental effects of exposure to intimate partner violence in early childhood: a review of the literature. Child Youth Serv. Rev. 31 (8), 831–839. Cisler, J., Begle, A., Amstadter, A., Resnick, H., Danielson, C., Saunders, B., Kilpatrick, D., 2012. Exposure to interpersonal violence and risk for PTSD, depression, delinquency, and binge drinking among adolescents: data from the NSA-R. J. Trauma. Stress 25 (1), 33–40. Cohen, J., Mannarino, A., Iyengar, S., 2011. Community treatment of PTSD for children exposed to intimate partner violence: a randomized controlled trial. Arch. Pediatr. Adolesc. Med. 165, 16–21. Cornelius, T.L., Resseguie, N., 2007. Primary and secondary prevention programs for dating violence: a review of the literature. Aggress. Violent Behav. 12, 364–375. Davies, P., Sturge-Apple, M., Winter, M., Cummings, E., Farrell, D., 2006. Child adaptational development in contexts of interparental conflict over time. Child Dev. 77 (1), 218–233. Espelage, D., Low, S., Polanin, J., Brown, E., 2013. The impact of a middle school program to reduce aggression, victimization, and sexual violence. J. Adolesc. Health 53 (2), 180–186. Fantuzzo, J., Boruch, R., Beriama, A., Atkins, M., Marcus, S., 1997. Domestic violence and children: prevalence and risk in five major US cities. J. Am. Acad. Child Adolesc. Psychiatry 36 (1), 116–122. Farrell, A., Meyer, A., White, K., 2001. Evaluation of Responding in Peaceful and Positive Ways (RIPP): a school-based prevention program for reducing violence among urban adolescents. J. Clin. Child Psychol. 30 (4), 451–463. Felitti, V., Anda, R., Nordenberg, D., Williamson, D., Spitz, A., Edwards, V., Koss, M., Marks, J., 1998. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. Am. J. Prev. Med. 14 (4), 245–258. Finkelhor, D., Turner, H., Shattuck, A., Hamby, S., 2015. Prevalence of childhood exposure to violence, crime, and abuse: results from the national survey of children’s exposure to violence. JAMA Pediatr. 169 (8), 746–754. Flay, B., Allred, C., Ordway, N., 2001. Effects of the positive action program on achievement and discipline two matched-control comparisons. Prev. Sci. 2, 71–89. Foshee, V., Bauman, K., Ennett, S., Suchindran, C., Benefield, T., Linder, G., 2005. Assessing the effects of dating violence prevention program “safe dates” using random coefficient regression modeling. Prev. Sci. 6 (3), 245–258. Garner, A., Shonkoff, J., 2012. Early childhood adversity, toxic stress, and the role of the pediatrician: translating developmental science into lifelong health. Pediatrics 129, e224–e231. Gelles, R., Straus, M., 1988. Intimate Violence. New York. Ghosh Ippen, C., WW, H., Van Horn, P., Lieberman, A., 2011. Traumatic and stressful events in early childhood: can treatment help those at highest risk? Child Abuse Negl. 35, 504–513. Gordis, E., Margolin, G., John, R., 2001. Parents’ hostility in dyadic marital and triadic family settings and children’s behavior problems. J. Consult. Clin. Psychol. 69 (4), 727–734. Gorman-Smith, D., Tolan, P., 1998. The role of exposure to community violence and developmental problems among inner-city youth. Dev. Psychopathol. 10 (1), 101–116. Graham-Berman, S., Levondosky, A., 1998. The social functioning of preschool aged children whose mothers are emotionally and physically abused. J. Emot. Abuse 1, 59–84. Habib, M., Labruna, V., Newman, J., 2013. Complex histories and complex presentations: implementation of a manually-guided group treatment for traumatized adolescents. J. Fam. Violence 28, 717–728. Hawkins, D., Catalano, R., Miller, J., 1992. Risk and protective factors for alcohol and other drug problems in adolescence and early adulthood implications for substance abuse prevention. Psychol. Bull. 112, 64–105. Holden, G., Ritchie, K., 1991. Linking extreme marital discord, child rearing, and child behavior problems: evidence from battered women. Child Dev. 62, 311–327. Johnson, S., Riley, A., Granger, D.A., Riis, J., 2013. The science of early life toxic stress for pediatric practice and advocacy. Pediatrics 131, 319–327. Jouriles, E., Barling, J., O’Leary, K., 1987. Predicting child behavior problems in martially violent families. J. Abnorm. Child Psychol. 15, 165–173. Kann, L., Kinchen, S., Shanklin, S., et al., 2014. Youth risk behavior surveillance– United States, 2013. Morb. Mortal. Wkly. Rep. 63 (Suppl. 4), 1–168. Leaf, P., Keys, S., 2005. Collaborating for violence prevention: training health professionals to work with schools. Am. J. Prev. Med. 29, 279–287. Lieberman, A., Van Horn, P., Ghosh Ippen, C., 2005. Toward evidence-based treatment: child-parent psychotherapy with preschoolers exposed to marital violence. J. Am. Acad. Child Adolesc. Psychiatry 44, 1241–1248. McCloskey, L., Figueredo, A., Koss, M., 1995. The effects of systemic family violence on children’s mental health. Child Dev. 66, 1239–1261.

McCord, J., Spatz-Widom, J., Crowell, N.E., 2001. Juvenile Crime, Juvenile Justice. Panel on Juvenile Crime: Prevention, Treatment, and Control. N. A. Press, Washington, DC. McDonald, R., Jouriles, E., Ramisetty-Mikler, S., Caetano, R., Green, C., 2006. Estimating the number of American children living in partner-violent families. J. Fam. Psychol. 20, 137–142. Miller, L., Wasserman, G., Neugebauer, R., Gorman-Smith, D., Kamboukos, D., 1999. Witnessed community violence and antisocial behavior in high-risk, urban boys. J. Clin. Child Psychol. 28 (1), 2–11. Moyer, V., U.S. Preventive Services Task Force, 2013. Screening for intimate partner violence and abuse of elderly and vulnerable adults: U.S. preventive services task force recommendation statement. Ann. Intern. Med. 158 (6), 478–486. Schwab-Stone, M.E., Ayers, T.S., Kasprow, W., et al., 1995. No safe haven: a study of violence exposure in an urban community. J. Am. Acad. Child Adolesc. Psychiatry 34 (10), 1343–1352. Shonkoff, J., Garner, A., The Committee on Psychosocial Aspects of Child and Family Health, Committee on Early Childhood, Adoption, and Dependent Care, and Section on Developmental and Behavioral Pediatrics, 2012. The lifelong effects of early childhood adversity and toxic stress. Pediatrics 129, e232–e246. Subramanian, S., Ackerson, L., Subramanyam, M., Wright, R., 2007. Domestic violence is associated with adult and childhood asthma prevalence in India. Int. J. Epid. 36, 569–579. Suglia, S., Enlow, M., Kullowatz, A., Wright, R., 2009. Maternal intimate partner violence and increased asthma incidence in children: buffering effects of supportive caregiving. Arch. Pediatr. Adolesc. Med. 163, 244–250. Taylor, L., Zuckerman, B., Harok, V., Groves, B., 1994. Witnessing violence by young children and their mothers. J. Dev. Behav. Pediatr. 15 (2), 120–123. Tjaden, P., Thoennes, N., 1998. Prevalence, Incidence and Consequences of Violence against Women: findings from the National Violence against Women Survey. U. S. D. O. Justice, Washington, DC. Unicef, 2006. Behind Closed Doors: The Impact of Domestic Violence on Children. Retrieved October 17, 2014, from. http://www.unicef.org/protection/files/ BehindClosedDoors.pdf. Wade, R., Cronholm, P., Fein, J., Forke, C., Davis, M., Harkins-Schwarz, M., Pachter, L.M., Bair-Merritt, M., 2016. Household and community-level adverse childhood experiences and adult health outcomes in a diverse urban population. Child Abuse Negl. 52, 135–145. Weiner, D., Schneider, S., Lyons, J., 2009. Evidence-based treatments for trauma among culturally diverse foster care youth: treatment retention and outcomes. Child. Youth Serv. Rev. 31, 1199–1205. Wolfe, D., Jaffe, P., Wilson, S., Zak, L., 1995. Children of battered women: the relation of child behavior to family violence and marital stress. J. Consult. Clin. Psychol. 53, 657–665.

Further Reading Groves, B., 2003. Children Who See Too Much: Lessons from the Child Witness to Violence Project. Beacon Press, Boston, MA. Lieberman, A.F., Ghosh Ippen, C., Van Horn, P., 2006. Child-parent psychotherapy: 6month follow-up of a randomized controlled trial. J. Am. Acad. Child Adolesc. Psychiatry 45 (8), 913–918. Osofsky, J., 2004. Young Children and Trauma. Guilford Press, New York.

Relevant Websites http://www.cdc.gov/violenceprevention/ – Center for Disease Control and Prevention (last accessed on 02.05.16.). http://www.nctsn.org/content/interventions-children-exposed-domestic-violence-coreprinciples – The National Child Traumatic Stress Network, Interventions for Children exposed to Domestic Violence: Core Principles (last accessed on 02.05.16.). https://www.futureswithoutviolence.org – Futures without Violence (last accessed on 02.05.16.). http://www.who.int/violence_injury_prevention/publications/violence/IPV-SV.pdf – World Health Organization. Primary Prevention of Intimate-Partner Violence and Sexual Violence: Background Paper for WHO Expert Meeting May 2–3, 2007. Harvey, A., Garcia-Moreno, C., Butchart, A. (last accessed on 02.05.16.).

Childhood Infectious Diseases: Overview Amira M Khan and Zulfiqar A Bhutta, Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON, Canada Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Zulfiqar Ahmed Bhutta and M.A. Saeed, volume 1, pp. 620–640, Ó 2008, Elsevier Inc.

Infectious diseases account for almost half of the 5.9 million children under 5 years of age who die each year. Infections such as pneumonia (16%), diarrhea (9%), neonatal sepsis (7%), and malaria (5%) account for a large proportion of under-5 deaths worldwide (Figure 1). Importantly, of the 2.7 million neonatal deaths each year, 23% are due to infection-related causes including sepsis (15.1%), pneumonia (6%), tetanus (1.3%), and diarrhea (0.6%) (Black et al., 2016). However, in the late neonatal period, nearly half of the deaths are due to infection. With the progressive rise in antimicrobial resistance and growing incidence of emerging infections, infectious diseases continue to pose a considerable challenge to neonatal and child health. There are now sufficient data available to show that evidence-based interventions can make a difference and impact under-5 mortality significantly. It is estimated that almost two-thirds of these deaths are potentially preventable if interventions can be delivered at scale. Newborn infections and related mortality can be reduced by a number of interventions such as appropriate antenatal care, clean delivery, cord hygiene, exclusive and early breastfeeding, and prompt diagnosis and therapy. The global burden of pneumonia deaths can be reduced by vaccination strategies for measles,

Haemophilus influenzae type b (Hib), and pneumococcal disease; timely case detection; and treatment with appropriate antibiotics. Similarly, diarrheal deaths can be prevented by adequate attention to breastfeeding, hand washing, and sanitation strategies; rotavirus vaccine; oral rehydration therapy; appropriate dietary therapy; and oral zinc administration.

Introduction Substantial reductions in child mortality have been achieved in low- and middle-income countries (LMICs) in the past few decades. Under-5 deaths have decreased from 12.7 million in 1990 to 5.9 million in 2015. The annual rate of under-5 mortality reduction has increased from 1.8% in 1990–2000 to 3.9% in 2000–15 (UN IGME, 2015). In 2015, of the 5.9 million under-5 children who died, 2.7 million were neonates. Only five countries account for half of the world’s under-5 and neonatal deaths. The predominant causes of mortality are pneumonia, diarrhea, and neonatal disorders with additional contributions from malaria and AIDS (Figure 1). Although 2.2 million fewer under-5 children died from pneumonia, diarrhea, malaria,

Pneumonia, 13%

Other disorders, 15% Preterm birth complicaons, 2%

Pneumonia, 3%

Meningis, 2% AIDS, 1% Malaria, 5%

Preterm birth complicaons, 16%

Neonatal death (45%)

Injury, 6%

Measles, 1%

Diarrhea, 9%

Intrapartum-related events, 11%

Tetanus, 1% Other neonatal disorders, 3% Congenital abnormalies, 5%

Sepsis or meningis, 7%

Figure 1 Global causes of child deaths (low- and middle-income countries). Reproduced from Black, R., Laxminarayan, R., Temmerman, M., Walker, N., 2016. Reproductive, maternal, newborn, and child health. In: Jamison, D., Nugent, R., Gelband, H. (Eds.), Disease Control Priorities, third ed. International Bank for Reconstruction and Development/The World Bank, Washington, DC.

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measles, and AIDS in 2013 as compared to 2000 (UNICEF, 2014), these five diseases still continue to be responsible for a substantial number of deaths. With 83 deaths per 1000 live births annually, sub-Saharan Africa has the highest under-5 mortality rate among all regions (Table 1), accounting for nearly half of global under-5 deaths. Importantly, these include 96.4% of global child deaths due to malaria and 90.6% of global child deaths due to HIV/AIDS (Black et al., 2016; Table 2). Apart from the 5.9 million under-5 deaths that occurred in 2015, there were 2.6 million stillbirths, 12% of which were attributable to fetal infections. It is now being proposed that stillbirths be counted in the under-5 mortality statistic to bring focus to the morbidity and mortality associated with the period of gestation following 28 weeks.

Table 1

Regional classification of child mortality rates

Region Global Northern Africa Sub-Saharan Africa Latin America and the Caribbean Caucasus and Central Asia Eastern Asia Southern Asia Southeastern Asia Western Asia Oceania

18 h before delivery), maternal fever (>38
C during labor), and/or foul-smelling amniotic fluid.

Nosocomial Infections in Neonates Unfortunately, hospitals in developing countries are also hotbeds of infection transmission, especially multidrugresistant (MDR), hospital-acquired infections. Such infections are most common in preterm babies and term babies requiring prolonged hospital admission. It is estimated that 40% of neonatal deaths in developing countries are associated with nosocomial infections (Zaidi et al., 2005). Commonly seen hospital-acquired infections include bloodstream infections, neonatal sepsis, pneumonia, and omphalitis (Table 3).

Childhood Infectious Diseases: Overview Table 3 Major reasons for the nosocomial spread of sepsis and meningitis in a neonate

Table 4 a neonate

Lack of aseptic technique for procedures Inadequate hand hygiene and glove use Lack of essential equipment and supplies Failures in sterilization/disinfection or handling/storage of multiuser equipment, instruments, and supplies, leading to contamination Inadequate environmental cleaning and disinfection Overuse of invasive devices Reuse of disposable supplies without safe disinfection/sterilization procedures Pooling or multiple use of single-use vials Overcrowded and understaffed labor and delivery rooms Excessive vaginal examinations Failures in isolation procedures/inadequate isolation facilities for babies infected with antibiotic-resistant or highly transmissible pathogens Unhygienic bathing and skin care Lack of early and exclusive breastfeeding Contaminated bottle feeding Absence of mother–baby cohorting Lack of knowledge, training, and competency regarding infection control practice Inappropriate and prolonged use of antibiotics

Sepsis

Neonatal Sepsis and Meningitis Sepsis and meningitis are significant causes of newborn morbidity and mortality, particularly in preterm and LBW infants. Neonates usually have nonspecific and subtle signs of infection such as lethargy, irritability, and feeding intolerance. However, neonatal sepsis can still be diagnosed both clinically (Table 4) and microbiologically, by positive blood and/or cerebrospinal fluid (CSF) cultures. It may also be classified as either early-onset sepsis (EOS) or late-onset sepsis (LOS). Meningitis can occur as a part of either EOS or LOS, or as focal infection with late-onset disease. The distinction has clinical relevance, as EOS is mainly due to bacteria acquired before and during delivery, and LOS, to bacteria acquired after delivery (nosocomial or community sources). In the literature, however, there is little consensus as to what age limits define both, with the EOS onset ranging from within 24 h to within 7 days after birth and LOS from 3 days after birth to 8 days after birth. The WHO’s recommended clinical criteria for diagnosing sepsis and meningitis in neonates are shown in Table 4. Survival of neonatal meningitis relates to factors such as age, time, and clinical stability before effective antibiotic treatment; the exact microorganism and number of bacteria or quantity of active bacterial products in the CSF at the time of diagnosis; intensity of the child’s inflammatory response; and time required to sterilize CSF cultures through antibiotic treatment. The highest rates of mortality and morbidity occur following meningitis in the neonatal period.

Global and Regional Epidemiology The reported incidence of neonatal sepsis in LMICs varies from 170/1000 live births to as few as 5.5/1000 live births. Neonatal sepsis and meningitis are responsible for an estimated 420 000 deaths annually, accounting for almost 7% of all under-5 mortality (Black et al., 2016). Home deliveries, unregistered

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Possible symptoms and signs of sepsis and meningitis in

Commonly seen signs:

Grunting Not feeding well Drowsiness or unconscious Lethargy Reduced movements Fast breathing (60 breaths per minute or more) Severe chest indrawing Raised body temperature (>38
C) Hypothermia (2 cm, and increase in hematocrit with a fall in platelet count. Any of these signs warrants strict observation and prompt management to avoid further complication and severe disease. Clinical manifestations in infants and young children may be nonspecific (fever, cough, cold, sore throat) and vary from the typical presentation in older children and adults. Most children recover completely, but a small proportion may develop the hemorrhagic disease.

Severe Dengue (Dengue Hemorrhagic Fever)

WHO defines severe dengue by the presence of one or more of the following: plasma leakage that may lead to shock (dengue shock) and/or fluid accumulation with or without respiratory distress, and/or severe bleeding, and/or severe organ impairment.

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Plasma leakage, if sufficient, can lead to shock. Shock usually occurs 4–5 days after symptoms appear and can be manifested by low pulse pressure (20 mmHg), cold extremities, delayed capillary refill, rapid weak pulse, and hypotension. Nearly 20–30% of cases of dengue hemorrhagic fever progress to shock (dengue shock syndrome), and 40–50% of patients who develop shock die. Most deaths in children with dengue are a consequence of dengue shock syndrome. Rarely, dengue hemorrhagic survivors may have residual brain damage secondary to shock or an intracranial hemorrhage.

Diagnosis Differential diagnosis for dengue fever includes viral respiratory and influenza-like illnesses, malaria, mild yellow fever, typhoid fever, leptospirosis, Epstein–Barr virus, cytomegalovirus, HIV seroconversion illness, measles, and rubella. Table 14 outlines the clinical categorization of dengue fever, and Table 15 summarizes clinical features that would raise suspicion of severe dengue fever in children. The diagnosis of dengue fever is a combination of clinical assessment with laboratory testing. Apart from nonspecific blood tests, viral isolation can also be done in serum, plasma, circulating blood cells, and other tissues for 4–5 days after appearance of symptoms. Thus, virus isolation, nucleic acid, or antigen detection can be used in the earlier phase of the disease. At the end of the acute phase of infection, antibody serology can be utilized for diagnosis. Table 14 Clinical categories of dengue fever and dengue hemorrhagic fever World Health Organization (WHO) (2009) Dengue fever Lives in/travel to dengue endemic area. Fever with two or more of the following: l Anorexia and nausea l Rash l Aches and pains l Warning signs l Myalgia l Leukopenia l Tourniquet test positive Laboratory confirmed dengue (important when no sign of plasma leakage) Warning signs (requiring strict observation and medical intervention) l Abdominal pain or tenderness l Persistent vomiting l Clinical fluid accumulation l Mucosal bleed l Lethargy, restlessness l Liver enlargement > 2 cm l Laboratory: increase in hematocrit concurrent with rapid decrease in platelet count Severe dengue (dengue hemorrhagic fever) Patients with any of the following features: l Severe plasma leakage with shock and/or fluid accumulation with respiratory distress l Severe bleeding l Severe organ impairment Adapted from World Health Organization, 2009. Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control. [online]. World Health Organization.

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Table 15 Criteria for suspicion of severe dengue in a child (in a high-risk area) Fever  2 days with any of the following features: Evidence of plasma leakage l High or progressively rising hematocrit l Pleural effusions or ascites Circulatory compromise or shock l Cold, clammy extremities l Prolonged capillary refill time (>3 s) l Weak pulse l Narrow pulse pressure Spontaneous bleeding l From the nose or gums l Black stools or coffee ground vomit l Skin bruising or extensive petechiae Altered level of consciousness l Lethargy or restlessness l Coma l Convulsions Severe gastrointestinal involvement l Persistent vomiting l Increasing abdominal pain with tenderness in right upper quadrant l Jaundice Adapted from World Health Organization, 2013. Pocket Book of Hospital Care for Children. World Health Organization, Geneva.

Evidence-Based Interventions Rapid urbanization has led to an increase in the environmental factors that contribute to the proliferation of Aedes mosquito which transmits dengue. These factors include uncontrolled urbanization, inadequate management of water and waste, and provision of a range of large water stores and disposable, nonbiodegradable containers that become habitats for the larvae. Such environmental factors can change a region from nonendemic (no virus present) to hypoendemic (one serotype present) to hyperendemic (multiple serotypes present).

Preventive Measures In the absence of a vaccine, environmental control of the vector mosquito, A. aegypti, is the only effective preventive measure. The risk of mosquito bites in children may be reduced by the use of protective clothing and repellents and screening of homes. The single most effective preventive measure for travelers in areas where dengue is endemic is to avoid mosquito bites by using insect repellents containing DEET. The insect repellents should be used in the early morning and late afternoon, when Aedes mosquitoes are most active. These measures require constant reinforcement and may be difficult to sustain because of their cost. At a public health level, the risk of dengue fever outbreaks can be reduced by removing neighborhood sources of stagnant water or by using larvicides or lids for water containers (especially for containers that cannot be eliminated). In addition, predatory crustaceans may be introduced into water bodies.

Vaccines for Dengue Fever

The first recommended dengue vaccine (CYD-TDV) is a live recombinant tetravalent vaccine evaluated in phase 3 trials as

a three-dose series (0-, 6-, 12-month schedule). The WHO Strategic Advisory Group of Experts (SAGE) on Immunization has recommended the introduction of this vaccine in geographic settings with high endemicity, in individuals 9– 45 years of age. A long-term follow analysis of the vaccine showed that there was a reduced risk of hospitalization for participants 9 years or older, but not in children under the age of 9 (Hadinegoro et al., 2015). Based on data from this and other similar studies, the vaccine is not recommended in children under 9. In the meantime, other live-attenuated as well as purified inactivated vaccines are also undergoing clinical trials.

Medical Treatment No specific therapeutic strategies exist for dengue fever apart from supportive management using analgesics and antipyretics. Further key components of treatment are fluid management (usually administered orally and only rarely parenterally) and regular follow-ups. Antivirals are not recommended for treatment; however, in studies, ribavirin, interferon a, and 6azauridine have shown some antiviral activity in vitro. Most cases of nonsevere dengue can be managed on an outpatient basis. The management of dengue hemorrhagic fever and the dengue shock syndrome should be inpatient but is purely supportive with a prominent role for accurate fluid management and, if needed, for transfusion (blood, packed cells, platelet concentrates). Aspirin and other nonsteroidal antiinflammatory drugs should be avoided owing to the increased risk for Reye’s syndrome and hemorrhage.

Soil-Transmitted Helminthiasis Parasitic worms may be the commonest cause of chronic infection in humans. There are a number of major helminth infections of humans, and all have public health significance, but the most common are the geohelminths which affect the most vulnerable and deprived populations. In many lowincome countries, it is more common to be infected than not. Indeed, a child growing up in an endemic community can be infected soon after weaning and continues to be infected and reinfected for life.

Etiology and Epidemiology Recent global estimates indicate that nearly a quarter of the world’s population is infected with one or more helminths. The global burden of soil-transmitted helminths (STH) is presented in Table 16. In LMICs, about 1.2 billion people are infected with roundworms (Ascaris lumbricoides), and more than 740 million are infected with hookworms (Necator americanus or Ancylostoma duodenale) and 795 million with whipworms (Trichuris trichiura). The highest prevalence of STH infections is in sub-Saharan Africa, Southeast Asia, China, and the Americas. Infection is transmitted by ingestion of eggs from contaminated soil (A. lumbricoides and T. trichiura) or by penetration of the skin by larvae in the soil (N. americanus or A. duodenale).

Childhood Infectious Diseases: Overview Table 16

Global burden of soil-transmitted helminths

Soil-transmitted helminths Ascaris lumbricoides Hookworm (Necator americanus or Ancylostoma duodenale) Trichuris trichiura

Number infected (millions)

Disability-adjusted life years lost (millions)

Mortality (thousands)

800 600

1.2–10.5 1.8–22.1

3–60 3–65

600

1.6–6.4

3–10

Clinical Features and Complications Health consequences are directly related to worm burdens – the greater the number of worms, the worse will be the consequences. Children of school age are at greatest risk for developing clinical manifestations of disease. Although STH infections can remain asymptomatic in some cases, the following clinical features are possible in others: l l l l l l l l

Loss of appetite Malaise and weakness Anal pruritus Abdominal pain Diarrhea or dysentery Intestinal bleeding Intestinal obstruction Rectal prolapse

Studies have shown associations between helminth infection and undernutrition, iron deficiency anemia, stunted growth, poor school attendance, and poor performance in cognition tests. Some 44 million pregnancies are currently complicated by maternal hookworm infection, placing both mothers and children at higher risk of anemia and death during pregnancy and delivery. Intense whipworm infection in children may result in trichuris dysentery syndrome, the classic signs of which include anemia and stunting. Heavy burdens of both roundworm and whipworm are associated with protein-energy malnutrition.

Preventive Measures WHO’s global target aims to control STH morbidity in children by 2020. Prevention of STH involves a three pronged approach comprised of deworming, improvement of water and sanitation, and health education.

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deworming campaign was organized which targeted 270 million children in 1 day with a single-dose anthelminthic. According to WHO, to meet the 2020 target, at least 75% of the children in endemic regions (873 million children) will have to be regularly treated. Recommended drugs for use in public health settings include benzimidazole anthelmintics, albendazole (single dose: 400 mg, reduced to 200 mg for children between 12 and 24 months), or mebendazole (single dose: 500 mg), as well as levamisole or pyrantel pamoate. Ensuring home-use of antihelminthics is problematic for several reasons, and thus school-based deworming programs are preferred. These programs prove to be practical as schools offer a readily available, extensive, and sustained infrastructure with a skilled workforce that can be readily trained. Earlier studies showed that such programs had far-reaching health gains, improved school performance, and reduced school absenteeism. However, more recently a Cochrane review concluded that although individual treatment of children had nutritional benefits, mass treatment programs do not improve average nutritional status, hemoglobin, cognitive skills, or school performance (Taylor-Robinson et al., 2015).

Sanitation and Health Education

Improved WASH practices reduce soil and water contamination with egg-carrying feces. Systematic reviews have shown that the benefit could be a 33% reduction in risk of STH infection (Strunz et al., 2014). WASH interventions for STH do not include sanitation but access to clean drinking water, hygiene, and hand washing. Community behavior change strategies are critical in reducing contamination of soil and water by promoting the use of latrines and hygienic behavior. Without a change in defecation habits, periodic deworming cannot attain a stable reduction in transmission.

Medical Treatment The WHO recommends the use of albendazole, mebendazole, pyrantel, and levamisole. A review of 14 studies showed that both benzimidazoles have high efficacy against roundworm and moderate efficacy against whipworm. Single-dose mebendazole is much less effective against hookworm with cure rates typically below 60%. In cases with intestinal obstruction or rectal prolapse, surgical intervention is often required.

Deworming

WHO recommends periodic deworming with anthelminthic medicines to all at-risk populations in endemic areas to reduce worm burden. At-risk populations include preschool-aged children, school-aged children, and women of childbearing age. The medicines are recommended to be administered annually in areas where STH prevalence is >20% and twice a year where the prevalence is >50%. Deworming interventions can be integrated with other health programs or supplementation days. However, some LMICs are carrying out independent, large-scale deworming initiatives such as India where recently the world’s largest

Emerging Infections of Childhood Chikungunya: Chikungunya is a viral disease transmitted by A. aegypti mosquitoes. Older adults, children (especially infants), and pregnant women are at high-risk groups. The clinical picture of the disease is similar to dengue, although fever and joint pain are more pronounced in chikungunya. Treatment and prevention strategies are parallel to that of dengue. Although discovered in 1952, chikungunya outbreaks have been recorded since 2004 in Africa, Southeast Asia, and most recently in the Americas.

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Childhood Infectious Diseases: Overview Table 17

Interventions and their effects on diseases

Major intervention

Disease prevented or treated

Effective antenatal care Skilled maternal and neonatal care Maintenance of personal hygiene Drug treatment

Neonatal deaths, infections, pneumonia Neonatal deaths, neonatal tetanus, infections Neonatal deaths, typhoid, diarrhea, infections Diarrhea, pneumonia, infections, typhoid, dengue, malaria, neonatal deaths, infections, meningitis Pneumonia, typhoid, rotavirus, meningitis Diarrhea Diarrhea, malaria Diarrhea, pneumonia, malaria Neonatal deaths, diarrhea, pneumonia, typhoid, helminths Diarrhea, pneumonia, infections, typhoid, neonatal deaths Diarrhea, pneumonia, malaria, neonatal deaths Malaria and other infections Malaria, dengue

Vaccines Oral rehydration therapy Vitamin A Zinc Water/sanitation/hygiene Breastfeeding Complementary feeding Intermittent preventive treatment in pregnancy Insecticide-treated nets

While the bulk of child morbidity and mortality attributable to infectious diseases is due to the infections already discussed, there are many emerging infections globally which are impacting child health in all regions. Ebola: Caused by the Ebola virus, Ebola virus disease belongs to the category of viral hemorrhagic fevers, and the most recent outbreak in West Africa has claimed more than 11 000 lives with nearly 29 000 reported cases. According to reported statistics from the West African outbreak, nearly 80% of confirmed and probable cases were in individuals 16 years or older. Thus the incidence of cases in pediatric population has been consistently less than adults in all countries of the region. However, the disease progression in children is rapid with a shorter incubation period and higher CFRs in the under-5 population. The lower reported incidence in this age group could be because children are less likely to be involved in care of or be near Ebola patients and therefore at less risk for infection. However, age-related biases in Ebola surveillance and different health-seeking behavior for children could also be the reasons. Ebola prevention is based on reduction of risk of wildlife-tohuman transmission, human-to-human transmission, and sexual transmission. Ebola vaccine research is underway, and two potential vaccines (rVSV-ZEBOV and ChAd3-EBOZ) are undergoing human safety testing. Interim results are promising. Treatment of Ebola is purely supportive with management of symptoms and hydration. Zika virus: Though discovered in 1947, it was only in 2007 when an outbreak occurred on Yap Island and subsequently in French Polynesia in 2013 that human transmission of Zika virus was noticed extending from the eastern hemisphere to the west. The current outbreak of Zika virus is not only affecting the Americas but also West Africa (Cape Verde) as well as various islands in the South Pacific. The virus is transmitted by the A. aegypti mosquito (the same vector for dengue, chikungunya, and yellow fever) and through sexual contact. Zika is a mild or even asymptomatic denguelike disease; however, an increased incidence of Guillain–Barré syndrome and other neurological conditions has been documented in

populations where Zika is pandemic, leading researchers to suspect these could be complications of the disease (Cao-Lormeau et al., 2016). Infants or children who reside in or have traveled to the areas with ongoing transmission of Zika virus are at risk of infection. Also, infants of mothers infected during pregnancy are at risk of perinatal transmission, fetal demise, or impaired fetal neurological complications. Some regions have seen a 20-fold increase in microcephaly cases in newborn, which has led to scientific consensus that Zika virus is a cause of microcephaly and Guillain–Barré syndrome. The preventive measures for Zika are similar to as for dengue where the breeding of mosquitoes is prevented as well as protection is taken against mosquito bites. Public health officials in the pandemic regions also caution women to protect themselves from mosquito bites during pregnancies or even delay pregnancies till the virus is controlled. There is currently no vaccine for Zika. Treatment, as in dengue fever, is supportive based on symptomatic and fluid management.

Conclusions The global burden of infectious diseases contributing to child mortality is considerable. The situation is further compounded by increasing antimicrobial resistance and the emergence of new infections. With increasing global population, growing urbanization and international travel as well as threatening human behaviors, the threat of infectious diseases is greater than ever. The contribution of neonatal infections to overall child mortality is well recognized, but the persistence of global burden of deaths due to pneumonia and diarrhea also underscore the need for improved public health strategies for change. Sepsis as a cause of death in older children, other than neonates, should be recognized and recorded for improved management strategies. We have interventions that can make a difference to childhood infectious diseases (Table 17). What is needed is their implementation at scale to populations at greatest risk. This will require not only

Childhood Infectious Diseases: Overview biomedical approaches but also measures to address the social determinants of disease.

See also: Arboviruses; Bacterial Infections: Overview; Contaminants Associated with Drinking Water; Dengue; Drinking Water and Sanitation; Gastrointestinal Disorders: Overview; History of Malaria and Its Control; Infant Mortality; Meningitis, Bacterial; Protozoan Diseases: Cryptosporidiosis, Giardiasis, and Other Intestinal Protozoan Diseases; Protozoan Diseases: Malaria Clinical Features, Management, and Prevention; Typhoid Fever.

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Global and national burden of diseases and injuries among children and adolescents between 1990 and 2013. JAMA Pediatr. 170 (3), 267. Lassi, Z., Haider, B., Bhutta, Z., 2012. Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months [online] Cochrane Database Syst. Rev. 12. Available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858. CD005978.pub2/pdf/abstract (accessed 23.02.16.). Lassi, Z., Middleton, P., Crowther, C., Bhutta, Z., 2015. Interventions to improve neonatal health and later survival: an overview of systematic reviews. EBioMedicine 2 (8), 985–1000. Lawn, J., Blencowe, H., Oza, S., et al., 2014. Every newborn: progress, priorities, and potential beyond survival. Lancet 384 (9938), 189–205. Lazzerini, M., Ronfani, L., 2013. Cochrane review: oral zinc for treating diarrhoea in children. Evid. Based Child. Health 4 (4), 1351–1417. Lengeler, C., 2004. Insecticide-treated bed nets and curtains for preventing malaria. Cochrane Database Syst. Rev. [online] (2). Available at: http://onlinelibrary.wiley. com/doi/10.1002/14651858.CD000363.pub2/epdf (accessed 15.04.16.). Liu, L., Oza, S., Hogan, D., et al., 2015. Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet 385 (9966), 430–440. Luby, S., Agboatwalla, M., Feikin, D., Painter, J., Billhimer, W., Altaf, A., Hoekstra, R., 2005. Effect of handwashing on child health: a randomised controlled trial. Lancet 366 (9481), 225–233. Mogasale, V., Maskery, B., Ochiai, R., Lee, J., Mogasale, V., Ramani, E., Kim, Y., Park, J., Wierzba, T., 2014. Burden of typhoid fever in low-income and middleincome countries: a systematic, literature-based update with risk-factor adjustment. Lancet Glob. Health 2 (10), e570–e580. Munos, M., Walker, C., Black, R., 2010a. The effect of oral rehydration solution and recommended home fluids on diarrhoea mortality. Int. J. 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Prüss-Üstün, A., Bos, R., Gore, F., Bartram, J., 2008. Safer Water, Better Health: Costs, Benefits and Sustainability of Interventions to Protect and Promote Health [online]. World Health Organization, Geneva. Available at: http://apps.who.int/iris/ bitstream/10665/43840/1/9789241596435_eng.pdf (accessed 25.02.16.). Salam, R., Das, J., Darmstadt, G., Bhutta, Z., 2013. Emollient therapy for preterm newborn infants – evidence from the developing world. BMC Public Health 13 (Suppl. 3), S31. Strunz, E., Addiss, D., Stocks, M., Ogden, S., Utzinger, J., Freeman, M., 2014. Water, sanitation, hygiene, and soil-transmitted helminth infection: a systematic review and meta-analysis. PLoS Med. 11 (3), e1001620. Tshefu, A., Lokangaka, A., Ngaima, S., Engmann, C., Esamai, F., Gisore, P., Ayede, A., Falade, A., Adejuyigbe, E., Anyabolu, C., Wammanda, R., Ejembi, C., Ogala, W., Gram, L., Cousens, S., 2015. Simplified antibiotic regimens compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with clinical signs of possible serious bacterial infection when referral is not possible: a randomised, open-label, equivalence trial. Lancet 385 (9979), 1767–1776. Taylor-Robinson, D.C., Maayan, N., Soares-Weiser, K., Donegan, S., Garner, P., 2015. Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin, and school performance. Art. No.: CD000371 Cochrane Database Syst. Rev. (Issue 7). http://dx.doi.org/10.1002/ 14651858.CD000371.pub6. UN Inter-agency Group for Child Mortality Estimation, 2015. Levels & Trends in Child Mortality Report 2015-Estimates Developed by the UN Inter-agency Group for Child Mortality Estimation. UNICEF/WHO/World Bank/United Nations. United Nations Children’s Fund (UNICEF), 2014. Committing to Child Survival: A Promise Renewed. Progress Report 2014. United Nations Children’s Fund, New York. Victora, C., Bahl, R., Barros, A., et al., 2016. Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. Lancet 387 (10017), 475–490. World Health Organization/The United Nations Children’s Fund (UNICEF), 2013. Ending Preventable Child Deaths from Pneumonia and Diarrhoea by 2025. The Integrated Global Action Plan for Pneumonia and Diarrhoea (GAPPD). World Health Organization, 2009. Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control [online]. World Health Organization. World Health Organization, 2011. Guidelines on Optimal Feeding of Low Birthweight Infants in Low- and Middle-income Countries [online]. World Health Organization. Available at: http://www.who.int/maternal_child_adolescent/documents/ 9789241548366.pdf (accessed 11.02.16.). World Health Organization, 2013a. WHO Policy Brief for the Implementation of Intermittent Preventive Treatment of Malaria in Pregnancy Using Sulfadoxinepyrimethamine (IPTp-SP). World Health Organization. World Health Organization, 2013c. Seasonal Malaria Chemoprevention with Sulfadoxine–pyrimethamine Plus Amodiaquine in Children: A Field Guide. World Health Organization. World Health Organization, 2014. Revised WHO Classification and Treatment of Childhood Pneumonia at Health Facilities – Evidence Summaries [online]. World Health Organization. Available at: http://www.who.int/maternal_child_adolescent/ documents/child-pneumonia-treatment/en/ (accessed 20.01.16.). World Health Organization, 2013b. Pocket Book of Hospital Care for Children. World Health Organization, Geneva. World Health Organization/UNICEF, 2011. Intermittent Preventive Treatment for Infants Using Sulfadoxinepyrimethamine (SP-IPTi) for Malaria Control in Africa: Implementation Field Guide. World Health Organization. Zaidi, A., Huskins, W., Thaver, D., Bhutta, Z., Abbas, Z., Goldmann, D., 2005. Hospitalacquired neonatal infections in developing countries. Lancet 365 (9465), 1175–1188. Zaman, K., Roy, E., Arifeen, S., Rahman, M., Raqib, R., Wilson, E., Omer, S., Shahid, N., Breiman, R., Steinhoff, M., 2008. Effectiveness of maternal influenza immunization in mothers and infants. N. Engl. J. Med. 359 (15), 1555–1564.

Further Reading Black, R.E., Morris, S.S., Bryce, J., 2003. Where and why are 10 million children dying every year? Lancet 361, 2226–2234. Capeding, M., Tran, N., Hadinegoro, S., et al., 2014. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet 384 (9951), 1358–1365.

Fauci, A., Morens, D., 2016. Zika virus in the Americas – yet another arbovirus threat. N. Engl. J. Med. 374 (7), 601–604. Frasch, C., Kapre, S., Lee, C., Preaud, J., 2015. Technical development of a new meningococcal conjugate vaccine. Clin. Infect. Dis. 61 (Suppl. 5), S404–S409. Helleringer, S., Noymer, A., Clark, S., McCormick, T., 2015. Did Ebola relatively spare children? Lancet 386 (10002), 1442–1443. Kissoon, N., Uyeki, T., 2016. Sepsis and the global burden of disease in children. JAMA Pediatr. 170 (2), 107. Munos, M., Walker, C., Black, R., 2010b. The effect of rotavirus vaccine on diarrhoea mortality. Int. J. Epidemiol. 39 (Suppl. 1), i56–i62. Naz, F., Azmatullah, A., Zaidi, A., 2014. A three year review of antimicrobial resistance of Salmonella enterica serovars Typhi and Paratyphi A in Pakistan. Int. J. Infect. Dis. 21, 82. Oza, S., Lawn, J., Hogan, D., Mathers, C., Cousens, S., 2014. Neonatal cause-ofdeath estimates for the early and late neonatal periods for 194 countries: 2000– 2013. Bull. World Health Organ. 93 (1), 19–28. Pakistan Multicentre Amoxicillin Short Course Therapy (MASCOT) Pneumonia Study Group, 2002. Clinical efficacy of 3 days versus 5 days of oral amoxicillin for treatment of childhood pneumonia: a multicentre double-blind trial. Lancet 360 (9336), 835–841. Peacock, G., Uyeki, T., Rasmussen, S., 2014. Ebola virus disease and children. JAMA Pediatr. 168 (12), 1087. Rudan, I., O’Brien, K., Nair, H., 2013. Epidemiology and etiology of childhood pneumonia in 2010: estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for 192 countries. J. Glob. Health 3 (1). Sabchareon, A., Wallace, D., Sirivichayakul, C., et al., 2012. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 380 (9853), 1559–1567. Soofi, S., Ahmed, S., Fox, M., MacLeod, W., Thea, D., Qazi, S., Bhutta, Z., 2012. Effectiveness of community case management of severe pneumonia with oral amoxicillin in children aged 2–59 months in Matiari district, rural Pakistan: a cluster-randomised controlled trial. Lancet 379 (9817), 729–737. Távora, A., Castro, A., Militão, M., Girão, J., Ribeiro, K., Távora, L., 2008. Risk factors for nosocomial infection in a Brazilian neonatal intensive care unit. Braz. J. Infect. Dis. 12 (1), 75–79. Wain, J., Hendriksen, R., Mikoleit, M., Keddy, K., Ochiai, R., 2015. Typhoid fever [online] Lancet 385, 1136–1145. Available at: http://www.thelancet.com/pdfs/ journals/lancet/PIIS0140-6736(13)62708-7.pdf (accessed 16.02.16.). World Health Organization, 2015. Global Technical Strategy for Malaria 2016–2030 [online]. World Health Organization. Available at: http://apps.who. int/iris/bitstream/10665/176712/1/9789241564991_eng.pdf?ua¼1 (accessed 18.01.16.). World Health Organization, 2016. Training Module on Malaria Elimination [online]. WHO. Available at: http://who.int/malaria/publications/atoz/9789241549424/en/ (accessed 10.02.16.). Whoint, 2015. WHO j Meningococcal Meningitis [online] Available at: http://www.who. int/immunization/diseases/meningitis/en/ (accessed 16.02.16.).

Relevant Websites http://www.cdc.gov/ – Centers for Disease Control and Prevention (last accessed 07.06.16.). http://who.int/en/ – World Health Organization (last accessed 07.06.16.). http://who.int/topics/infectious_diseases/en/ – World Health Organization, (n.d.). Infectious Diseases (last accessed 07.06.16.).

Children and Adolescents, Measuring the Quality of Life of Elise Davis, Dana Young, and Elizabeth Waters, School of Population Health and Global Health, University of Melbourne, Carlton, VIC, Australia Lisa Gold, School of Health and Social Development, Deakin University, Burwood, VIC, Australia Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Elise Davis, Elizabeth Waters, Amy Shelly, Lisa Gold, volume 1, pp. 641–647, Ó 2008, Elsevier Inc.

Introduction Consistent with the World Health Organization’s definition of health as “a state of complete physical, mental, and social wellbeing and not merely the absence of disease or infirmity” (World Health Organization, 1948), the concept of good health has moved from the absence of disease to a more positive concept that embraces subjective well-being and quality of life (QOL). In pediatrics and child health, as in other areas of health care, awareness is growing that traditional outcome measures such as survival or reduction of symptoms do not capture the whole range of ways in which a patient may be affected by illness or treatment. Patient-reported outcomes, such as QOL, are now considered to be key outcome measures for clinical trials and for evaluating health systems (Janssens et al., 2015b).

QOL in Pediatrics and Child Health

Quality of Life Due to differing opinions, theories, and professional perspectives, QOL is variously defined. Researchers often cite the World Health Organization’s definition of QOL as “the individual’s perception of their position in life, in the context of culture and value systems in which they live and in relation to their goals, expectations, standards and concerns” (WHOQOL Group, 1993). For children, QOL includes, but is not limited to, the child’s perception of their social, physical, and emotional well-being, and as such must be sensitive to the changes that occur throughout development (Waters et al., 2009). Although there are many different definitions, a core theme is that QOL refers to well-being, or feelings about life, across multiple domains of life.

Objective and Subjective QOL

There are now a range of potential interventions for children and adolescents with chronic illnesses and disabilities, as well as a spectrum of public health population-based interventions. Over the past 20 years, there have been increasing efforts to demonstrate empirically that interventions are effective in improving a child’s life. A range of outcome measures are used depending on the disability or illness; however, they are often focused on outcomes at the level of body structure and function. These outcomes on their own are inadequate for evaluating medical and health interventions that impact not only on symptoms but on a child’s whole life. For example, some interventions may result in discomfort, pain, inconvenience, or embarrassment for the child, as well as increased well-being, self-esteem, happiness, or improved sleeping. To examine the impact of an intervention on a child’s whole life, researchers and clinicians increasingly refer to a child’s QOL. The realization that measuring how children feel about their life is equally as important as measuring the reduction of symptoms, and improved survival to evaluate medical outcomes has increased the prominence in measuring QOL. QOL is now considered to be a key outcome variable to evaluate the effectiveness of interventions for children and adolescents. There are unique measurement challenges in assessing the QOL of children and adolescents. The language, content, and setting all need to be pertinent to the activities and stages of children’s experience and development. Furthermore, the use of parent-proxy reports and the discordance between self-reports and proxy reports are important and complex issues.

International Encyclopedia of Public Health, 2nd edition, Volume 1

Defining QOL and Health-Related QOL for Children and Adolescents

QOL can be measured by objective indicators and subjective indicators, although the latter are more common. Objective indicators of QOL can be observed by other people, such as family income, number of sick days from school, and number of medications a person takes. Subjective indicators, in theory, cannot be completed by another person as they refer to a person’s feelings such as their feelings about their health, school, or family. Objective indicators of QOL generally have a poor relationship with subjective indicators. A child may take several medications but may still perceive their health to be good. The remainder of this article, as with much of the empirical literature on QOL, concerns subjective QOL.

Is QOL the Same as Health-Related QOL? Researchers and clinicians tend to use the terms QOL and health-related quality of life (HRQOL) interchangeably. Although theoretically HRQOL includes domains that are impacted on by a medical condition or disability, it is difficult to discern differences between QOL instruments and HRQOL instruments, in terms of the domains. Given this, it is advisable that researchers/clinicians review both QOL and HRQOL instruments when choosing an instrument.

Measuring QOL Multidimensional versus Global Instruments QOL is quantifiable and there are two major types of instruments. Multidimensional instruments focus on domains of life and

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assess well-being, or feelings about each domain (e.g., health, school, family, friends). Global instruments ask the person to rate his or her whole life and include more general questions such as ‘Overall, how do you feel about your life as a whole?’ For children, the majority of instruments are multidimensional.

There are measurement challenges in measuring the QOL of children and adolescents. There is recognition that the language and content of children’s QOL instruments need to be appropriate to children’s experience and development, and therefore researchers cannot apply the principles and definitions of adult QOL to child and adolescent QOL. One issue that has generated much discussion concerns the reporter of QOL.

primary method of assessing QOL. In the child QOL literature, it is proposed that because of children’s cognitive immaturity, limited social experience, and continued dependency, parents may be more able to rate some aspects of their child’s QOL than the child themselves. Increasingly, in an attempt to capture both parent and child opinions, instrument developers are now producing parent-proxy and child/adolescent selfreport versions. A recent review demonstrated that over half of the patient-reported outcomes for children offered both self-report and parent-proxy versions (Janssens et al., 2015b). The majority of child self-report instruments start at about 8 years of age. This is because, according to Piaget (1929), children at age 7 are in their preoperational stage of development, which means that their understanding is limited by their inability to carry out a variety of logical operations. Researchers have commenced examining the degree of concordance between parent-proxy and child self-report scores. A recent systematic review (Jardine et al., 2014) of 21 studies found that the majority of included studies reported that a child’s perception of their QOL differed from that of their parents, with parents frequently reporting lower scores than their children, particularly for subjective domains (e.g., emotional and psychosocial). Another systematic review of generic QOL tools found that all included studies (i.e., studies of five instruments) reported poor reliability between selfreport and parent-proxy (Janssens et al., 2015a), leading the authors to suggest that parent instruments should include items and concepts that are important to parents and in ways that parents can respond to accurately. The differences between parent-proxy reported QOL and child self-reported QOL become particularly problematic when only parent-proxy data can be collected, due to a variety of reasons such as the child’s age, severity of illness, type of disease, cognitive ability, or communication ability. In these cases, where parent-proxy reported QOL is used to guide clinical decisions, it is important to understand how and why scores differ. There are several reasons why parents and children may report different levels of QOL. Parents and children may think about different events that have happened or interpret events differently. Additionally, parents and children may use different response styles (i.e., approach questions, items, response scales differently) or differ in their understanding and interpretation of the items. Our research suggests that parents and children may draw on different experiences when answering an item and had different response styles (Davis et al., 2007). This is clearly an area that requires more research and discussion. We suggest that both perspectives are valuable and important in their own right. The term proxy may be problematic when such discrepancy exists between child and parent reports, and it may be useful to consider them as two different reports. It would be useful to understand more about the predictors of parent scores, such as parental mental health and parental stress, particularly when only parent report can be collected and is used to guide decision making with the child.

Child Self-Report and Parent-Proxy

Child Development

In the adult QOL literature, QOL refers to an individual’s perceptions and self-report instruments are regarded as the

There are several developmental issues that researchers and clinicians need to be aware of when measuring a child’s QOL

Condition-Specific and Generic Instruments The QOL literature includes generic and condition-specific instruments, both of which have different purposes. Generic instruments are designed to be applicable to all population subgroups. They are useful for comparing outcomes between groups, such as the QOL of children with asthma compared to the QOL of children with diabetes. They may be less useful to evaluate the effectiveness of an intervention for children with a specific illness or disability because they do not include domains that are specific to the illness or disability. Hence, if a child with asthma completed a generic QOL instrument, the scores may not completely capture their QOL, as some important domains that impact their life (i.e., medication) would not have been assessed. Condition-specific instruments are designed to be applicable to one group (i.e., individuals with asthma) and are useful to detect changes following an intervention. As they include domains that are specific to an illness, it is more likely that if a change occurs as the result of an intervention, it will be detected. Increasingly, instrument developers are producing QOL instruments that have a generic core and additional condition-specific modules. This means that even for a specific condition, the core module can be compared to the general population. For example, KIDSCREEN is a generic crosscultural QOL instrument that assesses the subjective health and well-being of children and adolescents aged 8–18 years. The KIDSCREEN instrument comes in 10-, 27-, and 52-item versions and has child/adolescent self-report and parentproxy versions. The core QOL domains included in the KIDSCREEN-52 are physical well-being, psychological wellbeing, moods and emotions, self-perception, autonomy, parent relation and home life, financial resources, peers and social support, and school environment and bullying (Ravens Sieberer et al., 2014). KIDSCREEN also has condition-specific instruments referred to as DISABKIDS Disease Modules that include arthritis, asthma, atopic dermatitis, cerebral palsy, cystic fibrosis, diabetes, and epilepsy (Baars et al., 2005).

Challenges in Measuring QOL/HRQOL for Children and Adolescents

Children and Adolescents, Measuring the Quality of Life of using self-report methods. The child needs to understand the question, understand the response scale, and be able to formulate a response. There is some variation in the type of response scales that are used, although most use a Likert scale (Janssens et al., 2015b). Other scales include happy–sad faces scale and visual analogue scale (VAS). Although a happy–sad faces scale appears to be a suitable option for young children, the scale is based on the assumption that pointing to faces to indicate relative levels of satisfaction or happiness is a simpler task than verbal responding; however, further research needs to be undertaken to test this assumption. Furthermore, often questions require the child to think about the previous week or month. The child’s ability to respond to a time frame will be influenced by their developmental status. Often, in order to address these developmental issues, instrument developers produce separate instruments for children based on their age. A systematic review (Janssens et al., 2015b) identified four generic instruments which have different versions for different age groups. For example; the Auto Questionnaire Enfant Image Child Pictured Self-Report (five versions) (Manificat, 1998, 1999; Manificat and Dazord, 2002), Functional Status II Revised (four versions) (Stein and Jessop, 1990), Pediatric Quality of Life Inventory (six versions) (Varni et al., 1998, 2011; Chan et al., 2005), and TNO-AZL (four versions) (Fekkes et al., 2000; Vogels et al., 1998; Bruil et al., 2001).

Domains of QOL In designing a pediatric QOL instrument, one question that requires consideration is which domains constitute QOL for children. Although, in the past, domains of QOL were decided a priori by researchers and clinicians, there is increasing recognition that families and children need to be consulted in this process. Qualitative research is the most suitable design for researching the underpinning elements of QOL for children. For example, Ronen et al. (1999) identified domains of QOL for children with epilepsy by conducting focus groups with both parents and children to discuss how epilepsy impacted on their lives.

QOL Instruments for Children and Adolescents Condition-Specific and Generic Instruments Many pediatric QOL instruments have been developed and several reviews have been published (see section titled Further Reading). A 2015 review identified 35 generic instruments to measure QOL in children and adolescents (Janssens et al., 2015a,b). Janssens et al.’s systematic review did not include condition-specific instruments but a review conducted in 2008 identified 64 condition-specific instruments exist for the pediatric population, covering a range of illnesses such as asthma, cancer, and epilepsy (Solans et al., 2008).

Domains of QOL Common domains of QOL included in pediatric QOL instruments are emotional well-being, social interactions, medical treatments, cognition, activities, school, family, independence/autonomy, pain, behavior, future, leisure, and body

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image. Common domains for adolescents include emotional well-being, social well-being, self-esteem, physical health, relationships, school, environment, participation, and leisure. Some of the domains may be different in condition-specific instruments, as the factors that impact on QOL may vary by condition. For example, domains of QOL that children with cerebral palsy and their parents believe are important include social well-being and acceptance, functioning, participation and physical health, emotional well-being, access to services, pain and impact of disability, and family health.

QOL Items Items measuring QOL are often framed in terms of problems or difficulties, intensity of feelings, frequency of feelings, or comparisons between current state and ideal self or other children. Instruments that examine problems include items such as ‘How much of a problem have you had with . ?’ ‘Have you had any difficulty with . ?’ and ‘How much were you bothered by . ?’ Instruments that assess intensity of feelings examine feelings of satisfaction and being upset such as ‘How do you feel about . ?’ Instruments that examine frequency of feelings include items such as ‘Have you felt . ?’ (never–always). Instruments that examine comparisons between actual self and ideal self or other children include items such as ‘How much are you like . ?’ and ‘How much do you want to be like . ?’

Scoring and Interpretation of QOL Instruments Each QOL instrument has specific scoring instructions; however, most QOL instruments provide domain scores and/ or a total QOL score. To calculate domain scores, items within each domain are totaled or averaged. A total QOL score is the (weighted) average of all the domain scores. Scores must be calculated separately for parent-proxy reports and child/ adolescent self-reports. It is recognized, however, that if parent and child scores are significantly different, it may be difficult to select an appropriate course of action. In a clinical context, if parent and child scores are very different, it may be useful to interview the parent and child together to understand why the discrepancy exists. In a research context, a follow-up qualitative study with a subsample of parents and children may be useful.

Example of a Generic Instrument: KIDSCREEN KIDSCREEN is a generic HRQOL instrument for children and adolescents. KIDSCREEN was developed across 13 European countries to ensure cross-cultural applicability, with participants of the project including Austria, Czech Republic, France, Germany, Greece, Hungary, Ireland, Poland, Spain, Sweden, Switzerland, the Netherlands, and the United Kingdom (Ravens Sieberer et al., 2014). KIDSCREEN consists of 10 dimensions: physical well-being, psychological well-being, mood and emotions, self-perceptions, autonomy, parent relations and home life, social support and peers, school environment, bullying, and financial resources (Ravens-Sieberer et al., 2005). There are three versions of KIDSCREEN: the original

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long version consisting of 52 items, a 27-item version covering five dimensions, and a 10-item index version, with all versions having a self-report (8–18 years) and parent-proxy report version available (Ravens Sieberer et al., 2014). KIDSCREEN can be administered in hospitals, medical establishments, and schools by professionals in the fields of public health, epidemiology, and medicine.

Expressing cost-effectiveness in natural units of clinical outcome measures makes it hard to compare the cost-effectiveness of different interventions that are competing for the same limited health-care resources. Even when cost-effectiveness is expressed using QOL instruments, the outcomes are not comparable if different QOL instruments have been used to evaluate different interventions.

Example of a Condition-Specific Instrument: Cerebral Palsy QOL for Children

Quality-Adjusted Life Years

The cerebral palsy QOL questionnaire for children and adolescents (CP QOL – Child, CP QOL – Teen) is a condition-specific QOL instrument for children with cerebral palsy aged 4–18 years. The CP QOL – Child and CP QOL – Teen was developed by an international team of researchers. The CP QOL – Child and Teen both include domains measuring social well-being, feelings about functioning, participation and physical health, access to services, and family health and well-being (refer to Figure 1 for sample items). There are two versions of each instrument: a child/adolescent self-report (9–12 years, 13–18 years) and a parent report (4–12 years, 13–18 years) (Waters et al., 2007; Davis et al., 2013).

Economic Evaluation Resources (both workforce and health budgets) are limited and treatment for children with chronic illnesses or disabilities can be expensive. Researchers, clinicians, and policy makers increasingly need to demonstrate that the effects of a treatment warrant the costs. Economic evaluation builds on the results of analyses of clinical effectiveness to explicitly compare the effectiveness of an intervention (over and above the best alternative care) to the additional costs of that intervention. Economic evaluation produces estimates of the cost-effectiveness of interventions in a variety of formats, most frequently in the form of ‘additional cost per additional unit of effect’ using clinical outcome measures in their natural measurement units (e.g., ‘additional cost per unit increase in pulmonary function’).

Figure 1

The quality-adjusted life year (QALY) is a composite health outcome measure that combines a measure of QOL with a measure of survival. QALYs provide a common currency for measuring the extent of health gain that results from healthcare interventions and, when combined with the costs associated with the interventions, can be used to assess their relative worth from an economic perspective. QALYs therefore offer the potential for all evaluations of child health interventions to be comparable in terms of the improvement to generic child health and, where economic evaluation has been included, in terms of the relative value-for-money of the intervention. However, to combine QOL and survival, the QOL instrument used to construct QALYs must have particular methodological properties. The QOL instrument must be able to express any health state as a single numerical utility score, where a utility score of 0 equates to being dead (the absence of health status) and a score of 1 equates to perfect health. Negative scores can be used to represent health states considered worse than being dead. Most of the generic QOL instruments of child and adolescent health, such as KIDSCREEN and PedsQL, do not hold these properties. There are a small number of generic QOL instruments that can be used to construct QALYs: some are adult instruments that have been adapted for children and/or adolescents (e.g., EQ-5D-Y (Wille et al., 2010) and AQoL-6D (Moodie et al., 2010)), others have been derived from a child or adolescent population (e.g., Child Health Utility 9D (CHU9D) (Stevens, 2012) and Health Utilities Index (HUI) (Feeny et al., 1998)). As detailed above, there are additional domains that are particularly relevant to child

Example of the cerebral palsy quality-of-life questionnaire for children (CP QOL – Child), child self-report version.

Children and Adolescents, Measuring the Quality of Life of health (including autonomy, body image, cognitive skills, and family relationships) that are not captured by these generic QOL instruments. There are a number of ways to generate the health utility scores required to express the item responses from the QOL instrument as a 0-1 preference-based scale. Three broad strategies include expert judgment, indices from relevant literature, and direct measurement of the preferences of an appropriate population (Dolan, 2000). The third strategy is the most common, given that experts may focus on different attributes than patients, and valuations in one study may be inappropriate for another study. There are several ways to obtain direct measures of preferences, including VAS, standard gamble (SG), and the time trade-off (TTO). The VAS requires respondents to directly rate their health state on a scale from 0 to 1. The SG asks the respondent to choose between the certainty of an intermediate health state and the uncertainty of a treatment with two possible outcomes, one of which is better than the certain outcome and one of which is worse. The TTO asks the respondent to choose between a defined length of life in an intermediate health state and a shorter length of life in full health. Use of these instruments in pediatrics and child health has been vigorously debated. As children do not have the cognitive ability to comprehend and complete valuation or preferences, parent-proxy reports are required, which may be influenced by the parent’s beliefs (Griebsch et al., 2005). Health utility scores are usually derived from adults; scores from adolescents are available for AQoL-6D and CHU9D and the use of child and adolescent scores is an area of ongoing research (Ratcliffe et al., 2012).

Evaluating and Selecting QOL Instruments There are an increasing number of QOL instruments for children and adolescents and it is becoming increasingly difficult for researchers and clinicians to choose the best instrument (Waters et al., 2009). A good QOL instrument is l l l

l l l l

designed to measure QOL, assess feelings about life, be appropriate for children’s developmental status (i.e., number of items, wording of items, response scales, age groupings), structured using domains of QOL that are based on consultations with children/adolescents and parents, available in parent-proxy and child/adolescent self-report format, reliable and valid (for the particular country and sample), and sensitive to clinically significant changes in condition.

(Further information is provided in the next section about the desired psychometric properties.)

Reliability An instrument is judged to be reliable when it consistently produces the same results when applied to the same subjects, when there is no evidence of underlying change in the health state being assessed. Reliability of an instrument is most

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frequently evaluated by internal consistency and test–retest reliability. For internal consistency, Cronbach’s alpha coefficient (a) measures the average correlation among the items in the scale. This measure has a range of 0–1 with higher values indicating a closer correlation, which suggests that the set of questions is assessing a single domain. A low alpha coefficient (e.g., 1:256), or a rise in antibody titer in a convalescent sample. Immunofluorescent and enzyme immunoassays are commercially available, but have not been rigorously evaluated.

Treatment Chlamydiae are intracellular and hence insensitive to aminoglycosides and other antibiotics that do not penetrate cells efficiently. Tetracyclines and macrolides are the mainstay of treatment. Treatment is often started before a microbiological diagnosis can be established, so additional broad-spectrum antibiotics may be needed to cover gonococcal and, in the case of PID, anaerobic infections. Treatment of patients’ sexual partners is essential to prevent reinfection. Uncomplicated C. trachomatis infections are treated with a single dose of azithromycin 1 g, or with doxycycline 100 mg twice daily for 7 days. Chlamydial PID is treated with a 14-day-course of doxycycline 100 mg twice daily. Clinically significant resistance to these antibiotics has not been reported. Doxycycline is contraindicated in pregnancy. Azithromycin 1 g as a single dose, and amoxicillin 500 mg three times daily for 7 days have both been shown to be safe and effective in pregnant women. Ofloxacin is active against C. trachomatis at a dose of 300 mg twice daily for 7 days, but is not widely used. Ophthalmia neonatorum and neonatal pneumonia due to C. trachomatis should be treated with erythromycin syrup by mouth, 50 mg kg1 day divided into four doses, for 14 days.

Lymphogranuloma Venereum Lymphogranuloma venereum (LGV) is a systemic, sexually transmitted disease caused by serovars L1, L2, L2a, and L3 of C. trachomatis. These are more invasive than the other serovars and cause disease primarily in lymphatic tissue. Although a small papule or necrotic genital lesion may be the first sign of infection, with the rectosigmoid colon also a primary site, the chlamydiae are soon carried to regional lymph nodes. These enlarge rapidly and inflammation of the capsule causes them to mat together. Multiple minute abscesses form in the parenchyma and, in the absence of treatment, they may coalesce and form sinus tracts, which rupture through the overlying skin. Scar tissue may obstruct lymphatic flow, causing lymphedema and elephantiasis of the genitalia; and strictures, ulcers, and fistulas may develop.

Clinical Features The clinical course of LGV can be divided into three stages. The primary stage at the site of inoculation; the secondary stage in the regional lymph nodes, and/or the anorectum; and the

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tertiary stage of late sequelae affecting the genitalia and/or rectum. Primary stage – After an incubation period of 3–30 days, a small, painless papule, which may ulcerate, occurs at the site of inoculation. The primary lesion is self-limiting and may pass unnoticed by the patient. Among patients with LGV, presenting with buboes in Thailand, more than half had not been aware of an ulcer. The secondary stage occurs some weeks after the primary lesion. It may involve the inguinal lymph nodes, or the anus and rectum. The inguinal form is more common in men than women, since the lymphatic drainage of the upper vagina and cervix is to the retroperitoneal rather than the inguinal lymph nodes. LGV proctitis occurs in those who practice receptive anal intercourse, probably due to direct inoculation. The cardinal feature of the inguinal form of LGV is painful, usually unilateral, inguinal, and/or femoral lymphadenopathy (bubo). Enlarged lymph nodes are usually firm and often accompanied by fever, chills, arthralgia, and headache. Biopsy reveals small discrete areas of necrosis surrounded by proliferating epithelioid and endothelial cells, which may enlarge to form stellate abscesses that may coalesce and breakdown to form discharging sinuses. In women, signs include a hypertrophic suppurative cervicitis, backache, and adnexal tenderness. Clinical features of anorectal disease include a purulent anal discharge, pain and bleeding due to an acute haemorrhagic proctitis or proctocolitis, often with fever, chills, and weight loss. Proctoscopy reveals a granular or ulcerative proctitis. CT or MRI scans may show pronounced thickening of the rectal wall, with enlargement of iliac lymph nodes. Enlarged inguinal nodes may also be palpable. Cervical adenopathy due to LGV has been reported after oral sex. A follicular conjunctivitis has also been described following direct inoculation of the eye, which may be accompanied by preauricular lymphadenopathy. Other rare manifestations of the secondary stage include acute meningoencephalitis, synovitis, and cardiac involvement. The tertiary stage appears after a latent period of several years, but is rare. Chronic untreated LGV leads to fibrosis, which may cause lymphatic obstruction and elephantiasis of the genitalia in either sex or rectal strictures and fistulae. Rarely, it can give rise to the syndrome of esthiomene (Greek: ‘eating away’), with widespread destruction of the external genitalia.

Epidemiology Due to its nonspecific clinical features and the difficulty in confirming the diagnosis, the epidemiology of LGV is not welldefined. It is found worldwide, but its major incidence is thought to be in endemic foci in sub-Saharan Africa, Southeast Asia, South America, and the Caribbean. In North America and Europe, there has been an increasing incidence of proctocolitis due to LGV among homosexual men, often associated with HIV infection (de Vrieze and de Vries, 2014).

Diagnosis The differential diagnosis of LGV includes other causes of genital ulceration such as genital herpes, syphilis, chancroid, and donovanosis; and other causes of lymphadenopathy with

fever, including extrapulmonary tuberculosis, cat-scratch disease, plague, filariasis, lymphoma, and other malignant diseases. LGV proctocolitis needs to be distinguished from bacillary and amebic dysentery, Crohn’s disease, and ulcerative colitis. Lymphadenitis of the deep iliac nodes may mimic appendicitis or PID. Tuberculosis and certain parasitic and fungal infections of the genital tract cause lymphedema and elephantiasis of the genitalia that may cause confusion. NAATs are widely used to diagnose anorectal LGV in the developed world, but commercially available NAATs cannot distinguish between LGV and other strains of C. trachomatis. Serological tests may also be useful, since high antibody titers are usually found in LGV.

Treatment There has been no adequately powered study comparing antibiotic regimens for the treatment of LGV. Recommended treatment is doxycycline 100 mg twice daily, or erythromycin 500 mg four times daily, for 21 days. Azithromycin has been used successfully in some cases, although a 1 g single dose is unlikely to be sufficient. There is some evidence that azithromycin is less effective than doxycycline in the treatment of anorectal chlamydial infection, including LGV. Large collections of pus should be aspirated, using a lateral approach through normal skin. Fever and bubo pain rapidly subside after antibiotic treatment is started, but buboes may take several weeks to resolve. Suppuration and rupture of buboes with sinus formation is usually prevented by antibiotic treatment.

Trachoma Magnitude A public health problem in 51 countries (Figure 2), trachoma is the most common infectious cause of blindness, accounting for about 3% (1.2 million) of the estimated global total of 39 million blind individuals. A further 7.3 million have trachomatous trichiasis and are at imminent risk of being blinded from trachoma, while some 21 million have active trachoma and face the prospect of possible blindness in the next few decades if successful interventions are not provided in time. The estimated total worldwide productivity loss due to trachoma is US$2.9 billion each year (Frick and Colchero, 2003; WHO, 2012a, 2013; Pascolini and Mariotti, 2012). Efforts to more fully delineate the global burden and distribution of trachoma are underway (Solomon and Kurylo, 2014).

Clinical Features and Pathogenesis Most conjunctival infections with C. trachomatis are subclinical. In patients seen during an acute infection, a mild mucopurulent conjunctivitis may be noted. Such signs are nonspecific, however, and a single infection generally resolves spontaneously without obvious sequelae. With repeated infection, signs of active trachoma may develop. The key feature of active trachoma is the appearance of lymphoid follicles immediately subjacent to the conjunctival epithelium. In severe inflammation, there may be accompanying papillary hypertrophy and inflammatory thickening of

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Figure 2 Global distribution of active trachoma. Reproduced from World Health Organization, 2014. WHO Alliance for the Global Elimination of Blinding Trachoma by the year 2020. Progress report on elimination of trachoma, 2013. Wkly. Epidemiol. Rec. 89, 421–428, with permission from the World Health Organization.

the conjunctiva. Infiltration of the edge of the cornea by fibrovascular tissue (pannus) may be noted. Resolution of the inflammatory changes of active trachoma is accompanied by deposition of collagen in the form of scar. Over many years, scar laid down within the conjunctiva by multiple cycles of inflammation and resolution may become visible to the naked eye. Resolution of follicles at the sclerocorneal junction can leave craterlike depressions known as Herbert’s pits; such pits are pathognomonic of previous episodes of active trachoma. In some individuals, contraction of scar tissue in the conjunctiva and subconjunctival tissues ultimately leads to distortion of the architecture of the lid, with the development of trichiasis (in which one or more eyelashes are pulled inward so that they touch the eye) with or without entropion (in which there is inversion of a segment of the lid margin). In either case, abrasion of the cornea by in-turned lashes leads directly to corneal scarring and opacification, as well as providing a route of entry into corneal tissues for pathogenic bacteria and fungi, which generate their own burden of corneal scar. Destruction of mucous and serous glands by scarring elsewhere in the eyelid reduces the volume and alters the composition of the tear film, which also potentiates secondary infection. Patients with trichiasis or entropion complain of a foreign body sensation, eye pain, blepharospasm,

photophobia, excessive tearing (due to obstruction of the nasolacrimal duct or malposition of the puncta lacrimalia) or impaired vision, which may be due to a combination of blepharospasm and corneal edema. These are intensely irritating conditions: sufferers often use home-made forceps to pluck out their eyelashes or attempt to keep the lids elevated with strips of cloth tied around the head. Corneal scar overlying the visual axis permanently impairs vision and results eventually in blindness.

Diagnosis Diagnosis of trachoma is based on clinical criteria. Using binocular magnifying loupes in good light, the examiner should first inspect the eyes from the side to determine the presence or absence of trichiasis and entropion. The corneas should then be inspected for opacities. If trichiasis, entropion, or corneal opacities are present, visual acuity should be recorded for each eye. The eyelids should then be gently everted to expose the tarsal conjunctiva, and a decision made as to whether there are any signs of active trachoma or trachomatous conjunctival scarring in each eye. To facilitate standardization, a number of different scoring systems have been developed. The one most commonly used is the World Health Organization’s simplified trachoma

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(a)

(b)

(c)

(d)

(e)

(f)

Figure 3 Appearance of trachoma. (a) Normal everted upper tarsal conjunctiva shown for the purposes of comparison; it is pink, smooth, thin, and transparent. Over the whole area of the tarsal conjunctiva, there are normally large deep-lying blood vessels that run vertically. The dotted line shows the area to be examined. (b) Trachomatous inflammation–follicular (TF). (c) Trachomatous inflammation–follicular and intense (TF þ TI). (d) Trachomatous scarring (TS). (e) Trachomatous trichiasis (TT). (f) Corneal opacity (CO). Reproduced with permission from the World Health Organization.

grading scale, which requires the examiner to assess for the presence or absence of each of five signs (Figure 3): l

l

l l

l

Trachomatous inflammation–follicular (TF): The presence of five or more follicles at least 0.5 mm in diameter, in the central part of the upper tarsal conjunctiva. Trachomatous inflammation–intense (TI): Pronounced inflammatory thickening of the upper tarsal conjunctiva obscuring more than half the normal deep tarsal vessels. Trachomatous conjunctival scarring (TS): The presence of easily visible scars in the tarsal conjunctiva. Trachomatous trichiasis (TT): At least one eyelash rubs on the eyeball, or evidence of recent removal of in-turned eyelashes. Corneal opacity (CO): Easily visible corneal opacity over the pupil, so dense that at least part of the pupil margin is blurred when viewed through the opacity.

In this scheme, active trachoma is defined as the presence of TF and/or TI in either or both eyes. A prevalence of TF of 5% or more in 1- to 9-year-old children and/or a prevalence of TT

unknown to the health system of 1 or more per 1000 total population (WHO, 2010) are now taken to indicate that trachoma presents a public health problem in the population.

Epidemiology Patterns of Distribution

Blinding trachoma is found principally in Africa, with lesser foci in Asia, the Middle East, South America, and the Aboriginal communities of Australia. Within endemic areas, the distribution of disease is heterogeneous. Some communities are badly affected, while others with seemingly similar risk factors (see below) are not. In affected communities, clustering of active disease by subvillage, compound, and bedroom has been noted.

Risk Factors for Active Trachoma Poverty and Crowding

Trachoma is found almost exclusively in poor countries, with occasional pockets of disease in disadvantaged populations

Chlamydia (Trachoma and Sexually Transmitted Infections) of more industrialized nations. It is a disease associated with poverty and sociocultural, economic, or geographic upheaval. In all of these circumstances, overcrowding is typical. There is an established association between risk of active trachoma and the number of people per sleeping room. Usually, all infected members of a household harbor the same C. trachomatis serotype and strain variant. Sharing a bedroom with an active case doubles one’s risk of having active disease. These findings probably reflect an increased risk of exposure to infected secretions, due to a scarcity of living and sleeping space, though other characteristics of impoverished populations (such as poor nutrition or inadequate access to water and sanitation; see below) could be responsible.

Age and Exposure to Children

The prevalence of both active trachoma and laboratory evidence of ocular C. trachomatis infection generally decline with age after a peak in early childhood. In a hyperendemic area, for example, the prevalence of active disease might be 60% or more in preschool children, falling to 10% in young adults, and 2% in those over the age of 50. Studies using quantitative PCR suggest that the bulk of the C. trachomatis reservoir in a community is found in children below the age of 10 years (Solomon et al., 2003).

Gender

In most cross-sectional surveys, females are more likely than males to have trachoma. Usually, the prevalence difference between genders is small or minimal in childhood and increases with age.

Education

Education of the household head associates negatively with risk of active trachoma in household children, while parental illiteracy has shown a positive association. These associations may be confounded by exposures related to poverty or hygiene.

Water and Face Washing

Trachoma is typically found in dry dusty regions where water is scarce. In many settings, increased distance of a household to the nearest water correlates with increased risk of trachoma. It is postulated that decreasing the distance that people must travel to collect water might increase the volume of water collected and so increase water availability in the household, which might in turn increase the amount of water allocated to personal hygiene activities. In practice, these associations are not invariably true. Dirty faces are associated with the presence of active trachoma, however. Face washing might impact trachoma by decreasing the accessibility of infected secretions to flies and fingers, which are putative carriers of infectious inocula; by washing fly-attracting substances off both infected and yet-to-be-infected faces; or by removing Chlamydia-free secretions that could provide a portal of entry for the organism into a new eye. Similarly, hand washing might reduce transmission of trachoma if fingers provide a mechanism for carriage of Chlamydiae from infected to uninfected eyes. Unfortunately, no rigorously controlled intervention study to evaluate the effect of an improved water supply on trachoma has been performed; data on the impact of facial cleanliness education programs will be discussed below.

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Flies and Latrines

Synanthropic flies (flies that live in close proximity to humans) have for centuries been suspected to be vectors of trachoma. In trachoma-endemic villages of the Gambia, the bazaar fly (Musca sorbens) has been shown to make 90% of fly–eye contacts, with the house fly (Musca domestica) accounting for the remainder. These fly species are able to carry viable C. trachomatis, both externally and in their gut, and to transmit active trachoma from the eyes of experimentally infected to disease-free guinea pigs. Household fly density is significantly associated with active trachoma and with ocular C. trachomatis infection; the number of flies landing on an individual’s face during a 5-s facial inspection is an even stronger personal risk factor. Data from trials of fly control as an intervention will be presented in the section Management.

Cattle

Active disease is more common in children whose families keep cows. Though there is some evidence that human feces is the optimal (and preferred) larval medium for M. sorbens, and that the flies caught from children’s eyes are from the same population as those found emerging from human feces, female M. sorbens do oviposit on the manure of cows and other domestic animals. It has therefore been suggested that positioning cattle pens away from living quarters might help to control trachoma. No proof of this hypothesis exists, and a recommendation to families that they increase the distance between themselves and their most valuable livestock is generally unpopular.

Nutrition

In Mali, night blindness and Bitot spots – the clinical features of vitamin A deficiency – seem to be associated with active trachoma, even after controlling for socioeconomic status. However, no association has yet been found between overall nutritional status (as measured by mid-upper arm circumference) and active trachoma.

Extraocular reservoirs of C. trachomatis

Ocular C. trachomatis strains can be isolated from nasopharyngeal and rectal swabs taken from a proportion of children living in endemic villages. No animal reservoirs of human C. trachomatis strains have been identified.

Mechanisms of transmission

The actual mechanisms of transmission of ocular C. trachomatis infection are unproven. Flies, fingers, and fomites are probably responsible for carriage of EBs from infected to uninfected eyes. Droplet transmission is probably also possible.

Risk Factors for Cicatricial Trachoma Age

The prevalences of TS, TT, and CO all increase with age.

Gender

Conjunctival scarring occurs more commonly in women, as does trichiasis. In some areas, women may have up to a fourfold increased risk of trichiasis and of visual impairment as a result of trachoma compared to men.

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Cumulative C. trachomatis–induced conjunctival inflammation

The excess risk of scarring and trichiasis borne by women is usually thought to result from increased exposure to ocular C. trachomatis infection, related to the traditional role of women as primary caretakers of young children. Obtaining accurate information on chronic exposures (such as lifetime contact with young children) is inherently difficult, however. The few longitudinal studies that have been published seem to support a link between inflammatory trachoma and later development of scarring. In Tanzania, constant, severe trachoma (defined as the presence of severe inflammatory trachoma (TI) on at least three of four examinations over the course of the first year of follow-up) was associated with the development of conjunctival scarring over a 7-year interval (West et al., 2001). Similarly, children with constant infection (defined as PCR positivity on at least three of five occasions over the first 18 months of follow-up) was associated with the presence of conjunctival scar after 5 years (Wolle et al., 2009).

Cumulative Exposure to Other Conjunctival Irritants

Sleeping in a room with a cooking fire and the use of kohl (an eye cosmetic made from crushed lead sulfide ore and applied to the inside of the eyelid) have both been identified as possible risk factors for trichiasis. Whether eye powder or smoke induces chronic conjunctival inflammation and thereby contributes to scarring, or whether – in the case of kohl – sharing of the applicator is a transmission mechanism, is not known.

Immunological Factors

Conjunctival scarring and trichiasis tend to cluster in families, though whether this is due to common environmental exposures or shared genes has been difficult to determine. Various polymorphisms in gene loci important in the human immunological response to chlamydial infection have been associated with a propensity to scarring in case–control studies.

Management An eye blind from trachoma is a permanently blind eye. Corneal transplantation has poor results in the dry, scarred conjunctival sacs of blind trachoma patients, and, in any event, such technology is generally beyond the reach of the impoverished populations in which blindness from trachoma occurs. The management strategy therefore focuses on prevention: provision of corrective eyelid surgery to those with trichiasis, clearance of C. trachomatis infections with antibiotics, and reduction in transmission of infection through promotion of facial cleanliness and improvements in the environment. These interventions are encapsulated by the acronym SAFE (surgery, antibiotics, facial cleanliness, and environmental improvement). Surgery takes first priority, since people with trichiasis are at most immediate risk of blindness. However, SAFE represents a package of interventions that should be delivered at community level to whole populations that are at risk: trachoma blindness will not be prevented simply by treating symptomatic individuals presenting to health-care facilities. Using the SAFE strategy, the WHO and its partners aim to eliminate trachoma as a public health problem by the year 2020. The campaign is guided, encouraged, and monitored by the Alliance for the Global Elimination of Trachoma by

2020 (GET2020), a network of multilateral agencies, national governments, nongovernmental development organizations, research institutions, and other interested parties, with a secretariat based at WHO. GET2020 has defined its trachoma elimination goal as a reduction in the prevalence of TT unknown to the health system to less than 1 per 1000 total population, and a reduction in the prevalence of TF in 1- to 9-year-old children to less than 5%. Elimination of trachoma as a public health problem is one of the targets within the 2012 WHO roadmap for overcoming the global impact of neglected tropical diseases.

Surgery

Many different techniques are described for the correction of trachomatous trichiasis and entropion. Two randomized surgical trials conducted in the 1990s (Reacher et al., 1990, 1992) suggested that tarsal rotation produces the best results. In this procedure, the tarsal plate is divided through an incision made a few millimeters from the lid margin, and the distal fragment is rotated outward and sutured in the everted position under moderate tension. Tarsal rotation can be safely, effectively, and rapidly performed by trained paramedical staff in relatively basic surroundings, such as village dispensaries. This is fortunate, since in sub-Saharan Africa, where most of the world’s trichiasis sufferers live, there are on average only two to three ophthalmologists for every one million people (Resnikoff et al., 2012). Uptake of trichiasis surgery is highest when surgery is offered at no cost to the recipient, in her own community, by surgeons who are trusted by the population they serve. Trichiasis surgery is one of the most cost-effective interventions to control visual loss (Baltussen and Smith, 2012). Randomized controlled trials suggest that one oral dose of azithromycin in the perioperative period reduces the risk of postsurgical trichiasis recurrence in Ethiopia (West et al., 2006) and in severe trichiasis in Nepal (Zhang et al., 2006), but not for trichiasis of any severity in The Gambia (Burton et al., 2005), where community prevalence of active trachoma and ocular C. trachomatis infection are very low. In cases where only a few eyelashes touch the eye, provision of quality epilation forceps with training in their use probably has similar visual acuity outcomes to trichiasis surgery (Rajak et al., 2011). Due to the large backlog of patients requiring lid surgery and the relative scarcity of trained trichiasis surgeons, it may be advisable to advocate epilation rather than surgery where surgery is inaccessible, declined, or delayed.

Antibiotics

Antibiotics are used against trachoma with two overlapping goals. They are given to an individual with signs of active disease in an effort to cure the presumed underlying C. trachomatis infection, lessen inflammation, and decrease the likelihood of transmission of infection from the patient to his or her contacts. Recognizing that many infected individuals do not have clinical signs, antibiotics may also be given to entire populations to try to reduce the community load of C. trachomatis and thereby produce sustained changes in the intensity of transmission in a community (Schachter et al., 1999). The latter mass treatment approach is the one recommended by the WHO wherever the prevalence of TF in 1- to 9-year-old children is 10% or more. WHO recommends that

Chlamydia (Trachoma and Sexually Transmitted Infections) programs aim for 100% coverage, with a minimum acceptable coverage of 80%. A trial investigating whether additional effort to achieve higher coverage within the 80–100% band was worthwhile did not show evidence for greater impact of greater effort (West et al., 2013). A meta-analysis of available data on antibiotics for trachoma concluded that mass treatment reduces the population prevalence of active trachoma and ocular C. trachomatis infection (Evans and Solomon, 2011). Until the 1990s, the standard antibiotic treatment employed against trachoma was 1% tetracycline eye ointment, applied to both eyes twice a day for 6 weeks or (following the intermittent schedule) twice a day for 5 consecutive days a month, for at least 6 months a year. Such treatment schedules have low adherence, particularly since most individuals to whom they are recommended are asymptomatic and the ointment stings on application. Bailey et al. (1993) provided a practical alternative, by demonstrating that a single oral dose of azithromycin was at least as effective as these prolonged courses of tetracycline ointment. The discovery prompted azithromycin’s manufacturer to establish a donation program through which this expensive antibiotic could be provided free of charge to trachoma-endemic populations. Work using quantitative PCR has demonstrated that children under 10 have the highest ocular C. trachomatis loads, with particularly heavy infections being found in children below 12 months of age (Solomon et al., 2003). In many settings, because of a lack of data demonstrating its safety in this age group, oral azithromycin is felt to be contraindicated for children less than 6 months of age. Solutions to ensure that this group is adequately treated must be found. There are few empirical data to help determine the optimal frequency of antibiotic treatment in settings of different endemicity, the best method for monitoring the effect of treatment, and criteria for discontinuing treatment. In the absence of such data, WHO currently recommends that once a decision has been taken to initiate mass treatment, antibiotics be offered to a community on an annual basis for at least 3 years before reassessment to determine whether to stop or continue. There is some evidence to suggest that where baseline infection prevalence is moderate or low and azithromycin coverage is high, infection may be virtually cleared after a single treatment round (Solomon et al., 2004, 2008), so such a strategy could result in unnecessary distribution of antibiotics. On the other hand, such dramatic results are not seen everywhere, and a recent trial suggests that mass azithromycin treatment may as much as halve all-cause mortality in 1- to 9-year-olds (Porco et al., 2009). Research to identify optimal algorithms for assessing treatment impact and deciding whether to continue mass distribution of antibiotics is underway. No evidence has yet been found of the emergence of either azithromycin- or tetracycline-resistant ocular C. trachomatis strains. There is some evidence that mass azithromycin distribution may lead to the emergence of macrolide resistance in nasopharyngeal Streptococcus pneumoniae, but this may depend on the extent of background antibiotic use in the community and the number of doses or frequency of dosing with azithromycin.

Facial Cleanliness

Children with clean faces tend not to have trachoma. Stimulating changes in behavior that will lead to people having clean faces

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where they previously did not is extremely difficult. West et al. (1995) conducted a community-randomized trial comparing mass topical antibiotics to mass topical antibiotics plus a month-long package of highly intensive community-based interventions to encourage face washing. Children in facewashing villages were more likely to have clean faces at followup, but there was no impact on the prevalence of TF. The effect of less-intensive behavior change campaigns is unproven.

Environmental Improvement

In the context of trachoma control, environmental improvement is generally taken to mean (1) improvement in water supply and (2) fly control. The rationale for each of these has been presented in the section Epidemiology. There are no data from randomized controlled trials to show whether or not improving water supplies to trachoma-endemic communities can have an impact on trachoma. However, such interventions are popular with recipient communities, and have health and economic impacts that go far beyond their importance for trachoma control. Unfortunately, improving rural water supply is beyond the resources (and often beyond the influence) of trachoma control programs or Ministries of Health in most countries. Collaborations must be forged that will facilitate provision of water to these communities. Two community-randomized trials (Emerson et al., 1999, 2004) in The Gambia have shown a reduction in the number of new prevalent cases of active trachoma in villages in which flies were controlled with insecticide. Because M. sorbens preferentially breeds on human feces but is not found emerging from the drop holes of pit latrines, and because a number of surveys have associated having a household latrine with decreased risk of disease, it seems intuitive to suggest that improved availability and use of latrines could reduce muscid fly density and the prevalence of trachoma. One arm of Emerson et al. (2004) was designed to demonstrate this; unfortunately, it showed evidence of an effect, but lacked sufficient power to definitively prove the impact of the intervention.

References Bailey, R., Duong, T., Carpenter, R., Whittle, H., Mabey, D., 1999. The duration of human ocular Chlamydia trachomatis infection is age-dependent. Epidemiol. Infect. 123, 479–486. Bailey, R.L., Arullendran, P., Whittle, H.C., Mabey, D.C., 1993. Randomised controlled trial of single-dose azithromycin in treatment of trachoma. Lancet 342, 453–456. Baltussen, R., Smith, A., 2012. Cost effectiveness of strategies to combat vision and hearing loss in sub-Saharan Africa and South East Asia: mathematical modelling study. BMJ 344, e615. Burton, M.J., Kinteh, F., Jallow, O., et al., 2005. A randomised controlled trial of azithromycin following surgery for trachomatous trichiasis in the Gambia. Br. J. Ophthalmol. 89, 1282–1288. Brunham, R.C., Rey-Ladino, J., 2005. Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine. Nat. Rev. Immunol. 5, 149–161. Emerson, P.M., Lindsay, S.W., Walraven, G.E., et al., 1999. Effect of fly control on trachoma and diarrhoea. Lancet 353, 1401–1403. Emerson, P.M., Lindsay, S.W., Alexander, N., et al., 2004. Role of flies and provision of latrines in trachoma control: cluster-randomised controlled trial. Lancet 363, 1093–1098. Evans, J.R., Solomon, A.W., 2011. Antibiotics for trachoma. Cochrane Database Syst. Rev. 3, CD001860. Frick, K.D., Basilion, E.V., Hanson, C.L., Colchero, M.A., 2003. Estimating the burden and economic impact of trachomatous visual loss. Ophthalmic Epidemiol. 10, 121–132.

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Kari, L., Whitmire, W.M., Crane, D.D., et al., 2009. Chlamydia trachomatis native major outer membrane protein induces partial protection in nonhuman primates: implication for a trachoma transmission-blocking vaccine. J. Immunol. 182, 8063–8070. Low, N., Egger, M., Sterne, J.A., et al., 2006. Incidence of severe reproductive tract complications associated with diagnosed genital chlamydial infection: the Uppsala Women’s Cohort Study. Sex. Transm. Infect. 82, 212–218. Mabey, D.C.W., Hu, V., Bailey, R.L., Burton, M.J., Holland, M.J., 2014. Towards a safe and effective chlamydial vaccine: lessons from the eye. Vaccine 32, 1572–1578. Pascolini, D., Mariotti, S.P., 2012. Global estimates of visual impairment: 2010. Br. J. Ophthalmol. 96, 614–618. Porco, T.C., Gebre, T., Ayele, B., et al., 2009. Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial. JAMA 302, 962–968. Rajak, S.N., Habtamu, E., Weiss, H.A., et al., 2011. Surgery versus epilation for the treatment of minor trichiasis in Ethiopia: a randomised controlled noninferiority trial. PLoS Med. 8, e1001136. Rasmussen, S.J., 1998. Chlamydial immunology. Curr. Opin. Infect. Dis. 11, 37–41. Reacher, M.H., Huber, M.J., Canagaratnam, R., Alghassany, A., 1990. A trial of surgery for trichiasis of the upper lid from trachoma. Br. J. Ophthalmol. 74, 109–113. Reacher, M.H., Munoz, B., Alghassany, A., Daar, A.S., Elbualy, M., Taylor, H.R., 1992. A controlled trial of surgery for trachomatous trichiasis of the upper lid. Arch. Ophthalmol. 110, 667–674. Resnikoff, S., Felch, W., Gauthier, T.M., Spivey, B., 2012. The number of ophthalmologists in practice and training worldwide: a growing gap despite more than 200,000 practitioners. Br. J. Ophthalmol. 96, 783–787. Schachter, J., West, S.K., Mabey, D., et al., 1999. Azithromycin in control of trachoma. Lancet 354, 630–635. Solomon, A.W., Harding-Esch, E., Alexander, N.D., et al., 2008. Two doses of azithromycin to eliminate trachoma in a Tanzanian community. N. Engl. J. Med. 358, 1870–1871. Solomon, A.W., Holland, M.J., Alexander, N.D., et al., 2004. Mass treatment with single-dose azithromycin for trachoma. N. Engl. J. Med. 351, 1962–1971. Solomon, A.W., Holland, M.J., Burton, M.J., et al., 2003. Strategies for control of trachoma: observational study with quantitative PCR. Lancet 362, 198–204. Solomon, A.W., Kurylo, E., 2014. The global trachoma mapping project. Community Eye Health 27, 18. de Vrieze, N.H., de Vries, H.J., 2014. Lymphogranuloma venereum among men who have sex with men. An epidemiological and clinical review. Expert Rev. Anti Infect. Ther. 12, 697–704. Wang, Y., Cutcliffe, L.T., Skilton, R.J., et al., 2013. Transformation of a plasmid-free, genital tract isolate of Chlamydia trachomatis with a plasmid vector carrying a deletion in CDS6 revealed that this gene regulates inclusion phenotype. Pathog. Dis. 67, 100–103. West, S., Munoz, B., Lynch, M., et al., 1995. Impact of face-washing on trachoma in Kongwa, Tanzania. Lancet 345, 155–158. West, S.K., Munoz, B., Mkocha, H., Hsieh, Y.H., Lynch, M.C., 2001. Progression of active trachoma to scarring in a cohort of Tanzanian children. Ophthalmic Epidemiol. 8, 137–144. West, S.K., Bailey, R., Munoz, B., et al., 2013. A randomized trial of two coverage targets for mass treatment with azithromycin for trachoma. PLoS Negl. Trop. Dis. 7, e2415.

West, S.K., West, E.S., Alemayehu, W., et al., 2006. Single-dose azithromycin prevents trichiasis recurrence following surgery: randomized trial in Ethiopia. Arch. Ophthalmol. 124, 309–314. Wolle, M.A., Munoz, B.E., Mkocha, H., West, S.K., 2009. Constant ocular infection with Chlamydia trachomatis predicts risk of scarring in children in Tanzania. Ophthalmology 116, 243–247. WHO, 2012a. Global WHO Alliance for the elimination of blinding trachoma by 2020. Wkly. Epidemiol. Rec. 87, 161–168. WHO, 2012b. Global Incidence and Prevalence of Selected Curable Sexually Transmitted Infections – 2008. WHO, Geneva. World Health Organization, 2014. WHO Alliance for the Global Elimination of Blinding Trachoma by the year 2020. Progress report on elimination of trachoma, 2013. Wkly. Epidemiol. Rec. 89, 421–428. World Health Organization, July 2010. Report of the 3rd Global Scientific Meeting on Trachoma. Johns Hopkins University, Baltimore, MA. World Health Organization, Geneva, Switzerland, pp. 19–20. Zhang, H., Kandel, R.P., Atakari, H.K., Dean, D., 2006. Impact of oral azithromycin on recurrence of trachomatous trichiasis in Nepal over 1 year. Br. J. Ophthalmol. 90, 943–948.

Further Reading Black, C.M., 1997. Current methods of laboratory diagnosis of Chlamydia trachomatis infection. Clin. Microbiol. Rev. 10, 160–184. Solomon, A.W., Zondervan, M., Kuper, H., Buchan, J.C., Mabey, D.C.W., Foster, A., 2006. Trachoma Control: A Guide for Program Managers. World Health Organization, Geneva, Switzerland. Stephens, R.S., Kalman, S., Lammel, C., et al., 1998. Genome sequence of an obligate intracellular pathogen of humans: Chlamydia trachomatis. Science 282, 754–759. Taylor-Robinson, D., 1997. Evaluation and comparison of tests to diagnose Chlamydia trachomatis genital infections. Hum. Reprod. 12, 113–120.

Relevant Websites http://www.cdc.gov – Centers for Disease Control and Prevention. http://www.hpa.org.uk – Health Protection Agency. http://www.trachoma.org/ – International Trachoma Initiative. http://www.trachomaatlas.org – Global Atlas of Trachoma. www.who.int/topics/sexually_transmitted_infections/en/ – World Health Organization, Sexually Transmitted Infections. http://www.who.int/std_diagnostics/index.htm – World Health Organization, Sexually Transmitted Diseases Diagnostic Initiative.

INTERNATIONAL ENCYCLOPEDIA OF PUBLIC HEALTH SECOND EDITION VOLUME 2 CHOeESS

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INTERNATIONAL ENCYCLOPEDIA OF PUBLIC HEALTH SECOND EDITION EDITOR IN CHIEF STELLA R. QUAH Duke-NUS Medical School, Singapore

ASSOCIATE EDITOR IN CHIEF WILLIAM COCKERHAM University of Alabama at Birmingham, Birmingham, AL, USA

VOLUME 2

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Publisher: Oliver Walter Associate Acquisition Editor: William Smaldon Content Project Manager: Justin Taylor Associate Content Project Manager: Katherine Finn Cover Designer: Matthew Limbert

EDITORIAL BOARD EDITOR IN CHIEF Stella R. Quah (PhD) is Adjunct Professor at the Duke-NUS Medical School, Singapore. She received her BA in Sociology from the Universidad Nacional de Colombia, her MSc in Sociology from Florida State University as a Fulbright-Hays Scholar, and her PhD in Sociology from the National University of Singapore (formerly University of Singapore). Prior to her current appointment she was Professor at the NUS Department of Sociology where she was a faculty member from 1977 to 2009. Before joining the Sociology Department, she worked at the Department of Social Medicine and Public Health of the Faculty of Medicine, University of Singapore. Her work on Medical Sociology and Public Health has continued throughout her career. She introduced and taught medical sociology at both the Department of Sociology and the Faculty of Medicine. She designed different medical sociology modules for social science students, nursing students, and graduate medical students at the Department of Community, Occupational, and Family Medicine, NUS. When the Graduate School of Medical Studies was set up at the Faculty of Medicine, she taught the medical sociology modules as part of the ‘Foundations of Public Health’ and ‘Lifestyle and Behaviour in Health and Disease’ for the MMed (Public Health). During her long career at NUS, she spent research sabbaticals as Research Associate and Visiting Scholar, by invitation, at the Institute of Governmental Studies, University of California Berkeley (1986–87); the Center for International Studies, MIT, and the Department of Sociology, Harvard University (1993–94), the Harvard-Yenching Institute (1997); the Stanford Program in International Legal Studies, Stanford University (1997); the National Centre for Developmental Studies, Australian National University (2002); and the Walter H. Shorenstein Asia–Pacific Research Center, Stanford University (2006). Her professional activities include her work as Chair of the Medical Sociology Research Committee (RC15) of the International Sociological Association (ISA) 1990–94; ISA Vice President for Research (1994–98); Chairperson of the ISA Research Council (1994–98); and consultant to WHO and UN-ESCAP, among other international and national organizations. She is member of the American Sociological Association and member of several institutional review Boards. On publications, she was Associate Editor of International Sociology (1998–2004) and is member of editorial advisory boards of several international peer-reviewed journals including the British Journal of Sociology; Associate Editor in Chief of the first edition of this Encyclopedia (2008); Coeditor of the Wiley Blackwell Encyclopedia of Health, Illness, Behavior and Society (2014); and Section Editor of Public Health of Elsevier’s Reference Module in Biomedical Sciences. Her areas of research and consultancy include health services utilization; self-medication; health risks behaviors (including smoking, alcohol consumption, and psychoactive substance use); sociocultural factors in infectious diseases, heart disease, and cancer; the governance of epidemics; and the role of family caregivers in mental health. She has published many journal articles and book chapters and has authored nine books; six as sole author. She is also editor and coeditor of 13 books. Her most recent publications include ‘Caring for persons with schizophrenia at home: Examining the link between family caregivers’ role distress and quality of life,’ Sociology of Health and Illness (2013); the Blackwell Encyclopedia of Health, Illness, Behaviour and Society (coeditor and contributor, 2014); ‘Sociology and Psychology in Public Health’ in the Oxford Textbook of Global Public Health (2015); ‘Partnership: The missing link in the process of de-institutionalization of mental health care,’ International Journal of Health Services (2015); Routledge Handbook of Families in Asia (editor and contributor, 2015); and ‘Public Health and Epidemiology: Prevention and surveillance of health risks,’ Elsevier’s Reference Module in Biomedical Sciences (2015).

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Editorial Board

ASSOCIATE EDITOR IN CHIEF William Cockerham is Distinguished Professor and Chair of the Department of Sociology at the University of Alabama at Birmingham. He holds a PhD from the University of California at Berkeley. Among his books are Medical Sociology, 13th ed. (Routledge, 2016), with an earlier edition included on the International Sociological Association’s List of 100 Sociology Books of the Century (2000) and Social Causes of Health and Disease, 2nd ed. (Polity, 2013), listed as one of the key books in medical sociology in the twenty-first century in Contemporary Sociology (2014). Other recent books include Sociology of Mental Disorder, 10th ed. (Routledge, 2016) and Medical Sociology on the Move: New Directions in Theory (Springer, 2013). In addition, he is Editor in Chief of the five-volume Encyclopedia of Health, Illness, Behavior, and Society (Wiley-Blackwell, 2014) and Guest Coeditor of a forthcoming special issue of the American Journal of Preventive Medicine. He is also past President of the Research Committee on Health Sociology of the International Sociological Association and has served on the Medical Sociology Council of the American Sociological Association and the Editorial Board of the American Sociological Review.

EDITORIAL BOARD Annette Braunack-Mayer is a bioethicist and Professor of Health Ethics in the School of Public Health at the University of Adelaide. Her research, teaching, and community service focus on combining rigorous and robust analyses of health systems, policies, and practices with the views and experiences of community members. She is passionate about ensuring that the experiences and views of members of communities, including citizens, patients, consumers, and stakeholders, contribute to health services, policies, and systems. She has particular expertise in the use of deliberative methods of engagement with communities, but her research skill set extends across the full range of qualitative research methods. Professor Braunack-Mayer’s current research spans vaccination policy and programs, the appropriate use of big data, obesity prevention, and chronic disease prevention in Aboriginal and Torres Strait Islander communities. She has also completed studies of ethical reasoning among general practitioners, ethics in health technology assessment, and decision-making around the beginning and ending of life. She has published the first and second edition of a text on general practice ethics and over 110 refereed papers and book chapters. Professor Braunack-Mayer chairs a range of health councils and committees, including a government ethics advisory committee and human research and animal ethics committees. She teaches graduate and undergraduate courses in health ethics and qualitative research methods.

Karen Glanz, PhD, MPH, is George A. Weiss University Professor, Professor in the Perelman School of Medicine and the School of Nursing, and Director of the UPenn Prevention Research Center, at the University of Pennsylvania. A globally influential public health scholar whose work spans psychology, epidemiology, nutrition, and other disciplines, her research in community and healthcare settings focuses on obesity, nutrition, and the built environment; reducing health disparities; and health communication technologies. Her research and publications about understanding, measuring, and improving healthy food environments, beginning in the 1980s, has been widely recognized and replicated. Dr Glanz was elected to membership in the Institute of Medicine (IOM) of the National Academy of Sciences in 2013. She was named a Highly Cited Author and one of The World’s Most Influential Scientific Minds 2015 by Thomson Reuters.

Editorial Board

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Davidson H. Hamer, MD, is a graduate of Amherst College and the University of Vermont College of Medicine. After internship and residency in internal medicine at the Washington Hospital Center, he completed a fellowship in infectious disease at Tufts-New England Medical Center. Dr Hamer has a special interest in tropical infectious diseases and has more than two decades of field experience in diarrheal diseases, pneumonia, malaria, and maternal and newborn health. His research interests include emerging infections, neonatal sepsis, antimicrobial resistance, Water, Sanitation and Hygiene (WASH), integrated community case management, interventions for the treatment and prevention of malaria, micronutrient deficiencies, diarrheal disease, and childhood pneumonia. Dr Hamer is a Professor of Global Health and Medicine at the Boston University Schools of Public Health and Medicine, and he holds a position as an Adjunct Professor of Nutrition at the Tufts University Friedman School of Nutrition Science and Policy and adjunct scientist at the Jean Mayer USDA Human Nutrition Research Center on the Aging. Dr Hamer also is the current Principal Investigator for GeoSentinel, a multicountry emerging infections surveillance network.

Japhet Killewo is a professor of Epidemiology at the Muhimbili University of Health and Allied Sciences (MUHAS) in Tanzania. He teaches epidemiology and biostatistics to undergraduate and postgraduate students in the university and offers short courses in data management, research methodology, and monitoring and evaluation to other scholars. He does research in communicable and noncommunicable diseases, and he was the first in Tanzania to design the largest field study for monitoring HIV infection trends and evaluating the impact of HIV interventions in one of the 20 or so regions of Tanzania. He has also worked with the International Center for Diarrheal Disease Research (ICDDRB) in Bangladesh monitoring and evaluating reproductive health interventions in a health and demographic surveillance system. Since 2010 Professor Killewo has been involved in initiating an urban-based health and demographic surveillance system in Tanzania where more than 100,000 residents of all ages are being followed up for in- and out-migration, vital events, socioeconomic status, and food insecurity issues. The population is also being followed up for noncommunicable diseases of various kinds. Professor Killewo has critically reviewed a considerable number of research proposals and manuscripts for various peer-reviewed international journals. Professor Killewo has published widely in local as well as international journals and has written chapters in books and edited a section in the International Encyclopedia of Public Health. He is also the Editor in Chief of the derivative volume on Epidemiology and Demography in Public Health and has more than 80 published articles in journals to his credit.

Jonathan D. Mayer, The overriding emphasis in Professor Mayer’s career has been synthesizing the epidemiologic, geographic, and clinical understanding of health and disease. Health and disease cannot be easily separated into individual disciplines, and so doing may introduce bias into the overall understanding. Professor Mayer’s current position, spanning three different schools at the University of Washington (Public Health, Arts and Sciences, and Medicine) is ideal for this. Similarly, his joint position in Epidemiology and Geography facilitates this. In addition, Professor Mayer has adjunct appointments in two clinical departments: Internal Medicine (Division of Allergy and Infectious Diseases) and Family Medicine, as well as two additional departments in the School of Public Health: Health Services and Global Health. Several leadership positions in the School of Public Health have further facilitated insights into an integrative understanding. Specific interests include (1) diarrheal diseases, especially in sub-Saharan Africa; (2) tuberculosis (TB), especially in densely settled slum areas; (3) vector-borne diseases, including malaria, dengue, and Zika; and (4) emerging infectious diseases – previously unrecognized or genuine de novo diseases, such as Ebola, HIV, Zika, and the emergence of new forms of antimicrobial (‘antibiotic’)-resistant infections. Professor Mayer is particularly interested in understanding the underlying epidemiologic, social, demographic, and political factors underlying disease emergence. Recent attention has been devoted to the epidemiology and geography of pain – especially chronic pain – and the conditions that underlie pain, such as low back pain, postherpetic neuralgia, and injury. Professor Mayer is also interested in health services and the provision of health care. Recent work includes organ transplantation, especially inequities in access to organs; access to pain treatment and pain medications; evolution of hospital systems and consolidation; and, throughout his career; rural health and the urban–suburban–rural inequities in access to care.

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Editorial Board Wayne D. Rosamond, PhD, MS, is a Professor in the Department of Epidemiology, Gillings School of Global Public Health at the University of North Carolina (UNC) at Chapel Hill (USA) and an Adjunct Professor in the Department of Emergency Medicine at UNC. Professor Rosamond is an investigator and teacher in cardiovascular disease (CVD) epidemiology with research expertise in design, conduct, and analysis of community-based surveillance studies and registries of coronary heart disease, heart failure, and stroke. He has also published on the etiology of myocardial infarction, heart failure, sudden cardiac death, venous thromboembolism, and stroke. Dr Rosamond is principal investigator for the North Carolina Stroke Care Collaborative and a coprincipal investigator with the Atherosclerosis Risk in Communities (ARIC) study and Comprehensive Post Acute Stroke Service (COMPASS) trial. Dr Rosamond has collaborated on international CVD epidemiology studies including the WHO-MONICA Project, the Stroke Registry of the Canadian Stroke Network, and the Emerging Risk Factor Collaboration at the University of Cambridge, the United Kingdom. Dr Rosamond is Director of the Cardiovascular Epidemiology NRSA-NIH T32 training grant at UNC. He is past Chair of both the American Heart Association’s (AHA) Statistics and Executive Database Steering Committees and is immediate past President of the Board of Directors of the AHA Mid-Atlantic Affiliate.

Dr Vijay K. Sharma is currently working as Associate Professor at YLL School of Medicine, National University of Singapore, Singapore, and as Senior Consultant, Division of Neurology, National University Hospital, Singapore. He is the current recipient of the prestigious Clinician Scientist Award from National Medical Research Council, Singapore. He has published 187 peerreviewed scientific papers and 19 book chapters. Dr Sharma is Associate Editor for BMC Neurology and serves on the editorial boards of many scientific journals including Stroke, Neural Regeneration Research, Recent Patents on Medical Imaging, Journal of Behavioral and Brain Science, World Journal of Hypertension, ISRN Neurology, American Journal of Cardiovascular Diseases, World Journal of Neurology, Journal of Neurology & Translational Neuroscience (JNTN), International Journal of Medical Sciences and Biotechnology, Advances in Neuroscience Research and Neurological Research and Therapy.

CONTRIBUTORS TO VOLUME 2 Susana Aguas International Network for the Prevention of Elder Abuse, Buenos Aires, Argentina

John F P Bridges Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

Igor Akushevich Duke University, Durham, NC, USA

Linda M Brown RTI International, Rockville, MD, USA

Edson C Araujo The World Bank, Washington, DC, USA

Carole H Browner University of California, Los Angeles, CA, USA

Nicholas A Ashford Massachusetts Institute of Technology, Cambridge, MA, USA

Jessica N Busch University of Hawai’i, Honolulu, HI, USA

Colin Baigent Oxford University, Oxford, UK Jonathan D Baker University of Hawai’i, Honolulu, HI, USA Joan K Bardsley MedStar Research Institute, Hyattsville, MD, USA Jan J Barendregt Epigear International, Sunrise Beach, QLD, Australia Justin D Barlow The Ohio State University, Columbus, OH, USA Criel Bart Prince Leopold Institute of Tropical Medicine, Antwerpen, Belgium Daniel G Bausch World Health Organization, Geneva, Switzerland Lalita Bhattacharjee National Food Policy Capacity Strengthening Programme, FAO, Dhaka, Bangladesh Marcel Bilger Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore Rob Boer Health Economics and Epidemiology, Palm Desert, CA, USA

Charles C Caldart Massachusetts Institute of Technology, Cambridge, MA, USA Malwina N Carrion International Society for Infectious Diseases, Brookline, MA, USA Deoraj Caussy Regional Office for South-East Asia, World Health Organization, New Delhi, India David P Check National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Chris Church Community Environment Associates, London, UK Robert Clarke Oxford University, Oxford, UK John G Cleland London School of Hygiene and Tropical Medicine, London, UK Erika L Crable Boston University School of Public Health, Boston, MA, USA Gemma Crawford School of Public Health, Faculty of Health Sciences, Curtin University, Perth, WA, Australia Breda Cushen Beaumont Hospital, Beaumont, Ireland

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Contributors to Volume 2

Garry R Cutting McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Lia Susana Daichman International Network for the Prevention of Elder Abuse, Buenos Aires, Argentina; and International Longevity Center Argentina, Buenos Aires, Argentina

Marwa E Farag Brandeis University, Waltham, MA, USA Richard Franklin College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia; and Royal Life Saving Society, Australia

Sabitha R Dasari Emory University, Atlanta, GA, USA

Omar Fuentes PAHO/WHO Collaborating Center for the Study of Dengue and Its Vector, ‘Pedro Kouri’ Tropical Medicine Institute, Havana, Cuba

Hsion-Wen David Kuo Tunghai University, Taichung, Taiwan

Lisa Gibbs University of Melbourne, Carlton, VIC, Australia

Diana De Graeve Universiteit Antwerpen, Antwerp, Belgium

Nora Ellen Groce Leonard Cheshire Disability and Inclusive Development Centre, University College London, London, UK

Mel Denehy School of Public Health, Faculty of Health Sciences, Curtin University, Perth, WA, Australia Jack T Dennerlein Northeastern University, Boston, MA, USA Susan S Devesa National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Dale A Dickinson School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA Jeroen Douwes Massey University, Wellington, New Zealand C F Drescher University of Mississippi, Oxford, MS, USA; and Georgia Regents University, Augusta, GA, USA Gilles Dussault Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa, Portugal Daniel Engelman Centre for International Child Health, Murdoch Childrens Research Institute, University of Melbourne, Royal Children’s Hospital, Melbourne, VIC, Australia James E Enstrom University of California at Los Angeles, Los Angeles, CA, USA Nina L Etkin University of Hawai’i, Honolulu, HI, USA Majid Ezzati Harvard School of Public Health, Boston, MA, USA Michelle V Fanucchi School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA

María G Guzman PAHO/WHO Collaborating Center for the Study of Dengue and Its Vector, ‘Pedro Kouri’ Tropical Medicine Institute, Havana, Cuba H Haak Consultants for Health and Development, Leiden, The Netherlands J Dik F Habbema Erasmus MC, University Medical Center, Rotterdam, The Netherlands Davidson H Hamer Center for Global Health and Development, Boston University School of Public Health, Boston, MA, USA; and Section of Infectious Diseases, Department of Medicine, Boston Medical Center, Boston, MA, USA William R Harlan National Institutes of Health, Rockville, MD, USA T S Harvey University of California Riverside, Riverside, CA, USA R Brian Haynes Kilgore S. Trout Research & Education Centre, Irish Lake, ON, Canada Peter C Hindmarsh Institute for Child Health, London, UK Roger Ho Yong Loo Lin School of Medicine, National University of Singapore, Singapore H D Holder Prevention Research Center, Pacific Institute for Research and Evaluation, Berkeley, CA, USA Frank B Hu Harvard School of Public Health, Boston, MA, USA

Contributors to Volume 2

Karen E Iles School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA Lorentz M Irgens University of Bergen, Bergen, Norway; and Norwegian Institute of Public Health, Osla, Norway Robert Jakob World Health Organization, Geneva, Switzerland Jonine Jancey School of Public Health, Faculty of Health Sciences, Curtin University, Perth, WA, Australia

Eric Martinez PAHO/WHO Collaborating Center for the Study of Dengue and Its Vector, ‘Pedro Kouri’ Tropical Medicine Institute, Havana, Cuba C Mathers World Health Organization, Geneva, Switzerland Els Mathieu Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA Ann S McAlearney The Ohio State University, Columbus, OH, USA

Mike Joffe Imperial College, London, UK

J McCallum Victoria University, Melbourne, VIC, Australia

Satish Joshi Michigan State University, East Lansing, MI, USA

Michael J McDermott University of Mississippi, Oxford, MS, USA; and University of Mississippi Medical Center, Jackson, MS, USA

Chin Meng Khoo Yong Loo Lin School of Medicine, National University of Singapore, Singapore; National University Health System (NUHS), Singapore; and Duke-National University of Singapore Graduate Medical School, Singapore Ann Marie Kimball University of Washington, Seattle, WA, USA; and Chatham House, London, UK Julia S Kravchenko Duke University, Durham, NC, USA Ranjani Krishnan Eli Broad School of Business, Michigan State University, East Lansing, MI, USA Maree Kulkens Moreland Community Health Service, Coburg, VIC, Australia Vicki L Lamb North Carolina Central University, Durham, NC, USA Kenneth C Land Duke University, Durham, NC, USA Jennifer Leaning FXB Center for Health and Human Rights, Boston, MA, USA Justine E Leavy School of Public Health, Faculty of Health Sciences, Curtin University, Perth, WA, Australia Sebalda C Leshabari Tanzania Midwives Association, Dar es Salaam, Tanzania Caroline Ly USAID, Washington, DC, USA

Ollie S Miettinen McGill University, Montreal, QC, Canada Reid Miller Independent Consultant, Chapel Hill, NC, USA Emmanuel Mitry Hôpital Ambroise Paré, Boulogne, France Ross Morgan Beaumont Hospital, Beaumont, Ireland John G Morris, Jr. University of Florida, Gainesville, FL, USA Peter Muenning Columbia University, New York, NY, USA Jacqueline Müller-Nordhorn Charité University Medical Center, Berlin, Germany Germano Mwabu School of Economics, University of Nairobi, Nairobi, Kenya A K Nandakumar Brandeis University, Waltham, MA, USA Ellen Nolte London School of Economics and Political Science, London, UK; and London School of Hygiene and Tropical Medicine, London, UK Scott A Norton Children’s National Health System, Washington, DC, USA; and George Washington University, Washington, DC, USA Anne H Outwater Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

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Contributors to Volume 2

Reena Oza-Frank Emory University, Atlanta, GA, USA

Mikiko Senga World Health Organization, Geneva, Switzerland

Neil Pearce Massey University, Wellington, New Zealand

Yao Sodahlon Lymphatic Filariasis Elimination, Decatur, GA, USA

Ana B Perez PAHO/WHO Collaborating Center for the Study of Dengue and Its Vector, ‘Pedro Kouri’ Tropical Medicine Institute, Havana, Cuba

Paula H Song The Ohio State University, Columbus, OH, USA

Richard J Pollack Harvard University, Cambridge, MA, USA; Harvard T.H. Chan School of Public Health, Boston, MA, USA; and Identify US LLC, Newton, MA, USA Jan T Poolman Bacterial Vaccine Discovery & Early Development, Janssen, Leiden, The Netherlands Naomi Priest University of Melbourne, Carlton, VIC, Australia Andre Renzaho Deakin University, Burwood, VIC, Australia Helaine E Resnick MedStar Research Institute, Hyattsville, MD, USA Susan B Rifkin London School of Economics and Political Science, London, UK Elisha Riggs University of Melbourne, Carlton, VIC, Australia

Charmaine Spencer Simon Fraser University, Vancouver, BC, Canada; and Canadian Network for the Prevention of Elder Abuse, Toronto, ON, Canada Andrew C Steer Centre for International Child Health, Murdoch Childrens Research Institute, University of Melbourne, Royal Children’s Hospital, Melbourne, VIC, Australia Carolyn Stephens UCL Institute of Health Equity, Universidad Nacional de Tucumán, Tucumán, Argentina; and London School of Hygiene & Tropical Medicine, London, UK Ross Summer Jefferson University, Philadelphia, PA, USA U Than Sein Regional Office for South-East Asia, World Health Organization, New Delhi, India; and People’s Health Foundation, Yangon, Myanmar James C Thomas University of North Carolina, Chapel Hill, NC, USA

Peter G Robinson School of Oral and Dental Science, Bristol, UK

Tejpratap S P Tiwari Centers for Disease Control and Prevention, Atlanta, GA, USA

Eduardo Romero-Hicks University of Guanajuato, Guanajuato, México; and Guanajuato State Emergency System, Guanajuato, México

Kraisid Tontisirin Institute of Nutrition Mahidol University (INMU), Salaya, Thailand

José R Romero University of Arkansas for Medical Sciences, Little Rock, AR, USA Robin Root Baruch College, City University of New York, New York, NY, USA David L Sackett Kilgore S. Trout Research & Education Centre, Irish Lake, ON, Canada Thomas Schramme Hamburg University, Hamburg, Germany Eric E Seiber The Ohio State University, Columbus, OH, USA

James A Trostle Trinity College, Hartford, CT, USA Tevfik Bedirhan Üstün World Health Organization, Geneva, Switzerland Raf Van Gestel Universiteit Antwerpen, Antwerp, Belgium Jeroen K van Ginneken Netherlands Interdisciplinary Demographic Institute, The Hague, The Netherlands K M Venkat Narayan Emory University, Atlanta, GA, USA

Contributors to Volume 2

Taryn Vian Boston University School of Public Health, Boston, MA, USA Maria-Pia Waelkens School of Public Health, Université libre de Bruxelles (ULB), Brussels, Belgium Hong Wang Yale University School of Public Health, New Haven, CT, USA Elizabeth Waters University of Melbourne, Carlton, VIC, Australia Soors Werner Prince Leopold Institute of Tropical Medicine, Antwerpen, Belgium

Trenton White USAID, Washington, DC, USA Stefan N Willich Charité University Medical Center, Berlin, Germany Lok Wong Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Irene Xagoraraki Michigan State University, East Lansing, MI, USA Ke Xu World Health Organization, Manila, Philippines Anatoliy I Yashin Duke University, Durham, NC, USA

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GUIDE TO USING THE ENCYCLOPEDIA Structure of the Encyclopedia

3.

All articles in the encyclopedia are arranged alphabetically as a series of entries.

A subject classification list has been developed by the editors to group articles under broad topics. This index is useful for making broad connections between articles and locating the relevant article for a topic that is covered in more than one article. This can be found in the front matter of Volume 1.

1.

Alphabetical Contents List

Your first point of reference will likely be the contents. The contents list appears at the front of each volume providing volume and page numbers of the entry. We also display the article title in the running headers on each page so you are able to identify your location and browse the work in this manner. 2.

Cross-references

All articles within the encyclopedia have an extensive list of cross-references which appear at the end of each article, for example: See also: HIV Prevention and Treatment in Children and Adolescents; Mental Health and Substance Abuse; Mental Illness, Historical Views of; Specific Mental Health Disorders: Child and Adolescent Mental Disorders.

4.

Subject Classification List

Index

The index provides the volume and page number for where the material is located, and the index entries differentiate between material that is a whole article; is part of an article, part of a table, or in a figure. This can be found at the rear of Volume 7. 5.

Contributors

A list of volume contributors appears in the front matter of each volume.

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CONTENTS OF VOLUME 2 Editorial Board

v

Contributors to Volume 2

ix

Guide to Using the Encyclopedia

xv

VOLUME 2 Cholera and Other Vibrioses John G Morris, Jr.

1

Cholesterol and Lipids Robert Clarke and Colin Baigent

9

Chronic Disease Modeling J Dik F Habbema, Rob Boer, and Jan J Barendregt

22

Chronic Obstructive Pulmonary Disease Breda Cushen, Ross Morgan, and Ross Summer

28

Circulatory Diseases and Aging Igor Akushevich and Anatoliy I Yashin

36

Classic Concepts of Disease Thomas Schramme

44

Classification of Mental Disorders: Principles and Concepts Tevfik Bedirhan Üstün and Roger Ho

51

Clinical Epidemiology David L Sackett and R Brian Haynes

58

Clinical Trials William R Harlan

62

Codes of Ethics in Public Health James C Thomas and Reid Miller

71

Colorectal Cancer Emmanuel Mitry

75

Community Health Insurance in Low- and Middle-Income Countries Maria-Pia Waelkens, Soors Werner, and Criel Bart

82

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Contents of Volume 2

Community Health Workers Susan B Rifkin

93

Community-Based Nutrition Programmes Kraisid Tontisirin and Lalita Bhattacharjee

103

Comparative Health Systems Hong Wang

111

Comparative Risk Assessment Majid Ezzati

117

Competition in Health Care Paula H Song, Justin D Barlow, Eric E Seiber, and Ann S McAlearney

129

Compression of Morbidity J McCallum and C Mathers

134

Consumerism: Overview Lok Wong and John F P Bridges

142

Contaminants Associated with Drinking Water Hsion-Wen David Kuo and Irene Xagoraraki

148

Coronary Heart Disease Jacqueline Müller-Nordhorn and Stefan N Willich

159

Corruption and the Consequences for Public Health Taryn Vian and Erika L Crable

168

Cost-Influenced Treatment Decisions and Cost-Effectiveness Analysis Marcel Bilger

177

Cultural Competence in Public Health Elizabeth Waters, Lisa Gibbs, Elisha Riggs, Naomi Priest, Andre Renzaho, and Maree Kulkens

181

Cultural Contexts of Reproductive Health Carole H Browner and Robin Root

187

Cultural Epidemiology James A Trostle

191

Cultural Factors Influencing Therapeutic Practice Nina L Etkin, Jonathan D Baker, and Jessica N Busch

198

Cultural Issues and Linguistic Complications in Health Communication T S Harvey

202

Cystic Fibrosis Garry R Cutting

208

Decision Analytic Modeling Peter Muenning

211

Demand for Health Care Germano Mwabu

217

Demography, Epidemiology, and Public Health Ollie S Miettinen

223

Demography of Aging Kenneth C Land and Vicki L Lamb

226

Contents of Volume 2

xix

Dengue María G Guzman, Omar Fuentes, Eric Martinez, and Ana B Perez

233

Dental Epidemiology Peter G Robinson

258

Determinants of National Health Expenditure A K Nandakumar, Marwa E Farag, Caroline Ly, and Trenton White

264

Diabetes Mellitus, Epidemiology Joan K Bardsley and Helaine E Resnick

274

Diabetes Mellitus Prevention Sabitha R Dasari, Reena Oza-Frank, and K M Venkat Narayan

282

Diabetes Mellitus Treatment Chin Meng Khoo

288

Diet and Cancer Julia S Kravchenko

294

Diet and Heart Disease Frank B Hu

305

Diphtheria Tejpratap S P Tiwari

313

Disability and Rehabilitation Nora Ellen Groce

318

Disasters and Emergency Planning Jennifer Leaning

322

Disease Classification Robert Jakob

332

Disease Prevention: An Overview Anne H Outwater, Sebalda C Leshabari, and Ellen Nolte

338

Drinking Water and Sanitation Michelle V Fanucchi

350

Drowning Justine E Leavy, Gemma Crawford, Richard Franklin, Mel Denehy, and Jonine Jancey

361

Drugs, Illicit e Primary Prevention Strategies Michael J McDermott and C F Drescher

366

Dynamics of the Health-Care Labor Markets Edson C Araujo and Gilles Dussault

382

East Asia and Pacific States, Health Systems of Deoraj Caussy and U Than Sein

387

Ebola and Other Viral Hemorrhagic Fevers Daniel G Bausch and Mikiko Senga

396

Economic Models of Hospital Behavior Satish Joshi and Ranjani Krishnan

410

Ectoparasites Richard J Pollack, Daniel Engelman, Andrew C Steer, and Scott A Norton

417

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Contents of Volume 2

Educational Attainment and Health: Survival John G Cleland and Jeroen K van Ginneken

429

Effective Alcohol Policy H D Holder

437

Elder Abuse Lia Susana Daichman, Susana Aguas, and Charmaine Spencer

443

Emergence of Novel Human Infections: New Insights and New Challenges Ann Marie Kimball

448

Emergency Medical Technicians Eduardo Romero-Hicks

455

Endocrine Diseases: Overview Peter C Hindmarsh

460

Energy Use, Health Implications of Mike Joffe

468

Enteroviruses José R Romero

474

Environmental and Occupational Epidemiology Neil Pearce and Jeroen Douwes

479

Environmental Health: Overview Dale A Dickinson and Karen E Iles

487

Environmental Justice and Health Carolyn Stephens and Chris Church

499

Environmental Protection Laws Nicholas A Ashford and Charles C Caldart

507

Epidemic Investigation Els Mathieu and Yao Sodahlon

518

Epidemiology, Historical Lorentz M Irgens

530

Epidemiology of the Acquired Immunodeficiency Syndrome Malwina N Carrion and Davidson H Hamer

547

Epidemiology of Vitamin C James E Enstrom

559

Equity in Health Financing Diana De Graeve, Ke Xu, and Raf Van Gestel

569

Ergonomics and Musculoskeletal Issues Jack T Dennerlein

577

Escherichia coli Jan T Poolman

585

Esophageal Cancer Linda M Brown, David P Check, and Susan S Devesa

594

Essential Drugs Policy H Haak

603

Cholera and Other Vibrioses John G Morris, Jr., University of Florida, Gainesville, FL, USA Ó 2017 Elsevier Inc. All rights reserved.

Cholera is a disease that has been known, and feared, since antiquity. It is the only disease that can consistently cause fatal, dehydrating diarrhea in adults as well as children. India, and, in particular, the delta of the Brahmaputra and Ganges Rivers, is the disease’s ancestral home. The Sushruta Samhita, written about 500–400 BC, includes the Sanskrit term generally used to refer to cholera, as well as the description of a representative case. Reports can be found in the Arab literature by AD 900, with descriptions subsequently appearing with increasing frequency in Europe, India, and China. The modern history of cholera begins in 1817, with the occurrence of what has been designated as the first of what are now seven cholera pandemics or worldwide epidemics (Barua, 1992). It was during the spread of the third pandemic to London in 1854 that John Snow demonstrated the association between illness and consumption of sewagecontaminated water. His work established the role of epidemiology in public health, and highlighted the efficacy of simple interventions, in this case the removal of the handle of the Broad Street pump, which had been linked with illness. The seventh (and most recent) cholera pandemic began in 1961, with an outbreak of disease in the Celebes Islands. The strain responsible for this outbreak (Vibrio cholerae O1 biotype El Tor) has subsequently spread through Asia, Africa, Europe, and the Americas, resulting in substantial global morbidity and mortality. The microbiologist Robert Koch, studying outbreaks of cholera in Egypt and Calcutta, India in 1883–84 that were part of the fifth pandemic, is credited with demonstrating that cholera is caused by the microorganism that we now call V. cholerae. While the focus of early microbiologists was the identification of the causative agent of cholera, it became increasingly apparent as microbiologic sophistication increased that the disease cholera was associated with a distinct subset of strains within the species V. cholerae. These strains were initially identified by their agglutination with specific antisera, and were designated as being within O group 1 (V. cholerae O1). All other Vibrios were called ‘nonagglutinating’ Vibrios (NAGs) or ‘noncholera’ Vibrios (NCVs). Work done during the past 50 years has demonstrated that NAGs/NCVs are a very heterogeneous group, including a number of other V. cholerae O groups as well as other Vibrio species. Table 1 lists the Vibrio species that have been associated with human disease; V. cholerae is subdivided between the serogroups that have been associated with the disease cholera (primarily O groups 1 and 139), and all other serogroups, loosely grouped as non-O1/non-O139 V. cholerae. Table 1 also includes data from the U.S. Centers for Disease Control and Prevention (CDC) from 2011 on frequency of isolation of Vibrio species from patients in the United States; while this reflects disease incidence in a temperate, developed country, it does provide insight into the relative public health impact of other Vibrio species. Vibrios are free-living bacteria found in aquatic environments throughout the world. They tend to be more common in warmer waters (temperatures >17–20
C), with recent studies suggesting that increases in water temperatures associated with global warming are resulting in an increase in the frequency with which

International Encyclopedia of Public Health, 2nd edition, Volume 2

Vibrio-associated diseases (particularly Vibrio parahaemolyticus) are being identified. Depending on the species, they tolerate a range of brackish, saline waters. As would be anticipated given their abundance in water, Vibrio species are also commonly isolated from fish and shellfish, and may be concentrated up to 100-fold by filter-feeding shellfish such as oysters. During warm summer months, virtually 100% of oysters harvested in the United States will carry Vibrio vulnificus and/or V. parahaemolyticus, with densities in U.S. Gulf Coast oysters often exceeding 104 g1 of oyster meat. In addition to being found as a planktonic organism in the water column and in shellfish, V. cholerae has been reported in association with the mucilaginous sheaths of blue-green algae, and on the chitinous exoskeletons of molts of copepods (with chitin apparently having the ability to induce natural competence in the microorganism (Meibom et al., 2005)). It has also been linked with egg masses of chironomids (nonbiting midges), which are the most widely distributed and frequently the most abundant insects in freshwater (Broza and Halpern, 2001). In the following sections, further information is provided about V. cholerae O1/O139 and the disease cholera. Subsequent sections deal with illness associated with the three most common NAGs: non-O1/non-O139 V. cholerae, V. parahaemolyticus, and V. vulnificus.

Table 1

Vibrio species implicated as a cause of human disease Clinical presentation a

Species Vibrio cholerae ‘epidemic’ strains (O1, O139) Other serotypes Vibrio mimicus Vibrio parahaemolyticus Vibrio fluvialis Vibrio furnissii Grimontia hollisae (formerly Vibrio hollisae) Vibrio vulnificus Vibrio alginolyticus Photobacterium damselae (formerly Vibrio damsela) Vibrio cincinnatiensis Vibrio carchariae Vibrio metschnikovii

# U.S. cases (deaths), Wound/ Gastroenteritis ear Septicemia 2011b 42 (0)c

þþ

(þ)

þþ þþ þþ

þ þ þ

þ

þþ þþ þþ

þ

þ

þ

(þ)

þ

þþ þþ þþ

þþ

113 (34)d 156 (0) 7 (0)

(þ)

0 0 0

(þ)

(þ)

(þ)

(þ)

86 (3) 15 (0) 334 (7) 37 (0) 0 (0) 7 (0)

a

þþ denotes most common presentation, þ denotes other clinical presentations, and (þ) denotes very rare presentation. Data reflect Vibrio infections reported to CDC during 2011. Data are from 43 states; for many of these states, reporting of Vibrio infections is not routine, and consequently numbers may underestimate the true number of cases. Data from U.S. Centers for Disease Control and Prevention (http://www.cdc.gov/ncezid/dfwed/pdfs/ covis-annual-report-2011-508c.pdf). b

http://dx.doi.org/10.1016/B978-0-12-803678-5.00070-9

1

2

Cholera and Other Vibrioses

Figure 1

Cholera (V. cholerae O1/O139) Cholera is characterized by the rapid onset of profuse, watery diarrhea, which, if untreated, can lead to dehydration, circulatory collapse, and death. Cholera is still a major cause of illness in the developing world. In World Health Organization (WHO) data from 2012, 245,393 cases of cholera were reported from 48 countries (Figure 1). Actual numbers of cases are probably at least one to two orders of magnitude higher, with several countries with known endemic foci of cholera reporting no cases to WHO. Cases are increasingly reported from Africa, where vestiges of the seventh pandemic have established clear endemicity. While the global case fatality rate was 1.2% (reflecting the widespread acceptance and availability of oral rehydration therapy), fatality rates among vulnerable groups in ‘high-risk’ areas can range up to 40%, and an estimated 91 000 people die each year from cholera (Ali et al., 2012). Overall, the WHO statistics suggest that we are not making great headway in controlling this disease: Case rates remain high, and, in the words of WHO, “this disease remains a significant unresolved public health problem” (WHO, 2013).

Microbiology/Physiology Vibrio cholerae is traditionally classified by O group serotype (with >150 O serotypes currently recognized in the widely

used Sakazaki grouping system) and by biotype (Classical and El Tor), with each biotype having two distinct and one intermediate serotype (Ogawa, Inaba, and Hikojima, respectively). Until recently, V. cholerae strains belonging to serogroup O1 were regarded as the sole etiologic agents of cholera. However, since 1992, V. cholerae serogroup O139 has emerged as a second etiologic agent of cholera in the Indian subcontinent and neighboring countries (Nair et al., 1994). While there were initial concerns that V. cholerae O139 would form the basis for the eighth cholera pandemic, it has remained confined to the Asian continent; it remains to be seen whether it will ultimately spread globally. It is also becoming apparent that cholera-like disease can be caused by strains in other V. cholerae serogroups (such as O37 and O141) that produce CT and have a genetic background similar to that of O1 and O139 strains. The signs and symptoms of cholera are caused by CT, a protein enterotoxin that elicits profuse diarrhea. Net gastrointestinal chloride and sodium absorption are absent and net secretion is present during cholera; glucose, potassium, and bicarbonate absorption, however, remain intact, as does glucose-linked enhancement of sodium and water absorption. Thus, although plain salt water is not absorbable during cholera and aggravates the diarrhea, the addition of glucose renders the solution absorbable, providing the physiologic basis for oral rehydration. This remarkable public health

Cholera and Other Vibrioses advance, based on sophisticated physiological studies in Bangladesh and India, was developed in the 1960s and 1970s. Genes for CT are carried by the CTX phage, and are capable of transfer among V. cholerae strains. Virulence has also been linked with the presence of the Vibrio pathogenicity island, which carries key genes involved in intestinal colonization. As molecular studies have progressed, we have come to realize that cholera-associated strains demonstrate a remarkable degree of overall genetic similarity, particularly when compared with the rest of the species. Many attempts to genetically distinguish among clinical isolates of V. cholerae have found only minimal variability, based on biochemical tests, pulsed field gel electrophoresis, ribotyping, and studies with multilocus sequence typing. Vibrio cholerae undergoes striking changes in gene expression patterns as strains pass from the environment into and out of the human intestine. Recent studies have suggested that as part of this process, strains acquire the ability to become ‘hyperinfectious’ for a period of up to 18 h after passage in the feces, demonstrating a 700-fold increase in infectivity in animal models. While these findings are still under investigation, inclusion of this observation in mathematical models of disease transmission provides results that are consistent with the explosive nature of cholera epidemics (Hartley et al., 2006).

Epidemiology After passage of a pandemic wave through a geographic region, cholera generally settles into an endemic pattern of seasonal outbreaks separated by periods of quiescence. Factors responsible for triggering these seasonal epidemics are not completely understood, although there is an increasing body of literature linking such events (and their intensity) to large-scale environmental dynamics such as monsoon rains and the El Nino Southern Oscillation (Rodo et al., 2002). At a local level, studies in Peru during the epidemics in the early 1990s suggest that the seasonal (summer) cholera epidemics were heralded 2 months before by increases of V. cholerae in the environment (triggered, in turn, by seasonal increases in water temperature) (Franco et al., 1997), with apparent subsequent ‘spillover’ of the bacterium into human populations. What is clear is that as humans become infected, one sees the initiation of rapid person-to-person (or person-to-food/water-to-person) transmission, a process that may be facilitated by the hyperinfectious state noted above. In household studies conducted in Calcutta, transmission within households has been closely linked with contamination of water stored in the household (that is, water brought in from community pumps and stored for later use). Data further suggest that use of containers with a narrow mouth, preventing insertion of potentially contaminated hands, can prevent much of this household transmission. There are also increasing data highlighting the importance of food as a vehicle of transmission for the microorganism within households and within the community (through street vendors). Cooked rice appears to be a particularly effective vehicle for transmission of cholera, with rice implicated as the cause of a number of outbreaks in settings as diverse as meals served at African funerals, on the US oil rig platform, and to a group of luxury cruise ship passengers in Thailand.

3

In the United States and Australia, outside of traditional cholera-endemic areas, there are small environmental foci of potentially epidemic V. cholerae, reflecting the global distribution of the microorganism. Of particular note, there is evidence for persistence of a single, unique clone of V. cholerae along the US Gulf Coast for over 30 years; cholera cases caused by this strain have generally been linked with consumption of undercooked crab or raw oysters harvested from the Gulf Coast (Blake et al., 1980). Between 1995 and 2000, there were six cholera cases in the United States linked with this focus. However, with rare exceptions, the sporadic seafood-associated cholera cases that have occurred in the US population have not spread beyond the index, seafood-associated case, presumably because of high extant levels of sanitation. For unknown reasons, persons with blood group O are significantly more likely to have severe disease. Factors that predispose to a lack of gastric acid, or hypochlorhydria (malnutrition, gastrectomy, acid-reducing medications), decreasing the gastric acid barrier to infection, also increase susceptibility to illness. The atrophic gastritis and hypochlorhydria associated with chronic Helicobacter pylori infection has also been associated with an increased risk of severe illness.

Clinical Presentation Despite the dread inspired by the term ‘cholera,’ the majority of persons infected with epidemic V. cholerae strains do not have severe illness: 75% of persons infected with strains of the classical biotype have inapparent or mild disease, while 93% of infections with biotype El Tor strains (which are responsible for the most recent pandemic) have illnesses that are inapparent or mild. The incubation period for cholera ranges from 12 h to 5 days. In the most severe cases (cholera gravis), rates of diarrhea rapidly increase during the first 24 h of illness, peaking at rates of up to 1 l per hour, with diarrheal stools assuming a pale gray, ‘rice-water’ appearance. In the absence of appropriate rehydration, this degree of purging can lead to circulatory collapse and death within a matter of hours. Clinically, dehydration is generally not detectable until patients have lost fluid equal to 5% or more of their body weight. Such moderately dehydrated patients are restless and irritable, with sunken eyes and dry mouth and tongue, poor skin turgor (a skin pinch returns to normal slowly), and no urine output. Patients are thirsty, and drink eagerly. As illness progresses toward severe dehydration (loss of approximately 10% of body weight), patients become lethargic and drift into unconsciousness, with low blood pressure, decreased or absent pulses, and worsening skin turgor; they drink poorly, or are not able to drink (Sack et al., 2004). Dehydration is reflected in abnormal metabolic parameters and laboratory tests, such as a higher plasma protein concentration, hematocrit, serum creatinine, urea nitrogen, and plasmaspecific gravity. Stool bicarbonate losses and lactic acidosis associated with dehydration can result in a severe acidosis manifested by depression of blood pH and plasma bicarbonate and an increased serum anion gap. Despite profound potassium loss, uncorrected acidosis may result in a normal or high serum potassium level; with correction of the acidosis, this may rebound, with dangerously low serum potassium levels. Plasma sodium and chloride concentrations remain in the

4

Cholera and Other Vibrioses

normal range. Most cholera patients have low blood glucose, and some may be severely hypoglycemic. Acute renal failure may result from prolonged hypotension.

Diagnosis The clinical diagnosis of cholera is based on the rapid onset of diarrhea and vomiting with dehydration and the profuse, ricewater stool, in an appropriate epidemiologic setting; cholera is the only disease that can consistently cause severe dehydration (leading to death) in adults. Laboratory diagnosis is based on isolation of the organism from stool. This generally requires use of a selective media such as thiosulfate-citrate-bile salt-sucrose (TCBS) agar. For specimens sent to clinical microbiology laboratories in the developed world, it is generally necessary to specifically request use of this media (which is also required for isolation of other Vibrio species) in suspected cholera cases. Rapid immunologic tests are commercially available for testing of stool for the microorganism. In the hands of a trained technician, it is possible to identify V. cholerae with a reasonable degree of certainty by using dark-field microscopy. The diagnosis can also be made retrospectively by serologic testing.

Treatment Treatment of cholera is based on replacement of fluids and salts lost through diarrhea. For persons with moderate dehydration, this can almost always be done by oral rehydration. In severe cases, intravenous rehydration is generally required. The composition of recommended oral rehydration solutions and intravenous fluids is outlined in Table 2. Packets of oral rehydration solutes are now widely available throughout the developing world, with rice-based solutions, when available, generally preferred to glucose-based solutions. Recent data further suggest that supplementation of rice-based oral rehydration solution with L-histidine can further reduce stool volume and frequency (Rabbani et al., 2005). Patients undergoing rehydration must be carefully monitored, and ongoing diarrheal output should be measured. This is done optimally with a ‘cholera cot,’ a simple camp cot with a hole in the middle and a plastic sheet that has a sleeve Table 2

Prevention Outside of the setting of endemic or seasonal epidemic cholera, the risk of acquiring the disease is low, and can be further reduced by maintenance of good sanitation and provision of safe potable water. Because the infectious dose of cholera is relatively high (1 million bacteria), boiling water and cooking food are effective methods for preventing transmission through these routes. The use of squeezed citrus juice, such as lemon, on suspect foods has been reported to decrease the risk of cholera. However, as long as there are environmental foci of epidemic strains (such as the one seen along the US Gulf Coast), it is not possible to totally eliminate the risk of V. cholerae infection. Cooking of seafood/shellfish reduces but does not eliminate the risk: In studies conducted by the

Composition of cholera stools and electrolyte rehydration solutions used to replace stool losses

Fluid Cholera stool Adults Children ORS Glucose (WHO) Rice IV fluids Lactated Ringer’s Dhaka solution Normal saline a

draining into a plastic bucket for collection of stool (Figure 2). Patients with severe dehydration should have a volume equal to 10% of their body weight replaced as rapidly as possible (over a period no longer than 2–4 h). For patients with moderate levels of dehydration, replacement can be by mouth using oral rehydration solution, starting with replacement of 5–7.5% of body weight. After initial stabilization by either intravenous or oral fluids, oral rehydration solution should be administered so that, at a minimum, ongoing fluid losses are matched by oral intake. Patients should be encouraged to eat whenever they are hungry, with free water provided. Antibiotics have been shown to shorten the duration of diarrhea and reduce the period of excretion of the microorganism. However, antibiotics should always be regarded as ancillary therapy to vigorous rehydration. Recommended antibiotic regimens are included in Table 3. While the drug of choice is doxycycline administered as a single oral dose, resistance to tetracycline has become increasingly common throughout the developing world. In areas where tetracycline resistance is known to occur, single-dose ciprofloxacin or azithromycin provides reasonable alternatives (Harris et al., 2012). However, resistance to these latter two drugs is also being reported. Clinicians need to be familiar with resistance patterns in their region. Cholera isolates from travelers should always be tested for resistance.

NA (mmol l 1)

Cl (mmol l 1)

K (mmol l 1)

Bicarb (mmol l 1)

130 100

100 90

20 33

44 30

75 75

65 65

20 20

10a 10a

130 133 154

109 154 154

4 13 0

28d 48e 0

Carbohydrate (g l 1)

Osmolality (mmol l 1)

13.5b 30–50c

245 180

Trisodium citrate (10 mmol l1) is generally used rather than bicarbonate. Glucose 13.5 g l1 (75 mmol l1). c 30–50 g rice contains about 30 mmol l1 glucose depending on degree of hydrolysis. d Base is lactate. e Base is acetate. Reproduced with permission from Sack, D.A., Sack, R.B., Nair, G.B., Siddique, A.R., 2004. Cholera. Lancet 363, 223–233. b

271 292 308

Cholera and Other Vibrioses

5

Figure 2 Cholera cot. From Hirschhorn, N., Pierce, N.F., Kobari, K., Carpenter, C.C.J., 1974. The treatment of cholera. In: Barua, D., Burrows, W. (Eds.), Cholera. W.B. Saunders Company, Philadelphia, PA, pp. 235–252.

U.S. Centers for Disease Control, epidemic V. cholerae could still be isolated from infected crabs that had been boiled for eight or steamed for 25 min, cooking times that resulted in crabs that were red in appearance, with meat that was firm and appeared well-cooked (Blake et al., 1980). Oral-killed whole-cell cholera vaccines are now available at a global level, with large-scale field trials demonstrating good protective efficacy. Dukoral (Crucell, Sweden), an internationally licensed recombinant CT B subunit, killed whole-cell vaccine, demonstrated 79% direct protection against cholera among persons receiving two doses in a field trial in Zanzibar in 2009–10 involving some 24 000 people (Khatib et al., 2012). However, with the inclusion of the recombinant cholera toxin B subunit, costs for this vaccine make it less practical for large-scale administration in the developing world. A secondkilled whole-cell oral cholera vaccine (Shanchol, Shantha Biotechnics, Hyderabad, India), which contains the same V. Table 3

Antibiotic therapy for cholera

Antibiotic Single-dose therapy Doxycycline Ciprofloxacin Azithromycin Multiple-dose therapy Tetracycline Trimethoprim (TMP)sulfamethoxazole (SMX) Furazolidone

Children

Adults

– 20 mg kg1 single dose 20 mg kg1 single dose

300 mg single dose 1 g single dose 1 g single dose

12.5 mg kg1 500 mg QID  3 days QID  3 day TMP 5 mg kg1 and SMX TMP 160 mg and 25 mg kg1 SMX 800 mg BID  3 days BID  3 days 1.25 mg kg1 400 mg single dose QID  3 days

cholerae O1 whole-cell strains as Dukoral, at different doses, and killed V. cholerae O139 bacteria but not the B subunit component, was developed and licensed in India. In a major double-blind, cluster-randomized, placebo-controlled trial in Kolkata, the vaccine had a cumulative protective efficacy at 5 years of 65% (Bhattacharya et al., 2013). This latter vaccine has now been used in several international trials, and appears to be effective in reducing case numbers in outbreak situations (Luquero et al., 2014). It was used in pilot immunization studies in Haiti after the 2010 epidemic there (Rouzier et al., 2013), and substantial progress has been made in creating an international stockpile of the vaccine to use in emergency/ epidemic situations.

‘Nonepidemic’ V. cholerae Strains of V. cholerae that do not carry virulence factors necessary to cause epidemic cholera have been implicated as a cause of diarrheal disease and seawater-associated wound and ear infections. In susceptible hosts (persons with liver disease, a history of alcoholism, diabetes, or immunosuppression), exposure/infection may result in septicemia, with high-associated mortality rates. Strains associated with diarrheal illness represent a subset of all non-O1/non-O139 isolates. Strains within this subset, in turn, cause disease through a variety of mechanisms (or postulated mechanisms), each of which has its own set of associated genes. Diarrheal disease has been linked with production of a heat-stable enterotoxin (NAG-ST) similar to that produced by enterotoxigenic Escherichia coli; with production of CT or a CT-like toxin; and with the ability of a strain to colonize the intestine. Recent molecular studies have demonstrated the

6

Cholera and Other Vibrioses

presence of genes encoding a type III secretion system in nonO1/non-O139 strains, which may also play a role. In contrast to V. cholerae O1, which is not encapsulated (and which, with one or two possible exceptions, does not cause sepsis), >90% of nonepidemic V. cholerae produce a polysaccharide capsule. Heavily encapsulated strains are significantly more likely to be isolated from patients with septicemia than strains with minimal or no encapsulation. As is true for other Vibrios, nonepidemic strains of V. cholerae are part of the normal, free-living bacterial flora in estuarine areas throughout the world. In areas such as the US Gulf Coast, these strains are several orders of magnitude more common than epidemic V. cholerae strains in the environment. Isolation is not associated with the presence of fecal coliforms, which is the marker currently used by state and national regulatory agencies to regulate shellfish-harvesting waters. Diarrheal illness due to nonepidemic V. cholerae has been linked at a global level with contaminated water and a variety of different foods, with seafood most commonly implicated. In the United States, infection has been associated primarily with eating raw oysters, particularly during warmer, summer months, when counts of the bacterium are highest in harvest waters. The most common manifestation of nonepidemic V. cholerae infection is diarrhea. Based on outbreak reports and volunteer studies, the incubation period is short (5 days) may benefit from treatment with tetracycline or a quinolone. In the absence of data, it would appear reasonable to use the

Cholera and Other Vibrioses treatment protocols recommended for V. vulnificus infections (outlined in the following) for severe V. parahaemolyticus wound infections or septicemia.

Vibrio vulnificus Vibrio vulnificus, first identified in 1979, causes severe wound infections, septicemia, and gastroenteritis. The majority of clinical and environmental V. vulnificus isolates reported to date are in Biotype 1. Strains in Biotype 2 (now known as serovar E) cause sepsis in eels, but do not affect humans; Biotype 3 strains were described in association with wound infections related to handling of live fish (tilapia) from fish farms in Israel (Bisharat et al., 1999). As reported for non-O1 V. cholerae, V. vulnificus strains produce a polysaccharide capsule that has been strongly linked with virulence. Typing systems based on the capsule have not been developed, due in part to the great diversity seen in capsular types: In one study of 120 strains, 96 different capsular types (‘carbotypes’) were identified. Vibrio vulnificus is very sensitive to the presence of iron, and consequently illness is more common in patients with hemochromatosis or other ironoverload conditions. Estrogen has been found to play a protective role in mouse models of V. vulnificus sepsis, perhaps accounting for the increased incidence of serious infections in men. As is true for other Vibrios, V. vulnificus is a naturally occurring bacterium in estuarine or marine environments. Highest numbers (in water and oysters) are found in areas with intermediate salinities (5–25 ppt) and warmer temperatures (optimally, >20
C). Vibrio vulnificus is the most common cause of Vibrio-related deaths in the United States (Table 1), with an incidence in community-based studies in coastal regions of approximately 0.5 cases/10 000 population/year. Sepsis without an obvious focus of infection (‘primary septicemia’) occurs in persons who are alcoholic or who have chronic underlying illnesses, such as liver disease, cirrhosis, diabetes, or hemochromatosis (Table 4). Infection is generally acquired by eating oysters containing the organism, or exposure to the bacterium while swimming or boating. Patients with primary septicemia present with fever and hypotension (Table 4): One-third have shock when first seen or become hypotensive within 12 h of hospitalization. 50–90% of patients have been reported to have distinctive bullous skin lesions (Figure 3). Thrombocytopenia is common, and there is often evidence of disseminated intravascular coagulation. Over 50% of patients with primary septicemia die; the mortality rate exceeds 90% for those who are hypotensive within 12 h of initial presentation. Wound infections range from mild, self-limited lesions to rapidly progressive cellulitis and myositis. Patients who survive severe V. vulnificus infections often have some degree of residual disability. This does not appear to be related to the actual infection, which clears readily with antibiotic therapy, but rather to the consequences of multiple organ system failure and the prolonged hospitalization associated with occurrence of a shock syndrome. A definitive diagnosis requires isolation of V. vulnificus from blood, wounds or skin lesions (if present), or stool. Blood agar and other nonselective media, including media used in commercial blood culture systems, are adequate for isolation from blood and wounds. TCBS agar is necessary for isolation from stool.

7

Table 4 Epidemiologic features and clinical manifestations of patients with primary septicemia caused by Vibrio vulnificus

Feature Major risk factorsa Liver disease Alcoholism Diabetes Heart disease Hematologic disorder Peptic ulcer disease Malignancy Immunodeficiency Renal disease GI surgery Any of above Patient characteristics median age, years (range) % Male Symptoms/signs Fever Diarrhea Abdominal cramps Nausea Vomiting Shockb Localized cellulitis Bullous skin lesions Hospitalized Death

Primary Gastroenteritis septicemia (n ¼ 23) (n ¼ 181)

Wound infections (n ¼ 189)

14% 14% 5% 10% 0 0 16% 5% 5% 11% 35% 35 (0–84)

80% 65% 35% 26% 18% 18% 17% 10% 7% 7% 97% 54 (24–92)

22% 32% 20% 34% 8% 10% 10% 9% 7% 6% 68% 59 (4–91)

57

89

88

59% 100% 84% 71% 68% 0 – 0 65% 9%c

91% 58% 53% 59% 54% 64% – 49% 97% 61%

76% – – – – 30% 91% – 89% 17%

a

Conditions are not mutually exclusive. Systolic blood pressure Marburg) and Rift Valley fever virus occurs, these viruses have most often been associated with outbreaks of less than a few hundred cases. The 2013–16 outbreak of Ebola virus disease in West Africa was a marked exception, with over 28 500 reported cases. d The case fatality ratio was 22% in the first recognized outbreak of Marburg HF in Germany and Yugoslavia in 1967 but has been consistently over 80% in outbreaks in central Africa where the virus is endemic. Possible reasons for this discrepancy include differences in quality of care, strain pathogenicity, route and dose of infection, underlying prevalence of immunodeficiency and comorbid illnesses, and genetic susceptibility. e In addition to the arenaviruses listed in the table, Flexal and Tacaribe viruses have caused human disease as a result of laboratory accidents. Another arenavirus, Whitewater Arroyo, has been noted in sick persons in California, but its role as a pathogen has not been clearly established. f Discovered in 2008 in an outbreak of five cases (four of them fatal) in South Africa. The index case came to South Africa from Zambia. The other four cases were nosocomially transmitted. g Discovered in 1990. Only three cases (one fatal) have been noted, two of them from laboratory accidents. h Discovered in 2003 from a small outbreak in Cochabamba, Bolivia. Blood was obtained from one fatal case and Chapare virus isolated but few other details from the outbreak have been reported. i Although Rift Valley fever virus can be found throughout sub-Saharan Africa, large outbreaks usually occur in East Africa. j Based on estimates from the World Health Organization. Significant underreporting occurs. Incidence may fluctuate widely depending on epidemic activity. k Numerous variants of Kyasanur Forest disease virus have been identified, including Nanjianyin virus in Yunnan Province, China, and Alkhumra virus (also spelled ‘Alkhurma’ in some publications) in Saudi Arabia.

Ebola and Other Viral Hemorrhagic Fevers

Geographic distribution of disease

Ebola and Other Viral Hemorrhagic Fevers

399

Sudan

Guinea Sierra Leone Liberia

Uganda

Côte d’Ivoire Gabon

Kenya

Republic of the Congo Democratic Republic of the Congo Angola

Zimbabwe

Figure 1 Endemic areas for filoviruses. Only filoviruses known to cause hemorrhagic fever are shown. Gray indicates countries where Ebola hemorrhagic fever has been seen and diagonal lines indicate countries with Marburg hemorrhagic fever. Incidence and risk of disease may vary significantly within each country.

Mali

Guinea Sierra Leone

Togo Benin Nigeria

Liberia Zambia

Figure 2 Endemic areas for Old World arenaviruses. Only the two arenaviruses, Lassa and Lujo, known to cause hemorrhagic fever are shown. Countries where clinical cases of Lassa fever have been confirmed are depicted in dark gray. Indirect evidence, such as anecdotal reports or seroprevalence data, exists for most of the other countries in West Africa, shown in light gray. Endemic countries for Lujo virus are depicted by diagonal lines. Incidence and risk of disease may vary significantly within each country.

400

Ebola and Other Viral Hemorrhagic Fevers Venezuelan hemorrhagic fever (Guanarito virus)

Bolivian hemorrhagic fever (Machupo virus)

Chapare hemorrhagic fever (Chapare virus) Argentine hemorrhagic fever (Junín virus)

Brazilian hemorrhagic fever (Sabiá virus)

Figure 3 Endemic areas for New World arenaviruses. Only the arenaviruses known to cause hemorrhagic fever are shown. Incidence and risk of disease may vary significantly within each country.

Figure 4 Endemic areas for Crimean-Congo hemorrhagic fever virus. Incidence and risk of disease may vary significantly within each country. Variable intensity of surveillance may underlie the absence of confirmed cases in some countries.

a few virions (Franz et al., 1997). Although most of the animal reservoirs and vectors are known, with the exception of the arthropod-borne HF viruses, few definitive data exist on precise routes of infection to humans. Consequently, the published literature on this subject contains considerable speculation.

Batborne Viruses After decades of mystery, evidence points increasingly to fruit bats as the filovirus reservoir (Figure 5). Numerous cases of Marburg virus disease have been noted in humans after

exposure to bat-infested caves and mines, and Marburg virus has been isolated from Egyptian fruit bats (Towner et al., 2007). Although Ebola virus has yet to be isolated from a bat, PCR data and epidemiological studies again implicate these animals. The precise mode of filovirus transmission from bats to humans remains unknown, but is believed to be from exposure to infected bat’s excreta or saliva. Nonhuman primates, especially gorillas and chimpanzees, and other wild animals often serve as intermediate hosts. These animals are presumably also infected by exposure to bats and then pass the virus to

Ebola and Other Viral Hemorrhagic Fevers

401

Figure 5 Ebola virus ecology and transmission. Used with permission from the US Centers for Disease Control and Prevention (http://www.cdc. gov/vhf/ebola/resources/virus-ecology.html).

humans through contact with their blood and body fluids, usually associated with hunting (Georges et al., 1999). Like humans, nonhuman primates are dead-end hosts, developing a severe and usually fatal disease similar to human HF. Sick animals may be easier prey for hunters, increasing the probability of transmission. Since HF viruses are rapidly inactivated by heating, infection likely occurs through exposure during butchering and preparation, rather than via consumption of cooked meat. Marburg virus infection has also occurred in persons harvesting organs from wild-caught monkeys for use in vaccine production (Martini et al., 1968). Ebola Reston virus has caused outbreaks of fatal disease in nonhuman primates in research facilities in the United States and Europe in imported monkeys from the Philippines, where the virus has also been isolated from pigs (Blumberg et al., 2013). Both the pigs and nonhuman primates were presumably infected through bat exposure.

Rodentborne Viruses Arenaviruses and hantaviruses are rodentborne (although some small-mammal reservoirs of the hantaviruses are technically not of the order Rodentia, but rather insectivores – shrews and moles belonging to the order Soricomorpha – for

convenience we nevertheless use the term ‘rodentborne’). In general there is a strict pairing between specific virus and mammalian reservoir species, suggesting long-term coevolution. Arenaviruses and hantaviruses are each divided taxonomically into New World (i.e., the Americas) and Old World (i.e., Africa, Europe, and Asia) groups (Table 1). These viruses are maintained in nature via chronic asymptomatic infection in rodents of the superfamily Muroidea (family Muridae, subfamily Murinae for viruses in the Old World and family Cricetidae, subfamilies Sigmodontinae and Neotominae in the New World, and subfamily Arvicolinae in the Old and New World Northern Hemisphere). One possible exception is the arenavirus Tacaribe that has been isolated from bats of the genus Artibeus, although confirmation of this animal as the definitive reservoir remains to be shown. Transmission of arenaviruses between animals may be vertical (i.e., from mother to offspring before birth or in the perinatal period), horizontal (i.e., from one individual to another in the same generation), or both, depending on the specific virus (Figure 6). Hantaviruses are transmitted horizontally among rodents, probably usually by bites of adult animals exhibiting aggressive behavior.

402

Ebola and Other Viral Hemorrhagic Fevers Chronically infected rodent

Chronically infected rodent

Rare sexual transmission

Vertical and/or horizontal transmission between rodents

Occasional transmission to humans through mucous membrane exposure, skin breaches, ingestion and/or aerosol (routes unclear) Uncommon human-to-human transmission, most likely through mucous membrane exposure

Figure 6 Transmission cycle of arenaviruses and hantaviruses illustrating chronic infection in rodents. Transmission between rodents may be vertical or horizontal depending upon the specific virus. Humans are incidental hosts who play no role in virus maintenance in nature. Adapted with permission from Enria, D.A., Mills, J.N., Shieh, W., Bausch, D., Peters, C.J., 2011. Arenavirus infections. In: Guerrant, R.L., Walker, D.H., Weller, P.F. (Eds.), Tropical Infectious Diseases: Principles, Pathogens, and Practice. Elsevier Inc., Philadelphia, pp. 449–461.

Transmission of arenaviruses and hantaviruses to humans occurs primarily via exposure to rodent excreta, from direct inoculation to the mucous membranes, inhalation of primary aerosols produced when rodents urinate, or inhalation of aerosolized or dustborne virus, especially while occupying or cleaning rodent-infested structures (Stephenson et al., 1984; Kenyon et al., 1992). However, since few studies specifically document any mode of transmission, their relative importance remains unknown. Arenaviruses are relatively stable and infectious to nonhuman primates in aerosol form, suggesting that human infection from primary aerosols is at least possible. In West Africa, Lassa virus is sometimes contracted when rodents are trapped and prepared for consumption, or possibly through rodent bites. Experimental data suggest that humans may be infected with arenaviruses by the oral route (Rai et al., 1997). Regardless of the precise mode, transmission of the rodentborne HF viruses to humans appears to be relatively inefficient, occurring infrequently even in areas where infected rodents are common (Demby et al., 2001). The rodents that transmit Lassa, Machupo, and many of the Old World hantaviruses commonly invade domestic environments, putting housewives, children, and others in the home at risk. In contrast, the reservoirs for Junín, Guanarito, and

many New World hantaviruses typically inhabit agricultural fields, wood lots, or other rural habitats, putting agricultural and other outdoor workers, as well as people spending time outdoors for leisure activities, such as camping and hiking, at risk. The microhabitat of some hosts may be very specific; for example, in the Argentine pampas, the corn mouse (Calomys musculinus), the reservoir for Junín virus, tends to inhabit linear, agriculturally related locations, such as fence lines and roadsides (Bond et al., 2012). Radiotelemetric studies have shown increased nocturnal foraging of muroid rodents in areas where crops are close to human habitations, potentially increasing risk of hantavirus transmission (Armien et al., 2009).

Mosquito-Borne Viruses Yellow fever virus is maintained in a cycle between monkeys and forest canopy mosquitoes. Sporadic cases, termed ‘sylvan’ or ‘jungle yellow fever,’ occur when humans entering forests are bitten by these sylvatic vectors. Larger outbreaks of ‘urban yellow fever’ may occur when infected humans bring the virus from the forest to more settled environments, where the common mosquito Aedes aegypti, which typically lays eggs in artificial containers of clean standing water around the home, can spread the virus between humans. Mosquitoes usually become infective a few weeks after feeding on a viremic monkey or human, depending on temperature and other environmental factors. The principal vector of dengue virus is also A. aegypti, although Aedes albopictus can transmit the virus as well. Although nonhuman primates serve as reservoirs for sylvatic strains of dengue, the virus has now become adapted to and is largely maintained in human populations, with a regular maintenance cycle similar to that of urban yellow fever. Urbanization and uncontrolled human population growth often lead to substandard housing and inadequate water, sewage, and waste management systems, all of which can contribute to larger Aedes populations and increased transmission of mosquito-borne pathogens, especially dengue virus, which has the highest yearly incidence of any viral HF. Rift Valley fever virus is maintained in a cycle involving domestic livestock such as cattle, buffalo, sheep, goats, and camels, and mosquitoes, primarily floodwater Aedes and Culex. Transmission to humans may occur by mosquito bite or via direct exposure to the blood, body fluids, or tissues of infected animals. Farmers, abattoir workers, and veterinarians are thus at particular risk. Increasing irrigation that expands larval habitats may contribute to outbreaks (Gould and Higgs, 2009). Rift Valley fever virus often provokes spontaneous abortions in livestock, with potentially serious economic consequences due to diminished herd sizes. Transovarial transmission (i.e., the transfer of pathogens to succeeding generations through invasion of the ovary and infection of the eggs) in mosquitoes plays a significant role in maintenance of Rift Valley fever virus, providing a mechanism for the virus to endure harsh climatic conditions (Gould and Higgs, 2009). For example, in areas of eastern and southern Africa, mosquitoes typically lay eggs in shallow, transient bodies of water called vleis or dambos that form after heavy rains. Both the eggs and virus remain viable during subsequent dry periods, which can last months or even years. Finally, with

Ebola and Other Viral Hemorrhagic Fevers

403

the next heavy rains, the eggs hatch, giving rise to mosquitoes that are infected even though they have never taken a blood meal.

of Lassa fever, but extensive experience since then has not supported this hypothesis (Carey et al., 1972).

Tickborne Viruses

Clinical Presentation and Management

Kyasanur Forest disease, Crimean-Congo HF, and Omsk HF viruses are maintained in small mammals such as rodents, hares, and hedgehogs, between which the viruses are spread by ticks. Humans are infected either through tick bites or by exposure to contaminated blood or excreta of the reservoir animals. Ticks also spread Crimean-Congo HF virus to large mammals, including cattle and other domestic livestock, producing transient and asymptomatic viremia and putting farmers, abattoir workers, and veterinarians at risk. Ticks attached to migratory birds could potentially introduce Crimean-Congo HF virus into new regions. The spread of tickborne diseases may be influenced by land use, land cover, soil type, elevation, and weather conditions; for example, conversion of forest to animal pasture may bring humans into closer contact with both animal reservoirs and vectors of tickborne HF viruses.

Viral HF is seen in both genders and all age groups, with a spectrum from relatively mild or even asymptomatic infection to severe vascular permeability, multiorgan system failure, and death. Although the clinical presentation may differ for each viral HF as it progresses, in most cases it is not possible to distinguish the various syndromes at presentation. Distinct phases of disease and recovery are classically described for HF with renal syndrome and yellow fever, although not seen in all cases. Biphasic illnesses are classically noted for the flavivirus HFs, in which a quiescence period of days (yellow fever and dengue) to weeks (Kyasanur Forest disease and Omsk HF) occurs after which the most severe manifestations may set in, including hemorrhage, shock, renal failure, and meningoencephalitis. After an incubation period ranging from days to weeks (Table 1), depending upon the infecting virus, illness typically begins with fever and constitutional symptoms, including general malaise, anorexia, headache, myalgia, arthralgia, sore throat, chest or retrosternal pain, and lumbosacral pain. Neck pain and stiffness, retro-orbital pain, and photophobia are common in Rift Valley fever and may be noted in viral HFs in which meningitis is common, such as Omsk HF and Kyasanur Forest disease. Orthostatic hypotension is also common. Gastrointestinal signs and symptoms follow in the first few days of illness, including nausea, vomiting, epigastric and abdominal pain, abdominal tenderness, diarrhea, and constipation. Diarrhea may become bloody in the later stages of disease. A misdiagnosis of appendicitis or other acute abdominal emergency sometimes occurs, prompting unneeded and dangerous (in terms of risk of nosocomial spread) surgical interventions. Conjunctival injection or hemorrhage is frequent. Various forms of skin rash, including morbilliform, maculopapular, petechial, and ecchymotic, may be seen, depending on the specific viral HF. In severe cases, toward the end of the first week of illness, patients progress to vascular instability that may be manifested by facial flushing, edema, bleeding, hypotension, shock, and proteinuria. The likelihood of clinically discernible hemorrhage varies with the infecting virus. Increasing recognition that frank bleeding is seen in the minority of cases of most Ebola HF has prompted a change in terminology to ‘Ebola virus disease.’ Hematemesis, melena, hematochezia, metrorrhagia, petechiae, purpura, epistaxis, and bleeding from the gums and venipuncture sites may develop, but hemoptysis and hematuria are infrequent. Central nervous system manifestations, including disorientation, tremor, gait anomalies, convulsions, and hiccups, may be noted in endstage disease in some viral HFs, as is renal insufficiency or failure. Radiographic and electrocardiographic findings are generally nonspecific and correlate with the physical examination (Blumberg et al., 2013). Pregnant women often present with spontaneous abortion and vaginal bleeding, with maternal and fetal mortality approaching 100% in the third trimester.

Human-to-Human Transmission Secondary transmission between humans occurs with many of the HF viruses, especially Ebola, Marburg, Crimean-Congo HF, Lassa, and the recently discovered Lujo virus (Table 1). However, contrary to popular belief, secondary attack rates for HF viruses are generally low (only 15–20% even for Ebola virus, which is probably the most transmissible) (World Health Organization, 1978). Transmission between humans requires direct contact with contaminated blood or body fluids (Figure 1). Human-to-human infection probably usually occurs through oral or mucous membrane exposure, most often in the context of providing care to sick family members at home or patients in health-care centers. With the exception of flavivirus and hantavirus infections, people are generally most infectious late in the course of severe disease, especially when shedding virus into the environment through bleeding, diarrhea, or vomiting. The risk of transmission during the incubation period or from asymptomatic persons is negligible. Funeral rituals that entail the touching of the corpse prior to burial have also played a significant role in transmission of some HF viruses, especially Ebola and Marburg (Brainard et al., 2016). Infection through fomites cannot be ruled out, although virus culture and PCR were usually negative from environmental samples taken in an isolation ward for Ebola virus disease, unless the samples were obviously contaminated with blood or body fluids (Bausch et al., 2007). Epidemiologic and limited laboratory-based data do not suggest aerosol transmission of HF viruses between humans in natural settings (Dowell et al., 1999; Ndambi et al., 1999), although infectious and moderately stable aerosols have been artificially produced in the laboratory (Miller et al., 1963; Stephenson et al., 1984; Kenyon et al., 1992; Johnson et al., 1995), a finding of concern with regard to the potential of HF viruses as bioweapons (Bausch and Peters, 2009). Aerosol spread of Lassa virus was speculated to have occurred in the first recognized outbreaks

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Treatment of viral HF is usually limited to general supportive care, although specific antiviral drugs or convalescent plasma therapy is indicated for some of the viruses (Blumberg et al., 2013). Various experimental therapies, especially for Ebola virus disease, are in development and have undergone limited evaluation in clinical trials.

Sequelae, Virus Persistence, and Recrudescent Disease Survivors of viral HF usually make a full recovery, but convalescence may be prolonged and complicated by various sequelae that may last for months or even years after resolution of acute disease. Sequelae vary with the infecting virus, but often include persistent arthralgia, abdominal pain, extreme fatigue, anorexia, hearing loss (especially for Lassa fever), and uveitis and other potentially sight-threatening ocular complications (especially for Ebola and Marburg virus diseases). Mental health sequelae may also be frequent and include sleep and memory disturbances, anxiety disorders, depression, posttraumatic stress disorder, and survivors’ guilt in not only survivors, but also in other family and community members (Vetter et al., 2016). Studies from the 2013–16 West Africa outbreak have shown that Ebola virus may persist in survivors in selected immunologically protected tissue compartments and fluids for months or even years. These include the testes/semen, chambers of the eye, central nervous system, and the fetus, placenta, and amniotic sac/fluid of women infected during pregnancy (Vetter et al., 2016). The biggest concern is with persistent virus in the semen, which has resulted in sexual transmission over 6 months past the onset of acute disease (Christie et al., 2015). Although rare, cases of sexual transmission from survivors illustrate the need for continued surveillance even after the immediate threat from more common modes of transmission has been extinguished. Due to the risk, the World Health Organization recommends abstinence or condom use until the semen can be tested and confirmed cleared of Ebola virus. Although thought to be rare, on at least two occasions, prolonged persistence of Ebola virus has been associated with recrudescent disease, including cases of uveitis and meningoencephalitis in patients 14 weeks and 9 months, respectively, after disease onset (Varkey et al., 2015; Jacobs et al., 2016). Both patients were medically evacuated to receive intensive care in the United States and United Kingdom, perhaps keeping them alive despite extremely severe disease that would have likely have been fatal had the patients remained in West Africa, where such life-saving intensive care is not routinely available. Severe disease is associated with high virus loads, which in these two cases may have deeply seeded the immuneprivileged sites, thus predisposing to persistence and recrudescence. Nevertheless, recent anecdotal reports exist of recrudescent disease in West Africa, in some cases thought to be related to underlying HIV infection, although this association remains to be validated (Howlett et al., 2016). With the exception of sexual transmission, no cases of secondary transmission resulting from Ebola virus disease survivors have been suspected. Nonstigmatizing but heighted surveillance for recrudescent disease is warranted.

Laboratory Diagnosis Rapid laboratory testing of suspected cases is essential. The reverse transcriptase polymerase chain reaction (RT-PCR) assay has become the diagnostic mainstay because it can readily be performed on inactivated samples with commercially available equipment and reagents (Trombley et al., 2010). When possible, virus isolation on cell culture, which must be performed in a biosafety level 4 laboratory, is an important confirmatory tool, especially when it is important to distinguish samples with infectious virus from those with residual, but not infectious, nucleic acid that would nevertheless still be detected with RT-PCR. The enzyme-linked immunosorbent assay (ELISA) and immunofluorescent antibody (IFA) test are useful tools to detect antibodies indicative of past infection. ELISA IgM antibody detection is also useful in identifying acute infection with many of the flaviviruses, which are generally rapidly cleared from the blood, even during acute disease (Trombley et al., 2010). Postmortem diagnosis of some viral HFs may be established by immunohistochemical staining of formalin fixed tissue, especially the skin, liver, and spleen (Zaki et al., 1999). No laboratory test can reliably diagnose viral HF before the onset of illness. Consequently, testing of contacts or other asymptomatic persons is not recommended, even if the suspicion of infection is high. Cases of viral HF should be reported to government health authorities as well as to the World Health Organization in keeping with International Health Regulations.

Vaccines With the exception of the yellow fever 17D (YF-17D) liveattenuated vaccine, there are no widely licensed and validated vaccines for viral HF in humans. Everyone with potential exposure to yellow fever virus should receive this vaccine unless medically contraindicated. Yellow fever vaccination, along with improved sanitation and vector control, has virtually eliminated urban yellow fever in the Americas, although it still occurs in Africa, as exhibited by an outbreak of thousands of cases in numerous countries in Central Africa in 2016. However, supplies of yellow fever vaccine are often insufficient, especially to meet larger outbreaks. A tetravalent vaccine for dengue virus infection using a chimeric yellow fever 17D virus vector has recently been licensed in a few countries in Asia and Latin America and is under consideration in many others (Hadinegoro et al., 2015). Candid #1 is a live-attenuated vaccine with proven efficacy for Argentine HF. It may also protect against Bolivian HF, although it does not appear to cross-protect against other arenaviruses (Ambrosio et al., 2011). However, Candid #1 is only available in Argentina and is not recommended for children or pregnant women. Various experimental vaccines for the viral HFs are in development. Inactivated vaccines for the Hantaan and Seoul virus species of hantavirus have been developed but are generally approved and in use only in a few Asian countries (Falzarano and Feldmann, 2013). Similarly, an inactivated vaccine against Crimean-Congo HF has been developed and used in

Ebola and Other Viral Hemorrhagic Fevers Bulgaria, where it has been associated with a fourfold reduction in cases, but it is not approved in other countries (Falzarano and Feldmann, 2013). Both modified liveattenuated and inactivated vaccines for Rift Valley fever have been developed for use in livestock and have shown efficacy. However, the live-attenuated vaccine currently in use may result in spontaneous abortions. The inactivated vaccine does not have this side effect, but multiple doses are required to provide protection. Both vaccines may be perceived by farmers as increasing the cost and complexity of livestock rearing, lessening enthusiasm for vaccination. Some experimental vaccines show promise on the scientific front, but face logistical and economic challenges to eventually being licensed and widely available. The massive 2013–16 Ebola virus disease outbreak in West Africa provoked accelerated development and testing of numerous vaccines for that disease. A replication-competent vesicular stomatitis virus–vectored vaccine expressing the Zaire ebolavirus surface glycoprotein was 100% efficacious in a Phase III trial conducted in Guinea during the outbreak (HenaoRestrepo et al., 2015). However, further testing is necessary to fully determine optimal dosing to maximize immunogenicity with minimal toxicity as well as efficacy in children and pregnant and breastfeeding women (Huttner et al., 2015). Vesicular stomatitis virus–vectored vaccines have also shown efficacy as both preventive and postexposure prophylaxis vaccination in animal models of infection with other species of Ebola, as well as Marburg and Lassa viruses (Whitt et al., 2016). A number of other experimental vaccines for Ebola virus disease show progress, including a replication-incompetent recombinant chimpanzee adenovirus-3-vectored vaccine that appears safe and effective in Phase I and II trials (De Santis et al., 2016). Although various logistical complications, including the need for an adjuvant boost to confer longterm immunity, threaten to reduce the vaccine’s utility during outbreaks, it may have a favorable profile for more stable settings, such as vaccination of health-care workers or members of the military, or even inclusion in routine childhood vaccination schedules in high-risk areas of subSaharan Africa.

Reservoir and Vector Control In the absence of vaccines for most viral HFs, effective and sustainable control measures usually entail avoidance of known reservoir habitats or, when this is not feasible, implementation of measures to prevent direct contact with virus vectors and reservoirs and their excreta. Most successful prevention programs integrate biological and chemical control measures with education and/or regulation to change human behaviors that put people at risk (Ballenger-Browning and Elder, 2009; Ellis and Wilcox, 2009). In most cases, eliminating reservoir animals and vector arthropods from the environment is not feasible or even desirable, considering their importance to overall healthy ecosystems. However, short-term and localized trapping of rodents and use of insecticides and acaricides against mosquitoes and ticks may be useful to control outbreaks.

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Batborne Diseases Avoiding contact with bats, primarily by not going into caves and mines in endemic areas, is a key prevention measure for Ebola and Marburg virus diseases. Building maintenance to avoid invasion by bats may also be called for, considering that on numerous occasions Ebola and Marburg viruses appear to have been transmitted to humans from bats roosting in buildings and homes (Bausch et al., 2006). Humans should also avoid exposure to fresh blood, body fluids, or meat of wild animals, especially nonhuman primates, although this may not be practical in some areas where people rely heavily on hunting wild animals for food.

Rodent-Borne Diseases Measures to prevent human contact with rodents are important in control of diseases caused by arenaviruses and hantaviruses. For Lassa, Machupo, and some hantaviruses, whose reservoirs often colonize human dwellings, measures to improve ‘village hygiene’ are advocated, such as assuring proper waste disposal, eliminating unprotected storage of garbage and foodstuffs, reducing clutter and vegetation around houses that give rodents shelter, and plugging holes that allow rodents to enter homes. These measures may not always be possible with the rudimentary construction of houses in some regions, especially in areas ravaged by war or civil unrest. Rodent trapping may help to control outbreaks in some village settings and indeed apparently played a role in curtailing an outbreak of Bolivian HF, but it must be sustained to be an effective long-term control measure, because rodents from surrounding fields and forests will likely recolonize villages and homes after a short time (Bond et al., 2012). None of these measures is likely to be effective for the agents of Argentine and other HFs that are spread principally by rodents inhabiting agricultural fields.

Mosquito-Borne Diseases Prevention of the mosquito-borne viral HFs, especially dengue HF, hinges on controlling A. aegypti populations in and around the home. The most effective mosquito control measure is larval source reduction, primarily through eliminating water containers (Ballenger-Browning and Elder, 2009). However, a high degree of community cooperation is required for this measure to be effective. In some cases, it may make sense to supplement physical elimination of larval habitats with measures of biological and chemical control. Biological control may include use of bacteria, copepods, and fish that feed on mosquito larvae, although these measures are often timeconsuming and expensive (Ballenger-Browning and Elder, 2009). Chemical measures, such as insecticide spraying to kill adult mosquitoes, may be indicated during epidemics. Chemical and some biological control measures carry the risk of development of resistance, as well as environmental toxicity. An alternative control method under development is lethal oviposition traps that attract, trap, and kill gravid female mosquitoes. On a personal protection level, the usual measures – screened windows and doors, insecticide-treated bed nets, protective clothing, mosquito repellent, and aerosol bomb insecticides in enclosed spaces – are indicated.

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Tickborne Diseases The principal means of protection from tickborne viral HFs include treatment of livestock with acaricides and avoidance of direct contact with ticks via use of repellents and protective clothing. Preventing exposure to the blood of cattle and other livestock at the time of slaughter is also important in preventing Crimean-Congo HF and Rift Valley fever.

Occupational Safety There are four main groups at risk of viral HF from occupational exposures: (1) health-care workers; (2) laboratory workers; (3) farmers, veterinarians, slaughterhouse workers, and other field workers exposed to livestock or terrestrial wild animals and associated ticks; and (4) miners, forest workers, and other persons working in areas inhabited by bats.

Health-Care Workers Person-to-person transmission of HF viruses in the health-are setting is well documented, most often in the developing world, especially in war-torn countries in sub-Saharan Africa where public health systems, and thus the capacity to maintain routine infection control practices, have been decimated (Bausch and Clougherty, 2015). In this setting, gloves and clean needles may be absent or be reused without proper sterilization, and environmental disinfection is often inadequate. Effective application of barrier nursing may also deteriorate during outbreaks when surge capacity is exceeded. Since transmission of most HF viruses between humans requires direct contact with blood and body fluids, transmission can be prevented by isolation of the patient and adoption of infection prevention and control measures for HF viruses, which includes the use of appropriate personal protective equipment (double gloves, gowns, face masks or shields, boots or shoe covers, and aprons) (World Health Organization, 2014). If the patient is being seen in a facility where mosquito bites are likely, such as the open air wards common in low- and middle-income countries, insecticide-treated bed nets and/or room screens should be employed to prevent transmission of arthropod-borne HF viruses to surrounding patients and hospital staff. Yellow fever vaccination may also be indicated for surrounding patients and staff.

Laboratory Workers Fortunately, because most HF virus infections are rare in humans, and routine laboratory safety procedures are generally adequate to prevent transmission, infection in hospital laboratories is extremely rare. The more common HF virus infections, such as dengue, are not readily transmissible in the laboratory, although such infection has been reported on rare occasions. Of more concern is the risk to laboratorians specifically working with HF viruses in research laboratories. This risk has over the years brought about the development of designated laboratory safety levels for each pathogen based on its pathogenicity and transmissibility, with many of the HF viruses designated at the highest safety

level, biosafety level 4. Laboratory infections with HF viruses in such high-level laboratories are extremely rare and virtually always entail a discrete mishap, such as an accidental needlestick or broken test tube.

Farmers and Others Exposed to Livestock and Terrestrial Wild Animals and Ticks Persons working with livestock should use appropriate personal protective equipment when exposure to animal blood or body fluids is anticipated, especially during slaughter or while attending births or abortions. The logistical and cost implications of this recommendation may be challenging in some settings, especially in low- and middle-income countries. Acaricide use on livestock and regular self-inspection and rapid removal of ticks from the worker’s body may limit transmission of tickborne HF viruses. Inadvertent exposure to contaminated rodent excreta by agricultural and other field workers is difficult to prevent. Fortunately infection in this setting is rare, making routine use of protective personal equipment not feasible or costeffective. Although field workers trapping rodents for pest control or scientific research would seem to be at high risk, the few studies on the subject, as well as empirical observation, suggest that HF virus infection in this group is rare; field workers who handled rodents in North America showed a prevalence of exposure to HF viruses of less than 1%, and not all infection could be clearly attributed to occupational exposure (Fulhorst et al., 2007). Risk may vary depending on the prevalence of the pathogen in the animals and the specific procedure conducted. For example, simple elimination of pests via snap-trapping and disposal of intact dead animals would likely be less risky than live-trapping with subsequent euthanasia and necropsy to procure organs for scientific research. Lacking a clear consensus on the risk of infection, a wide variety of biosafety practices are employed by field workers, ranging from no personal protective equipment to use of gloves, gowns, safety glasses, and high-efficiency particulate air filter masks or even positive-pressure respirators (Fulhorst et al., 2007). Although the inclination of those responsible for workers’ safety is understandably to err on the side of caution and thus requires the full complement of protective personal equipment, significant cost and practical implications must be considered. More research is needed to assess the true risk to field workers and thus the cost–benefit balance of the various protective measures if a widely agreed-upon standard procedure is to be set. Because risk depends on geographic location, pathogens expected to be encountered, species handled, specific tasks, and worker training, any such standards will have to address multiple situations. In the meantime, it seems prudent to follow established safely guidelines when specifically dealing with rodents known or suspected to be infected with HF viruses (Mills et al., 1995).

Miners and Others Exposed to Bats Personal protective equipment such as gloves and masks may be indicated for miners and others who work in environments where bat exposure is likely. However,

Ebola and Other Viral Hemorrhagic Fevers recommendation of specific measures, and their cost efficacy, is difficult, because the precise exposures (i.e., direct contact with bats and their excreta versus respiratory droplet/aerosol spread) that result in human infection remain unknown.

Environmental Shedding and Disinfection Little published literature exists on the viability of HF viruses once shed into the environment, especially data applicable to settings other than research laboratories. However, the lipid envelope of all HF viruses is relatively easily disrupted, generally limiting their viability outside a living host. The survival of HF viruses in animal excreta is likely affected by factors such as the animal’s diet and urinary pH and protein. When shed naturally in animal excreta or human body fluids, which would then usually dry, infectivity appears to be on the order of hours to days, varying with the specific virus and environmental conditions (Sinclair et al., 2008). However, HF viruses have been isolated from samples kept for weeks at ambient temperatures if stored hydrated in a biological buffer, such as blood or serum. The viruses are also quite stable when frozen or freeze-dried (Bazhutin et al., 1992). Little concern is required regarding HF viruses seeping into groundwater or posing any long-term risk through casual exposures in the general environment, where harsh thermal and pH conditions would likely readily inactivate them. Routine environmental surveillance (i.e., in soil, water, or air) for the HF viruses is generally not feasible or routinely conducted, although concerns about bioterrorism have spurred activity in this area in recent years, especially around specific events attracting large crowds, such as sporting events, that might be perceived as potential bioterrorist targets. Detection of an HF virus outside its usual endemic area would be highly suspicious for bioterrorism. Such an approach would not be feasible for some of the more widely distributed pathogens, however, such as dengue and the hantaviruses. The specificity of any test employed would have to be high to avoid the considerable alarm and expenditure of resources that a falsepositive result would likely involve. When contamination, such as in homes or hospitals treating persons with viral HF, may have recently occurred, disinfection is warranted. HF viruses can be inactivated by exposure to temperatures above 60  C for 1 h, acidic or basic pH, gamma irradiation, ultraviolet light (surface disinfection only), surfactant nanoemulsions, and a host of chemicals and detergents, including chlorine compounds, alcohols, phenols, quaternary ammonium compounds, formaldehyde, cupric and ferric ions, zinc finger–reactive compounds, photoinducible alkylating agents, and various proprietary detergent-containing lysis buffers (Bond et al., 2012). Toxicity and corrosion may be concerns with some of these compounds, depending on the frequency of use and concentrations. Alcohol-based gel disinfectants and soap and water are presently recommended by the World Health Organization (Worlth Health Organization, 2015). Bleach solutions may be used when alcohol-based disinfectants are not available. Bleach solutions should be prepared daily. A 0.5% bleach

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solution should be used to disinfect reusable equipment (e.g., boots, goggles, and face masks), excreta, corpses, and items to be discarded. Workers’ cleaning areas potentially contaminated by the excreta of small mammals should let the area aerate before entering, then clean the area with the 0.5% bleach solution before mopping or wet sweeping. Bed linens should be soaked in a 0.05% bleach solution before laundering. A site with appropriate security should be dedicated for waste disposal if routine autoclaving is not available. Specific guidelines exist regarding handling and burial of corpses of victims of viral HF (World Health Organization, 2014). A particular issue that arises from time to time is the safety of exhuming remains of persons who died of viral HF, most often in the case of soldiers or others contracting and dying of viral HF overseas. It is unlikely that HF viruses would survive very long under the harsh pH conditions of a decomposing corpse unless the ambient temperature was below freezing, which is not usually the case for the endemic areas of most viral HFs, with the exception of some hantaviruses. In the corpses of Ebola virus–infected monkeys kept at conditions designed to mimic those in tropical countries up to a week, infectious virus could be recovered up to a week after death and viral RNA up to 10 weeks (Joseph et al., 2015). If corpses are to be exhumed, the same personal protective measures used for burial of victims of viral HF, including placing the cadaver in a sealed body bag, should be used.

Case Identification and Contact Tracing Control of outbreaks due to HF viruses that are directly communicable between humans relies on the classic public health principles of rapid case identification and contact tracing. While routine public health surveillance often takes a passive approach, relying on reporting by physicians, laboratories, and health facilities, active surveillance is needed to supplement passive surveillance during outbreaks.

Case Identification

Active investigation and identification of cases early in the course of disease is imperative in that it allows patient isolation to halt virus transmission in the community and also early implementation of therapy to give the patient the best chance of survival. Unfortunately, the nonspecific presentation of most viral HFs poses a serious challenge to early recognition. Agreeing in advance on definitions for alerts, suspected, probable, and confirmed cases is essential. The best case definitions usually employ a combination of clinical and epidemiological criteria, including travel and exposure history. Nevertheless, finding the right balance of sensitivity and specificity is almost always a challenge, making prompt laboratory testing essential. Low secondary attack rates from patients early in the course of disease afford a measure of reassurance regarding risk of secondary transmission even when cases go unrecognized as long as proper barrier nursing is maintained. Furthermore, because mild cases, which may be especially difficult to recognize, are probably not very infectious, missed or delayed diagnosis of these patients is unlikely to pose a problem from an

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infection control standpoint. Persons who meet the case definition should be isolated and treated until laboratory results are available.

Contact Tracing

Persons considered contacts (i.e., with unprotected direct contact with someone in the symptomatic phase disease) should be monitored daily for evidence of disease for the duration of the longest possible incubation period starting after their last contact (Table 1). Despite lack of evidence for transmission during the incubation period, it is usually recommended that exposed persons remain at home during this time and avoid close contact with household members that might result in exposure to body fluids, such as sex, kissing, and sharing of utensils. When possible, contacts should check their temperature daily and record the results in a log. Confinement of contacts is generally not warranted, but persons who develop fever or other signs and symptoms suggestive of viral HF should be immediately isolated until the diagnosis can be ruled out. Given the generally low secondary attack rates, especially outside of caretakers, widespread tracing is not indicated for persons with casual exposures, such as briefly being on the same premises as an infected person but with no direct physical contact.

Future Trends The majority of the HF viruses have been discovered in the last 50 years. In this short time, significant progress has been made in understanding the biology and epidemiology of these pathogens. We stand now at a point where this knowledge may soon translate into real opportunities to prevent transmission and decrease morbidity and mortality. However, significant challenges remain: we now understand that pathogen emergence is an ongoing process, and there are undoubtedly new HF viruses to be discovered. Rapid globalization, with massive international movement of humans, animals, and goods, and ongoing drastic human alteration of the global landscape bring daily risk of expanded transmission of HF viruses and other infectious pathogens. The massive outbreak of Ebola virus disease in West Africa in 2013–16 is a prime example. These processes will likely be further exacerbated by global climate change. The threat of bioterrorism with HF viruses poses yet another concern. Control of HF viruses will require further research and public health investment, especially in enhancing surveillance and expanding laboratory capacity, understanding the precise mode of transmission of each virus and its environmental stability, and collecting objective operational data on the effectiveness of various prevention methods. Effective disease control will likely require integration of the many prevention modalities available, including vaccination, reservoir and vector control, and alteration of human behavior.

See also: Arboviruses; Bioaerosols; Dengue; Re-emerging Diseases: Overview; Viral Infections, an Overview with a Focus on Prevention of Transmission; Yellow Fever.

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Economic Models of Hospital Behavior Satish Joshi, Michigan State University, East Lansing, MI, USA Ranjani Krishnan, Eli Broad School of Business, Michigan State University, East Lansing, MI, USA Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Xingzhu Liu, Anne Mills, volume 2, pp. 276–281, Ó 2008, Elsevier Inc.

Introduction

18 16 14

Canada

12 The United States

10 8

The United Kingdom

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Denmark

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2

Germany

0

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1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013

Health-care expenditure % GDP

Health care is one of the critical sectors of the economy and comprises a substantial portion of the GDP of most industrialized nations (Figure 1). For the past several decades, rising health-care costs have been a topic of intense debate, not only in the United States, but also in other countries of the world (Figure 2). According to projections by the U.S. Congressional Budget Office, health-care costs will exceed 40% of the US GDP by 2080. Within the health-care sector, the hospital industry is a major provider of services accounting for 30– 50% of total expenditures (Figure 3). Because of its critical economic as well as social role, the hospital industry has been extensively studied by health-care professionals, economists, sociologists, and business management scholars. Economics of health care is often called ‘abnormal economics’ because of the special nature of health-care

services which can be considered as either private goods, public goods, or merit goods depending on the context. Treatment of illness benefits the suffering individual directly, which is consistent with the nature of a private good. Treatment of communicable diseases and immunizations create obvious public benefits. Vulnerable populations such as children, elderly, the disabled, and possibly the poor and unemployed, can be considered deserving of health care regardless of their ability to pay, especially emergency care, as a merit good, i.e., as an ethical societal obligation. Uncertainty of illness, which implies consumers do not have free choice in its consumption, and market failures due to information gaps between consumers and health-care providers add another layer of complexity. These features of health care in turn call for different roles for the government and private markets, and health-care sectors in different countries have evolved depending on the predominant view of the

Current expenditure on health: percent of GDP. Source: OECD Health Statistics (2015).

10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0

Canada The United States The United Kingdom Denmark Germany 1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013

Health expenditure per capita US$

Figure 1

Figure 2

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Current expenditure on health per capita, US dollars purchasing power parity. Source: OECD Health Statistics (2015).

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60

Hospital share %

50 40

Canada

30

The United States Denmark

20

Germany 10

Japan

Figure 3

2013

2012

2011

2010

2009

2008

2007

2006

2005

2004

2003

2002

2001

2000

0

Hospital industry share of total health-care cost. Source: OECD Health Statistics (2015).

populace. Some countries consider health care primarily as a merit good, and as a result either provide or finance it universally, while other countries have a mix of public and private market health-care provision and financing. The hospital sector as a major provider of health-care services has also historically evolved in response to these societal/ political decisions. A substantial body of literature in economics examines the characteristics and behaviors of individual hospitals as well as hospital markets in general. While this literature has proposed numerous normative and positive models of hospital economic behavior, there is no consensus on what constitutes a generally accepted model. Challenges to developing such a generally accepted economic model of hospital behavior arise from the simultaneous presence of nonprofit, for-profit, and government hospitals, which have different missions, objective functions, yet provide similar services and compete for the same patient pool. Hospitals have complex production, cost, and revenue functions, because they treat a very wide variety of ailments and patients using numerous types of inputs, and receive revenues from an assortment of payers including individual patients, insurers, employers, donors, and governments. Rapid innovations in both clinical and business technologies have continuously altered hospital cost and production functions. Additionally, the hospital industry has been subject to massive regulatory changes in the last few decades. The most significant of these regulatory changes in the United States include the shift from cost-plus to fixed-price reimbursement structures under the prospective payment system (PPS) in the 1980s and the effects on both hospital and insurance markets from the Affordable Care Act (ACA) since 2010. The primary goal of the policy changes has been to ‘bend the curve’ and control the increasing healthcare costs while improving efficiency, effectiveness, and quality. These changes have also affected hospital cost functions, revenue functions, financial risk, and competitive market dynamics, and in turn hospitals have responded strategically to these external changes. This article provides a summary of the important features of the hospital industry, covering ownership pattern, objectives, cost and revenue functions, and the effects of competition and regulations on hospital behavior.

Theories of Hospital Behavior Hospital Ownership and Objective Functions A distinctive feature of the hospital industry is the presence of hospitals of different ownership types that compete in the same market and provide comparable services to a similar patient pool. The three major hospital ownership forms include nonprofit, for-profit, and government hospitals (Figures 4 and 5). Nonprofit hospitals are usually owned by religious

State and local government 22%

For profit 20%

Nonprofit 58%

Figure 4 Proportion of US hospitals by ownership type. Source: American Hospital Association Annual Survey of Hospitals, Hospital Statistics, 2009.

State and local government 16%

For profit 15%

Nonprofit 69%

Figure 5 Proportion of US hospital beds by ownership type. Source: American Hospital Association Annual Survey of Hospitals, Hospital Statistics, 2009.

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institutions such as the church, private philanthropic trusts, or educational institutions such as universities. For-profit hospitals are owned by individuals, partnerships, or corporations. Physician groups may, for example, own and operate a single for-profit specialty hospital. Corporations typically operate a chain of hospitals. Prior research concludes that, similar to for-profit business enterprises in other industries, for-profit hospitals emphasize the maximization of shareholder or owner value (Gray, 1986). Similarly, for-profit hospitals typically link compensation of hospital mangers to financial performance to motivate them to maximize profitability (Eldenburg and Krishnan, 2008). For-profit hospitals tend to have private board meetings and smaller governance boards consisting mostly of physicians and professional managers. A large number of hospitals are also owned and operated by federal, state, county, or municipal governments including veterans’ and military hospitals. Government hospitals typically obtain a higher share of indigent patients (as a result they are often referred to as ‘safety net’ or ‘last resort’ hospitals) and also provide higher levels of community education programs and outreach. Most government hospitals have soft-budget constraints, which imply that when a hospital’s costs exceed the budget, the government may offset the deficit; and if the hospital’s costs are below the revenues, the surplus may not remain with the hospital. Government hospitals are generally considered social welfare maximizers subject to bureaucratic behavior. In most countries, including the United States, Japan, Germany, and Britain, nonprofit hospitals are dominant players. The ability of the nonprofit form to survive and thrive is a feature of the hospital market that has garnered considerable interest among economists for a long time. An early theory that attempts to explain the predominance of the nonprofit hospital form is by Arrow (1963), who posits that the nonprofit hospital form arises from the asymmetry of information between the provider (hospital) and the recipient of service (patient). In the presence of information asymmetry and the latitude in determining the optimal level of care needed, the hospital has an incentive to ‘chisel’ the quality of service provided and increase its revenues/profits, and the patient may not be in a position either to prove that such exploitation occurred or take effective precautions. The nonprofit organizational form mitigates such information problems by establishing trust. The nondistributional constraint enables the nonprofit hospital to provide a credible signal that it is not interested in profit maximization at the cost of the recipient’s welfare. Following Arrow (1963), a large body of literature on hospital objectives and cost functions emerged in economics. Chang and Jacobson (2010) categorize the literature on nonprofit hospital objective functions into four streams: (1) for-profits in disguise, (2) output maximizers, (3) perquisite maximizers, and (4) social welfare maximizers. The ‘for-profit in disguise’ theory refers to nonprofits that are able to effectively provide a façade to tax authorities, but in reality exist for the benefit of the managers and the board. That is, these nonprofits abuse the nonprofit status for their own financial advantage. This theory posits that ambiguous and lax legal and tax enforcement allows nonprofits to act as profit maximizers with little adverse consequences

(Weisbrod, 1988). Although in theory this appears plausible, demonstrating empirical evidence of whether such abuse exists and calibration of the extent of abuse is far from straightforward. Determination of what constitutes ‘welfare leakage’ and the measurement thereof is difficult. One empirical model used to test the ‘for-profit in disguise’ theory is to examine the differences between nonprofits and for-profits in the provision of unprofitable activities such as charity and education. This literature explores the convergence and divergence in the behaviors of for-profit and nonprofit hospitals and finds equivocal results. Some research has found empirical support of convergence, i.e., little to no differences in charity care or bad debt expense among for-profits and nonprofits (Gaumer, 1986; Norton and Staiger, 1994). However, many other empirical studies support the divergence theory suggesting: nonprofit hospitals provide substantially higher unprofitable services relative to for-profits (Horwitz, 2005); nonprofit hospitals have a higher proportion of unprofitable services in their product mix; and following a merger, for-profits spin off a larger share of their unprofitable patients (Krishnan et al., 2004). Convergence tends to be higher when the hospital market competition is high, indicating that convergence is a strategy to enable nonprofits to survive in a competitive market. In most analyses of convergence/divergence, government hospitals have been either excluded or included with the nonprofit sample. Newhouse (1970) proposed the ‘output maximizer’ theory, and hypothesized that nonprofit hospitals seek to maximize quantity and quality of services provided, subject to a break-even constraint. The ‘medical arms race’ phenomenon observed during the 1970s and 1980s wherein, higher competition in hospital markets was associated with higher cost and higher quality of care, which is contrary to the predictions of conventional neo-classical economics, is supportive of the output maximizer model. In an era of cost-plus reimbursements, hospitals are insensitive to the cost of providing service. To attract physicians and thereby the patients, hospitals provided higher than optimal levels of technology, a wide range of facilities and amenities, and targeted promotion schemes to build brand loyalty among physicians, culminating in a medical arms race. As a result, there were huge service duplications and excess capacity, especially in highly competitive markets. The ‘perquisite maximizer’ theory argues that hospitals operate to maximize the welfare of physicians (Pauly and Redisch, 1973). This theory contends that physicians effectively control the hospital because they have authority over patient admissions, resource allocation, and the quality and quantity of outputs. Physicians’ decisions are designed to maximize their personal utilities, rather than the efficiency of the hospital. Physicians distort the production function to maximize their income and perquisites (such as technology and facilities). Indeed, extending this argument, physicians also exercise considerable control over medical regulation. Restricting the entry of foreign medical graduates, and maintaining strict control over the medical certification process, serve to maximize physicians’ incomes. The perquisite maximizer theory contends nonprofit hospital form facilities such as maximization of physician income without opposition from shareholders.

Economic Models of Hospital Behavior The ‘social welfare maximizer’ theory argues that hospitals are nonprofit because their founders/managers have altruistic motives. This theory, which has its roots in Arrow (1963), argues that the nonprofit form is the optimal response to the information asymmetry between the provider and the patient. The nonprofit form not only facilities trust, but also ensures that the provider does not exploit the noncontractible information advantage at the cost of the patient’s welfare. The nonprofit form also attracts altruistic managers. The empirical evidence that nonprofits provide higher level of uncompensated care whereas for-profit are more likely to adopt policies to discourage admission of uninsured patients supports the social welfare maximization theory. Frank and Salkever (1991) further refine the social welfare maximizer theory and model two alternative models: (1) an impure altruism model and (2) a pure altruism model. In the former model, the hospital’s utility function includes profit as well as charity components. If another hospital increases its provision of uncompensated care, it ‘crowds out’ the hospitals’ level of charity care. In the latter model, hospitals compete for charity patients and therefore may take a lessdeserving patient to compensate for the loss of a charity patient. In sum, many factors drive the dominance of the nonprofit ownership form including information asymmetry, physician dominance, competition for patient quantity, and altruistic motives of managers. However, regardless of the ownership form and the objective functions, hospitals in order to survive and thrive as economic entities have to manage their costs and revenues. The next section summarizes the nature and behavior of hospital cost functions, followed by a discussion on hospital revenue management.

Hospital Cost Behavior Hospital Cost Functions There is considerable literature on hospital cost functions, which has analyzed several aspects of hospital cost behavior such as economies of scale and scope, shapes of short run and long run average cost and marginal cost curves, input factor substitutions, cost elasticity, and cost stickiness. Literature has also examined the effect of regulation and technology in shifting hospital cost functions. Despite the large size and sophistication of extant literature, generalizable consensus about the nature of hospital cost functions is lacking. Indeed even in two of the most extensively researched topics related to the hospital cost function, i.e., scale and scope economies, there is little consensus. Reasons cited for the mixed findings include the tremendous variety in patient care needs that impedes precise calibration of output units as well as the difficulty in aggregating from an individual patient to the hospital as a whole. The limitations of relatively parsimonious empirical specifications employed in the past literature, have been addressed in recent studies by more expansive or targeted empirical models, but the findings regarding scale/scope economies continue to be mixed. Recently, research has explored the effect of uncertainty on cost structure, and finds empirical evidence that hospitals respond to increased uncertainty imposed by regulatory and competitive pressures by making their cost structure more flexible. Holzhacker et al. (2015) find evidence that changes

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in environmental uncertainty, resulting from indemnity to prospective methods of payment, are associated with an increase in cost elasticity (that is the ratio of variable costs to total cost). Further, they also find that hospitals respond to uncertainty and regulatory changes by decreasing cost stickiness. Cost stickiness occurs when costs tend to increase to a greater extent with an increase in activity compared to the extent of cost decline when activity falls by an equivalent amount. Research also has explored the mechanisms through which changes to cost structure occur, which include outsourcing, changes to the composition of labor, technology, leasing versus purchasing of assets, and factor substitution.

Medical Technology and Cost Growth Medical technology changes in terms of new drugs and diagnostic techniques, new procedures, or new knowledgeinduced changes in diagnostic or treatment practice can alter hospital cost functions by changing the factor input mix, effectiveness of treatment and side effects, while creating increased demand for the new products. Some of these technology changes can reduce costs due to more efficient use of resources or substitution of costly alternatives (substitution effects), but others can create more expensive treatment pathways that can contribute to increased costs and overall spending, but justifiable by improved health outcomes (complementary effects). Overall impact of medical innovation on cost and total expenditure is the net effect of these complementary and substitution effects. A number of empirical studies have attempted to estimate the contribution of medical technology changes to the growth in health-care costs by employing two general approaches. The ‘residual approach’ attributes the residual growth in spending after accounting for all other potential growth factors such as inflation, population changes, spread of insurance, income changes etc., to medical technology changes. In comparison, the ‘affirmative’ approach attempts to track complementary and substitution effects of specific medical technologies. Both methods have well-recognized strengths and weaknesses. The consensus from the empirical studies employing both approaches is that medical technology changes are major contributors to the increase in health-care costs and spending, with individual study estimates of technology change contribution ranging from 27% to 70% (Chernew and Newhouse, 2011).

Medical Information Technology Traditionally, the hospital industry has been proactive in employing information technology to enhance efficiency and to improve health outcomes. Hospitals have witnessed tremendous changes to technology including, electronic health records, business and clinical decision-support systems, health information exchanges, computerized prescriptions in partnership with pharmaceuticals, and telemedicine. Social media has revolutionized the dissemination of information about hospital outcomes and patient care experiences. Big data analytics provides the ability for hospitals to process large quantities of real time and variegated data and use it for

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decision making. Hospitals have also begun to leverage analytics and information technology to provide evidencebased medicine and to develop clinical pathways that deliver the most effective order of treatment interventions based on the characteristics of the individual patient. The effect of information technology on hospital outcomes has been extensively studied, but the results have been inconclusive. Part of the challenge arises in developing appropriate empirical methods, and the difficulty in identifying and isolating the contributions of information technology from other hospital-level factors. Furthermore, the returns from hospital investments in information technology are subject to long lags before becoming widely accepted and effective, and often contingent on the hospital’s environment and patient privacy concerns.

Regulatory Environment and Hospital Revenue Behavior Health-care markets in most developed counties are highly regulated, because of the mixed nature of health-care services, which can be considered as either private, public, or merit goods; market failures due to information gaps; and the risky nature of illnesses which demand creation of efficient insurance markets and appropriate risk pooling. Most of these regulations directly affect hospital revenue functions because a large portion of fees for hospital services are received from government insurance programs or regulated private health insurance programs.

Regulatory Changes to the US Hospital Industry A substantial proportion of patients (about 40%) admitted in US hospitals are over the age of 65 years, and therefore covered by public insurance programs, particularly Medicare. About 5% of patients are covered by Medicaid, which is another public insurance program that provides insurance for children under the age of 18 years, pregnant women, and disabled individuals. Private insurance programs usually mirror the structure of public programs, particularly with respect to setting reimbursement rates and reimbursement mechanisms. For example, it is common for private insurance patients to negotiate ‘Medicare rates’ with hospitals. The method of payment for hospitals services for patients covered by public insurance programs has witnessed considerable changes, which has direct impacts on hospital revenue and cost functions. We can classify the major price-regulatory changes for Medicare patients that have occurred over the last 50 years into three phases – the indemnity phase, the PPS phase, and the ACA phase. The first price-regulatory phase that lasted until the mid1980s was the indemnity phase wherein hospitals were reimbursed for their costs of treating patients based on the actual cost of treatment plus a mark-up to buffer against risks. Because cost-plus reimbursement provided no incentives to be efficient, hospitals started competing on the basis on quality, which ushered a period of rapidly rising costs. Because of health insurance, the patient was not the payer and therefore demand was not price sensitive. During this period, hospitals competed to offer superior technology and extensive services to attract doctors and their patients resulting in the ‘medical arms race.’

By 1980, there were increasing concerns about the excessive inflation in health-care costs. In response, the PPS price regulation was introduced in 1983. Under the PPS, ailments and treatments were classified into diagnosis-related groups or ‘DRGs.’ Hospitals received a fixed amount per DRG, based on the national average cost of treating a patient in that DRG, with some adjustments for the cost of living of the area where the hospital was located, the proportion of indigent patient population, and teaching status. The PPS caused a massive shift to hospital revenue functions. Previously hospital revenues functions matched their cost functions, but under the PPS, hospital revenues were capped. As a result, the risks of cost overruns, which had been entirely borne by Medicare and other insurers, now completely shifted to the hospitals. PPS changed the nature of competition in the industry from quality to cost. A large body of literature has examined the effect of PPS on hospital behaviors and outcomes. Overall, the PPS resulted in the following outcomes. a. large and steady decrease in the lengths of stay for hospital inpatients; b. an increase in the proportion of outpatients; c. shifting of costs from fixed-fee services to services that were still indemnity based (such as specialized procedures and outpatient care); d. substantial merger and acquisition activity in the hospital sector aimed at increasing the price negotiating power with insurers and other payers; e. reduced access to unprofitable services such as trauma care and drug detox, because of changes in hospital service mix, selective closures, and relocation. f. marginal slowing down of health-care cost inflation rate; g. marginal increases in productivity; h. large variability in margins across hospital types and hospital markets; i. increased use of bonus-based compensation contracts aimed at increasing managerial effort toward improving hospital efficiency. The third and most recent regulatory change is the Patient Protection and ACA signed into law in 2010. The ACA has three broad components, which influence health insurance markets and individual citizens. First, it includes changes to the nongroup insurance market by disallowing discriminatory practices such as exclusions for preexisting conditions, and limiting the ability of insurers to charge differential prices by health status. Second, like in most EU countries, the ACA requires individual citizens to have insurance coverage or to pay a penalty. Third, low-income families can obtain insurance coverage through government subsidies. Two provisions of the ACA have substantial influence on hospital revenue functions. First, the ACA began phasing in reductions in Medicare reimbursement by diminishing the annual Medicare inflation adjustment. Second, it introduced a pay-for-performance system through the value-based purchasing (VBP) program. The VBP program measures hospital quality on four dimensions: patient satisfaction, medical outcomes, process protocols, and cost efficiency. Based on their national performance, hospitals could receive upward or downward adjustments to their DRG base rate. Specifically, high-performing hospitals could receive an upward adjustment

Economic Models of Hospital Behavior of up to 1% while poorly performing hospitals could receive a 1% reduction to their DRG base rate. The 1% bonus/penalty is slated to increase to 2% by 2017. Operation of health-care exchanges under the ACA, where individuals can choose to buy health insurance from a number of competing offers, will change the nature of health insurance business, which previously negotiated group insurance policies mainly with large employers and other groups. Thus the ACA has implications on the demand side (through health insurance) as well as the supply side (through hospital-based incentives and quality measurement), which can have major influences on health-care markets in the future.

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in the health-care system. Research indicates that many hospitals avoid admitting high-risk and low-profit patients, who then end up in public hospitals or fall out of the health system with obvious negative implications on the aggregate health of the country. Research analyzing the implications for the hospital and insurance industries, due to large-scale purchases of health insurance by individuals through health-care exchanges under the ACA is warranted. Significant horizontal and vertical consolidation occurring in the hospital industry in response to regulatory pressures for cost control, has resulted in increased market power and bargaining power with insurers and other payers. Antitrust treatment of hospital consolidation, especially by nonprofit hospitals needs attention.

Conclusions and Future Research In this article, we discuss the key research questions addressed in the literature related to hospital economics. While there is consensus in some topics, a vast majority of the topics related to hospital costs and the impact of regulations have found equivocal results. Empirical challenges arise from complex hospital production functions, ambiguous objective functions, multiplicity of outputs, constant changes in technology, and an array of negotiated/regulated prices and copays which may vary even for similar services within the same hospital. Defining relevant hospital markets is difficult because hospitals tend to be local monopolies for some services, especially emergency care, but compete regionally or nationally for specialized or discretionary procedures. Health care in general is a wicked problem because of the value judgments involved at all stages beginning with the nature of health-care services as goods (i.e., private/public or merit?) and the appropriate role of private markets, nonprofits and the government, to deciding on the metrics for evaluating hospital performance. As a result, the health-care sector is characterized by heterogeneity of systems/approaches adopted by different countries and subnational units, and constant tweaking of structures, regulations, incentives, and policies, in search of the optimal balance between cost efficiency, effectiveness, access, equity, privacy, and personal choice. Hospitals as the primary deliverers of health-care services have been constantly adapting to these policy changes. Research is needed to compare, contrast, and synthesize results from the number of policy experiments across the globe, and to draw generalizable lessons. The latest in the series of such grand policy experiments is the ACA in the United States, which if it survives the various administrative and legal challenges, is expected to reshape the US health-care system. Because these changes have occurred very recently, comprehensive studies of the effect of ACA on hospital revenues, costs, and outcomes are just emerging. For example, research can not only examine if the ACA can reduce health-care costs, but also explore the mechanisms by which such changes to cost can occur. These could include reductions in the demand for unnecessary procedures and more effective use of technology. The quality-based penalties and bonuses have the potential to increase health-care quality and reduce subsequent hospitalizations for the same ailment. However, quality-based incentives can also lead to changes in the way high-risk patients get allocated

See also: Community Health Insurance in Low- and MiddleIncome Countries; Equity in Health Financing; Governance Issues in Health Financing.

References Arrow, K., 1963. Uncertainty and the welfare economics of medical care. Am. Econ. Rev. 53, 941–973. Chang, T., Jacobson, M., 2010. What Do Nonprofit Hospitals Maximize? Evidence from California’s Seismic Retrofit Mandate. National Bureau of Economic Research, Cambridge, MA. Chernew, M.E., Newhouse, J.P., 2011. Healthcare spending growth. In: Pauly, M.V., McGuire, T.G., Barros, P.P. (Eds.), Handbook of Health Economics, vol. 2. North Holland-Elsevier, Amsterdam, pp. 1–43. Eldenburg, L.G., Krishnan, R., 2008. The influence of ownership on accounting information expenditures. Contemp. Account. Res. 25 (3), 739–772. Frank, R.G., Salkever, D.S., 1991. The supply of charity services by nonprofit hospitals: motives and market structure. RAND J. Econ. 430–445. Gaumer, G., 1986. Medicare patient outcomes and hospital organizational mission. In: Gray, B.H. (Ed.), For Profit Enterprise in Health Care. National Academy Press, Washington, DC, pp. 354–374. Gray, B., 1986. The For-Profit Enterprise in Health Care. National Academy Press, Washington, DC. Holzhacker, M., Krishnan, R., Mahlendorf, M.D., 2015. Unraveling the black box of cost behavior: an empirical investigation of risk drivers, managerial resource procurement, and cost elasticity. Account. Rev. 90 (6), 2305–2335. Horwitz, J.R., 2005. Making profits and providing care: comparing nonprofit, for profit, and government hospitals. Health Aff. 24 (3), 790–801. Krishnan, R., Joshi, S., Krishnan, H., 2004. Effects of mergers on firms’ product mix strategies. Strateg. Manag. J. 25, 587–611. Newhouse, J.P., 1970. Towards a theory of non-profit institutions: an economic model of a hospital. Am. Econ. Rev. 60, 87–92. Norton, E.C., Staiger, D.O., 1994. How hospital ownership affects access to care for the uninsured. RAND J. Econ. 25 (1), 171–185. OECD Health Statistics, 2015. http://www.oecd.org/health/health-data.htm. Pauly, M.V., Redisch, M., 1973. The not-for-profit hospital as a physician’s cooperative. Am. Econ. Rev. 63, 87–99. Weisbrod, B.A., 1988. The Nonprofit Economy. Harvard University Press, Cambridge.

Further Reading Blumenthal, D., Abrams, M., Nuzum, R., 2015. The Affordable Care Act at 5 years. N. Engl. J. Med. 372 (25), 2451–2458. Congressional Budget Office, 2007. The Long-Term Outlook for Health Care Spending. Congressional Budget Office, Washington, DC. Devraj, S., Kohli, R., 2000. Information technology payoff in the health-care industry: a longitudinal study. J. Manag. Inf. Syst. 16 (4), 41–67.

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Dranove, D., Shanley, M., White, W., 1993. Price and concentration in hospital markets: the switch from patient-driven to payer-driven competition. J. Law Econ. 36, 179–204. Pauly, M.V., McGuire, T.G., Barros, P.P., 2011. Handbook of Health Economics, vol. 2. Elsevier, Amsterdam. Porter, M.E., Teisberg, E.O., 2006. Redefining Health Care: Creating Value-Based Competition on Results. Harvard Business School Publishing, Boston, MA. Shleifer, A., 1985. A theory of yardstick competition. RAND J. Econ. 16 (3), 319–327. Sloan, F.A., 2000. Not-for-profit ownership and hospital behavior. In: Culyer, A.J., Newhouse, J.P. (Eds.), Handbook of Health Economics, vol. 1. Elsevier Science, Amsterdam.

Relevant Websites http://www.ahrq.gov/ – Agency for Healthcare Research and Quality (accessed 18.06.16.). http://www.aha.org/research/index.shtml – American Hospital Association – Research (accessed 18.06.16.).

http://www.oshpd.ca.gov/ – California Office of Statewide Health Planning and Development (accessed 18.06.16.). http://www.euro.who.int/en/about-us/partners/observatory – European Observatory on Health Systems and Policies (accessed 18.06.16.). http://www.kff.org – Kaiser Family Foundation (accessed 18.06.16.). https://www.data.medicare.gov/ – Medicare Datasets for Researchers (accessed 18.06.16.). http://www.nashp.org/ – National Academy for State Health Policy (accessed 18.06.16.). https://www.nlm.nih.gov/hsrinfo/index.html – National Institute of Health – Health Services Research Information Central (accessed 18.06.16.). http://www.oecd.org/health/ – OECD Country Health Statistics and Reports (accessed 18.06.16.).

Ectoparasites Richard J Pollack, Harvard University, Cambridge, MA, USA; Harvard T.H. Chan School of Public Health, Boston, MA, USA; and Identify US LLC, Newton, MA, USA Daniel Engelman and Andrew C Steer, Centre for International Child Health, Murdoch Childrens Research Institute, University of Melbourne, Royal Children’s Hospital, Melbourne, VIC, Australia Scott A Norton, Children’s National Health System, Washington, DC, USA; and George Washington University, Washington, DC, USA Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Hermann Feldmeier, volume 2, pp. 282–294 Ó 2008, Elsevier Inc.

Scabies Scabies is a ubiquitous ectoparasite and common cause of skin disease globally. Human scabies is a significant public health issue, particularly in tropical and resource-poor settings, and in institutional settings in industrialized countries. Although scabies has traditionally been a neglected disease, there is potential for progress toward global control.

Life Cycle and Transmission Human scabies is caused by the ectoparasitic mite Sarcoptes scabiei var. hominis. The female mite burrows into the epidermis and lays up to four eggs per day for 6 weeks before dying. Larvae hatch 2–4 days after the eggs are laid, and development from egg to adult takes 2 weeks. The parasite burden of patients is usually low, around 10–15 mites. However, in the severe form of disease known as crusted (Norwegian) scabies, patients have extremely high mite burdens of thousands of mites. Transmission most commonly occurs through prolonged skin-to-skin contact, particularly within families and households, but also through sexual contact. Successful direct transmission takes 15–20 min of close contact. It appears that either immature or adult females may be capable of humanto-human transmission. Mites are able to survive and remain infective off the host for up to 36 h in temperate conditions, but survival may be longer in high humidity. Below 20  C (68  F), mites can survive off the host longer, but are immobile and cannot penetrate into the skin. Therefore, under normal conditions, fomites (commonly bedding and clothing) are unlikely to play a significant role in transmission. In classic experiments in the 1940s, Mellanby (1941) showed that transmission was infrequent when unclothed volunteers climbed into warm beds just vacated by patients with normal mite loads. In contrast, fomites may be more important in transmission from patients with a high parasite load, such as those with crusted scabies. Sarcoptes scabiei is thought to be a single species that has evolved into genetically distinct mite populations affecting a variety of mammalian hosts. Cross-infectivity between host species, however, is limited (Walton et al., 1999). Therefore, although scabies can affect domestic animals such as pigs and dogs, human infestation with mites of animal origin is self-limiting as these mites are unable to reproduce, and usually the infestation will resolve without treatment. Scabies mites promote their own survival by depressing host inflammatory and immune responses. Infestation promotes secondary bacterial infection through direct breach

International Encyclopedia of Public Health, 2nd edition, Volume 2

of the stratum corneum (the outermost barrier layer of the epidermis) as well as via molecular mechanisms, including inhibition of complement (Swe et al., 2014).

Epidemiology Scabies occurs in every country, yet the greatest burden is seen in countries with warm, humid climates, especially in the tropics. Estimates of the global burden are limited by scarce prevalence data, although it has been estimated that more than 100 million people are infested at any time (Vos et al., 2012). Scabies may occur as a sporadic disease, in epidemics or exist endemically. Sporadic cases are typically observed in industrialized countries, and epidemics mainly occur in institutional settings or in socially deprived groups. Scabies is endemic in many resource-poor communities of the developing world, with an average prevalence of 5–10% in children (World Health Organization, 2005). In developing countries, scabies is unevenly distributed and tends to disproportionately affect the most vulnerable and poor, including children, elderly, institutionalized and disabled people. In selected communities, particularly tropical areas in the Pacific and Northern Australia, prevalence has been documented up to 50%. The differences in distribution sometimes observed between sexes and racial groups likely represent sociocultural and behavioral practices rather than any intrinsic differences in susceptibility. Overcrowding, particularly of sleeping areas, contributes to mite transmission. Residential institutions and other closed, crowded communities may have a high baseline prevalence. Some reports have identified 30–90% prevalence in displacement camps, welfare homes, and orphanages. Outbreaks of even more widespread infestation are common, especially in nursing homes. Poor hygiene is not a significant factor for infestation. Mites burrowed in the epidermis continue to be viable even after daily hot baths and regular use of soap. In temperate zones, rates of infestation are higher in the cooler seasons, probably related to increased host crowding and prolonged mite survival at lower temperatures. Although scabies was once thought to occur with regular, cyclical hyperendemic peaks (the so-called ‘7-year itch’), long-term studies suggest epidemics and observed fluctuations are related to the multiple factors described above. The high endemic prevalence, without seasonal variation, observed in warm, humid climates suggests herd immunity does not play a significant role.

Clinical Presentation The predominant symptom of human scabies is itch, which results from a delayed hypersensitivity reaction to mite excreta

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and presents within 6 weeks of primary infestation, but much sooner, within days, of subsequent infestations. The itch may be intense, is often perceived as worse at night, and can severely affect sleep and quality of life (Walton and Currie, 2007). In communities with endemic scabies, families may spend a significant part of their income on treatments for scabies (Hay et al., 1994). The primary skin manifestations include burrows, papules, and nodules. The characteristic burrow features a short wavy line, representing the course of the mite in the epidermis. Small, erythematous papules are the most common lesions, sometimes developing into vesicles. Nodules are less common but highly suggestive, and may persist for several months after successful treatment. In older children and adults, scabies lesions are most commonly seen on the hands (between fingers), volar wrists, elbows, axillae, ankles, genital area, buttocks, and nipples. In infants, the scalp and head may also be involved and lesions on the palms and soles are more common (Boralevi et al., 2014). Secondary dermatologic signs arise from scratching and bacterial superinfection. Excoriations from scratching may be widespread. Secondary infection is common, particularly in tropical areas, due to Streptococcus pyogenes and Staphylococcus aureus, frequently causing impetigo, and less commonly cellulitis and abscess formation. This bacterial infection then predisposes to serious systemic complications, including sepsis and invasive infection, acute poststreptococcal glomerulonephritis, and possibly acute rheumatic fever (Parks et al., 2012). Glomerulonephritis contributes to chronic kidney impairment, accompanied by proteinuria and elevated blood pressure, in adulthood (Hoy et al., 2012). These conditions cause a huge public health burden in many developing countries and are partly attributable to the cascade of events that follow infestation with scabies (Figure 1). Crusted scabies is a severe form of the disease, usually seen in patients with immunosuppression or neurological conditions such as infections with human immunodeficiency virus or

human T-cell lymphotropic virus type 1, iatrogenic (e.g., posttransplant) immunosuppression, Down syndrome, and developmental or intellectual disabilities. Of note, crusted scabies is also reported in Aboriginal Australians without identifiable immunodeficiency. Patients typically have thousands of mites in exfoliating scales and crusts, in similar areas to typical scabies, although the face, ears, and nails may also be involved. Generalized lymphadenopathy is common and mortality is often high, particularly due to secondary sepsis.

Diagnosis and Differential Diagnosis Diagnosis remains reliant on clinical manifestations in most settings and is based on the appearance of consistent skin lesions in a typical anatomical distribution with pruritus (Figure 2). A single burrow is pathognomonic and may be demonstrated by rubbing a felt-tip pen across the site and removing the ink with an alcohol wipe. However, in practice, burrows are often obliterated by scratching, formation of crusts, or superinfection and are infrequently seen in tropical areas. The clinical diagnosis of scabies is supported when another member of the household has similar symptoms and signs. Clinical diagnostic algorithms have been developed in Mali (Mahe et al., 2005) and Fiji (Steer et al., 2009), along with packages for training health workers to diagnose common skin conditions. The diagnosis can be confirmed through skin scrapings of burrows, using direct microscopy of scrapings mounted in potassium hydroxide (KOH) or mineral oil to identify mites, ova, or feces. The technique requires considerable expertise and time, and even then the sensitivity may be low. Dermoscopy (epiluminescence microscopy) may improve diagnostic yield, but has not been formally evaluated in tropical settings and is technically more difficult in dark-skinned people. Furthermore, the dermatoscope’s cost is prohibitive for clinical

Figure 1 Complications of scabies in resource-poor settings. Modified from Engelman, D., Kiang, K., Chosidow, O., et al., 2013. Toward the global control of human scabies: introducing the international alliance for the control of scabies. PLoS Negl. Trop. Dis. 7, e2167.

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Figure 2 Romani.

Typical appearance of scabies. Photo courtesy of Lucia

use in most resource-poor settings. Accurate diagnostic or serological tests have not yet been established. The clinical signs and symptoms of scabies can mimic many skin diseases, such as atopic dermatitis (eczema), allergic and irritant contact dermatitis (including reactions to topical treatments), bacterial impetigo, arthropod bites, and hypersensitivity reactions (including papular urticaria, id reactions, and papular pruritic eruption of HIV infection). Acute papular onchocerciasis should be considered in onchocerciasisendemic regions. Crusted scabies may be misdiagnosed as psoriasis.

Treatment Treatment of all cases and their close contacts remains the mainstay of case management. Several topical acaricides are effective. Selection of drug is frequently based on local availability and cost rather than efficacy. Permethrin 5% cream is the most effective (Strong and Johnstone, 2007), and therefore the first choice in many industrialized countries, but is prohibitively expensive for many other settings. Benzyl benzoate 10–25% preparations are more affordable and used widely. It can cause transient local irritation and burning and should be diluted with water to 6.25% for infants. Malathion 0.5% is uncommonly used outside of the United Kingdom. Crotamiton 10% cream is

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safe for infants, but less efficacious and also less practical as it requires repeat applications for 3–5 days. Lindane 1% is also effective but has been withdrawn from some markets due to risk of neurological complications and aplastic anemia, particularly in children, pregnant women, and when misused. Sulfurcontaining ointments (2–10%) are the only available treatments in some regions, but may not be well accepted as they are messy, malodorous, and cause local irritation. Topical agents are applied from the neck down, avoiding eyes, mouth, and nonintact skin for the recommended duration, and then washed off. Treatment should include the scalp for infants and the elderly. All household contacts should be treated, even if asymptomatic, to contain spread and limit reinfestation. All treatments are more likely to be effective if correctly applied and repeated after 7–14 days. Overtreatment should be avoided and can itself cause local irritation that may be mistaken for persistent infestation. Patients should be advised that itch and some irritation can occur for up to 2 weeks following successful treatment, due to ongoing hypersensitivity, scratching, and eczematization. This can be managed with oral antihistamines, emollients, or cautious use of topical steroids if required. Because of low acceptance of the topical treatments, adherence may be poor or application suboptimal, especially in contacts. Relapses – for individuals and entire households – are therefore common. There is emerging evidence of resistance to some of the treatments currently in use, but this is unlikely to be a major factor in clinical treatment failure. Oral ivermectin is also highly effective for scabies. Ivermectin has been administered to many millions of people as part of control campaigns for onchocerciasis and lymphatic filariasis and is considered very safe. However, there is a paucity of safety data regarding use during pregnancy, lactation, or in young children (50%. Approximately 70 countries support the life cycle of human tungiasis. Many case reports from nonendemic countries describe recent travelers and immigrants who arrived with Tunga infestations acquired in endemic areas. In addition, reports of tungiasis acquired on the coasts of Italy and India raise the possibility of spread to new areas as well. Tunga penetrans is widespread in poorly resourced communities in rural and urban areas, in villages along coasts and rivers, farmlands in the interior, and in urban slums. Tungiasis is associated with poor living conditions and poverty, where people go barefoot or wear open shoes at and around home and in the fields. It thrives best where soils are dry and sandy, or in moister environments, farms, and forests, where the soil is very well drained. The highest seasonal prevalence and greatest numbers of lesions per person occur in the dry season. One

Ectoparasites of the greatest risk factors is poor housing, especially where peridomestic animals, e.g., dogs and cats, as well as rats, have free access to the home’s interior. In rural areas, pigs are common reservoirs.

Clinical Presentation The natural history of tungiasis has been divided into five stages, called the Fortaleza classification, named after the city in Northeastern Brazil where tungiasis is hyperendemic and many studies have been conducted (Eisele et al., 2003). In stage I, the young adult flea penetrates the epidermis and appears as a minute, 1 mm diameter red-brown macule. In stage II (1–2 days after penetration), the abdominal segment of the parasite hypertrophies, in a process called neosomy, and develops into a round, slightly elevated, lens-shaped papule. The central area appears as a central black dot, from which the flea’s anogenital cone protrudes slightly. The black punctum is surrounded by a white rim of thinned epidermis. There are usually clusters of lesions; if these are adjacent, the borders of individual lesions are obscured and the cluster takes on a honeycombed appearance. In stage III (2 days to 3 weeks after penetration), the uterus is fully enlarged and constitutes nearly the entire body mass of the flea. The papule is roughly 5–7 mm in diameter, the size of a pea, and is often exquisitely tender. Individual lesions have a strikingly uniform appearance: a round, white, slightly elevated or edematous, 4–10 mm diameter papule, with a central black punctum. The surface is often hyperkeratotic and accompanied by desquamation of the surrounding skin. At this time, the eggs are released and fall to the ground. In stage IV (3–5 weeks after penetration), the adult female, free of its eggs, dies and the lesion begins to involute. A black hyperkeratotic crust covers the dead parasite and is eventually sloughed off, leaving a residual shallow, punched out depression (stage V) in the stratum corneum that may persist for several months. Although tungiasis is a self-limited infestation, secondary complications are common. Pain from the expanding abdominal segment, along with deep epidermal fissures, inflammation, and secondary infection, commonly impede normal ambulation. Sequelae include deformation and loss of toenails, as well as deformation of digits. The open punctum, caused by the protruding rear end of the flea, is an entry point for microbial pathogens. Bacterial superinfection is practically the norm, leading to pyogenic infections, abscesses, and cellulitis. Staphylococcus aureus and streptococci, as well as soil-based fecal bacteria, aerobic and anaerobic, easily enter the bare skin. In incompletely vaccinated individuals, tetanus may occur. Deaths associated with tungiasis are usually the consequence of tetanus or bacterial septicemia.

Diagnosis Within hyperendemic areas where the condition is well known, the diagnosis is usually obvious and is made by the infested individual or their family members, rather than by members of the medical or public health sectors. The diagnosis is based on the clinical picture, taking into account the location, number, and evolving morphology of lesions.

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Most lesions appear on periungual or interdigital skin of the feet. Individual lesions have a classic morphology but they are often clustered together to form a pitted or honeycombed texture on the surface. Even in the nonendemic medical setting, the diagnosis can usually be made clinically. During examination, light pressure on the lesions may provoke extrusion of the eggs or feces. A magnifying instrument, such as a dermatoscope, can make the central pore, protuberant anogenital apparatus, expelled eggs, and spiral-shaped fecal threads more obvious. A confirmatory biopsy is rarely required. Differential diagnoses include inflamed plantar warts, acute bacterial paronychia, pyogenic infection/abscess, infected insect bites, infected foreign bodies, foreign body reaction with hemorrhage (from a wood sliver, sea urchin spine, metal fragment), cutaneous larva migrans, myiasis, epidermal cysts, melanoma or squamous cell carcinoma, deep fungal infections (chromoblastomycosis or mycetoma), tache noire (from a tick bite), or poxvirus lesions.

Treatment Although tungiasis is naturally self-limited and will resolve if left untreated, the discomfort associated with it prompts most people to pursue treatment. The most common practice in poorer communities is crude mechanical removal of the embedded flea, usually by the patient, who uses a sharp object to unroof the lesion, then probe and tease out the egg mass and adult flea. Removal should be done soon after penetration to prevent onset of pressure-associated pain and to avoid secondary infections. In a health-care setting, the recommended procedure is mechanical extraction of the flea under sterile (or near sterile) conditions. This requires good lighting, a skilled hand, and good eyesight. The epidermal punctum must be opened carefully with an appropriate instrument such as a sterile needle or a scalpel to enable the extraction of the entire flea as a single, intact specimen. After extraction, one should irrigate the lesion with sterile saline and cover the sore with a topical antibiotic. Tetanus immunization status should be verified and, if inadequate, appropriate immunization or prophylaxis is indicated. If the flea is torn or ruptured during extraction or if the deep mouthparts remain behind, severe inflammation ensues. At present, there is no universally reliable oral or topic medication with satisfactory therapeutic efficacy. There are mixed reports with two agents, ivermectin and thiabendazole, that have been tried both orally and topically. Local or traditional topical remedies, often with hydrocarbons, tar, silicone/dimethicone lubricants, are often tried. Two treatment-related public health concerns include the reuse of nonsterile instruments among patients, which increases risk of inadvertent transmission of hepatitis or HIV viruses. Also, some people use hazardous agricultural pesticides on their skin to kill the fleas.

Prevention Personal measures to prevent tungiasis include wearing of closed shoes and socks, although complete protection cannot be achieved by these means. Nevertheless, this may be impractical in areas where barefoot and open shoes are the norm in

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and around the house. Daily inspection of the feet and early extraction of embedded fleas protects against complications. Household measures to prevent tungiasis include maintaining clean floors by regular sweeping and by use of pyrethrum products, repellant oils, and other household-approved pesticides. In addition, preventing domestic and peridomestic animals from wandering in and out of homes will reduce the release of eggs into the home. Inspecting and treating these animals will reduce the egg burden, too. An episode of tungiasis does not provide immunity or protection from future infestations.

Control Widespread community control and prevention of tungiasis is daunting. Eggs, larvae, and pupae may persist in homes and the environment for weeks, possibly months. The ubiquity of animal reservoirs nearly ensures rapid reinfestation in humans. Plausible control measures (such as surface spraying of floors within the homes and peridomestic soil with insecticides; improved sanitation and regular waste collection; surveillance and treatment among animal reservoirs) may reduce rates of infestation but await confirmatory studies. Health education should focus on secondary prevention, that is, to encourage people to inspect their feet daily and remove embedded fleas with sterile instruments.

Outlook Public health programs to control neglected tropical diseases often include MDA of agents such as ivermectin and albendazole. These may have an effect on the community’s tungiasis burden. Recent studies have shown that T. penetrans harbor endosymbiotic Wolbachia bacteria; however, it is not known if the endocymbionts affect flea fecundity or contribute to the inflammatory effects of tungiasis. As a result of human migration patterns, it is conceivable that tungiasis might be introduced to and able to establish itself in ecologically permissive areas, such as Mediterranean coasts, South and Southeast Asia, and islands of the Indo-Pacific region, including Australia.

Cutaneous Larva Migrans Cutaneous larva migrans (CLM) is a zoonotic infestation caused when larvae of animal hookworms enter human skin. The animal hookworm larvae, however, are not adapted to human tissues and cannot cross the human epidermis to enter the vasculature. Consequently, the nematodes are confined to the upper layer of the skin, where they seem to wander aimlessly. This creates the classic serpiginous tracks that give the condition its common name, creeping eruption, and its medical name, CLM. CLM is endemic in many tropical and subtropical regions where stray animals in the community contribute to high rates of human infection. Furthermore, CLM is associated with poverty, inadequate sanitation, and poor health education. Most cases of CLM are caused by canine and feline hookworms (specifically Ancylostoma caninum, Ancylostoma braziliensis, and

Unicinaria stenocephala), and humans acquire the worms when exposed to feces-contaminated soil. Thus CLM is among the group of neglected tropical diseases known as soiltransmitted helminth infections.

Life Cycle and Transmission Humans acquire CLM after contact with sandy soil that has been contaminated by feces of animals that are infected with animal hookworms. These can be household dogs and cats, but are very often free-roaming or feral animals that defecate freely in areas where humans walk barefoot or work. When an animal infected with (nonhuman) hookworms passes egg-laden feces onto the ground, the eggs hatch and develop into infective larvae within a week. In a warm, moist environment, larvae may remain infective for several months. When a human is exposed, the infective larvae can enter the skin’s upper layer, the epidermis, within minutes. The larvae, however, are unable to transit across the epidermis’s basement membrane into the capillaries of the superficial dermis. Therefore the larvae remain in the epidermis and appear to migrate aimlessly. The larvae cannot mature into adults and cannot reproduce, thus humans are paratenic hosts. The infestation is self-limited, lasting until the larvae die, usually within a few weeks.

Epidemiology CLM is common in tropical and subtropical regions throughout the world, where winter freezes do not kill eggs and larvae in the environment. The incidence peaks during rainy seasons. It occurs sporadically also in temperate zones (Heukelbach et al., 2003). The most common locations for humans to be exposed to feces-contaminated soil are beaches, sandy riverbanks, construction sites, and peridomestic sites, such as children’s play areas and crawl spaces under houses. Infestation can occur via fomites, such as clothing or towels that come into contact with contaminated soil while drying. Multiple family members are often affected from common exposures. In some communities, point prevalence may approach 3% of the population. In temperate medical clinics, the most common scenario is a person with recent vacation travel to a Caribbean beach, where free-roaming dogs had defecated. Walking barefoot or lying down on the beach is the typical exposure in travelers who acquire CLM when abroad.

Clinical Presentation CLM starts as a minute red papule at the penetration site a few hours after contact with the infective larva. Within one to several days, the characteristic slightly elevated, serpiginous track appears. The larva may advance 2–3 mm per day, finally reaching 20 cm in length. It is intensely itchy and, like scabies, it seems especially uncomfortable at night, presumably because there are fewer distractions. Many patients have multiple tracks. Children who are exposed in sandboxes often have multiple lesions on hands and buttocks. People who work in unfloored crawl spaces, where animals have defecated, often have large body surfaces

Ectoparasites infected, from prolonged skin–soil contact. Bacterial superinfection is common, especially in children. Two variants include larval folliculitis when the infective larvae enter hair follicles but still cannot pass into the vascularized dermis. This creates a patch of extremely itchy, inflamed folliculitis. Bullous CLM may occur in patients who mount a vigorous immunologic response, leading to vesicular reactions or occasionally rather large bullae. In these cases, the serpiginous tracks are often evident on the blister’s roof. On rare occasions, larvae may penetrate into the dermis and reach the circulation, leading to eosinophilic pneumonitis (Loeffler’s syndrome), which is often seen with human hookworm disease.

Diagnosis The diagnosis of CLM is made by clinical examination, based on the physical appearance of the lesion, coupled with an appropriate history. An elevated linear or serpiginous lesion that elongates each day, associated with intense pruritus, is pathognomonic. A confirmatory skin biopsy is rarely needed – and biopsy attempts are often nondiagnostic because the migrating larva is rarely captured in the site selected for the biopsy. Other laboratory investigations are not helpful. Differential diagnoses include linear contact dermatitis due to jellyfish sting or phytophotodermatitis (e.g., to juice of wild limes), scabies, and insect bites. Other entities in the differential may include loiasis, larva currens (a perianal rash caused by autoinfection with Strongyloides stercoralis), myiasis, dracunculiasis, cercarial dermatitis (swimmer’s itch), linear tinea corporis, and herpes zoster.

Treatment Treatment is effective with oral ivermectin (a single dose of 200 mg kg 1) or oral albendazole (three daily doses of 400 mg). Thiabendazole ointment (10–15%) applied to the track three times daily for 7 days is effective (although not widely available), but requires substantial compliance from the patient. Freezing the track with liquid nitrogen is not helpful because the active larva has usually moved beyond the track’s advancing edge. Without treatment, the larva will die in situ. Treatment of secondary bacterial infection and administration of tetanus prophylaxis may be required.

Control Control of CLM is difficult because it would require management of soil-transmitted helminths in the animal reservoirs in domestic, peridomestic, and agricultural settings. Regular treatment of animals with anthelminthics to interrupt transmission is hardly feasible in resource-poor countries where the incidence of infestation is highest. The most practical means to reduce the occurrence in this setting are health education and more widespread use of shoes. To prevent infestation of tourists, animals should be prevented from defecating freely on beaches. Unprotected skin should not come into contact with possibly

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contaminated ground; tourists should wear shoes and not lie directly on the sand where dogs or cats wander. Towels and clothes should not touch the ground when hung up for drying.

See also: Helminthic Diseases: Intestinal Nematode Infections; Helminthic Diseases: Onchocerciasis and Loiasis; Parasitic Diseases, an Overview; Streptococcal Diseases.

References Boralevi, F., Diallo, A., Miquel, J., et al., 2014. Clinical phenotype of scabies by age. Pediatrics 133, e910–e916. Bowen, A.C., Tong, S.Y., Andrews, R.M., et al., 2014. Short-course oral cotrimoxazole versus intramuscular benzathine benzylpenicillin for impetigo in a highly endemic region: an open-label, randomised, controlled, non-inferiority trial. Lancet 384, 2132–2140. Davis, J.S., McGloughlin, S., Tong, S.Y., et al., 2013. A novel clinical grading scale to guide the management of crusted scabies. PLoS Negl. Trop. Dis. 7, e2387. Eisele, M., Heukelbach, J., van Marck, E., Mehlhorn, H., Ribeiro, R., Feldmeier, H., 2003. Investigations on the biology, epidemiology, pathology and control of Tunga penetrans in Brazil: I. Natural history of tungiasis in man. Parasitol. Res. 90, 87–99. Engelman, D., Kiang, K., Chosidow, O., et al., 2013. Toward the global control of human scabies: introducing the international alliance for the control of scabies. PLoS Negl. Trop. Dis. 7, e2167. Finlay, G.A., Brown, J.S., Marcus, L.C., Pollack, R.J., 1999. Nasal myiasis – a “Noso”comial infection. Infect. Dis. Clin. Pract. 8, 218–220. Francesconi, F., Lupi, O., 2014. Myiasis. Clin. Microbiol. Rev. 25, 79–105. Hay, R.J., Estrada Castanon, R., Alarcon Hernandez, H., et al., 1994. Wastage of family income on skin disease in Mexico. Br. Med. J. 309, 848. Heukelbach, J., Wilcke, T., Meier, A., Saboia Moura, R.C., Feldmeier, H., 2003. A longitudinal study on cutaneous larva migrans in an impoverished Brazilian township. Travel Med. Infect. Dis. 1, 213–218. Heukelbach, J., Winter, B., Wilcke, T., et al., 2004. Selective mass treatment with ivermectin to control intestinal helminthiases and parasitic skin diseases in a severely affected population. Bull. World Health Organ. 82, 563–571. Hoy, W.E., White, A.V., Dowling, A., et al., 2012. Post-streptococcal glomerulonephritis is a strong risk factor for chronic kidney disease in later life. Kidney Int. 81, 1026–1032. James, M.T., 1947. The flies that cause myiasis in man. USDA Mis. 631, 175 pp. Lawrence, G., Leafasia, J., Sheridan, J., et al., 2005. Control of scabies, skin sores and haematuria in children in the Solomon Islands: another role for ivermectin. Bull. World Health Organ. 83, 34–42. Liu, X., Walton, S., Mounsey, K., 2014. Vaccine against scabies: necessity and possibility. Parasitology 141, 725–732. Mahe, A., Faye, O., N’diaye, H.T., et al., 2005. Definition of an algorithm for the management of common skin diseases at primary health care level in sub-Saharan Africa. Trans. R. Soc. Trop. Med. Hyg. 99, 39–47. Mellanby, K., 1941. Transmission of scabies. Br. Med. J. 2, 405–406. Mohammed, K.A., Deb, R.M., Stanton, M.C., Molyneux, D.H., 2012. Soil transmitted helminths and scabies in Zanzibar, Tanzania following mass drug administration for lymphatic filariasis – a rapid assessment methodology to assess impact. Parasites Vectors 5, 299. Mumcuoglu, K.Y., Friger, M., Loff-Uspensky, I., Ben-Ishai, F., Miller, J., 2001. Louse comb versus direct visual examination for the diagnosis of head louse infestation. Pediatr. Dermatol. 18, 9–12. Parks, T., Smeesters, P.R., Steer, A.C., 2012. Streptococcal skin infection and rheumatic heart disease. Curr. Opin. Infect. Dis. 25, 145–153. Pollack, R.J., Kiszewski, A.E., Spielman, A., 2000. Overdiagnosis and consequent mismanagement of head louse infestations in North America. Pediatr. Infect. Dis. J. 19, 689–693. Pollack, R.J., Norton, S.A., 2014. Ectoparasitic infestations and arthropod injuries. In: Braunwald, E., et al. (Eds.), Harrison’s Principles of Internal Medicine, nineteenth ed. McGraw Hill Medical Pub. Quintanilla-Cedillo, M.R., Leon-Urena, H., Contreras-Ruiz, J., Arenas, R., 2005. The value of Doppler ultrasound in diagnosis in 25 cases of furunculoid myiasis. Int. J. Dermatol. 44, 34–37.

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Sherman, R.A., 2009. Maggot therapy takes us back to the future of wound care: new and improved maggot therapy for the 21st century. J. Diabetes 3, 336–344. Speare, R., Thomas, G., Cahill, C., 2002. Head lice are not found on floors in primary school classrooms. Aust. N. Z. J. Public Health 26, 208–211. Steer, A.C., Tikoduadua, L.V., Manalac, E.M., et al., 2009. Validation of an integrated management of childhood illness algorithm for managing common skin conditions in Fiji. Bull. World Health Organ. 87, 173–179. Strong, M., Johnstone, P., 2007. Interventions for treating scabies. Cochrane Database Syst. Rev. CD000320. Swe, P.M., Reynolds, S.L., Fischer, K., 2014. Parasitic scabies mites and associated bacteria joining forces against host complement defense. Parasite Immunol. 36. Taplin, D., Porcelain, S.L., Meinking, T.L., et al., 1991. Community control of scabies: a model based on use of permethrin cream. Lancet 337, 1016–1018. Vos, T., Flaxman, A.D., Naghavi, M., et al., 2012. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the global burden of disease study 2010. Lancet 380, 2163–2196. Walton, S.F., Choy, J.L., Bonson, A., et al., 1999. Genetically distinct dog-derived and human-derived Sarcoptes scabiei in scabies-endemic communities in northern Australia. Am. J. Trop. Med. Hyg. 61, 542–547. Walton, S.F., Currie, B.J., 2007. Problems in diagnosing scabies, a global disease in human and animal populations. Clin. Microbiol. Rev. 20, 268–279. Wong, L.C., Amega, B., Connors, C., et al., 2001. Outcome of an interventional program for scabies in an indigenous community. Med. J. Aust. 175, 367–370. World Health Organization, 2005. Epidemiology and Management of Common Skin Diseases in Children in Developing Countries. World Health Organization, Geneva. Wyss, J.H., 2000. Screwworm eradication in the Americas. Ann. N.Y. Acad. Sci. 916, 186–193. Yoon, K.S., Gao, J.R., Lee, S.H., Clark, J.M., Brown, L., Taplin, D., 2003. Permethrinresistant human head lice, Pediculus capitis, and their treatment. Arch. Dermatol. 139, 994–1000.

Further Reading Burgess, I.F., 2004. Human lice and their control. Annu. Rev. Entomol. 49, 457–481. de Barros, N., D’Avila, M.S., de Pace, B.S., et al., 2001. Cutaneous myiasis of the breast: mammographic and ultrasound features: report of five cases. Radiology 218, 517–520.

Frankowski, B.L., Bocchini Jr., J.A., 2010. Clinical report: head lice. Pediatrics 126, 392–403. Holt, D.C., Fischer, K., 2013. Novel insights into an old disease: recent developments in scabies mite biology. Curr. Opin. Infect. Dis. 26, 110–115. Jackson, A., Heukelbach, J., LinsCalheiros, C.M., et al., 2006. A study in a community in Brazil in which cutaneous larva migrans is endemic. Clin. Infect. Dis. 43, e13–e18. Kerridge, A., Lappin-Scott, H., Stevens, J.R., September 2005. Antibacterial properties of larval secretions of the blowfly, Lucilia sericata. Med. Vet. Entomol. 19 (3), 333–337. La Vincente, S., Kearns, T., Connors, C., et al., 2009. Community management of endemic scabies in remote aboriginal communities of northern Australia: low treatment uptake and high ongoing acquisition. PLoS Negl. Trop. Dis. 3, e444. Mounsey, K.E., McCarthy, J.S., Walton, S.F., 2013. Scratching the itch: new tools to advance understanding of scabies. Trends Parasitol. 2013 (29), 35–42. Romani, L., Whitfeld, M.J., Koroivueta, J., et al., 2015a. Mass drug administration for scabies control in a population with endemic disease. N. Engl. J. Med. 373, 2305–2313. Romani, L., Steer, A.C., Whitfeld, M.J., Kaldor, J.M., 2015b. Prevalence of scabies and impetigo worldwide: a systematic review. Lancet Infect. Dis. 15, 960–967.

Relevant Websites www.controlscabies.org – The International Alliance for the Control of Scabies (IACS). http://www.ifd.org/protocols/scabies – The International Foundation for Dermatology. Management of scabies. http://www.who.int/neglected_diseases/diseases/scabies/ – World Health Organization, Neglected Tropical Diseases. Scabies.

Educational Attainment and Health: Survival John G Cleland, London School of Hygiene and Tropical Medicine, London, UK Jeroen K van Ginnekeny, Netherlands Interdisciplinary Demographic Institute, The Hague, The Netherlands Ó 2017 Elsevier Inc. All rights reserved.

Introduction There is nothing new about the belief that the spread of education with its impact on knowledge and outlook is a central force underlying mortality decline and fertility decline. However, in most early studies, education was regarded as an indicator of broad socioeconomic status and thus the common finding of a strong inverse relationship between length of schooling and mortality was accorded an economic interpretation. In recent decades, more attempts have been made to isolate the effect of education from its economic and other correlates and to identify the causal pathways. This literature falls into two distinct components: investigations of effects of parental education on child survival with a focus on poor countries; and effects of individual education on adult survival and health, with a focus on richer countries. The structure of this article follows this divide.

Parental Schooling and Child Survival Statistical Associations A pioneering analysis by Caldwell of Nigerian survey data in the late 1970s showed maternal education to be a stronger predictor of child survival than more obviously economic characteristics of households, such as father’s occupation (Caldwell, 1979). This article opened the floodgates to a deluge of studies on the link between parental education and child survival in low-income countries. The major focus of attention has been on mother’s education. A succession of multinational analyses together with numerous country-specific analyses have revealed a clear and broadly consistent picture of the statistical association between a mother’s schooling and survival of her offspring. Three key features of this association have been firmly established. First, the link is strong and essentially linear, with no threshold. A rise of 1 year of maternal schooling is typically associated with a 6–9% drop in under-five mortality and this relationship is apparent even at 1, 2, or 3 years of schooling. Second, the link is considerably stronger in childhood (years 1–5) than in infancy (see Figure 1). Third, crude associations between father’s schooling and child survival are similar in magnitude to those for mother’s education, but multivariate analyses have shown that mother’s education generally has a more decisive influence, thus justifying the focus on maternal influences. The very pronounced link to overall childhood mortality suggests that all major causes of death in childhood are implicated and the available, albeit sparse, evidence supports this expectation. A compilation of data from 19 low-income countries demonstrated that maternal education is associated with

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stunting and weight-for-age in a broadly parallel manner to its association with mortality. The median estimates of the percentage stunted among children aged 3–35 months were 35.6%, 28.9%, and 16.4% for children of mothers with no schooling, with primary schooling, and with secondary or higher schooling, respectively.

Sensitivity of Associations to Stage of Mortality Transition Much of the evidence concerning the association between parental schooling and child survival has taken the form of cross-sectional survey data collected in low- and mediumincome countries since 1970. In this section we consider whether the strength and nature of the link changes over the course of the transition from very high to lower mortality. The general expectation is that differentials will diminish as uptake of effective health information and services becomes more widespread within societies and high levels of child health are achieved. Under this macro-model of change, the very large differentials documented above for poorer countries in the latter decades of the twentieth century may be a passing phase. The evidence to support this expectation is weak. For example, a vivid demonstration of the tenaciousness of educational differences comes from India, a country with vast regional differences in both educational and mortality levels. In Uttar Pradesh in the late 1980s and early 1990s, 54% of females aged 6 or more years were illiterate and the level of under-five mortality was 161.5 per 1000 live births. The corresponding values in Kerala were 17.5% and 40.3 per 1000. Figure 2 shows under-five mortality by mother’s education for these two states, together with a moderate mortality state, Gujarat. For each educational category, huge interstate differences in mortality are apparent but the gradient across categories is closely similar in all three states. Thus, the relative advantage of maternal education is just as strong in lowmortality Kerala as in high-mortality Uttar Pradesh. Though the evidence is limited, the association between maternal schooling and child mortality also appears to persist in industrialized countries. After World War II, social class differentials in infant mortality in Hungary narrowed but large differences by maternal education persisted. In the United States, parental education was found to be more closely associated with infant mortality than income and associations persisted after controls for race and birthweight.

Selectivity, Confounding, and Causation In low-income countries, a host of factors influence the probability of enrollment and retention of girls in school, including parental education and aspirations and the child’s ability. To what extent does the strong statistical association between maternal schooling and child health reflect these potentially powerful forces of selectivity? Might length of

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Figure 1 Relative risks of death by mother’s years of schooling: average results from 24 national surveys. Adapted from Hobcraft, J.N., McDonald, J.W., Rutstein, S.O., 1984. Socio-economic factors in infant and child mortality: a cross-national comparison. Popul. Stud. 38, 193–223.

Figure 2 Child mortality by mother’s schooling: Selected Indian states circa 1990. International Institute for Population Sciences. National Family Health Survey 1991/2. Mumbai, International Institute for Population Sciences.

schooling simply be a marker of the intergenerational transmission of privilege? We are aware of only two studies (coincidentally both from Nicaragua) that have attempted to reassess the maternal education–child survival link after controlling for characteristics of the mother’s family of origin. Using data relating to adult sisters who differed in educational attainment, Behrman and Wolfe (1989) found that maternal education effects on infant survival and nutritional status were no longer statistically significant when family characteristics were controlled. Conversely, Sandiford et al. (1997) found little attenuation of the association between mother’s literacy and under-five mortality when the literacy of maternal grandparents along with other socioeconomic factors was introduced into the statistical model.

Sandiford’s study is also one of the very few to have assessed whether nonverbal intelligence (as measured by Raven’s Colored Progressive Matrices) and an internal locus of control (i.e., belief in personal ability to determine outcomes) can account for the literacy–child survival relationship. Nonverbal intelligence was found to be higher in the literate than the illiterate group and this difference accounted for about one third of the literacy–survival relationship. Furthermore, it was found that intelligence was a much stronger predictor of under-five mortality among the offspring of illiterate than of literate mothers. Similarly, an internal locus of control accounted for some of the literacy–survival relationship. In contrast to this inconclusive evidence concerning the extent to which the education–survival relationships may be

Educational Attainment and Health: Survival a spurious artifact of antecedent factors such as family characteristics or intelligence, many studies have reassessed the relationship after adjustments for contemporary economic factors. Though a few exceptions have been reported, the results of the large cross-national studies are supported by most localized studies. Broadly speaking, income and wealth account for about half of the unadjusted association between maternal education and child survival. Typically maternal education remains a stronger predictor of survival than indicators of income. While it is well established that maternal education is not merely a proxy for income or wealth, causal attribution of the education–mortality link remains uncertain. It is likely that some of its predictive strength is attributable to factors that influence school enrollment and retention rather than directly to the experience of schooling itself. On the other hand, it is entirely plausible that schooling does exert profound influences on girls that persist into adulthood in ways that influence child health and survival. These possible pathways of influence are now discussed.

Distal Pathways of Influence Whether or not the schooling–survival link is wholly or partially causal in nature, it is of considerable interest and importance to ascertain the intervening mechanisms. As shown in Figure 3, a multitude of possibilities exist. Indirect, or distal, factors are discussed first, followed by the direct, or proximate, factors. The most obvious way in which schooling may influence a mother’s care of her children is by providing her with the means of acquiring and understanding correct information about prevention and cure of childhood diseases. Literacy, in the narrow sense of ability to read and write, cannot be the only crucially important cognitive skill implicated. As shown in Figure 1, even 1–3 years of maternal schooling is associated with a large reduction in the risks of childhood death and this modest exposure to primary schooling is rarely sufficient to impart lasting reading and writing skills. However, even a few years at school may improve oral literacy, namely, the understanding of decontextualized language (i.e., formal distanced language in which meaning resides in the words and syntax alone rather than in shared contextual understandings). The

language of schoolteachers, health staff, and mass media is decontextualized. The work of LeVine et al. (2012) in Mexico, Venezuela, Nepal, and Zambia has demonstrated that unschooled adult women are less capable of understanding radio messages on health in their native language than primary schooled women – a powerful demonstration that oral literacy skills acquired in school persist into later life in ways that might be relevant to health care of children. This result has the immense appeal of explaining why the effect of schooling is so ubiquitous in low-income countries, despite wide variety in the quality of education and nature of curricula. Exposure to the use of decontextualized language and, at higher grades of primary school, the acquisition of print literacy are universal features of all modern educational systems. If schooling equips mothers to comprehend modern health messages, one might expect that knowledge and beliefs about health will differ between educated and less educated mothers. The evidence is limited but, on balance, negative. This lack of effect of primary schooling on a mother’s beliefs about disease causation and prevention does not necessarily invalidate the implications of LeVine’s work, because behavior may change faster than core beliefs about illness. With regard to sociopsychological, as opposed to cognitive, factors that may mediate the relationship between maternal schooling and the proximate or direct determinants of child health, the main possibilities discussed in the research literature are: (1) more intensive style of mother–child interaction and shifts in the valuation of children; (2) greater influence on domestic decision making, including health care of children; and (3) closer identification with modern institutions (including the health-care system) and greater confidence and skill in accessing them. The work of LeVine and colleagues also suggests that the experience of primary schooling may have a profound and lasting impression that, many years later, impacts on childrearing styles. The essence of the hypothesis is that schooling provides a new model of verbal interaction between an adult (the teacher) and the child, in contrast to the learning process in preliterate societies which is achieved by participation and imitation rather than verbal instruction. Girls exposed to this model at school apply it in their roles as mothers, and interact with children in a verbally active manner, which in turn leads to a verbally active and demanding child. The

Distal pathways: Determinants of school enrolment and retention: Community Family Individual

Years of schooling

Cognitive: health knowledge Psychosocial: more intensive child rearing; more autonomy in decisions; more identification and confidence with health systems

Proximate pathways: Susceptibility to infection Protection against infection Curative care Protection against accidents

Economic: employment, income Figure 3

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A framework for assessing links between maternal schooling and child survival at the individual level.

Survival and health

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possible implications for prompt attention to nutritional and health-care needs of children are obvious. Empirical support comes from a small-scale observational study in urban Mexico in which a strong correlation was recorded between length of schooling and mothers’ verbal responses to actions (verbal or otherwise) by the child. The possibility that educated mothers enjoy greater domestic decision-making power than uneducated ones has attracted substantial research attention, particularly in the gender-stratified societies of South Asia. As the prime caretaker of children, enhanced autonomy in this regard might pay high dividends in the speed and nature of responses to childhood illnesses. The results of most ethnographic studies agree that educated mothers are accorded considerable respect and esteem but there is little agreement on the extent to which this enhanced status translates into increased decisionmaking power. The potentially empowering effect of schooling may wither in the face of structural weakness – the lack of control over property or income. Another set of sociopsychological mechanisms linking maternal schooling to child health outcomes concerns identification with modern institutions and confidence in interacting with them. Once again, the potential relevance of these factors to health-care-seeking behavior is obvious, because it is well documented that skill and determination is often required to access adequate services in many low-income settings. The main body of evidence, which comes from large-scale studies of health-service utilization, is discussed in the next section on proximate determinants. The evidence from micro-studies is generally positive. In West Africa, Nepal, and rural South India, it has been found that educated mothers make more demands on health-care providers, are better able to describe symptoms of illness, and receive a better quality of service.

Proximate Pathways of Influence Following the well-known framework of Mosely and Chen, the four main proximate pathways of influence are shown in Figure 3. One of the strongest and most consistent links between maternal schooling and health behavior concerns use of preventive health services. Across 28 national surveys, complete immunization coverage rose from 41% for 1-yearold children of mothers with no schooling, to 54% among those with incomplete primary schooling, and further to 65% and 74% among the completed primary school and secondary or higher school categories, respectively. Uptake of routine preventive mother and child health care is highly sensitive to even a modest educational exposure, and most multivariate analyses show that the link persists strongly after adjustment for economic status, parity, and maternal age. Convincing evidence on nutrition is lacking, except for breastfeeding, which disadvantages children of the better educated because of earlier weaning. With regard to domestic hygiene a study in rural Bangladesh provides positive evidence. One of the very few features that distinguished educated from uneducated mothers was the former’s greater emphasis on cleanliness. This behavioral difference, it was suggested, did not stem from any realization of the health implications but from the acquisition of new codes at school which were considered socially desirable and

Table 1 Percentage of children with specified symptoms who were taken to a medical facility: average results from 30 surveys Maternal schooling Symptoms

None (%)

Primary (%)

Secondary and higher (%)

Diarrhea and fever Fever Cough and rapid breathing

30 35 36

35 45 45

54 57 59

Calculated from Ryland, S., Raggers, H., 1998. Childhood Morbidity and Treatment Patterns. Demographic and Health Surveys Comparative Studies No. 27, Macro International Inc., Calverton, MA.

persisted into adulthood. However, a more recent study in Bangladesh failed to replicate these results and the lack of consistent evidence that the occurrence of diarrheal disease in children is related to maternal schooling weakens the case that hygiene is a major behavioral mechanism. Resort to curative health services is strongly related to maternal schooling. Evidence from some 30 demographic and health surveys shows, with very few exceptions, a monotonic positive association between schooling and the probability that a sick child was taken to a medical facility (Table 1). Taken together with the results from ethnographic studies that educated mothers may be able to extract a higher quality of service, these survey data constitute compelling evidence that curative care of children is a major way in which education translates into higher survival and better growth of offspring.

Contribution of Rising Levels of Education to Child Mortality Declines

Between 1970 and 2009, the global mean number of years of education increased from 4.7 to 8.3 years for men aged 25 years or more and from 3.5 to 7.1 years for women. Gakidou et al. (2010) assembled an educational time series for 175 countries over this time span and linked it to databases on mortality, income and HIV. They estimated the country level associations between changes in these four factors since 1970 and found that about half of the 8.2 million fewer deaths to under-five children between 1970 and 2009 could be attributed to increased educational attainment of women of reproductive age. By comparison rising incomes accounted for only 7% of the drop in deaths. Of course, statistical associations do not prove causality and it is likely that nations choosing to invest strongly in the schooling of girls also choose to invest in primary health care services. Nevertheless, together with the material reviewed above, this analysis provides compelling evidence that the rise in schooling has been a major driver of improved child survival.

Conclusions The advantages parental schooling for the health and survival of children in low-income countries has attracted the attention of both researchers and policy makers. Advocacy of better schooling for girls has become part of the ideology of leading international institutions, such as the WHO and the World Bank. The research evidence shows emphatically that better

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Educational Attainment and Health: Survival educated mothers are able to protect their children against poor growth and death. Whether this enhanced ability stems directly from the schooling experience or whether schooling selects for (and perhaps reinforces) preexisting characteristics that favor mothering skills remains uncertain. The question may never be resolved beyond doubt because a prospective study spanning a generation would be required. The identification of intervening mechanisms greatly strengthens the case for a causal interpretation of the schooling–survival link. The balance of evidence suggests that even a modest exposure to primary school would allow girls to identify more closely with the outside world of health institutions and would equip them with the cognitive skills needed to access and comply with services and offered advice. What is beyond doubt is that educated mothers have a much greater propensity to use modern health services – both preventive and curative – than less educated mothers. This appears to be the major, though perhaps not the only, pathway of influence. While the advantages accruing to the offspring of educated mothers are remarkably pronounced and pervasive, typically persisting in societies with high levels of child survival and a good health infrastructure, secular improvements in the education of girls has not been the main driving force behind child survival gains of the past 50 years. These gains have been recorded in all educational strata and thus the forces of change transcend the characteristics of individual families.

Education and Adult Health Statistical Associations During the past 40 years many studies have been carried out by epidemiologists, social scientists, and statisticians on the relationship between educational attainment and mortality in European countries, the United States, Canada, and Oceania. These studies have focused on three topics in particular: (1) the extent of differences in the risk of dying by level of education in various industrialized countries; (2) the extent to which educational differences in mortality have changed over time; and (3) the processes or factors that explain the impact of education on mortality. All three topics deal with aspects of social and economic inequality in industrialized countries and have been (and still are) the subject of much public debate. The studies on education and mortality, to be summarized below, therefore, have considerable relevance because of their implications for formulation of public policy in education, income distribution, and public health. In this part of the review we limit ourselves to studies that were conducted in Western industrialized countries and Eastern Europe. We also concentrate on mortality as the outcome and, with one exception, leave aside research on morbidity. Most studies have used a longitudinal design with data sets consisting of two parts: one part with individual-level, baseline data on education and related variables derived from a census, register, or sample survey; and a second part with mortality data derived from a registration system collected during a follow-up period varying from 1 to 30 years. Some of the studies are nationally representative and have been carried out under the auspices of national governments, whereas others are longitudinal, population-based studies

dealing with sub-populations such as cities, regions in a country, employees in industrial enterprises, and government departments. Over 12 summary measures have been developed and applied measuring the impact of education on mortality. We limit ourselves here to the rate difference (RD) and the rate ratio (RR). The RD is the absolute difference in mortality rate between the highest and the lowest educational group, while the RR measures the relative rate of dying in the lowest educational group divided by that of the highest educational group. RDs and RRs are, in practice, difficult to compare by country or over time, because they are sensitive to at least three factors: the number and composition of the educational groups, the level of mortality in general, and the age groups used. Table 2 shows age-adjusted mortality rates by level of education in the age group 30–74 years old for Finland and Norway combined in the early 1980s and 1990s. Negative relationships existed between education and adult mortality for both sexes but RDs and RRs were larger for men than for women. Virtually all studies conducted in the United States, Europe (West and East), and other industrialized countries have found roughly similar results as those presented in Table 2. In most countries RRs for men varied from 1.60 to 2.20 (in the 1980s and 1990s) for the age group 30–74 years old, and with education classified into three groups, which means that the mortality of the lowest educational group was on average nearly twice as high as that of the highest educational group. For women the RRs varied from 1.20 to 1.90. The strength of the associations of education and adult mortality varies by cause of death. In most studies, it was found that in adults the RR of mortality in the lowest compared with the highest educational group was larger for cardiovascular diseases than for neoplasms and ‘other’ diseases. Different results, however, have also been reported. In a study carried out in six European countries it was found that, among middle-aged men, the RRs were highest for ‘other’ diseases and accidents and smallest for neoplasms. RRs for circulatory diseases were intermediate and close to the RRs for total mortality. In still another study carried out in Sweden, a larger association of education and mortality was found for the group of neoplasms than for cardiovascular diseases.

Table 2 Mortality rates (per 1000 person-years, 30–74 years old, age-adjusted) and inequality indices, by educational level, Finland and Norway combined Men

Women

Education

1981–85

1991–95

1981–85

1991–95

High (13þ years) Mid (9–12 years) Low (8 years) Indices Rate difference Rate ratioa

8.3 10.2 12.6

6.5 9.0 11.5

3.8 4.4 5.5

3.3 4.0 5.2

1.6 1.34

1.9 1.58

a

4.4 1.59

5.1 1.77

Regression-based. Recalculated from Mackenbach, J.P., Bos, V., Anderson, O., et al., 2003. Widening socioeconomic inequalities in mortality in six Western European countries. Int. J. Epidemiol. 32, 830–837.

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Sensitivity of Associations to Level of Mortality and to Changes over Time Studies on changes over time in the association of education with mortality are of fairly recent origin. An example of such a study is the one cited in Table 2 showing changes in Finland and Norway between 1980–84 and 1990–94. Total (ageadjusted) adult mortality rates declined between the first half of the 1980s and the first half of the 1990s for both men and women but declined faster in the high than in the low education group for both sexes. As a result, RDs remained nearly the same, but RRs increased. Results in other studies are broadly similar. There have also been exceptions, however. A U.S. study found an increase in the absolute and relative strength of the education–mortality relationship between 1960 and 1979–85 in 25- to 64-year-old men, but not for women (Preston and Elo, 1995). A study in Sweden found a decline in the absolute and relative strength of the education–mortality relationship and, therefore, of inequality for both men and women between 1980–84 and 1995–99. Sharp rises in inequality (measured with changes in the education–mortality relationships) were found in adults in Russia and Estonia between the 1980s and 1990s. More detailed analysis of the data of Finland and Norway showed that cardiovascular disease mortality played an important role in widening the gap in mortality by education. Decreases in cardiovascular disease mortality occurred at a faster rate in the high education group than in the low education group. However, this was not the case in Italy due to the smaller contribution of cardiovascular disease to overall mortality in that country (and in other Mediterranean countries as well). In summary, in many Western countries, mortality has declined, coinciding with an improvement in the level of education in general and with an increase in relative inequality in mortality by education. Various reasons for this pattern have been advanced. One of them is that the higher educational groups are quicker to adopt health-protective behavior and to take advantage of health-care innovations than low education groups. Another possible factor is a change in the composition of the low educational group over time: this group has become smaller, and perhaps more extreme in terms of maintaining unhealthy styles of behavior. Another factor plays a role in situations of falling death rates and no change over time in the level of absolute inequality (e.g., measured with RD). In such situations relative inequality (e.g., measured with RR) is bound to increase. A fourth reason could have been the implementation of free-market policies and the consequences of globalization, which may have favored the well educated more than the less educated.

Selectivity, Confounding, and Causation There has been a growing recognition that adoption of a life course perspective is the preferred strategy in the study of socioeconomic inequality. Leading researchers have pointed out that the parental environment, circumstances in utero, infancy, childhood, adolescence, and adulthood should all be considered as relevant factors influencing health and mortality (e.g., Davey Smith et al., 1998; Barker et al., 2001). One of these phases in the life cycle is between, say, 5–25 years old,

corresponding to the period during which schooling takes place. The role of education is thus one of the factors that should be considered in this life course perspective. In this section we focus on parental factors, in infancy and childhood, that could influence both education and health and mortality later in life. One hypothesis is that characteristics of the parents and the parental family have an impact on: (1) the health of the infant and child; (2) the education of these children; and (3) on adult health later in life. One of these characteristics is the occupationbased social class of the parents. A few studies provide evidence on the contribution of parents’ social class. In a Finnish study a strong association was found between parents’ social class and education of their children and a moderate association with mortality of these children in adulthood. After adjustment for parental social class, the relationship between children’s education and mortality later in life was reduced somewhat. The direct impact of parental social class on mortality was small; most of this impact was indirect and mediated through children’s education and their own social class (Pensola and Valkonen, 2002). In another Finnish study men born during the decade 1934–44 were followed longitudinally to determine predictors of incidence of coronary heart disease later in life. It was hypothesized that parent’s social class, factors operating in infancy – for example, ponderal index (thinness at birth), growth in the first year of life – education, income, and adult social class all had an impact on incidence of coronary heart disease. Parent’s social class, growth in infancy, education, and adult social class had strong unadjusted associations with coronary heart disease. After controlling for father’s social status, the relationship of education with coronary heart disease attenuated and the same was found after controlling for weight gain in the first year. Both parental class and weight gain had little direct impact on coronary heart disease; their contribution was largely indirect through education and adult social class (Barker et al., 2001). Both studies draw attention to the contribution of parental environment and factors in infancy and childhood to both education and health later in life. The impact of father’s social class on mortality of offspring and of growth velocity in the first year of life on adult mortality was largely indirect. More studies on these factors should be done using a life course perspective. Several studies have been undertaken on the relative importance of education and occupation-based social class on mortality. Nearly all of these studies found attenuation of the strength of the education–mortality association, but the degree of attenuation varied. One Finnish study found that the impact of education persisted after controlling for social class (Pensola and Valkonen, 2002). Conversely, another study undertaken in Scotland found that most of the education–mortality relationship disappeared after controlling for social class (Davey Smith et al., 1998). Other studies have found outcomes that fall roughly between these two. A factor to take into account is the age of the cohorts studied. When the age cohort studied is young, exposure to occupational risk factors has been of relatively short duration, which means that education could be more important compared with occupation or income. If the age cohort is older, occupational experiences could become more dominant.

Educational Attainment and Health: Survival Distal Pathways of Influence The framework of Figure 3 will be used to identify the distal and proximate factors through which education acts on adult mortality, but several adaptations are necessary. Economic, psychosocial, and cognitive factors are also expected to be important with respect to adult health, but they are specified differently. Highly educated people are more likely to be affluent, which means that they are more likely to be employed, to have a highly skilled job, to live in favorable material living conditions (e.g., owning a house and a car), and to have better health insurance. Well-educated people are also better off from a psychosocial point of view. This means they are better able to cope with stressful life events (a better ‘coping style’), are more successful in discussing personal problems with others, and receive more emotional social support from spouses, relatives, and so forth. Highereducated persons are also more knowledgeable about health and about what to do to prevent and cure illness. Then there are the proximate factors through which education exercises an influence on health; with respect to adult health they consist of lifestyle or behavioral factors (i.e., smoking, alcohol use, dietary habits, physical exercise, etc.). Highly educated people practice more health-protective behavior than less educated people. We now review the evidence on the mediating roles of the various factors of Figure 3, starting with the distal factors. Studies carried out in the United States and Europe have shown an impact of education on economic or material factors such as income, proxies of income, employment status, health insurance, and strategies for dealing with financial problems. For instance, persons with low education faced more serious financial problems and had less-complete health insurance. These and other factors were also associated with mortality later in life in the sense that the group of persons who experienced these economic problems had higher mortality. Multivariate analysis shows a considerable attenuation of the education–mortality relationship after controlling for these economic or material factors, indicating that to a considerable extent they explain this relationship. These economic factors had a direct impact and an indirect one due to their association with education. In a few studies not only economic, but also psychosocial, factors were included. In these cases it was shown that the economic factors contributed much more than the psychosocial factors (e.g., van Oort et al., 2005).

Proximate Pathways of Influence Many studies carried out in the United States, Europe, and other countries have shown a strong relationship between education and a variety of lifestyle factors. A low level of education was associated with, for instance, high levels of smoking and greater use of alcohol. All of these studies also found an impact of these proximate factors in the sense that unhealthy behavior was associated with higher mortality. Several studies were carried out on the impact of education on adult mortality after controlling for health behavior factors, and most found only modest attenuation of the education–mortality relationship after controlling for these factors. The implication of these findings is that behavioral

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factors contributed rather little to the explanation of the education–mortality relationship. Other factors must have had a much larger influence. A few studies have been carried out in Europe and the United States on the education–mortality relationship after controlling for both distal and proximate factors. Two studies concluded that the educational inequalities in mortality were nearly completely explained by distal (economic and psychosocial) and proximate determinants together. The three factors (economic, psychosocial, and proximate) together explained why education exercises its impact on mortality (at least in the setting in which the study took place). It was also concluded that the economic or material factors were much more important than the psychosocial and lifestyle factors in explaining mortality differences by education. Moreover, part of the contribution of economic or material factors was through psychosocial and lifestyle factors, meaning that the influence of the economic factors was partly direct and partly indirect (e.g., van Oort et al., 2005).

Conclusions We observed a strong impact of education on adult mortality in Western industrialized countries and in Eastern Europe. In many nations male adult mortality of the lowest educational group is 1.6–2.2 times higher than in the highest educational group. For adult women the impact is less. This impact of education on mortality and on health in general probably started many decades ago. At first the number of children who received primary and secondary education was small. However, over the course of the past century, numbers have increased continuously and are still expanding today. From a historical point of view education has had an enormous long-term impact on health and mortality. One could summarize its impact by saying that, statistically speaking, each time a nation succeeded in providing its population with one more year of education, adult mortality declined by 5–7%. A serious concern for health policy makers in industrialized countries is that over time absolute inequalities in education did not diminish and that in a number of countries mortality of the lowest educational group declined less fast than in the highest educational group. Evidence was summarized on the role of distal and proximate factors that explain the education–mortality relationship. A combination of economic, psychosocial, and behavioral factors explained this relationship in a few Western countries. Economic factors contributed most to the explanation, which means that improving the economic situation of less educated people may substantially reduce educational inequalities in adult mortality.

See also: Anthropological Perspectives on the Health Transition; Cultural Factors Influencing Therapeutic Practice; Social Gradients and Child Health; Social Science Contributions to Public Health: Overview; Sociocultural Construction of Medical Knowledge.

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References Barker, D.J., Forsen, T., Uutela, A., et al., 2001. Size at birth and resilience to effects of poor living conditions in adult life: longitudinal study. Br. Med. J. 323, 1273–1276. Behrman, J., Wolfe, B.L., 1989. Does more schooling make women better nourished and healthier? Adult sibling random and fixed effects estimates for Nicaragua. J. Hum. Resour. 24, 644–663. Caldwell, J.C., 1979. Education as a factor in mortality decline: an examination of Nigerian data. Popul. Stud. 33, 395–413. Davey Smith, G., Hart, C., Hole, D., et al., 1998. Education and occupational social class: which is the more important indicator of mortality risk? J. Epidemiol. Community Health 52, 153–160. Gakidou, E., Cowling, K., Lozano, R., Murray, C.J.L., 2010. Increased educational attainment and its effect on child mortality in 175 countries between 1970 and 2009; a systematic analysis. Lancet 376, 959–974. Hobcraft, J.N., McDonald, J.W., Rutstein, S.O., 1984. Socio-economic factors in infant and child mortality: a cross-national comparison. Popul. Stud. 38, 193–223. LeVine, R.A., LeVine, S.E., Schnell-Anzola, B., Rowe, M.L., Dexter, E., 2012. Literacy and Mothering: How Women’s Schooling Changes the Lives of the World’s Children. Oxford University Press, Oxford. Mackenbach, J.P., Bos, V., Anderson, O., et al., 2003. Widening socioeconomic inequalities in mortality in six Western European countries. Int. J. Epidemiol. 32, 830–837. van Oort, V., van Lenthe, J., Mackenbach, J., 2005. Material, psychosocial, and behavioural factors in the explanation of education inequalities in mortality in the Netherlands. J. Epidemiol. Community Health 59, 214–220. Pensola, T., Valkonen, T., 2002. Effect of parental class, own education and social class on mortality among young men. Eur. J. Public Health 12, 29–36. Preston, S., Elo, I., 1995. Are educational differentials in adult mortality increasing in the United States? J. Aging Health 7, 476–496.

Sandiford, P., Cassel, J., Sanchez, G., Coldham, C., 1997. Does intelligence account for the link between maternal literacy and child survival? Soc. Sci. Med. 45, 1231–1239.

Further Reading Bicego, G.T., Boerma, J.T., 1993. Maternal education and child survival: a comparative study of survey data from 17 countries. Soc. Sci. Med. 36, 1207–1227. Caldwell, J.C., Caldwell, P., 1985. Education and literacy as factors in health. In: Halstead, S.B., Walsh, J.A., Warren, K.S. (Eds.), Good Health at Low Cost. Rockefeller Foundation, New York, pp. 181–185. Cleland, J.G., Van Ginnekan, J.K., 1988. Maternal education and child survival in developing countries: the search for pathways of influence. Soc. Sci. Med. 17, 1357–1368. Desai, S., Alva, S., 1998. Maternal education and child health: is there a strong causal relationship. Demography 35, 71–81. Khang, Y., Lynch, J.W., Kaplan, G.A., 2004. Health inequalities in Korea: age- and sex-specific educational differences in the 10 leading causes of death. Int. J. Epidemiol. 33, 299–308. Molla, M.T., Madans, J.H., Wagener, D.K., 2004. Differentials in adult mortality and activity limitation by years of education in the United States at the end of the 1990s. Popul. Dev. Rev. 30, 625–646. Mosely, W.H., Chen, L., 1984. An analytical framework for the study of child survival in developing countries. Popul. Dev. Rev. 10 (Suppl.), 25–48. Schultz, T.P., 2002. Why governments should invest more to educate girls. World Dev. 30, 207–225. Shkolnikov, V.M., Leon, D.A., Adamets, S., et al., 1998. Educational level and adult mortality in Russia: an analysis of routine data 1979 to 1994. Soc. Sci. Med. 47, 357–369.

Effective Alcohol Policy HD Holder, Prevention Research Center, Pacific Institute for Research and Evaluation, Berkeley, CA, USA Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 2, pp. 303–309, Ó 2008, Elsevier Inc.

Alcohol use and abuse represents a significant public health issue across the world. Heavy drinking over a period of time in the life of an individual contributes to the alcohol-related burden of disease. Alcohol contributes to social, health, and safety problems in two ways, that is, drinking can have acute or immediate and chronic or long-term consequences. First, alcohol is a psycho-active drug which affects one’s ability to carry out complex tasks and/or to make socially appropriate or safe decisions, especially in a stressful situation. For example, an automobile driver who has been drinking, even one drink of alcohol, has a reduced ability to operate the vehicle. The more drinks consumed on the average the greater the driver’s impairment. Second, alcohol, consumed regularly in high amounts, can have a direct harmful effect on the body. The most obvious threat is the liver which must process alcohol for the body and where long-term drinking substantially increases the risk of liver cirrhosis, or fatty liver, and thus shortens the life of a heavy drinker. Many other diseases also have a substantial association with extended heavy drinking. Both domains of risk are important challenges for public health. Alcohol policy can be defined broadly as any public health effort to reduce alcohol problems by altering the social, economic, and physical environment that affects alcohol markets and manufacturing, production, promotion, distribution, sales, or consumption. Alcohol dependence for some individuals can create special demands for interventions and treatment. However, the majority of alcohol-related problems are associated not with the small minority of addicted or dependent persons but rather with those who occasionally drink to excess, or in ways or contexts where risk is increased. This article discusses policies that affect alcohol and our knowledge of relative effectiveness in promoting public health.

Retail Price The consumption of alcohol, like that of any retail product, is related to purchase price; the higher the price set for alcohol, the lower the consumption. Because alcohol consumption is influenced by price, the retail price of alcohol can have a direct effect on the level of alcohol consumption and related problems. Econometric studies suggest that raising the price of alcohol as a part of public health policy could reduce a number of public health problems related to alcohol use. Cirrhosis mortality has been shown to be responsive to price as locations with higher alcohol taxes have fewer such deaths. Furthermore, alcohol tax increases have the potential to reduce the rate of fatal car accidents involving alcohol. For example, it is estimated that a 10% increase in the price of alcoholic beverages in the United States could reduce the probability of drinking and driving by about 7% for men and 8% for women, with even larger reductions among those 21 years and under. One example of increasing retail price as a part of policy occurred in the Northern Territory of Australia under a ‘Living with Alcohol Program’ which increased the cost of standard drinks by five cents in 1992, followed by other problem reduction strategies in 1996 including lowering the legal blood alcohol content (BAC) limit and a special levy on case wine (Stockwell et al., 2001). Over these first 4 years, there were statistically significant reductions in acute conditions such as road deaths (34.5%) and other mortality (23.4%) as well as traffic crashes requiring hospitalization (28.3%). Several studies have examined the impact of the price of alcoholic beverages on homicides and other crimes, including rape, robbery, assaults, motor vehicle thefts, domestic violence, and child abuse. See section Further Reading for these studies.

Minimum Drinking Age of Alcohol Purchase

Policies and Evidence of Effectiveness Because alcohol is a legal product in most countries, the regulation of these products through policies has often been part of a public health approach to both limiting the damage associated with alcohol and increasing tax revenues in industrialized countries. Government policies can in some cases actually determine the retail price of beverages, the opening hours or days for retail sales, the number and location of retail outlets, how the alcohol can be advertised and promoted, and restrictions on who may purchase alcohol. Restricting alcohol availability through law has been a key policy in many parts of the world. All policy occurs within an individual society and reflects the unique attitudes and values of that society, and so the potential effectiveness of any policy relates directly to public acceptability and compliance with these policies. The following general policies have been utilized in public health efforts to reduce alcohol-related harm.

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Setting a higher minimum legal drinking age to reduce alcohol consumption among youth is also an important public policy. There are legal ages of alcohol purchase in many countries but most often they are ignored or not enforced. One example of a national policy to reduce youth drinking using minimum age occurred in the United States in the 1980s with a 21 minimum purchase or drinking age for all alcoholic beverages. Studies uniformly show that increasing the minimum drinking age significantly decreases self-reported drinking by young people, the number of fatal traffic crashes, and the number of arrests for ‘driving under the influence’ of alcohol. Studies using data from all 50 states and the District of Columbia for the years 1982 through 1997 concluded that the enactment of the uniform age 21 as minimum drinking age law was responsible for a 19% net decrease in fatal crashes involving young drinking drivers after controlling for driving exposure, beer consumption, enactment of zero tolerance laws, and other relevant changes in the laws during that time period. Studies in

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Canada report findings similar to those in the United States concerning youth drinking and alcohol problems. The most extensive summary of international research on the effects of minimum drinking age is that of Wagenaar and Toomey (2002) who analyzed all identified published studies from any country from 1960 to 1999 and found that a majority of studies reported that a higher legal drinking age was associated with reduced alcohol consumption among youth, whereas only a few found that a higher drinking age had little or no effect on adolescent drinking. Of the published studies that assessed the effects of changes in the legal minimum drinking age on incidents of drunk driving and traffic crashes, for example, fatal crashes, drunk-driving crashes, or self-reported driving-after-drinking, a clear majority found that raising the drinking age reduced crashes and associated problems and that lowering the minimum age raised the crash rate. Even with higher minimum drinking age laws, young people can and do purchase alcohol. Such sales result from low and inconsistent levels of enforcement of laws prohibiting underage alcohol sales, especially when there is little community support. Even moderate increases in enforcement can reduce sales of alcohol to minors by as much as 35–40%, especially when combined with media and other community and policy activities.

monthly assault rates for those hotels with the permits, due to greater sales of high-alcohol-content beer, wine, and spirits. In the 1980s Sweden re-instituted Saturday closings for liquor and wine sales in retail monopolies’ stores. As a result, as studies showed, Saturday sales had increased rates of domestic violence and public drunkenness. A recent Swedish study found a net 3% increase in alcohol sales in a new test of Saturday openings of liquor and wine stores, compared with other stores that were not opened on Saturday. A study of an isolated Aboriginal community (Tennant’s Creek) in Australia evaluated the effects of banning take-away sales of alcohol on Thursdays, limiting take-away sales to the hours of noon to 9 p.m. on other days, and closing bars until noon on Thursday and Friday. This policy produced a 19.4% decrease in drinking over a 2-year period, and a reduction in arrests, hospital admissions, and women’s refuge admissions. In one of the few studies focusing on youth, it was found that temporary bans on the sales of alcohol from midnight Friday through 10 a.m. Monday because of federal elections reduced cross-border drinking in Mexico by young Americans. A local policy in Diadema, Brazil, limited opening hours for alcohol sales and produced a significant decrease in murders. Thus, from a policy perspective, restricting hours and specific days of sale can have considerable impact on acute alcohol problems such as traffic crashes, violence, and heavy drinking.

Number and Densities of Alcohol Outlets

Government Alcohol Retail Monopolies

Alcohol outlets in every community are sources of alcohol. Their geographical concentration in neighborhoods and communities can either enhance or delay alcohol access. Gruenewald et al. (1993), using a time-series cross-sectional analysis of alcohol consumption and density of alcohol outlets over 50 U.S. states, found that a 10% reduction in the density of alcohol outlets would reduce consumption of spirits by from 1% to 3% and consumption of wine by 4% across all ages. Similar findings have been reported in other countries. A recent study by Treno et al. (2003) found that although outlet density did not directly affect either youth driving after drinking or youth riding with drinking drivers, density did interact with the driver licensing status of the youth on both behaviors. Thus, higher density was positively related to drinking and driving among licensed youth drivers and negatively related to riding with drinking drivers among youth who did not have driver’s licenses. This is the first solid evidence of a relationship between alcohol outlet densities and drinking-related risky behavior by youth. See Further Reading for a summary of alcohol outlet density and policy research.

One alcohol policy is for the government to operate a retail monopoly for the sale of alcohol. Such monopolies exist in several countries including Iceland, India, Norway, Sweden, Finland, Canada, and the United States. The evidence is quite strong that these government retail systems result in lower rates of alcohol consumption and alcohol-related problems. (See the recent study on youth drinking and harm by Miller et al. (2006) associated with the existence of retail monopolies.) Furthermore, the elimination of such monopolies does typically increase total alcohol consumption and alcohol-involved problems; for example, in the United States, those states with retail monopolies have lower numbers of alcohol outlets. A summary of seven time-series analyses of six U.S. states and New Zealand found a consistent increase in total consumption when government-owned or community-trust-operated off-premise outlets were replaced with privately owned outlets (Wagenaar and Holder, 1996). Typically, the networks of stores in these government-operated systems are sparse rather than dense, and the open hours are limited. Elimination of a private profit interest also typically facilitates the enforcement of rules against selling to minors or the already intoxicated and eliminates or reduces alcohol promotion.

Hours and Days of Retail Sale The length of time during a week when alcohol can be consumed and/or purchased has a demonstrated relationship with alcohol-involved harm. Reducing the days and times of alcohol sales restricts the opportunities for alcohol purchasing and can reduce heavy consumption, and is a common policy strategy for reducing drinking-related problems, although the trend in recent years has been to liberalize such restrictions in many countries. One policy change in Western Australia permitted ‘Extended Trading Permits’ which enabled longer opening hours. It was found that these extended hours significantly increased

Responsible Beverage Service or Sales In general, responsible beverage service or sales (RBS) involves the creation of clear policies, for example, making a public statement that the establishment does not wish to serve intoxicated persons, or requiring clerks and servers to check identification for all customers appearing to be under the legal alcohol purchase age. RBS also means training staff, for example, teaching clerks and servers how to recognize intoxicated patrons, teaching them effective approaches to intervention,

Effective Alcohol Policy and instructing them in the detection of false age identification. RBS can be implemented at both on-license establishments, which sell alcohol for consumption on site, and off-license establishments which sell alcohol for consumption elsewhere. The serving staff in bars, pubs, and restaurants who encounter heavily intoxicated patrons often frequently continue to serve them alcohol. It has been estimated that obviously intoxicated persons are served alcohol over 60% of the time when they attempt to purchase. As a result, RBS involves efforts to decrease service to intoxicated patrons. Studies of RBS have demonstrated that server training is most effective when coupled with changes in the serving policy and practices of a bar or restaurant. RBS has been found to reduce the number of intoxicated patrons leaving a bar and to reduce the number of car crashes. RBS training has also been associated with an increase in self-reported checking of age identification by servers, a behavior that can continue among trained servers for as long as 4 years. There is increasing recognition of the need to focus on house rules and management support for RBS, as well as regular enforcement by police and licensing authorities. Many RBS programs include training managers in the implementation of standard house policies, or use a ‘risk assessment’ approach to policy development (Saltz, 1997). A typical policy checklist for assessing risks covers the following topics: providing positive incentives for avoiding intoxication (e.g., food, cheaper prices for low or no-alcohol drinks), avoiding incentives for intoxication (e.g., specials on low-cost drinks), policies to minimize harm (e.g., increasing safe transportation options), and policies to minimize intoxication (e.g., slowing then refusing service to intoxicated patrons). An increased emphasis on alcohol serving policies often shows a dramatic impact on reducing bar, pub, or restaurant service to intoxicated individuals. The findings suggest that RBS training, if supported by actual changes in the serving policies of licensed establishments and reinforced by means of enforcement, can reduce heavy consumption and high-risk drinking.

Alcohol Promotion and Advertising Restrictions Restrictions and outright bans on alcohol promotion and commercial advertising have been employed as part of public health policy. The evidence of the effects of advertising bans has been mixed, but recent research suggests that limits on point-of-purchase advertising and promotion could have specific effects on youth drinking. Saffer (2002) completed a review of published international research literature on the potential effects of alcohol advertising on consumption and in particular the effects on youth drinking. He concluded that the results of his review suggest that alcohol advertising does increase consumption, but that a general alcohol advertising ban alone is insufficient to limit all forms of promotion and a comprehensive ban was needed. On the other hand, Nelson (2003), using a panel of 45 U.S. states for the period 1982–1997, studied the effect of several restrictive alcohol regulations, including advertising bans for billboards, bans of price advertising, state monopoly control of retail stores, and changes in the minimum legal drinking age. He concluded that “bans of advertising do not reduce total alcohol consumption, which partly reflects substitution effects.” Saffer and

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Dhaval (2003) concluded, following an analysis of national alcohol consumption related to total advertising expenditures across the world, that alcohol advertising bans decrease alcohol consumption. Their findings indicated that one more advertising ban on beer and wine or on spirits would reduce consumption by about 5%, and that one more ban on all alcohol advertising in a media would reduce consumption by about 8%. Promotion of alcohol and its effect on youth drinking has been a significant public health issue. Studies have examined the relationship between exposure to different forms of alcohol advertising and subsequent drinking among adolescents. It was found that for 12-year-old children exposure to in-store beer displays predicted drinking onset by age 14. Similar research concluded that exposure to magazines with alcohol advertisements and to beer concession stands at sports or music events for 12-year-olds predicted frequency of drinking at age 14. Snyder et al. (2006) found that youth who saw more alcohol advertisements on average drank more (each additional advertisement seen increased the number of drinks consumed by 1%). These researchers found that restrictions on point-ofpurchase price advertising at liquor stores reduced the probability of drinking and driving among all drinkers and that when price advertising is permitted, prices may be expected to fall, thereby leading to increases in overall consumption. They found that drinkers who lived in locations with policies permitting grocery stores to sell beer and wine had a significantly higher probability of drinking and driving, and concluded that advertising and availability of alcohol promotes drinking.

Drinking and Driving Policies Policies that discourage drinking and driving can reduce alcohol-related crashes and the injury and death that result from it. Strategies for reducing alcohol-related traffic crashes include increased and highly visible law enforcement, for example, sobriety checkpoints and random breath testing, and the level of legal blood alcohol concentration at which a driver is considered legally drunk or impaired.

Random Breath Testing

Random breath testing, or RBT, involves extensive and continuous random stops of drivers who are required to take a breath test to establish their blood alcohol concentration (BAC). Studies of RBT in Australia, Canada, and Great Britain show that it can reduce traffic crashes. Shults et al. (2001) reviewed 23 studies of RBT and intensive enforcement and found a median decline of 22% (range 13–36%) in fatal crashes, with slightly lower decreases for non-injury and other accidents. Sobriety checkpoints, a limited version of RBT, are often implemented in individual U.S. states under proscribed circumstances often involving prenotification about when and where they will be implemented. Even under these restricted circumstances there is some evidence that such selective enforcement can reduce drinking and driving.

Lowering BAC Limits

BAC limits are public laws that legally define drunk driving using a BAC at or above a prescribed level for the whole

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population (e.g., from 0.08 to as low as 0.02). Jonah et al. (2000) reviewed the evidence internationally for the impact of lower BAC laws, which outside of the United States involve BAC limits down to 0.05 or, in the case of Sweden, to 0.02, and found that consistently lower BAC limits produced positive results for all drivers, but especially for younger drivers.

Zero-Tolerance Laws for Youth

Zero-tolerance laws set lower specific BAC limits for young drivers and commonly invoke penalties such as automatic license revocation. An analysis of the effect of zero-tolerance laws in the first 12 U.S. states enacting them found a 20% relative reduction in the proportion of single vehicle nighttime (SVN) fatal crashes among drivers under 21, compared with nearby states that did not pass zero-tolerance laws. A study of all 50 U.S. states and the District of Columbia found a net decrease of 24% in the number of young drivers with low BACs as a result of the implementation of zerotolerance laws.

Administrative License Suspensions

Under administrative license suspensions or revocations for drinking and driving, licensing authorities can suspend licenses more quickly and closer in time to the actual offense without a court hearing. That administrative license suspension dramatically affects alcohol-related traffic accidents has been consistently positive in international studies. The threat of loss of license has been shown to be very effective in deterring drinkers from getting into their automobile and driving.

Graduated Licensing

Graduated licenses establish unique driving restrictions for young and novice drivers, for example, restricting nighttime driving and prohibiting driving with other adolescents. A graduated licensing program in Connecticut (USA) led to a 14% net reduction in crash involvement among the youngest drivers. Similarly, in New Zealand, a 23% reduction in car crash injuries among novice drivers was found after implementation of a graduated licensing system. In general, the most substantial evidence of effectiveness in reducing alcohol-involved traffic problems exists for RBT, lower BAC laws including special limits for young drivers, and administrative removal of driver’s licenses. These enforcement strategies have even greater potency when coupled with strategies to reduce the impairment level of drinkers leaving public drinking venues, with increases in and enforcement of the minimum drinking age, and with increased community support for drinking and driving enforcement.

Community Alcohol Policy Interventions Policies can be implemented at the community level. Local public policy can be reflected in any established process, priority, or structure that is purposefully sustained over time in the community. At the local level, policy makers can establish the priorities for community action to reduce risky behavior involving alcohol, which in turn can reduce the number of alcohol-involved problems. Possible local alcohol policies can

include making a priority of drinking and driving enforcement by the local police; mandating server training for bars, pubs, and restaurants; setting a written policy for responsible alcoholic beverage service by a retail licensed establishment; or allocating enforcement resources to prevent alcohol sales to underage persons. Local alcohol policy, at whatever level it is implemented, is an environmental or structural response to drinking problems. Following are three examples from international community prevention projects that illustrate how local alcohol policy has been used successfully.

Communities Mobilizing for Change on Alcohol A community intervention program called ‘Communities mobilizing for change on alcohol,’ or CMCA, was designed to bring about change in policies regarding access to alcohol by those under 21 years of age in communities in the United States. Through numerous contacts with groups and organizations that might be able to affect policies, practices, and norms for minors’ access to alcohol, a strategy team was created in each community to lead efforts to bring about change. Local news was used to bring public attention to issues involving drinking by children and youth. The local policy teams implemented quite a variety of activities to reduce alcohol access. These included steps to get alcohol merchants not to sell to young people, to increase enforcement of laws regarding underage sales, to instigate changes in community events to make alcohol less readily available to young people, and to prevent underage drinking parties at hotels. They provided information to parents, and encouraged alternative punishments for youth who violated drinking laws. Specific policy activities varied across communities. Communities involved in CMCA had lower levels of sales of alcohol to minors in their retail outlets and had marginally lower sales to minors at bars and restaurants compared with control communities. Phone surveys of 18- to 20-year-olds indicated that they were less likely to try to buy alcohol and less likely to provide alcohol to others. Arrests of 18- to 20-year-olds for driving under the influence of alcohol declined significantly more in CMCA communities than in control communities (Wagenaar et al., 2000).

The STAD (Stockholm Prevents Alcohol and Drug Problems) Project The STAD alcohol policy project, conducted in downtown Stockholm, was designed to reduce alcohol and drug problems in this area of Stockholm County. The effort comprised three elements: an emphasis on reducing the sales of beer to underage young people in food shops, an intervention with primary care physicians to increase their discussions with patients about harmful drinking, and an RBS program that followed the content of other RBS programs described in this article. The local effort achieved a modest effect on sales of medium-strength beer to youth. The RBS component achieved a reduction in sales to obviously intoxicated persons from 5% (pre-intervention) to 47% (post-intervention). As a result of manager and staff training and policy development in alcohol establishments, findings indicated, using interrupted time-series analyses, a decrease in violent crime in the area served (Wallin et al., 2003).

Effective Alcohol Policy The Community Trials Project The community trials project in the United States, a local alcohol policy project, tested a five-component three-community intervention to reduce alcohol-related harm among people of all ages. It sought to reduce acute injury and harm related to alcohol, that is, drunk-driving injuries and fatalities and injuries and deaths related to violence, drowning, burns, and falls. The effects of the program were evaluated by comparing three communities that received the intervention with matchedcomparisons communities. Overall, off-premise outlets in experimental communities were half as likely to sell alcohol to minors as were the comparison sites. This was the joint result of special training of clerks and managers to conduct age identification checks, the development of effective off-premise outlet policies, and, especially, the threat of enforcement on sales to minors. Moreover, the drinking and driving component produced increased enforcement of drinking and driving laws and a significant reduction in alcohol-involved traffic crashes overall. Comparing experimental and control communities, it was found that the policy intervention produced significant reductions in nighttime injury crashes (10% lower in experimental than in comparison communities) and in crashes in which the driver was found by police to ‘have been drinking’ (6%). Assault injuries observed in hospital emergency departments declined by 43% in the intervention communities versus the comparison communities, and hospitalized assault injuries related to drinking declined by 2%. There was a 49% decline in reports of driving after ‘having had too much to drink’ and 51% in self-reports of driving when ‘over the legal limit.’ There was a significant reduction in problematic alcohol use: average drinks per occasion declined by 6% and the variance in drinking patterns (an indirect measure of heavy drinking) declined by 21% (Holder et al., 2000).

Summary of Substance Abuse Prevention Effectiveness Public decision makers who have the difficult task to reduce alcohol use and alcohol-related problems are faced with many complex and competing forces. Decisions about which prevention strategies to actually implement (or provide funds for) at a local, state, or national level are usually a compromise between political values and scientific evidence. This article has sought to provide a summary of the international evidence on the effectiveness of potential alternative alcohol policy strategies across countries and communities. The greater the generalizability of the findings internationally, the greater confidence one can have that any one policy strategy works in diverse settings and cultures. Policy strategies that have been shown to be consistently effective over time and in two or more countries or cultural settings include the following: Retail price of alcohol Minimum age for drinking or purchase of alcohol l Density of alcohol outlets l Drinking/driving deterrence especially via regular and highly visible enforcement such as RBT l Hours and days of alcohol sales l l

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RBS – alcohol serving and sales policies and training Lower BAC limits for driving.

This article has emphasized the importance of evidence of effectiveness as a critical condition for any public health policy concerning alcohol. However, in a time of restricted resources for prevention, the cost of a public policy relative to its demonstrated (or potential) effectiveness should be increasingly considered in the modern approach to substance abuse prevention. For example, a particular policy or strategy may be shown to be effective in a number of controlled studies, but, compared with an alternative policy or strategy, its potential to yield desired effects must be considered in terms of its cost to design, implement, and sustain. These are additional standards that alcohol policy in all countries should meet in the future. One specific guide for decision makers in selecting cost-effective public policies in reducing alcohol harm is provided by the World Health Organization (see section Relevant Website). The analyses include taxation or retail price, RBT, a comprehensive ban on alcohol advertising, and brief intervention, as well as various combinations of these strategies. The research on which these recommendations are based can be found in the section Further Reading. Based on the research evidence, policy recommendations are best matched with the cultural, economic, and policy situation of the country. The following can provide further guidance in considering potential effectiveness as well as cost: Less developed alcohol policy. For countries or communities in which there is no tradition of alcohol policy, the most directly effective policy is to increase the retail price of alcohol, usually through increased excise or direct alcohol sales taxes, if allowed by law. This is a low-cost policy and can increase government revenue while reducing alcohol problems. Such a policy is often opposed by producers and sellers of alcohol and can stimulate illegal alcohol production and smuggling. l Moderately developed alcohol policy. For countries that have already implemented taxes on alcohol but wish to further reduce alcohol problems, adding restrictions on hours and days of sale as well as reducing the density and concentration of alcohol outlets is recommended. These two policies can be established at low cost but, to be effective, must be supported by sufficient government enforcement to ensure compliance. Some of this cost could be offset by licensing fees paid by alcohol outlets and by alcohol tax revenues. Retail outlets that sell alcohol will oppose such restrictions and will press for maximum hours and days of sale. l More developed alcohol policy. For countries that have already implemented more comprehensive alcohol policies involving retail price and restrictions on sales of alcohol, adding RBS and consistent enforcement will further reduce heavy drinking at bars, pubs, restaurants, and clubs. RBT and low BAC limits for driving will reduce traffic crashes involving alcohol, and lower minimum drinking or purchase ages supported by enforcement will reduce youth drinking, especially high-risk drinking. These more targeted policies have additional associated costs for enforcement and training, and require the support of citizens to implement and sustain. l

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This article has identified those public policies that have scientific evidence of effectiveness in reducing population-level alcohol problems. All of the policies for which effectiveness has been shown require a context that includes active implementation. This often requires regular police enforcement. It is also likely, based on the new research showing the impact of marketing, that regulation to reduce exposure, particularly of young people, to all forms of marketing could prove effective. In practice, the mix of policies that can actually be implemented reflects what is politically and economically possible within any country.

See also: Alcohol Consumption: An Overview of International Trends; Alcohol Industry; Alcohol: Treatment.

References Gruenewald, P.J., Ponicki, W.R., Holder, H.D., 1993. The relationship of outlet densities to alcohol consumption: a time series cross-sectional analysis. Alcohol. Clin. Exp. Res. 17, 38–47. Holder, H.D., Gruenewald, P.J., Ponicki, W.R., et al., 2000. Effect of community-based interventions on high-risk drinking and alcohol-related injuries. J. Am. Med. Assoc. 284, 2341–2347. Jonah, B., Mann, R., Macdonald, S., Stoduto, G., Bondy, S., Shaikh, A., et al., 2000. The effects of lowering legal blood alcohol limits: a review. In: Proceedings of the 15th International Conference on Alcohol, Drugs and Traffic Safety. Ekom Press, Stockholm, Sweden. Miller, T., Snowden, C., Birckmayer, J., Hendrie, D., 2006. Retail alcohol monopolies, underage drinking, and youth impaired driving deaths. Accid. Anal. Prev. 38, 1162–1167. Nelson, J., 2003. Advertising bans, monopoly, and alcohol demand: testing for substitution effects using state panel data. Rev. Ind. Organ. 22, 1–25. Saffer, H., 2002. Alcohol advertising and youth. J. Stud. Alcohol Suppl. 14, 173–181. Saffer, H., Dhaval, D., 2003. Alcohol consumption and alcohol advertising bans. Appl. Econ. 34, 1325–1334. Saltz, R.F., 1997. Prevention where alcohol is sold and consumed: server intervention and responsible beverage service. In: Plant, M., Single, E., Stockwell, T. (Eds.), Alcohol: Minimising the Harm. Free Association Books, London, pp. 72–84.

Shults, R.A., Elder, R.W., Sleet, D.A., The Task Force on Community Preventive Services, et al., 2001. Review of evidence regarding interventions to reduce alcohol-impaired driving. Am. J. Prevent. Med. 31, 66–88. Snyder, L., Milici, F., Slater, M., Sun, H., Strizhakova, Y., 2006. Effects of alcohol advertising exposure on drinking among youth. Arch. Pediatr. Adolesc. Med. 160, 18–24. Stockwell, T., Chikritzhs, T., Hendrie, D., et al., 2001. The public health and safety benefits of the northern territory’s living with alcohol programme. Drug Alcohol Rev. 20, 167–180. Treno, A.J., Grube, J.W., Martin, S.E., 2003. Alcohol availability as a predictor of youth drinking and driving: a hierarchical analysis of survey and archival data. Alcohol. Clin. Exp. Res. 27, 835–840. Wagenaar, A.C., Holder, H.D., 1996. The scientific process works: seven replications now show significant wine sales increases after privatization. J. Stud. Alcohol 57, 575–576. Wagenaar, A.C., Murray, D.M., Toomey, T.L., 2000. Communities mobilizing for change on alcohol (CMCA): effects of a randomized trial on arrests and traffic crashes. Addiction 95, 209–217. Wagenaar, A.C., Toomey, T.L., 2002. Effects of minimum drinking age laws: review and analyses of the literature from 1960 to 2000. J. Stud. Alcohol Suppl. 14, 206–225. Wallin, E., Norström, T., Andréasson, S., 2003. Alcohol prevention targeting licensed premises: a study of effects on violence. J. Stud. Alcohol 64, 270–277.

Further Reading Babor, T., Caetano, R., Casswell, S., et al., 2003. Alcohol: No Ordinary Commodity: Research and Public Policy. Oxford University Press, New York. Chisholm, D., Rehm, J., Van Ommeren, M., Monteiro, M., 2004. Reducing the global burden of hazardous alcohol use: a comparative cost-effectiveness analysis. J. Stud. Alcohol 65, 782–793. Cook, P.J., Moore, M.J., 2002. The economics of alcohol abuse and alcohol-control policies. Health Aff. 21, 120–133. Edwards, G., Anderson, P., Babor, T.F., et al., 1994. Alcohol Policy and the Public Good. Oxford University Press, Oxford, UK. Holder, H.D., 1998. Alcohol and the Community: A Systems Approach to Prevention. Cambridge University Press, Cambridge, UK.

Relevant Website http://www.who.int/choice/interventions/rf_alcohol/en/index.html Organization (WHO).

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Elder Abuse Lia Susana Daichman, International Network for the Prevention of Elder Abuse, Buenos Aires, Argentina; and International Longevity Center Argentina, Buenos Aires, Argentina Susana Aguas, International Network for the Prevention of Elder Abuse, Buenos Aires, Argentina Charmaine Spencer, Simon Fraser University, Vancouver, BC, Canada; and Canadian Network for the Prevention of Elder Abuse, Toronto, ON, Canada Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 2, pp. 310–315, Ó 2008, Elsevier Inc.

Introduction Elder abuse is a serious but preventable public health threat for many persons in later life (Summers and Hoffman, 2006). Since first identified more than 30 years ago as a social problem, elder abuse, like other forms of family or interpersonal violence, has become recognized as a universal phenomenon that cuts across cultural and socioeconomic lines. The mistreatment of older people is a complex issue with moral, sociocultural, political, and personal ramifications that often crosses health care, legal, human rights, and ethical domains within society’s major institutions. The level of research as well as public and professional understanding about the issue still lags 20 or more years behind other types of interpersonal or family violence. The emerging concept of elder abuse is markedly influenced by the rapidity of socioeconomic change, weakening of the extended family, the growth in the numbers of elderly populations and growing concern for human rights, equality, and justice. Dramatic demographic changes all over the globe have meant many more people successfully live to old age, which in itself is an important societal achievement (WHO, n.d.). However, the same trend may result in more older people being at risk of abuse or neglect if social conditions fail to meet their needs. Today, concern about elder abuse has driven a worldwide effort to increase awareness of the problem and encourage development of appropriate prevention and assistance programs. These efforts are predicated on the belief that elders are entitled to live out their advancing years in peace, dignity, good health, and security.

Definitions Over the years, there have been many efforts made to define elder abuse and neglect. There is no standardized definition used in either Europe or North America. This reflects the challenges in achieving a consensus on the scope of harm to be included in, or excluded from, a definition, as well as whether a definition of elder abuse should focus on a specific age at which one is an older person or other characteristics presumed to facilitate vulnerability. Despite these difficulties, a number of emerging definitions have been gaining growing acceptance. The following definition is now in common use in many parts of the world: Elder abuse is a single or repeated act or lack of appropriate action occurring within any relationship where there is an expectation of trust, which causes harm or distress to an older person. WHO, 2002. World Report on Violence and Health, p. 126.

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This definition was first developed by the United Kingdom’s Action on Elder Abuse (1995), a charity organization, following consultation with its membership in 1995. It was subsequently adopted by the International Network for the Prevention of Elder Abuse (INPEA) in 1997, as well as the World Health Organization (WHO, 2002) and the United Nations (2002). The Toronto Declaration on the Global Prevention of Elder Abuse (2002) published by the WHO goes on to explain that elder abuse: “. can be of various forms: physical, psychological/emotional, sexual, financial or simply reflect intentional or unintentional neglect.” The classic work of Stones (1995) on elder abuse definitions highlights that certain kinds of relationships may be treated as trust relationships as a result of social, cultural, or professional norms or legal expectations, irrespective of whether or not the older adult actually considers the other person as trustworthy. Whether a harm or collection of harms to an older adult reaches a threshold that can be considered abusive, neglectful, or exploitative will depend on a combination of subjective and objective perspectives. The first includes the older adult’s perception of the actions. Objective markers will include societal and cultural expectations of older adults and the other persons (such as spouse, family member, caregiver, trusted authority) as well as any identified legal norms within that country. Abuse and neglect exist on a continuum of harm ranging from less to more severe actions or inactions. The impact of abuse on the individual as well as on the family and the community may be affected by elements such as the frequency, duration, intensity, severity, and consequences of the actions. Living with abuse or neglect in later life is stressful and can have significant negative health effects on older adults’ lives, including increased mortality rates relative to nonabused older persons. Abuse and neglect of older persons is also recognized for its intergenerational effect (ONPEA/ UGO, n.d.). Abuse of older adults is generally divided into the following categories: Physical abuse: The infliction of physical harm or injury, physical coercion, or physical restraint (assault) to an older person. l Psychological abuse: The infliction of mental anguish (verbal, emotional abuse) to an older person. l Financial or material abuse: The illegal or improper use of funds or resources from an older person (e.g., financial exploitation, theft). l Sexual abuse: Sexual contact with the older person without their consent (e.g., sexual molestation, rape). l

Neglect of older adults refers to certain failures to live up to social or legal responsibilities to provide care, support, or

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assistance to an older adult. Elder neglect is subdivided into active and passive forms. Active neglect, where the other person refuses or fails to uphold an expected or legal caregiving obligation, such as providing food, medication, or shelter. Active neglect includes conscious and intentional attempts to inflict physical or emotional distress on an older person. l Passive neglect, failure to fulfill a caregiving obligation out of lack of awareness or knowledge of the older person’s needs and condition (which might occur where aging spouses are caring for each other or adult children do not understand the extent of an aging parent’s frail condition). l

Another form of elder abuse and neglect, sometimes described as societal, structural, or systemic abuse or neglect refers to a generalized social failure to fulfill societal expectation of trust, care, and respect of older adults. This type is expressed as discrimination, marginality, and social exclusion that consequently causes harm or distress to older adults (INPEA, 2003). Indicators may include the presence of social, community, and cultural norms that diminish older adults and offer predominantly negative images of aging, the lack of adequate health and social policies, lack of good practice, and nonfulfilment of existing legislation to protect.

Prevalence Most countries, including many in Europe, are still in the early days of identification and development of responses to elder abuse and neglect (Penhale, 2006). Some have not begun to tackle the issue yet. International prevalence estimates of elder abuse in community settings are based mainly on studies from five developed countries (Canada, the United States, the United Kingdom, Finland, and the Netherlands), most of which were conducted in the late 1980s to early 1990s. The rates of elder abuse ranged from 4% to 6% (Pillemer and Finkelhor, 1988; Podnieks, 1992a; Wolf et al., 2002). These figures are likely a significant underestimation of the actual extent, given the largely hidden nature of the problem (Kosberg and Garcia, 1995). More recent work shows considerable variability in rates, reflective of the definitions used, the types of harms considered, age groups, as well as whether the study measured past-year prevalence or lifetime prevalence (that is, harms occurring since age 60 or 65). Past year rates have ranged from 2.6% to 4% in the United Kingdom (O’Keeffe et al., 2007) to an estimate of 18.4% in Israel where the majority of situations involved neglect (Siegel-Itzkovich, 2005). A combination of cultural differences in the treatment of older people as well as variations in perceptions and definitions of abuse make any international comparisons very difficult. The rates are likely much higher in certain subpopulations of older persons, such as those with dementia who come to the attention of specialized health services (Compton et al., 1998) or those who are poor or marginalized (Kosberg and Garcia, 1995). The prevalence of abuse and neglect in institutional settings has been rarely measured, yet is thought to exceed that in community settings. A classic study conducted by Pillemer and Moore (1990) in the United States found that 10% of

nursing staff in institutional settings admitted committing acts of physical abuse and 40% admitted psychological abuse against residents in the previous year.

Risk and Protective Factors for Elder Abuse In an international overview of elder abuse, Kosberg and Garcia (1995) note several significant variables associated with elder abuse and neglect around the world. These include the socioeconomic level, marital status, substance abuse, personal problems, isolation, gender, cultural homogeneity, and housing. Wolf et al. (2002) suggested that structural inequalities in both developed and developing countries have contributed to the overall vulnerability of older persons. These include low wages, high unemployment, poor health services, gender discrimination, and lack of educational opportunities for younger and older generations, all factors that can cause power imbalances and inequities that may lead to exploitation of those persons perceived as weaker or less valued. While developed countries have emphasized individual and family attributes as predictors of elder mistreatment, the developing nations have given more weight to societal and cultural factors, including the fact that many cultures are undergoing major transitions. Most of the early work on abuse of the elderly has been limited to domestic (noninstitutional) settings and carried out in developed countries. To accommodate the complexity of elder abuse and the many factors associated with it, researchers have turned to the ecological model to take into account the interactions that take place across a number of systems (Schiamberg and Gans, 1999). Individual factors, interpersonal factors, and social context and sociostructural factors may interact to heighten or reduce the likelihood of abuse or neglect of older persons (Wolf et al., 2003). Successful prevention efforts within public health will need to focus on the three levels.

Individual Factors A large proportion of cases of abuse reported to the authorities involve older people who are socially isolated or physically or cognitively impaired (Bonnie and Wallace, 2002). It is less clear whether the very old are more at risk of abuse or neglect than younger cohorts of older persons. A study by Podnieks (1992b) and more recently in the United Kingdom by Mowlam et al. (2007) have emphasized the importance of understanding older adults’ strengths and often their hardiness in the face of living in abusive or neglectful relationships and environments. Gender has been also proposed by some as another defining factor in elder abuse, but in different ways for women and men (CNPEA, 2004a,b). Older women may have been subject to oppression and economically disadvantaged all of their lives. On the other hand, old age can become a great equalizer, leaving men at a similar risk of some harms. Studies of violence against older people in domestic settings have found that aggressors are more likely to have mental health and substance abuse problems than nonviolent or nonabusive family members or caregivers (Wolf and Pillemer, 1989).

Elder Abuse Alcohol misuse may be another important risk factor for elder abuse for both perpetrators and victims. Having an adult relative with a drinking problem is a key risk factor for being a victim of elder abuse, especially where the relative (often an offspring) is dependent on the older adult for financial support or housing. Elders are more likely to remain in an abusive relationship when the abuser is a highly dependent adult offspring or when the elder is dependent on the perpetrator (WHO, 2005).

Interpersonal Factors In early theoretical models, the level of stress of caregivers was considered a risk factor that linked elder abuse where a person was caring for an elderly relative (Steinmetz, 1988). Researchers now tend to look at abuse and caregiving in a wider context in which the quality of the relationship over the lifetime as a determining factor, where stress may be a contributing factor in cases of abuse but does not by itself account for the phenomenon. It may be that the violence is a result of the interplay of several factors, including stress, the relationship between the care provider and the care recipient, the existence of disruptive behavior and aggression by the care recipient, and depression in the caregiver. Living arrangements, particularly overcrowded conditions and a lack of privacy, have been associated with conflict within families. In almost all studies of risk factors, social isolation emerges as a significant community factor in elder mistreatment. As with battered women, the social isolation of older people can be both a cause and a consequence of abuse. Some older people may become isolated because of physical or mental decline. Furthermore, loss of friends and family members over the years reduces social networks and the opportunities for social interaction.

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Gender Gender-related issues may vary between different societies and cultures. Aging affects men and women in different ways as they have different roles throughout their lives. Women in developing countries are also more likely to have less access to education or have a poor education, may have poor nutritional status, and have restricted access to services and the labor market in earlier life. These factors often leave them with very few resources in their old age (Daichman, 2004). Gender also leads to different experiences and needs in old age and is related to unequal power relationships. In general, women have a greater chance than men of being widowed, losing social support, an important role, and often any financial security they may have had. In many countries, women may also experience lower status in society with a high risk of sexual violence, physical abuse, and exclusion from decision making (Clark and Till, 2002).

Institutional Abuse Mistreatment of older people has been identified in a range of regulated and unregulated facilities that provide care and support to older persons on an ongoing basis (such as nursing homes, residential care facilities, care homes, assisted living, hospitals, and day care facilities) in almost every country where these institutions exist. Various people may be responsible for the abuse: A paid member of the staff, the owner or administration, another resident, a volunteer, visitor, or relatives or friends. Bennett et al. (1997) suggested that the spectrum of abuse and neglect within institutions spans a considerable range and may be related to any of the following: Problems with staffing, for example, work-related stress and staff burnout, poor physical working conditions, insufficient training, and psychological problems among staff. l Difficulties in staff–resident interactions, for example, poor communication, aggressiveness on the part of residents, and cultural differences. l Environment, for example, a lack of basic privacy, dilapidated facilities, the use of restraints, inadequate sensory stimulation, and a proneness to accidents within the institution. l The provision of care, for example, resistance to changes in geriatric medicine, erosion of individuality in the care, inadequate nutrition and deficient nursing care (such as a lack of attention to pressure sores). l

Social Context and Sociostructural Factors Societal factors are currently considered important as risk factors for elder abuse in both developing and developed countries; cultural norms and traditions such as agism, sexism, and a culture of violence are also now recognized as playing an important underlying role. Developing nations have given more weight to societal and cultural factors such as the inheritance systems and land rights, social construction of gender, rural–urban migration, and a loss of tradition rituals and arbitration roles of elders within the family through the modernization process (Wolf et al., 2002). At the same time, the role of ageism in elder abuse has long been recognized: mistreatment is seen as the extreme end of a spectrum of a negative culture about older people (McCreadie et al., 2006). Neglect and abuse are culturally defined phenomena that reflect distinctions between acceptable and unacceptable interpersonal behaviors. These distinctions denote moral values, standards, and conduct. The perceptions of unacceptable behaviors, cultural norms, and moral standards can vary within complex societies. Therefore, it is necessary to examine elder abuse and neglect from different perspectives in order to understand the meaning of these phenomena (Hudson, 1998).

Interventions Suggested public health approaches to addressing violence and other harms have often included strengthening individual knowledge and skills, educating the community, training providers, building coalitions, changing organizational practices, and influencing policy and legislation (OPHA, 1999), all approaches under development for addressing elder abuse to a greater or lesser extent in many parts of the world.

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Summarizing approaches around the world in the mid1990s, Kosberg and Garcia (1995) noted in addition to general awareness building, the efforts to address elder abuse in community settings have included verifying the problem, social support for families, alternatives to family care, family life education and counseling, support groups for family caregivers, detection protocols, advocacy, public policies, housing resources, action by elderly persons, and publicity. In many jurisdictions in Europe, the efforts have begun with the development of networks, research groups, and the involvement of specialists (Penhale, 2006). Over the years, international authors have validated sets of indicators and developed screening questions for elder abuse for uses in clinical, adult protection, or social work settings (Lachs and Pillemer, 1995; Bennett, 1998; Mount Sinai Hospital, 1998; Daichman, 2000). In a recent study of effective interventions, Kalaga and Kingston (2007) note that ‘there is no magic bullet,’ but a number of primary, secondary, and tertiary interventions are emerging. The United Nations has noted (2002) that interventions to treat the social, economic, and political conditions that are fertile ground for abuse of elders can improve the general conditions of life of older persons, and can reduce the violation of their rights as well as those of other population groups. The response to the abuse of older persons has been largely focused on raising awareness and understanding of elder abuse within communities, countries, and internationally (United Nations, 2002). 15 June 2006 marked the debut of World Elder Abuse Awareness Day, which communities and agencies in many countries have used as an opportunity to heighten awareness and support for abuse prevention, help enable development of awareness into action, mobilize efforts, and galvanize community and policy action. Prevention events may be planned for the day, as well as weeks and the month around it. The activities may focus directly on abuse prevention and awareness to build public and professional awareness, or public awareness campaigns may concentrate on the underlying factors, such as ageism or diminished respect (INPEA, 2007).

Main Conclusions and Future Directions There is a significant need for greater knowledge about the problem, more effective prevention strategies, and stronger laws and policies to address the problem and its underlying factors (Wolf et al., 2002). It has been recognized that by reducing risk factors, strengthening resilience factors, and changing norms, violence and other mistreatment of older persons can be prevented. There is a growing recognition of the need to expand efforts from a focus on the aftermath of violence and mistreatment to upfront approaches that address it before it occurs. This may include a need to foster a comprehensive approach to prevention focusing on the underlying contributors as well as policies and infrastructure that support mistreatment, or contribute to it. “The desensitization process, facilitated by persistent exposure, contributes to an underlying feeling of helplessness – a sense that the vastness of the problem is too overwhelming” (Ontario Public Health Association, 1999). It is essential to address societal conditions such as racism, poverty, and inequality that foster violence.

A number of specific needs are beginning to be recognized and slowly addressed in this area. These include developing a more comprehensive knowledge about elder abuse based on sound research programs. This information will need to reach service providers and other professionals working with older people to shape appropriate practice, as well as older adults and their families to build understanding of the dynamics. There is a need for research and prevention programs, advocacy and information for older adults about their rights and ways to access services. Empowerment of elders should enable them to act for themselves and on their own behalf, to exercise their rights and advocate for their own interests. More solid knowledge based on comprehensive research to better inform policy, planning, and practice is required. Elder abuse is a multifaceted issue, often requiring the knowledge and skills of many types of individuals and agencies. There is a need at a community level for collaboration and formation of partnerships to promote the development of adequate services. In Missing Voices, a joint publication of the World Health Organization and the International Network for the Prevention of Elder Abuse (2002), it is emphasized that “Ultimately the challenge for us all is not only to listen to what has been said, but to believe and act upon it.”

See also: Long Term Care for Aging Populations.

References Action on Elder Abuse, May/June 1995. Actions on elder abuse: definition of elder abuse. Action Elder Abuse Bull. Bennett, G., 1998. Elder abuse. In: Study Guides in Geriatrics Medicine. Royal London School of Medicine and the Queen’s University of Belfast, London, pp. 2–22. Bennett, G., Kingston, P., Penhale, B., 1997. The Dimensions of Elder Abuse: Perspective for Practitioners. Macmillan, London. Bonnie, R.J., Wallace, R.B. (Eds.), 2002. Elder Mistreatment: Abuse, Neglect, and Exploitation in an Aging America. National Research Council, National Academies Press, Washington, DC. Canadian Network for the Prevention of Elder Abuse (CNPEA), 2004a. Abuse of Older Men. Canadian Network for the Prevention of Elder Abuse (CNPEA), 2004b. Abuse of Older Women. http://www.cnpea.ca/en/publications/reports/241-abuse-of-older-womenreport-of-the-standing-committee-on-the-status-of-women (accessed January 2008). Canadian Network for the Prevention of Elder Abuse (CNPEA), n.d. Health and Abuse. Clark, F., Till, C., 2002. Taking gender into account in violence and abuse. Ageways Pract. Issues Ageing Dev. 59, 13–14. Compton, A., Flanagan, P., Gregg, W., 1998. Elder abuse in people with dementia in Northern Ireland: prevalence and predictors in cases referred to a psychiatry of old age services. Int. J. Geriatr. Psychiatry 12 (6), 632–635. Daichman, L., 2000. Dimensiones del Abuso y Maltrato en la Vejez. University of Belgrano, Buenos Aires, Argentina. Daichman, L., 2004. Elder abuse in the Latin American countries. In: Tatara, T. (Ed.), A Survey on Intercultural Differences in the Perceptions about Future Concerns, Governmental Functioning and Elder Rights Protections in Five Countries. Tokyo. Hudson, M., 1998. Elder abuse: two native American views. Gerontologist 38 (5), 538–548. International Network for the Prevention of Elder Abuse (INPEA), 2003. Latin America. The Regional Intergovernmental Conference on Aging for LA and Caribe. CEPAL-CELADE. International Network for the Prevention of Elder Abuse, 2007. INPEA World Day Reports, 2007. http://www.inpea.net/ (accessed January 2008). Kalaga, H., Kingston, P., 2007. A Review of Literature on Effective Interventions that Prevent and Respond to Harm against Adults. Scottish Government Social Research. http://www.scotland.gov.uk/Publications/2007/11/ 15154941/0 (accessed January 2008).

Elder Abuse Kosberg, J., Garcia, J.L., 1995. Common and unique themes in elder abuse from a worldwide perspective. J. Elder Abuse Negl. 6 (3/4), 183–197. Lachs, M.S., 1998. Mortality risk from elder abuse rivals that of other major illnesses. Geriatrics 53 (10), 171. Lachs, M., Pillemer, K., 1995. Abuse and neglect of elderly persons. N. Engl. Med. J. 332 (7), 437–443. Lachs, M.S., Williams, C., O’Brien, S., Pillemer, K.A., Charlson, M.E., 1998. The mortality of elder mistreatment. J. Am. Med. Assoc. 280 (5), 428–432. McCreadie, C., O’Keeffe, M., Manthorpe, J., et al., 2006. First steps: the UK national prevalence study of the mistreatment and abuse of older people. J. Adult Prot. 8 (3), 4–11. Mount Sinai Hospital, 1998. Elder Mistreatment Guidelines. Mount Sinai Hospital, New York. Mowlam, A., Tennant, R., Dixon, R., McCreadie, C., August 2007. UK Study of Abuse and Neglect of Older People: Qualitative Findings. https://www.lemosandcrane.co. uk/resources/NatCen%20-%20UK%20study%20of%20abuse%20and%20neglect. pdf (accessed January 2008). National Center on Elder Abuse and American Public Human Services Association, 1998. The National Elder Abuse Incidence Study. Final Report. http://www.aoa.gov/eldfam/ Elder_Rights/Elder_Abuse/ABuseReport_Full.pdf (accessed January 2008). O’Keeffe, M., Hills, A., Doyle, M., et al., 2007. UK Study of Abuse and Neglect of Older People Prevalence Survey Report. National Centre for Social Research, Kings College London. https://www.lemosandcrane.co.uk/resources/NatCen%20-%20UK%20study %20of%20abuse%20and%20neglect.pdf (accessed January 2008). Ontario Network for the Prevention of Elder Abuse (ONPEA), United Generations of Ontario, n.d. Quality of Life across the Generations: An Intergenerational Approach to the Prevention of Elder Abuse – Intergenerational Programming. http://www.lin. ca/resources/quality-life-across-generations-intergenerational-approach-preventionelder-abuse (accessed January 2008). Ontario Public Health Association, 1999. A Public Health Approach to Violence Prevention. Position Paper 1999. http://www.cpha.ca/uploads/policy/violenceprevention_e.pdf (accessed January 2008). Penhale, B., 2006. Elder abuse in Europe: an overview of recent developments. J. Elder Abuse Negl. 18 (1), 107–116. Pillemer, K., Finkelhor, D., 1988. The prevalence of elder abuse: a random sample survey. Gerontologist 28 (1), 51–57. Pillemer, K., Moore, D.W., 1990. Highlights form a study of abuse of patients in nursing home. J. Elder Abuse Negl. 2, 5–30. Podnieks, E., 1992a. National survey on abuse of elderly in Canada. J. Elder Abuse Negl. 4, 5–58. Podnieks, E., 1992b. Emerging themes from a follow-up study of Canadian victims of elder abuse. J. Elder Abuse Negl. 4 (1/2), 59–111. Schiamberg, L.B., Gans, D., 1999. An ecological framework for contextual risk factors in elder abuse by adult children. J. Elder Abuse Negl. 11 (1), 79–103.

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Siegel-Itzkovich, J., 2005. A fifth of elderly people in Israel are abused. Br. Med. J. 330, 498. Steinmetz, S.K., 1988. Duty Bound: Elder Abuse and Family Care. Sage, Thousand Oaks, CA. Stones, M.J., 1995. Scope and definition of elder abuse and neglect in Canada. In: MacLean, M.J. (Ed.), Abuse and Neglect of Older Canadians: Strategies for Change. Thompson Educational Publishing, Inc, Toronto, Canada, pp. 111–115. Summers, R.W., Hoffman, A.M. (Eds.), 2006. Elder Abuse: A Public Health Perspective. American Public Health Association, Washington, DC. Toronto Declaration on the Global Prevention of Elder Abuse, 2002. http://www. who.int/ageing/projects/elder_abuse/alc_toronto_declaration_en.pdf (accessed January 2008). United Nations, 2002. Elder Abuse Widespread and Unreported, Says New Report by Secretary-General. Press Kit Second World Assembly on Ageing, Madrid Spain. http://www.un.org/ageing/prkit/elderabuse.htm (accessed January 2008). World Health Organization/INPEA, 2002. Missing Voices: Views of Older Persons on Elder Abuse. World Health Organization, Geneva, Switzerland. World Health Organization, 2005. Abuse of the elderly. In: World Report on Violence and Health, Chapter 5. World Health Organization, Geneva, Switzerland. http://www. whqlibdoc.who.int/publications/2002/9241545615_eng.pdf (accessed March, 2008). World Health Organization, n.d. Aging and Life Course. http://www.who.int/ageing/en/ (accessed January 2008). Wolf, R.S., Pillemer, K.A., 1989. Helping Elderly Victims: The Reality of Elder Abuse. Columbia University Press, New York. Wolf, R., Daichman, L., Bennett, G., 2002. Abuse of the elderly. In: Kruge, E. (Ed.), World Report on Violence and Health. World Health Organization, Geneva, Switzerland. Wolf, R., Bennett, G., Daichman, L., for the UN, 2003. Abuse of the elderly. In: International and Cultural Psychological Series: Trauma Intervention in War and Peace, Prevention, Practice and Policy. Kluwer, New York.

Relevant Websites http://www.elderabuse.org.uk – Action on Elder Abuse. http://www.ace.org.uk – Age Concern. http://www.cnpea.ca – Canadian Network for the Prevention of Elder Abuse. http://www.helpage.org – Help Age International. http://www.iagg.info/ – International Association of Gerontology and Geriatrics. http://www.inpea.net – International Network for the Prevention of Elder Abuse. http://www.who.org – World Health Organization.

Emergence of Novel Human Infections: New Insights and New Challenges Ann Marie Kimball, University of Washington, Seattle, WA, USA; and Chatham House, London, UK Ó 2017 Elsevier Inc. All rights reserved.

Background New human infections have continued to come forth over the last decade. This discussion will focus on the period from 2006 to 2016. Given the importance of the severe acute respiratory syndrome (SARS) as the harbinger of coronaviruses such as the Middle East respiratory syndrome (MERS), some discussion of SARS is also included. The phenomenon of emerging infections has been constant with the majority of human infections reflecting the introduction into humans of zoonotic pathogens. Over the last decade, great progress has been made in defining more fully how emergence occurs. In fact the emergence of new infections has expanded the paradigms of microbiology in a number of ways, which will be highlighted here. Specifically: (1) it is now well appreciated that influenza can migrate directly from avian sources to humans, and the appreciation of the actual directness of ‘species jumping’ has moved forward; (2) new infections have also introduced uncertainty in transmission dynamics with emphasis on super-spreader events as well as nosocomial transmission; (3) infectious particles are not confined to those organisms which contain genetic material; (4) a new paradigm such as ‘Planetary Health’ may be necessary for defining these trends; and (5) global preparedness and response is not in place for the next pandemic. For further background information, the reader is referred to the original article on this phenomenon (Kimball, 2008). A general discussion of antimicrobial resistance and xenotransplantation is not included in this discussion as they were thoroughly covered in the original article. Antimicrobial resistance will be covered in detail in another article of this volume. Nonetheless they continue to be important considerations.

Respiratory Pandemics: Highly Mobile, Highly Unpredictable While it has long been appreciated that the majority of human pathogens arise from zoonotic sources, the directness of the path from animal to human has become clear. Ideally detecting pathogens in animals could be seen as a harbinger for human outbreaks. In fact this has been a working hypothesis of major US Agency for International Development (USAID) funding to their pandemic agents program. However, recent outbreaks of influenza, SARS, and MERS coronavirus (CoV) demonstrate how emerging infections are shifting this longstanding paradigm. They lend further urgency to this area of research. In addition, these outbreaks have challenged our understanding of transmission dynamics. Empirical observation has shown that there is not a single transmission force ‘number’ which completely characterized the spread of infectious diseases. This further complicates efforts to control infection within populations.

Influenza

In 2009, a cluster of high mortality influenza cases was detected in Mexico. An observational study of 899 patients hospitalized in Mexico between late March and 1 June 2009 showed that

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pandemic (H1N1) disproportionately affected young people. Fifty-eight patients (6.5% of those hospitalized) became critically ill, with complications including severe acute respiratory distress syndrome and shock. Among those who became critically ill, the mortality rate was 41% (Domínguez-Cherit et al., 2009). The pandemic and its management have been the subject of an in-depth analysis commissioned by the World Health Organization (WHO), and that analysis proved prescient in more recent global outbreak events such as Ebola (WHO, 2005). This cluster heralded a global pandemic and the declaration by WHO of a Public Health Emergency of International Concern (PHIEC). It occurred in the context of a decade of planning for a potential H5N1 outbreak, which included WHO updating its pandemic guidance (Pandemic Influenza Preparedness and Response, 2009). In 1997 a small but lethal cluster of influenza occurred in children in a Hong Kong nursery. Of the 18 cases, 6 died (Mounts et al., 1999). Science shifted its understanding of influenza and recognized that flu could come directly from birds to humans. In fact H5N1, which emerged in 2003, acquired the popular moniker of ‘Bird Flu.’ The outbreak was curtailed through active surveillance, changes in practice, and poultry culling of live markets in Hong Kong. However, the outbreak proved a harbinger of more widespread recognition of ‘Bird Flu.’ H5N1 was identified through active surveillance of poultry and wild birds; waterfowl were particularly affected. Human cases were sporadic but carried a very high mortality rate (estimated at 60%) (Webster et al., 2006). Although the virus proved difficult to transmit to humans, case fatality was high. As of February 2011, about 500 laboratory-confirmed human cases had been reported to the WHO from 15 countries; about 60% of reported cases were fatal. The spread of H5N1 was geographically broad with extension into Nigeria and throughout Southern and SE Asia in waterfowl and in domestic fowl. Extensive planning for a potential pandemic was put into place given the apparent proximity of the threat and the high mortality in humans. Veterinary and human health collaboration was a central precept of this planning in the ‘One Health’ concept (Heymann and Dixon, 2013). The H5N1 threat did not materialize despite the high level of circulation in birds. Preparedness in SE Asia in particular included tabletop exercises, culling of birds through rapid response, and at least one joint investigation carried out between Laos and Thailand. In this setting, H1N1 ran its course, with a milder clinical syndrome (although it is estimated that the global death toll was 284 000). The pandemic of H1N1 precipitated some confusion as well as competition for access to antivirals and vaccines. In the aftermath of these contentious discussions, new policy initiatives were put into place. This included the ‘Pandemic Influenza Preparedness’ (PIP) (WHO) plan which took some years to negotiate. It balances access to new viral strains for vaccine production with access to these vaccines for poor countries. The Fineberg Commission to examine an

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Emergence of Novel Human Infections: New Insights and New Challenges ‘after action’ performance of the International Health Regulations (IHR) was central to potential reform as well. This will be more fully discussed below. In 2013 a new influenza virus, H7N9, was isolated from patients in the People’s Republic of China. Isolates were both from birds and from humans. Although 571 cases occurred globally with 212 deaths, international spread was limited to two countries. The national response to this epidemic was very strong which is a key to control (discussed below).

Severe Acute Respiratory Syndrome

The 2009 influenza pandemic also followed another global respiratory emergency, SARS. The etiology of SARS (a new coronavirus) was not known in late 2002 when cases and deaths began to occur in Guangdong province of the People’s Republic of China. Initially misdesignated as a chlamydial pneumonia early in the course, public alarm mounted as antibiotics proved futile in treatment. Between November 2002 and July 2003, a total of 8427 probable SARS cases were reported from 29 countries with 813 deaths for a mortality rate of 9.6% (MMWR, 2003). SARS effectively demonstrated the potential mobility of respiratory pathogens. While SARS was declared poorly transmissible, it effectively jumped continents in travelers and infiltrated populations through nosocomial spread. In contrast to influenza, which is highly transmissible, SARS still requires direct exposure to bodily fluids for transmission. However, SARS shifted the scientific paradigm of zoonotic transmission more fully – with incrimination of wet markets vending civet cats initially thought to be the source. This initial assessment has proved less robust in terms of ‘reservoir’ for new human pathogens as discussed below. SARS also challenged our understanding of transmission dynamics. For reasons that remain unclear, a single infected person who spent a single night in a hotel in Kowloon resulted in geographically broad transmission. The concept of a ‘superspreader’ was popularized (Lloyd-Smith et al., 2005). This phenomenon was also described in a second scenario in Beijing (Shen et al., 2004). Traditionally infection has been characterized by a ‘reproductive rate’ which is essentially the rate at which an infectious case replaces itself. If the rate is 1, then there will be no spread, as the infection will simply stay the same absolute number as the index case recovers. However, if the rate is higher (i.e., >1), then spread into the population will occur as a single case infects multiple individuals so the number of cases increases. Super-spreaders seem to have high infection rates although the overall rate for the pathogen in question may be low. This has, of course, changed our assumptions for modeling disease spread in populations.

Middle East Respiratory Syndrome Coronavirus

Following the 2009 H1N1 pandemic (and the avian influenza emergence of 1997) and the SARS pandemic of 2003, a new virus emerged on the Arabian Peninsula. MERS-CoV is a new human pathogen that also causes pneumonia and respiratory distress. The story of MERS is less history and more present in terms of defining its epidemic potential. It reinforces the need for ‘One Health’ collaboration between veterinarians, clinicians, and public health specialists, making use of their relative expertise.

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MERS was first reported in 2012 as a case report of a patient in an ICU with severe respiratory disease from Jordan (Hijawi et al., 2013). At the time of this writing, 1321 cases and 466 deaths have been reported to the WHO, with an average case fatality ratio of 35%. In one epidemiological analysis, the case fatality ratio for primary cases was 74% (95% CI, 49–91), whereas for secondary cases, it was 20% (95% CI, 7–42) (Alsolamy, 2015). Like its coronavirus cousin, SARS, MERS-CoV has demonstrated agile spread within hospitals (Oboho et al., 2015) and across continents. In 2015 a large outbreak occurred in South Korea (Cowling et al., 2015). That outbreak was characterized by a mortality rate of about 20% among 186 cases, 33 were fatal. It also featured ‘superspreading’ events. In fact a single case housed in the emergency room with persistent cough was linked to 81 cases in one hospital (Kucharski, 2015). To summarize, the recent episodes of respiratory infectious diseases related to influenza, SARS-CoV, and MERS-CoV have demonstrated increasingly direct links between animal and human infections, agile intercontinental geographic spread, and complex transmission dynamics including ‘superspreader’ events. Transmission within health-care settings has also been a prominent feature. These characteristics have challenged traditional assumptions about the pathogenesis and epidemiology of infectious diseases.

Beyond Biology: Auto-replicating Proteins Traditionally microbiology has held that microbes (bacteria, viruses, protozoa, fungi, etc.) are organisms that replicate through genetic mechanisms. That replication is a major factor in the illness in humans these agents cause. Recent emerging infectious events have brought an additional complexity into that decades’ old assumption.

New Biology-Prions A new form of a human neurodegenerative disease that emerged in Britain in the 1990s was linked to the emergence of bovine spongiform encephalitis (BSE) in cattle (‘mad cow disease’). This link was demonstrated through multiple case– control studies. The biological proof of a common etiology came somewhat later (Hill et al., 1997). Prions are not microbial life in the traditional sense. They are ‘autocatalytic proteins’ or proteins that make change. In the instance of ‘transmissible spongiform encephalopathies’ (TSEs) of mad cow disease (BSE), sheep ‘scrapie,’ elk chronic wasting disease, as well as in the human diseases of Creutzfeldt-Jakob disease (CJD), new variant CreutzfeldtJakob disease (vCJD) and kuru, these changes occur in the central nervous system. While the new vCJD epidemic related to ingestion of infected beef from BSE-affected cows has waned due to enhanced global surveillance and animal husbandry practices, research into prion disease continues. It appears that despite their lack of genetic material, prions do undergo mutation and strain diversification in response to selective pressures (Collinge et al., 2007). Soberingly, it is believed that some humans (estimated 1 in

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4000 Britons) silently carry pathogenic prions for many years. This risk persists and creates safety concerns for blood transfusions and organ transplantation. The story of BSE demonstrated the limitation of the traditional assumption that genetic reproduction of pathogens is necessary for infection as outlined above. The UK beef industry had historically been a relatively stable one when fragmented among many smaller farms across the British Isles. To protect this industry, the government maintained a tariff on the imports of competing products from abroad. With the explosion of global trading in beef after World War II, coincident with refrigerated transport, and the movement toward global free trade, the United Kingdom negotiated a timetable under the General Agreement on Tariffs and Trade to scale down tariffs on beef, which heightened competition in the UK beef industry and increased pressure for more efficient and less costly production methods. Against this backdrop, innovation in rendering was introduced into the slaughterhouses of the United Kingdom. The rendering or processing of carcasses of cows and other animals after the edible and usable bits of flesh and meat have been cut away has been done for centuries. And for decades, UK farmers used the meat and bone meal from rendering as a protein source for beef cattle. Historically, the rendering process was similar to pressure cooking – applying very high temperatures for very long times so eventually even the bones broke down into powder. It was an expensive, fuel-consuming, and timeconsuming process. When a new cold vacuum extraction method of rendering was introduced requiring lower temperatures (i.e., less energy) and less time, it seemed a win–win situation considering the increasing pressure on the UK beef industry in the face of global competition. But sometime after the new rendering practice was introduced into the United Kingdom, the prion disease known as mad cow disease emerged. The new process, discovered by UK beef industry, was not effectively disinfecting for prions. Existence of prion disease was unknown prior to its dramatic emergence, first in cows and then in people. The context is important to appreciate. Somehow the streamlining of the rendering process played a role. British scientists tested the new process by deliberately introducing animals with mad cow disease and assaying the resulting meat and bone meal product. They found that the newer rendering process does not remove the infection, whereas the older process did.

Zika Virus: Emergent Intergenerational Risk? Zika virus emerged in sub-Saharan Africa in the late 1940s. It is a close cousin of dengue virus and in the same family as yellow fever. All of these viruses are transmitted to humans through the bite of a mosquito. All of these diseases are clinically mild, but occasionally severe causing fever, rash, and joint pain. Unfortunately all of these diseases have become globally distributed. Zika is the most recent arrival in the Americas. It has circulated in Asia for some time (Chen and Hamer, 2016). While clinically relatively mild, epidemiologic studies in Brazil have suggested a link between Zika virus and severe birth defects in newborns. Viral infection in early pregnancy appears to be associated with microcephaly, which is associated with profound brain injury in newborns.

Again, the emergence of a new infectious disease is pushing the boundaries of biomedical knowledge. In the absence of certain prevention or treatment options, the government of Brazil has gone as far as advising women not to become pregnant (McNeil, 2015).

Antimicrobial Resistance in Small Packages The emergence of antimicrobial resistance has continued to be a major concern. In 2008 a new enzyme in gram-negative bacteria was detected which caused broad antibiotic resistance. This enzyme was produced by mobile genes that travel on plasmids. Plasmids are small circular DNA (genetic) packages, which are distinct from the DNA of the bacteria itself. These are mobile, with the ability to be taken in across classes of bacteria if and when they confer a selective advantage for survival, as in the case of antimicrobial resistance. The new enzyme NDM-1 (New Delhi metalloproteinase-1) was traced to an infection that occurred in patients who had been treated in India. A more complete study of the epidemiology of this enzyme in gram-negative bacterial isolates from the subcontinent suggested a broad range of gram-negatives were affected (Kumarasamy et al., 2010). This new biology, which was first described for extended spectrum beta lactamase (ESBL) resistance in the 1990s, has provoked renewed concern in antimicrobial resistance. 2011 was declared by the WHO as the year to address antimicrobial resistance. The pharmaceutical pipeline is bereft of new antibiotics to address this challenge. Chillingly another new panresistant plasmid has been reported from China, which is resistant even to the last line of defense, the polymixin class of antimicrobials (Liu et al., 2015). This report included isolates from pigs at slaughter, retail pig and chicken meat, and humans. Again, the specter of intensive agriculture fostering new biological threats calls for careful study. The isolates were largely from areas of intensive porcine agriculture in China. Figure 1 indicates sites sampled for polymixin plasmid resistance.

Reservoirs in Nature Links? The question of where new infections lurk in nature has been an active area of research. As noted above, the initial reservoir for SARS coronavirus was thought to be civet cats which are domestically raised for food in China. However, further investigation has suggested that there may be a single host involved in many emergent diseases. In an elegant demonstration of interdisciplinary research, Han et al. (2015) have recently published a persuasive article on the role of bats in emerging infections. Whether or not the theses of the article prove true with further research, the work provides additional evidence of how extremely powerful interdisciplinary research can be toward solving the puzzles of emergent diseases in humans. In discussing the spillover of viruses from bats to humans, the authors write: Factors that contribute to the intrusion of bats into human living environment can be summarized into a ‘push’ and a ‘pull’

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Figure 1

(Brüssow, 2012). A ‘push’ refers to the enormous demand for more space and resources brought by the human population explosion, which leads to the destruction of bat habitats and shortage of food. Natural environmental changes, such as typhoons and droughts, can also place stresses on bats. A ‘pull’ involves the living environments built by humans, characterized by urbanization, intensive agriculture and food animal breeding, which attracts bats into human living environments for an abundant of food supply.

Table 1

So coming full circle, this discussion highlights the critical importance of further understanding these events of ‘species jumping’ or ‘spillovers,’ given the pressures will only augment rather than abate. Infections potentially housed in bats as their natural reservoir (from Han and colleagues) is shown in Table 1. It is an impressive array, which brings us to consider how indispensible further understanding in these interactions is to gain insight into emergent human infections.

Summary for selective bat-borne viruses

Virus

Putative host

Intermediate host

Modes of transmission

Drivers

Nipah virus

Flying foxes

Pigs

Close contact with sick ones, drinking date palm juice, contact with pigs

Hendra virus

Flying foxes

Horses

Contact with horses

SARS-CoV

Horseshoe bats

Palm civets

Slaughtering, farming of wildlife

MERS-CoV

Batsa

Dromedary camels

Ebola virus

Egyptian fruit bats

Nonhuman primates

Direct contact with camels, consumption of camel milk/meat Slaughtering, hunt for bush meat

Climate changes, changes of farming practices (dual land use), transportation of pigs as merchandise, social/cultural practices, habitat destruction Climate changes, urbanization, social/ cultural practices Economic growth, desire for game meat, wildlife trading in wet markets, international travel Not known

a

Specific bat species not identified.

Preference for bush meat, burial practices, poor health-care practice

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Interplay of Infection with Human-Made Factors So what explains the apparent increased pace of emergence of new human infections? Is it simply that we are more able, with our new technologies, to detect them? Or are there forces at work that are fostering this trend? The stories of BSE and nvCJD recounted above were outlined because the United Kingdom, although a small country, has excellent epidemiologic, statistical, laboratory, and clinical acumen. While cases of BSE and nvCJD were not confined to the United Kingdom, the origin of emergence was tracked and described relatively efficiently. But, what of influenza? The potential contribution of intensive poultry and swine agriculture to the emergence of influenza A emergence was outlined in my earlier article for this publication. Research over the past decade has continued to provide evidence of this risk. As intensive practices have spread to developing countries, the assurance of biosecurity has become less sure as noted in the discussion (above) of polymixin resistance through plasmids in pigs and humans. While many new strains of influenza arise in wild birds (particularly waterfowl), the link to human populations appears to be through domestic poultry (Leibler et al., 2009). However, other anthropogenic mechanisms are also at play. Without the global ‘mobile’ environment of travel and trade, emergence would remain a largely local phenomenon. However, as we saw with the influenza discussion above that is not the case. Nor was it the case with SARS or with MERS-CoV. International tourism surpassed 1.1 billion arrivals in 2013 according to the World Bank (World Bank International Tourism). After a slump in global trade during the global recession exports of food in 2014 reached nearly $1.5 trillion in value for selected countries where data were available. This, of course, does not include all of global trade, which has surpassed $3 trillion in value (Merchandise Trade by Product). Guarding against transcontinental transmission in food or through human travel is a complex undertaking, with safeguards at the source the most likely answer. However, research, testing, and demonstration of effective measures remain wanting. Finally, climate change, largely attributed to human activity, seems to be readjusting the boundaries of mosquito borne diseases. The recent incursion of Zika into Brazil is attributed to the El Niño weather pattern now in force in that geography. While El Niño oscillation is not directly attributable to human activity, the shifting of such natural oscillations and their severity may well be. In his landmark 1993 book Planetary Overload: Global Environmental Change and the Health of the Human Species, Anthony J. McMichael outlines the human-generated stress on natural systems (McMichael, 1993). He posits that food will become increasingly scarce for the human community. The macroecologic effects of human activity on climate, water, food, agriculture, pollution, and human health are well described, but the systematic link between the macrolevel (what we can see) and what is occurring on the microlevel remains an important area of research. To address the emergence of new pathogens, we need more precise knowledge about the mechanisms that form the critical pathway to emergence. A follow-up report to the landmark IOM Report, Emerging Infections, Microbial Threats to Health: Emergence Detection and

Response was published in 2003 (Smolinski et al.) (Microbial Threats to Health). Additional factors of emergence were examined in this report: human susceptibility to infection, climate and weather, changing ecosystems, poverty and social inequity, war and famine, the lack of political will, and intent to harm. Thus the original 6 factors grew to 13. While enriching the discussion and description of emergence, this proliferation of factors also created overlapping domains within factors; for example, climate and weather are an integral physical science aspect of ecosystems, the failure of political will is integral to the neglect of public health systems, and so forth. From an analytic point of view, the need for in-depth study of factors and how they actually work has become critical for scientific insight into public health protection. McMichael has suggested the term ‘the anthropogenic epoch’ to describe our contemporary situation. In other words, human kind is changing the nature of our environment in unprecedented ways. More recently the Rockefeller-Lancet Commission has suggested the new scientific discipline of ‘Planetary Health’ as a unifying concept to bring the disparate strands of life sciences, and ecology more closely together to foster interdisciplinary research and insight (The Rockefeller Foundation, 2015). The key to success will require intense investment in transdisciplinary research which brings in disparate databases and talents into risk analysis.

New Tools While a full discussion is beyond the scope of this discussion, a number of new tools have come into use that allow more rapid diagnosis and response to newly emergent outbreaks. A few will be highlighted here.

Informal Disease Surveillance Networks

In addition to formal disease surveillance reporting a number of informal diseases, surveillance networks have arisen among countries which share common borders or work within a common economic bloc. These networks facilitate the flow of information across borders and allow collaborative investigations, tabletop exercises, and resource sharing on an ongoing basis. In postconflict areas such as the Mekong Basin, they contribute to health security (Gresham et al., 2013).

Modeling

Increasing sophistication of bringing disparate data sets together and creating models to understand possible scenarios has brought additional insight into prevention and control efforts for emerging diseases. Prediction of where outbreaks are most likely to occur remains a very imperfect science (Jones et al., 2008). Retrospective niche modeling has brought additional insight into how different factors may interact to foster outbreaks (Daszak et al., 2013).

Rapid Genomic Sequencing

Laboratory diagnosis of unknown agents has also advanced. During the SARS outbreak, the WHO convened an informal network approach to fully sequence the new agent in 1-month time (David, 2004). One group has put forward a vision of bringing full genomic sequencing into the

Emergence of Novel Human Infections: New Insights and New Challenges laboratories of developing countries (Aarestrup et al., 2012). Clearly the ability to quickly diagnose new agents without the necessity of culture would be an important advance. As importantly the integration of informatics linking genomic analyses to phylogenetic metadata would allow global tracking of agents.

Is the World Prepared? As the boundaries of microbiology are stretched with new insights from emergent diseases, the ability of the people of the world to protect against pandemics is more important than ever. Global traffic and trade continue to grow, confounding national approaches with their international span. In 2005 (following SARS) the WHO adopted the IHR (international health regulations). This is the only law with the force of an international treaty, which is in place to govern the conduct of countries during global security emergencies. The IHR outline ‘core capacities’ for national-level protection. It is not the optimal level for an emergent pandemic, but it is the minimum considered essential for global health security. The IHR implementation was to have been completed by all member countries by 2012. However, implementation has languished with only one-third of countries implementing and many not disclosing their status of implementation to the WHO in 2015. After the 2009 influenza pandemic, an independent expert panel was convened to assess how the IHR functioned. That panel, lead by Dr Harvey Fineberg, then President of the Institute of Medicine, was explicit in outlining the gaps in global health security. The world is ill-prepared to respond to a severe influenza pandemic or to any similarly global, sustained and threatening public-health emergency. Beyond implementation of core public-health capacities called for in the IHR, global preparedness can be advanced through research, reliance on a multisectoral approach, strengthened health-care delivery systems, economic development in low and middle-income countries and improved health status. Fineberg (2014).

In 2013, Ebola (a known infection) emerged in Guinea. At the time of its appearance, none of the countries in subSaharan Africa had implemented the core capacities of the IHR (Kimball and Heymann, 2014). The outbreak went on to create pandemonium in the three most affected countries (Guinea, Liberia, and Sierra Leone) killing over 11 000 people (and afflicting more than 28 000) (ebola-situation). Infection was introduced in other countries, but onward transmission was limited. Following Ebola, the international systems are again under review. Initial observations remain distressingly similar to those made in 2009. With reform of the UN and WHO, once again underway, it will be important to follow through. Of particular importance as highlighted above is the interdisciplinary (and in the case of the UN interagency) nature of prevention, detection, and response to emergent threats. Despite the new technological tools, the ecological factors in emergence are ever gathering force. Clearly additional efforts are required. Emerging infections remain an intersectoral challenge with every indication they will continue to be with us over the coming decades.

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Acknowledgment The author wishes to thank Ms Kellie Creamer for her assistance in preparing this manuscript.

See also: Antimicrobial Resistance in a One Health and One World Perspective – Mechanisms and Solutions; Arboviruses; Ebola and Other Viral Hemorrhagic Fevers; Global Health Law: International Law and Public Health Policy; Influenza.

References Aarestrup, F.M., Brown, E.W., et al., November 2012. Integrating genome-based informatics to modernize global disease monitoring, information sharing, and response. Emerg. Infect. Dis. 18 (11), e1. http://dx.doi.org/10.3201/eid/1811.120453. Alsolamy, S., June 2015. Middle East respiratory syndrome: knowledge to date. Crit. Care Med. 43 (6), 1283–1290. http://dx.doi.org/10.1097/CCM.0000000000000966. Chen, L.H., Hamer, D.H., February 1, 2016. Zika virus: rapid spread in the Western Hemisphere. published online Ann. Int. Med. Collinge, J., Sidle, K.C., et al., 2007. Science 318, 907. Cowling, B.J., Park, M., Fang, V.J., Wu, P., Leung, G.M., Wu, J.T., 2015. Preliminary epidemiological assessment of MERS-CoV outbreak in South Korea, May to June 2015. Eur. Surveill. 20 (25) pii:21163. Available online: http://www. eurosurveillance.org/ViewArticle.aspx?ArticleId¼21163. Daszak, P., et al., February 26, 2013. Interdisciplinary approaches to understanding disease emergence: the past, present, and future drivers of Nipah virus emergence. PNAS 110 (Suppl. 1), 3681. Heymann, David L., 2004. The international response to the outbreak of SARS in 2003. Philos. Trans. R. Soc. Lond. B 359, 1127–1129. Domínguez-Cherit, G., et al., 2009. Critically ill patients with 2009 influenza A(H1N1) in Mexico. J. Am. Med. Assoc. 302, 1880–1887. http://dx.doi.org/10.1001/ jama.2009.1536. PMID:19822626. Fineberg, H.V., 2014. Pandemic preparedness and responsedlessons from the H1N1 influenza of 2009. N. Engl. J. Med. 370, 1335–1342. Gresham, L.S., Smolinski, M.S., Suphanchaimat, R., Kimball, A.M., Wibulpolprasert, S., 2013. Creating a global dialogue on infectious disease surveillance: connecting organizations for regional disease surveillance (CORDS). Emerg. Health Threats J. 6 http://dx.doi.org/10.3402/ehtj.v6i0.19912. Epub 2013 January 25. Han, H.-J., et al., 2015. Bats as reservoirs of severe emerging infectious diseases. Virus Res. 205, 1–6. Heymann, D.L., Dixon, M., 2013. The value of the one health approach: shifting from emergency response to prevention of zoonotic disease threats at their source. Microbiol. Spectr. 1 (1) http://dx.doi.org/10.1128/microbiolspec.OH-0011-2012. Hijawi, B., Abdallat, M., Sayaydeh, A., et al., 2013. Novel coronavirus infections in Jordan, April 2012: epidemiological findings from a retrospective investigation. East Mediterr. Health J. 19 (Suppl. 1), S12–S18. Hill, A.F., Desbruslais, M., Joiner, S., Sidle, K.C.L., Gowland, I., Collinge, J., Doey, L.J., Lantos, P., October 2, 1997. The same prion strain causes vCJD and BSE. Nature 389, 448–450. http://dx.doi.org/10.1038/38925. Jones, K.E., et al., 2008. Global trends in emerging infectious diseases. Nature 451, 990–993. Kimball, A.M., Heymann, D.L., December 6, 2014. Ebola, international health regulations and global safety. Lancet 384. www.thelancet.com. Kimball, A.M., 2008. Factors Influencing the Emergence of New (and “Old”) Disease, International Encyclopedia of Pubic Health. Elsevier, pp. 552–563. Kucharski, A.J., 2015. Superspreading in MERS. Eurosurveillance 20 pii:21167. Kumarasamy, K.K., Toleman, M.A., et al., 2010. Emergence of a new antibiotic resistance mechanism in India, Pakistan and the UK: a molecular, biological and epidemiological study. Published Online August 11, 2010 Lancet Infect. Dis. 10, 597–602. http://dx.doi.org/10.1016/S1473-3099(10)70143-2. Leibler, J.H., Otte, J., Roland-Holst, D., Pfeiffer, D.U., Soares Magalhaes, R., Rushton, J., Graham, J.P., Silbergeld, E.K., 2009. Industrial food animal production and global health risks: exploring the ecosystems and economics of avian influenza. EcoHealth 6, 58–70. http://dx.doi.org/10.1007/s10393-009-0226-0. Liu, Yi-Y., Wang, Y., Walsh, T.R., et al., 2015. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Published Online November 18, 2015 Lancet Infect. Dis.. http://dx.doi.org/10.1016/S1473-3099(15)00424-7. See Online/Articles: http://dx.doi.org/10.1016/S1473-3099(15)00463-6 (accessed 01.01.16.).

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Lloyd-Smith, J.O., Schreiber, S.J., Kopp, P.E., Getz, W.M., 2005. Superspreading and the effect of individual variation on disease emergence. Nature 438, 355–359. http://dx.doi.org/10.1038/nature04153. McMichael, A.J., November 1993. Planetary Overload Global Environmental Change and the Health of the Human Species, ISBN 9780521457590. McNeil Jr., D.G., December 28, 2015. Zika Virus, a Mosquito-Borne Infection, May Threaten Brazil’s Newborns Global Health. NY Times. Microbial Threats to Health: Emergence, Detection, and Response by Committee on Emerging Microbial Threats to Health in the 21st Century, Board on Global Health, Institute of Medicine. Update: severe acute respiratory syndrome – Worldwide U.S. 2004. MMWR 52 (28), July 18, 2003, 664–665. Mounts, A.W., et al., 1999. Case-control study of risk factors for avian influenza A (H5N1) disease, Hong Kong, 1997. J. Infect. Dis. 180, 505–508. http://dx.doi.org/ 10.1086/314903. PMID:10395870. Oboho, I.K., Tomczyk, S.M., Al-Asmari, A.M., Banjar, A.A., Al-Mugti, H., Aloraini, M.S., Alkhaldi, K.Z., Almohammadi, E.L., Alraddadi, B.M., Gerber, S.I., et al., 2015. 2014 MERS-CoV outbreak in Jeddah–a link to health care facilities. N. Engl. J. Med. 372, 846–854. Pandemic Influenza Preparedness and Response, 2009. A WHO Guidance Document. World Health Organization, Geneva. ISBN:13: 978-92-4-154768-0. Shen, Z., Ning, F., Zhou, W., He, X., Lin, C., Chin, D.P., et al., February 2004. Superspreading SARS events, Beijing, 2003 [serial online] Emerg. Infect. Dis.. http://dx.doi.org/10.3201/eid1002.030732 [date cited]. Available from URL: http://wwwnc.cdc.gov/eid/article/10/2/03-0732.

The Rockefeller Foundation–Lancet commission on planetary health safeguarding human health in the Anthropocene epoch: report of the Rockefeller Foundation– Lancet commission on planetary health. Lancet, July 16, 2015. Webster, R.G., et al., 2006. H5N1 outbreaks and enzootic influenza. Emerg. Infect. Dis. 12, 3–8. PMID:16494709. WHO Document A64/10. Implementation of the International Health Regulations, 2005. Report of the Review Committee on the Functioning of the International Health Regulations (2005) in Relation to Pandemic (H1N1) 2009 (Commission chaired by H. Fineberg).

Relevant Websites http://www.apps.who.int/ebola/ebola-situation-reports – Ebola Situation Reports (accessed 01.01.16.). http://www.who.int/topics/international_health_regulations/en/ – International Health Regulations (accessed 01.01.16.). https://www.wto.org/english/res_e/statis_e/its2015_e/its15_merch_trade_product_e. pdf – Merchandise Trade by Product (accessed 01.01.16.). http://www.who.int/influenza/pip/en/ – WHO Pandemic Influenza Preparedness Framework: (accessed 01.01.16.). http://www.search.worldbank.org/all?qterm¼Travel&op – World Bank International Tourism (accessed 01.01.16.).

Emergency Medical Technicians Eduardo Romero-Hicks, University of Guanajuato, Guanajuato, México; and Guanajuato State Emergency System, Guanajuato, México Ó 2017 Elsevier Inc. All rights reserved.

Introduction Unfortunately, most of us may experience some kind of medical emergency during our lives; it can be something simple like a sprain or strain, or a life-threatening traumatic or medical condition. Emergency medical care is the general term used to describe the treatment provided to people who suddenly become seriously ill or injured. An emergency medical services (EMS) system is a network of people, vehicles, equipment, and facilities that is organized to respond rapidly and effectively to emergency medical incidents. EMS should occupy an important place in the health-care system; yet, in many countries it is still clearly a public safety service, much like police and fire service, while in others it is integrated into a wider health-care delivery system. The most common and recognized EMS type is an ambulance organization. In certain places, an EMS organization may also be called a First Aid Squad, Emergency Squad, Safety Squad, Rescue Squad, Ambulance Squad, Ambulance Service, Ambulance Corps, Life Squad, etc. An EMS system exists to fulfill three basic principles: preserve life, prevent further injury, and promote recovery. The series of events that need to happen can be outlined as: early detection (a member of the public finds the incident), early reporting (the emergency services are summoned), early response (the emergency services get to the scene quickly), good on-scene care (appropriate assessment and treatment is given), good care in transit (the patient is looked after on the way to the hospital), and transfer to definitive care (the patient is handed to the care of a physician). This system is traditionally symbolized by the Star of Life, where each of the ‘arms’ represents one of the six points above (Figure 1). The aim of an EMS is to provide treatment to those in need of urgent medical care, with the goal of either satisfactorily treating the malady, or arranging for timely removal of the patient to the next point of definitive care. This is most likely

Figure 1

The Star of Life.

International Encyclopedia of Public Health, 2nd edition, Volume 2

an emergency department at a hospital or another facility where physician care is available. Depending on the country, area within a country, or clinical need, EMS may be provided by one (or several) organizations, with different reasons for providing the service. The very heart of the EMS system is the emergency medical technician (EMT), a general term used to describe the majority of personnel involved in the actual provision of emergency medical care in an out-of-hospital setting. He or she is usually the first contact the patient has with the health-care system. No matter where an emergency occurs, how the patient is transported, or to what type of facility the patient is taken to, the person who actually provides the care is the constant factor.

The EMTs EMTs are individuals trained to provide efficient and immediate care for sick or injured people and transport them to appropriate medical facilities (Figure 2). The world of EMS can be both a great challenge and the greatest reward of someone’s life. The duties change with each call; no two calls are ever the same. One moment the EMT can be delivering a premature infant in a cramped bathroom, and on the next call he or she could be attempting to save the life of a teenage driver whose car has been torn apart in a high-speed collision. On a given day the EMT can respond to one emergency call after another without a break, and on another day he/she can spend an entire shift without a call. Some calls require a great deal of skill and strength, and others only involve a little more than assisting a patient to the ambulance. The EMT must be flexible in order to meet the demands of the ever-changing emergency scene; he or she must also be a confident leader who can accept the challenge and responsibility of the position. Additionally, this individual must have

Figure 2 Emergency medical technicians (EMTs). Photograph courtesy of Eduardo Romero-Hicks.

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Emergency Medical Technicians Table 1

Types of emergency calls

Medical emergencies Trauma emergencies Hazardous material exposures Obstetrical emergencies, including childbirth Child and domestic abuse Mass casualty incidents Crime scenes Psychiatric crises Fires Rescues

excellent judgment and be able to prioritize decisions so as to act quickly in the best interest of the patient. Those who provide this type of medical care have had training in prehospital care (out-of-hospital care), emergency scene management, rescue, stabilization, and transport. The modern EMT performs many duties and responds to many types of emergency calls (Table 1). Individuals trained to provide this type of care usually transport patients to the hospital in an ambulance or another vehicle that has been modified for this purpose. In low-income and middle-income settings, seriously injured people may be brought to small clinics that ordinarily provide only primary medical care. While specific responsibilities may vary from one area to another, the general duties include preparation, personal safety and the safety of others, patient assessment and emergency medical care, safe lifting and moving, patient transport and transfer, record keeping and data collection, and patient advocacy.

All in a Day’s Work Many people’s lives depend on the quick reaction and competent care of EMTs. Incidents such as automobile accidents, heart attacks, childbirth, gunshot wounds, and drownings all require immediate medical attention. In an emergency, EMTs typically are dispatched (usually working in teams of two) to the scene by an emergency operator, and often work with police and fire department personnel. After receiving the call from the dispatcher, they drive the ambulance to an address or location given, using the most expeditious route, depending on traffic and weather conditions, observing traffic ordinances and regulations concerning emergency vehicle operation. Upon arrival at the scene of the incident (Figure 3), they position the ambulance in a safe location to avoid additional injury. Prior to initiating patient care, the EMTs also determine that the scene is safe, the mechanism of injury or the nature of the illness, the total number of patients, and the need for additional help. In the absence of law enforcement, they create a safe traffic environment, such as placing road flares or markers, removing debris, and redirecting traffic for the protection of the injured and those assisting in their care. On arrival at the patient’s side, EMTs determine the extent of illness or injury, provide initial emergency care following strict rules and guidelines, and report the patient’s condition

Figure 3 Hicks.

Accident scene. Photograph courtesy of Eduardo Romero-

to the emergency department or medical control center. Emergency treatment for more complicated problems is carried out under the direction of medical doctors by radio, preceding or during transport. While transporting the patient to the medical facility, the team remains in contact with the health-care team at the hospital in order to receive special instructions and to prepare the hospital personnel for their arrival. EMTs are trained in practical emergency medical knowledge and skills that can be deployed within a rapid time frame. Patient treatment guidelines are described in protocols. The goal of EMT intervention is to rapidly evaluate a patient’s condition and to maintain a patient’s airway, breathing, and circulation. The EMT is trained in basic emergency skills such as opening airways; giving artificial respiration and cardiac resuscitation; administering oxygen; controlling bleeding; treating shock; stabilizing fractured limbs; bandaging; assisting in childbirth; caring for poison, burn, or drug overdose patients; and managing mentally disturbed people. The EMT is also trained in rescue techniques such as freeing people trapped in cars and handling hazardous materials. In addition, the EMT applies the necessary interventions, while expediting the safe and timely transport of the patient to a facility for definitive medical care. Other EMTs receive additional training in advanced life support techniques so they can administer medications, start intravenous infusion, provide advanced cardiac care, and carry out treatment ordered by the physician. EMTs may use special equipment, such as backboards, to immobilize patients before placing them on stretchers and securing them in the ambulance for transport to a medical facility. Usually, one EMT drives while the other monitors the patient’s vital signs and gives additional care as needed. Some EMTs work as part of the flight crew of helicopters that transport critically ill or injured patients to trauma centers or specialty hospitals (Figure 4). EMTs use communications skills in person, via radio and in writing. A solid foundation in the basic elements of emergency prehospital (out-of-hospital) care is developed and is required to make sound judgments in critical circumstances.

Emergency Medical Technicians

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Education and Training

Figure 4 Helicopter transport. Photograph courtesy of Eduardo Romero-Hicks.

At the medical facility, EMTs help transfer patients to the emergency department, report verbally and in writing their observations and actions to emergency room staff, and may provide additional emergency treatment on request. For every call an EMT receives, a variety of documents must be filled out noting the patient’s medical history, the treatment and drugs that were administered, the patient’s vitals, and much more. These documents help to make a smooth transfer of patient care from the EMTs to the hospital where the patient is being taken, and also for record keeping. This step ensures that EMTs are practicing good medicine and the techniques they are using are effective. After each call, EMTs must restock and replace linens, blankets, and other supplies in the ambulance, check and clean the equipment so that everything is ready for the next service, and decontaminate the interior of the ambulance if the patient had a contagious disease or was exposed to hazardous materials. They must ensure that the ambulance is clean and washed and kept in a neat, orderly condition. Beyond these general duties, the specific responsibilities of EMTs depend on their level of qualification and training, which varies from country to country, and even from state to state. Regardless of their level of training, EMTs actions in the field are governed by regulations and by organization policies. The development of these rules is guided by a physician, often with the advice of a medical advisory committee. The use of invasive skills is governed by complex protocols intended to maximize the lifesaving value of bringing these skills to the patient in the field while minimizing the risk of errors or additional injury to patients. Some skills may be performed according to protocol, given certain conditions. Other skills require the prior approval of a physician by radio or telephone. Some areas approve a modified level of care provided during communications failures or disasters. Within EMS a medical director is a physician who provides guidance, leadership, oversight, and quality assurance for the practice of EMT within a predefined area. The medical director is generally responsible for either the creation of protocols for treatment or providing leadership to a group of physicians who assist with the provision of medical oversight, generally referred to as medical direction.

Formal training and certification is needed to become an EMT. The training of EMTs may take place at universities, community colleges, technical schools, hospitals, or academies. Commonly, EMTs have three levels of proficiency: basic, intermediate, and advanced. Like the responsibilities of an EMT, training programs for certification (or licensure) vary greatly around the world, as do their denomination, but usually they are consistent with a three- or four-level-tiered emergency provider system (Table 2). In the United States, these are now called EMT, EMT-Advanced, and Paramedic, respectively; in South Africa, these same providers are called Basic Ambulance Assistants, Ambulance Emergency Assistants, and Critical Care Assistants; in Colombia they are called Prehospital Care Technicians and Prehospital Care Technologists; in Germany they are named Emergency Rescue Aid, Emergency Rescue Medic, and Emergency Rescue Assistant, and in México they are called EMTs (basic, intermediate, and advanced), just to name a few examples. In addition to the different levels of proficiency, other places issue licenses for more specialized levels of training, or simply use different names for the above positions. The basic EMT or the first level represents the first component of the EMS system. He or she is trained to care for patients at the scene of an accident and while transporting patients by ambulance to the hospital under medical direction. EMT-basic coursework typically emphasizes emergency skills, such as managing respiratory, trauma, and cardiac emergencies, and patient assessment. The program also provides instruction and practice in dealing with bleeding, fractures, airway obstruction, cardiac arrest, and emergency childbirth. Students learn how to use and maintain common emergency equipment, such as backboards, suction devices, splints, oxygen delivery systems, and stretchers. The EMT-basic training consists typically of classroom instruction, skills practice in a laboratory and/or hospital emergency room, ambulance experience, and a field internship. The intermediate EMT has more advanced training which allows the administration of intravenous fluids and certain medications, the use of manual defibrillators to give lifesaving shocks to a stopped heart, and the application of advanced airway techniques and equipment to assist patients experiencing respiratory emergencies. Advanced EMTs provide the most extensive prehospital care. In addition to carrying out the procedures already described, paramedics may administer lifesaving drugs orally and intravenously, interpret electrocardiograms (EKGs), perform tracheal intubations (inserting a breathing tube into Table 2 Level

Emergency medical technician (EMT) levels of training Denomination

Basic EMT-I, EMT-Basic, EMT, PCT, BAA Intermediate EMT-II, EMT-2, EMT-Intermediate, EMT-Advanced, AEA Advanced EMT-III, EMT-P, Paramedic, CCA

Training hours 120–250 35–80 (additional) 1000–1500 (additional)

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Figure 6 Hicks.

Figure 5 Emergency medical technician (EMT) training. Photograph courtesy of Eduardo Romero-Hicks.

the patient), and use monitors and other complex equipment. At this level, the caregiver receives additional training in body function and learns more advanced skills. Training for EMT-Paramedics includes classroom instruction, clinical rotations in hospitals, field internship, and laboratory experience. Refresher courses and additional certifications are available so that EMTs at all levels may enhance their capabilities and earn continuing education hours required for certification renewal. Emergency medicine is always changing, and the EMT must be willing to change with it. Refresher training is essential for learning about new treatments as well as new regulations (Figure 5).

The Well-Being of the EMT To maximize effectiveness, a number of professional attributes are required. They include appearance, knowledge, skills, and the ability to meet physical demands, as well as general interests and calm temperament. All EMTs, whatever their level may be, should be emotionally stable, have good dexterity, agility, and physical coordination, and be able to lift and carry heavy loads. They also need good eyesight (corrective lenses may be used) with accurate color vision. They also must remain calm and react quickly in life-or-death situations. The EMT is a special and unique person. The successful EMT likes people, takes responsibility seriously, and believes in what he or she is doing. Being an EMT is demanding – it requires both physical and emotional strength. EMTs work days and nights, both indoors and outdoors, and in all types of weather (Figure 6). They are required to do considerable kneeling, bending, and heavy lifting, but also

Night rescue. Photograph courtesy of Eduardo Romero-

spend a lot of time standing. These workers risk noise-induced hearing loss from sirens and back injuries from lifting patients. In addition, EMTs may be exposed to many contagious diseases, as well as violence from drug overdose victims or mentally unstable patients. The work not only is physically strenuous, but can be stressful, sometimes involving life-or-death situations and suffering patients. Nonetheless, many people find the work exciting, challenging, and especially rewarding given the opportunity to help others. Most work 45- to 80-h weeks, which may include being on call for extended periods of time. Because emergency services function 24 h a day, EMTs also have irregular working hours.

Employment EMTs are employed by many organizations, public and private, emergency and nonemergency. These include ambulance companies, fire departments, recreational facilities, law enforcement, hospitals, educational institutions, care centers, search and rescue squads, transfer services, and others. Most career EMTs work in metropolitan areas. In small cities, towns, and rural areas volunteers are more common. These individuals volunteer to help in fire departments, EMS, and hospitals, and may respond to only a few calls for service per month. On the other hand, volunteers may answer the majority of calls, especially in smaller communities. EMTs are employed by commercial, hospital, or municipal EMS agencies or fire departments. Some EMTs are hired by commercial ambulance services providing nonemergency patient transportation, or providing EMS to emergency calls under contract with municipalities or county governments. Some EMTs may work in clinical settings, such as a hospital’s emergency department, whereas others may be employed in an industrial setting, or as ‘home health-care’ providers. Private ambulance services often employ EMTs. These services sometimes provide nonemergency transportation of in-hospital patients, who, while not experiencing an emergency, nonetheless require medically supervised

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It must be recognized that either simple or sophisticated prehospital systems are essential in order to decrease preventable morbidity (incidence of a particular disease) and mortality (incidence of death in a population). Finally, we must accept that in certain areas of the world these prehospital systems do not exist. In these situations the most basic tier of a system can be established by involving community members and teaching them basic first aid techniques. It may be possible to identify very motivated workers, such as public servants, community leaders, taxi drivers, bus drivers, and others who are willing to get involved and become first responders.

See also: Drowning; Humanitarian Response to Complex Emergencies and Natural Disasters; Road Traffic Injuries. Figure 7 Volunteer emergency medical technicians (EMTs). Photograph courtesy of Eduardo Romero-Hicks.

Further Reading transportation. Bedridden patients must often be transferred between hospitals, are discharged to nursing homes or hospices, or are to undergo specialized treatment, therapy, or diagnostic procedures at another location. In many places, firefighters and some police officers are now also cross-trained as EMTs. Some large companies, especially industrial facilities, even maintain their own in-house EMTs as part of the plant’s firefighting or security guard force. Some colleges and universities train EMTs and host student-run EMS in their areas to respond to student medical emergencies. EMTs may also serve as unpaid volunteers for a volunteer ambulance service (Figure 7), volunteer rescue squad, or volunteer fire department, especially in rural or suburban areas. Rural communities often find it difficult to finance EMS, and recruiting, training, and retaining volunteer EMTs is a continuing challenge.

A Final Word Although primary prevention is a core value of any health system, nonetheless, many emergency health problems continue to occur. A significant burden of diseases is caused by time-sensitive illnesses and injuries where the priority is the provision of immediate or urgent medical interventions. At the center of such care is the EMT, ready to stabilize patients who suffer life-threatening or limb-threatening injury or illness. Considerable good may be accomplished by ensuring that these people receive even simple but lifesustaining care within minutes, and having trained personnel to provide it is a sign of a community’s and state’s responsibility for the care and welfare of its citizens.

American Academy of Orthopaedic Surgeons, 2011. Emergency Care and Transportation of the Sick and Injured, tenth ed. Jones & Bartlett Learning, Burlington, MA. Arreola-Risa, C., Mock, C.N., Lojero-Wheatly, L., et al., 2000. Low-cost improvements in prehospital trauma care in a Latin American city. J. Trauma 48, 119–124. Husum, H., Gilbert, M., Wisborg, T., 2003. Training pre-hospital trauma care in low-income countries: the “Village University” experience. Med. Teach. 25, 142–148. Kobusingye, O.C., Hyder, A.A., Bishai, D., Hicks, E.R., Mock, C., Joshipura, M., 2005. Emergency medical systems in low- and middle-income countries: recommendations for action. Bull. World Health Organ. 83, 626–631. Kobusingye, O.C., Hyder, A.A., Bishai, D., Joshipura, M., Romero, E., Mock, C., 2006. Emergency medical services. In: Jamison, D.T., Breman, J.G., Measham, A.R., et al. (Eds.), Disease Control Priorities in Developing Countries. The World Bank, Geneva, Switzerland, pp. 1261–1280. Limmer, D., O’Keefe, M.F., 2011. Emergency Care, twelfth ed. Prentice Hall, Upper Saddle River, NJ. Mistovich, J.J., Karren, K.J., 2013. Prehospital Emergency Care, tenth ed. Prentice Hall, Upper Saddle River, NJ. Mock, C., Lormand, J.D., Goosen, J., Joshipura, M., Peden, M., 2004. Guidelines for Essential Trauma Care. WHO, Geneva, Switzerland. Salomone, J.P., Salomone, J.A., 2012. Prehospital care. In: Mattox, K.L., Moore, E.E., Feliciano, D.V. (Eds.), Trauma, seventh ed. McGraw Hill. Sasser, S., Varghese, M., Kellermann, A., Lormand, J.D., 2005. Prehospital Trauma Care Systems. WHO, Geneva, Switzerland.

Relevant Websites http://www.ncbi.nlm.nih.gov/books/NBK11744/ – Disease Control Priorities in Developing Countries. Emergency Medical Services (Chapter 68). http://www.itrauma.org – International Trauma Life Support. http://www.naemt.org – National Association of Emergency Medical Technicians. http://www.ems.gov – National Highway Traffic Safety Administration. Emergency Medical Services. http://www.who.int/violence_injury_prevention/publications/services/en – World Health Organization – Violence and Injury Prevention. Care and Services Publications and Resources.

Endocrine Diseases: Overview Peter C Hindmarsh, Institute for Child Health, London, UK Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 2, pp. 332–341, Ó 2008, Elsevier Inc.

Glossary Acromegaly A condition produced by overproduction of growth hormone, leading to excessive growth of the hands, feet, and jaw in postpubertal individuals and giantism in prepubertal children. Adrenal glands Two endocrine organs situated above the kidneys that make a series of hormones: cortisol (stress hormone), aldosterone (salt-retaining hormone), and catecholamines (stress hormones). Autoimmunity A situation in which part of the body, often an endocrine organ, is recognized as ‘foreign,’ triggering an immune response that tends to lead to destruction of the endocrine gland. Cushing syndrome Excessive production of cortisol with loss of the normal circadian variation leading to weight gain, hypertension, and type 2 diabetes mellitus.

Introduction Specialized tissues function in an integrated manner as components of an intact organism, which is made possible in large part by three systems of extracellular communication: the nervous system, the endocrine system, and the immune system. Endocrinology concerns itself with the action of hormones and the organs in which these hormones are formed. Its boundaries include study of the anatomy and physiological function of the major endocrine organs, the secretory products of these organs, the mechanisms of hormone action, and the clinical manifestations of hormone dysfunction. Despite these sharp distinctions, it is increasingly clear that there is overlap between these three systems. The nervous system liberates chemical agents that can act as local mediators or true circulating hormones such as the secretory products of the adrenal medulla, epinephrine (adrenaline), and norepinephrine (noradrenaline), which have hormonal actions. At the level of the hypothalamus, there is an intimate link between the nervous and endocrine systems that serves to integrate the two into one functional control unit. The traditional definition of endocrinology has become more blurred recently by the recognition that circulating hormones can also have local effects in the cells in which they are synthesized or in adjacent cells after local diffusion. Likewise, the immune system, long considered to function autonomously, is now recognized as a regulated system subject to endocrine and neural control. In turn, it exerts a reciprocal controlling effect on neuroendocrine systems. There are some unifying principles with respect to the endocrine system. The first is that the synthesis of the hormones is controlled by similar types of regulatory mechanisms, namely feedback control loops, in which concentrations of hormones signal the need for more or less production. This feedback

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G protein Proteins within the cell that transfer the hormone message from the receptor to specific parts of the cell. Graves’ disease A combination of thyroid overactivity due to an autoimmune disorder and eye problems. Hypothalamus Part of the brain containing control centers for appetite, thirst, and pituitary hormone secretion. Pituitary Major regulator of hormone production. Secretion of hormones regulated by the hypothalamus. Thyroid gland An endocrine gland situated in the neck that makes thyroxine (important regulator of energy balance).

loop system is tightly regulated to maintain the circulating concentration of the hormone of interest within very tight margins. Any opening of this loop such as might occur in pathological situations is likely to result in a state of chaotic signaling. The second point, which derives from the first, is that the function of any endocrine therapy is to close the loop in as physiological a manner as is possible. Finally, the secretion of many hormones takes place in a pulsatile manner and the concept of a steady state of hormone secretion is not realized in many of the systems. This pulsatile secretion of hormones is important in terms of message delivery and receptor function and requires careful consideration when considering disease states and the methodologies used to test functionality of the system.

Function of Hormones Hormonal function involves four broad domains: reproduction, growth and development, maintenance of the internal environment, and production, utililization, and storage of energy. Figure 1 also depicts interaction with the immune, nervous, and cardiovascular systems, as well as the gastrointestinal tract. These interactions may overlap with the main four key functions. For example, cortisol produced by the adrenal cortex is important in determining heart rate as well as raising blood glucose concentrations.

Reproduction Hormones not only regulate gametogenesis but also control the dimorphic anatomical, functional, and behavioral development of males and females that is essential for sexual reproduction.

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Immune system Internal homeostasis e.g., water balance

Cardiovascular system

Reproduction

Hormone function

Production, utilization and storage of energy (e.g., carbohydrate, metabolism, appetite regulation) Figure 1

Alimentary system

Nervous system

Growth and development

Four key functions of the endocrine system (shown as solid lines) and interactions with other body systems (shown as dashed lines).

Sexual reproduction requires a precise genetic programming for the synthesis of an appropriate enzyme complement in the ovary or testis that in turn catalyzes the formation of the appropriate amount of hormones at the critical stages of life.

Growth and Development Endocrine control is fundamental for growth and development and involves the interaction of hormones of all classes, including peptides, steroids, catecholamines, and thyroid hormone. Not only are hormones necessary for normal growth and development but they are of equal importance for the limitation of growth. For example, if epiphyseal closure did not occur, skeletal growth would continue for an indefinite period, as occurs in abnormalities of the estrogen receptor.

Maintenance of the Internal Environment Hormones are critical for the maintenance of the internal environment necessary to maintain structure and function. They are involved in regulating and stabilizing body fluids and salt– water balance. These homeostatic mechanisms not only operate on a minute-to-minute basis but also make possible the adaptation to extreme environmental change.

Energy Production, Utilization, and Storage The endocrine system is the preeminent mediator of substrate flux and the conversion of food into energy production or storage. In the anabolic state, excess fuel is stored as glycogen and fat under the influence of insulin. In the catabolic state, as in starvation or fasting, glucagon and other counterregulatory hormones induce glycogen breakdown and mobilize amino acids and free fatty acids as substrates for gluconeogenesis. The functionality of hormones does not simply relate to the idea of one hormone for one particular job or function.

The effects of hormones are complex, as a single hormone can have different effects in various tissues and in the same tissue at different times of life. Similarly, some biological processes are under the control of a single hormone while others require complex interactions among several hormones for the full biological effect to be realized. An example of a hormone with multiple effects is testosterone. While its predominant actions are involved in the development of the male external genitalia in embryogenesis, it also acts to develop the secondary sexual characteristics of puberty. One of the most important aspects of testosterone action is that it can be explained by binding of the hormone or its more active metabolite, dihydrotestosterone, to a single receptor. The diverse effects of the hormone are due in large part not to different mechanisms of action but rather to the fact that different cells at different stages of development are programmed to respond to the hormone receptor complex in different ways. It is commonplace to think of hormones and their actions in isolation, but virtually all complex processes under endocrine regulation are influenced by more than one hormone. Plasma glucose concentrations are maintained within a very narrow range in humans, but such regulation is not accomplished by a single hormone (Figure 2). Primary control is through the secretion of insulin, which modulates hepatic glucose production and enhances glucose transport into cells. The process for elevating blood glucose concentrations, however, utilizes another hormone from the pancreas, glucagon, which stimulates glucose production in the liver by breakdown of stored glycogen. Because low blood glucose or hypoglycemia is a greater risk to life than hyperglycemia, a backup set of glucose-raising hormones is released as the plasma glucose concentration falls below about 3.5 mmol l 1 (normal range for blood glucose concentrations are 3.5– 7.0 mmol l 1). These include the catecholamines cortisol and growth hormone. Overall, about six hormones play important roles in directly maintaining the plasma glucose concentration.

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Glucose or insulin value

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Plasma insulin (mU L–1)

25 20 15 10

Blood glucose (mmol L–1)

5 0 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70 73 76 79 82 85 88 Time (min) Figure 2 Profile of blood glucose (lower trace) and plasma insulin (upper trace) concentrations obtained at 1-min intervals over a 90-min period of fasting. Note that blood glucose concentrations do not change, while there is constant oscillation of the insulin values.

The existence of such complex control mechanisms has two major implications. First, there can be a remarkable degree of fine-tuning, in that blood glucose concentrations can be maintained within normal limits under nutritional conditions that vary in the extreme. Second, complex control mechanisms for vital functions may provide safety insofar as alternative mechanisms can take over should one hormone in the series fail. In the case of the glucose–insulin axis, there is little redundancy, as there are additional hormones to raise blood glucose concentrations but only one (insulin) to reduce values, hence loss of insulin leads immediately to disease – diabetes mellitus.

Chemical Nature of Hormones Hormones fall into two broad categories: those that are peptides or amino acid derivatives and those that are steroids, which are derivatives of cholesterol. Regardless of their chemical structure, all hormones share several characteristics. First, they are present in the circulation in low concentrations. Second, they need direction to their target organs because they are present in such low concentration. This is the function of receptors either on the cell surface or within the nucleus of the cell for these hormones. This targeting of hormones to their tissue of action is extremely important in that it conserves the amount of hormone that is required to be generated. In addition, throughout the stages of the regulatory system, amplification of the signal takes place, so that the end result of hormone action might be to elevate the final hormone produced in the final series by orders of magnitude greater than that present in the initial start of the cascade. The synthetic mechanisms that result in hormone formation are not unique, and the peptide hormones are synthesized by the same biochemical pathways as other proteins. Catecholamines are synthesized from smaller precursors. In the case of steroid hormones, the parent molecule, cholesterol, is modified by several enzymatic steps. The rate of release of hormone is determined ultimately by the rate of synthesis. Most hormones and regulatory factors act by controlling their own

rate of synthesis, although there are exceptions. Most endocrine organs store a limited quantity of hormone and most secretion arises from de novo biosynthesis of the hormone. Water-soluble hormones are transported in plasma and require no specific transport mechanism. More insoluble hormones require carrier mechanisms – transport proteins. Transport proteins act as reservoirs, so that bound hormone is in dynamic equilibrium with the small amount of free hormone in the plasma. These transport proteins are of two types: albumin and pre-albumin, which are general transport molecules, and more specific proteins such as thyroxine-binding globulin or sex hormone-binding globulin, which have restricted binding sites of high affinity for a specific hormone, such as thyroxine in the case of thyroxine-binding globulin. The general features of the transport proteins are that they alter the clearance rates for hormones. The tighter the binding of the hormone to the transport protein, the slower the hormone will be cleared from the circulation. Generally, the binding capacities are usually much higher than the physiological concentration of the hormone. This means that when hormones are overproduced or given in pharmacological amounts for therapy, enormous quantities of even the most insoluble hormone can be delivered to tissues. Because the rate of hormone production is ultimately determined by the level of free hormone, synthesis can be adjusted appropriately to compensate for changes in the concentration of transport proteins.

Feedback System: Feedback and Biorhythms One of the characteristics of the endocrine system is the feedback control of hormone production. This relationship is the reason that simultaneous assessment of hormone/effect is almost always required for assessment of endocrine status – the plasma insulin concentration must be interpreted in terms of the plasma glucose in a simultaneously drawn sample. The measurement of thyroid-stimulating hormone concentrations may be interpretable only in terms of the plasma thyroxine

log TSH

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3.00

1. 2. 3. 4. 5. 6. 7.

2.00 1.00 0.00 −1.00 −2.00

0

5

10

15

20

25

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Subnormal hormone production Hormone excess Production of abnormal hormones Resistance to hormone action Abnormal hormone transport and/or metabolism Multiple hormone abnormalities Associated factors involved in hormone production

30

FT4 (pmol/L) Figure 3 Relationship between serum free thyroxine (FT4) and log-transformed serum thyrotropin-stimulating hormone (TSH) concentrations in patients with primary hypothyroidism (green squares), secondary hypothyroidism (blue circles), and in controls (red triangles).

concentration. Figure 3 illustrates this point, showing that there is a gradual shift toward the left upper zone with severity of illness. It also demonstrates a nomenclature of the hierarchy of the cascade. In hypothyroidism, lack of thyroxine can result from a primary problem in the thyroid gland itself, a secondary problem in the pituitary due to a lack of thyroid-stimulating hormone production, or a tertiary problem at the level of the hypothalamus due to a lack of thyrotrophin-releasing hormone. This feedback relationship also underpins most dynamic tests of endocrine function (see section Endocrine Pathology). The feedback system usually operates in a negative manner, but there are instances, for example, during the menstrual cycle, when positive feedback allows the generation of the midcycle luteinizing hormone surge. Many hormones are secreted in pulses or have specific oscillatory activity. Oscillations have been described with insulin, glucagon, growth hormone, and cortisol. The time course over which these regular recurring cycles of hormone secretion takes place is variable. Insulin has a dominant cycle of one pulse every 13 min, whereas growth hormone pulses appear on average once every 3 h. In addition, fuel substrates appear to have oscillatory characteristics that superimpose upon the hormone’s inherent rhythmicity. These oscillatory systems are usually analyzed using methodologies similar to those for the mathematical analysis of simple and complex waveforms. Not only might the analysis be complex but the inference as to what is influencing the hormone concentration at any particular point in time can become intricate. The whole process is actually a complex adaptive system, which means that it is not susceptible to a more linear approach to analysis, and the interpretation of pathological events is equally difficult because of the constraints of linear methodologies in systems that by their nature are highly complex and adaptive.

Endocrine Pathology Endocrine disorders can be divided into seven broad categories (Table 1). There is considerable overlap among these groups. For example, impaired hormone production because of enzymatic deficiency can lead to increased synthesis of another

hormone, as in the overproduction of adrenal androgens in patients with cortisol deficiency secondary to a defect in the enzyme 21-hydroxylase in the adrenal cortex. Hormone overproduction can accompany clinical evidence of deficient hormone action in hormone-resistant states. Finally, hormone overproduction, hormone underproduction, and resistance to hormone action may occur at different times in the course of disease in a single individual, as is frequently seen with insulin in patients with Type 2 non-insulin-dependent diabetes and obesity. For the purposes of clarity, the seven individual categories are described below.

Subnormal Hormone Production Diminished or absent hormone secretion can have several causes and may relate to an absence or malformation of the development of the endocrine organ. Congenital abnormalities may reflect a defect in the embryogenesis of the endocrine organ itself or the lack of some enzyme essential for hormone synthesis, as in the various types of congenital adrenal hyperplasia. Acquired conditions are more common, in which a normal endocrine gland is destroyed by a secondary process. This may be secondary to infectious agents such as tuberculosis of the adrenal glands or infarction of the pituitary gland postpartum. From a public health standpoint, autoimmune disorders such as Hashimoto thyroiditis, which destroys the thyroid gland, is one of the more common examples in which subnormal hormone production occurs in a large number of individuals secondary to the autoimmune process triggered by an as yet unknown factor(s).

Hormone Excess Hormone overproduction is less well-understood than hormone deficiency. Causes are diverse, and include tumors that may be either benign or malignant affecting an endocrine gland, as in Cushing syndrome, arising from a carcinoma or adenoma of the adrenal cortex and producing excess cortisol. A similar clinical picture can arise as a result of a benign adenoma of the adrenocorticotroph (ACTH)-producing cells of the pituitary gland (Cushing disease). ACTH stimulates the adrenal cortex to produce cortisol. Similarly, excess growth hormone production from the pituitary gland leads to acromegaly. The underlying pathology in these situations is only just becoming clear and relates to a monoclonal expansion of an abnormal cell line. Stimulatory substance can be produced as part of an autoimmune reaction. In Graves, disease, in which there is thyroid overactivity, autoantibodies are generated that mimic the

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action of thyroid-stimulating hormone on the thyroid gland, leading to, in effect, autonomous production of thyroxine. Our understanding of some of the causes of overproduction of hormones comes from the clinical cases resulting from activating mutations of genes that code for either the receptors themselves or the intracellular signaling pathways associated with those receptors. In the testes, an activating mutation of the luteinizing hormone receptor leads to precocious puberty due to unregulated overproduction of testosterone. In McCune–Albright syndrome, a mutation in one of the intracellular signaling components (G protein) leads to an inability to switch off the stimulated system and thereby autonomous production of sex steroid. In this latter condition, bone problems and skin pigmentation may also result from the same genetic abnormality.

Hereditary resistance to hormones that are essential for life, for example, cortisol, are inevitably partial because severe or complete defect in action of these hormones would probably be incompatible with life. Hormone resistance may be considered as taking place at several levels: prereceptor, receptor, or postreceptor. Prereceptor resistance is usually due to abnormal hormones or to antibodies to the hormones. Abnormalities of receptors themselves can be either hereditary or acquired. Postreceptor hormone resistance is a category that is becoming better understood and usually involves several points in the postreceptor signaling mechanism. Examples of these exist in a number of areas, such as STAT 5b in the growth hormone signaling cascade and IRS1 in the insulin signaling system.

Production of Abnormal Hormones

Abnormalities of Hormone Transport or Metabolism

Production of abnormal hormones is relatively unusual compared to the pathological states involving the production of too much or too little hormone. A single gene mutation may alter both structure and function. There is a mild form of diabetes mellitus produced by an abnormal insulin molecule formed as a result of a single gene mutation. The abnormal insulin does not bind well to the insulin receptor, leading to problems in handling glucose. The situation may be more complex. Certain abnormalities in the growth hormone gene lead to the generation of an abnormal growth hormone product. In this situation, the normal regulation of growth hormone secretion is maintained, but the molecule produced is of abnormal shape and size. In fact, the abnormality of the molecule does not allow for the growth hormone to be secreted from the pituitary in a normal manner, so that from the clinical and biochemical testing standpoint it looks as though these individuals are absolutely growth hormone deficient. This is true in the sense that they do not make the normal 22-kDa form of growth hormone, but from a theoretical standpoint it is not correct, as they make the abnormal 17-kDa form in abundance. The 17-kDa form accumulates in the cells of the pituitary, leading to cell damage and the death, ultimately, of all pituitary cells. The result is that, although growth hormone deficiency is the primary problem, the toxic damage leads to cell death of all the hormone-producing cells in the pituitary, leading to multiple pituitary hormone deficiencies.

Under ordinary circumstances, abnormalities of hormone transport or metabolism do not result in endocrine pathology. However, in situations where there is a marked impairment in protein synthesis in the liver, such as cirrhosis, major problems can result. Hormone production is controlled by the concentration of free hormone and consequently can be adjusted up or down as required. Usually alterations in protein concentrations lead to deviation of laboratory parameters from normal but do not cause either hyper- or hypofunction. The important point is to recognize that unusual hormonal values do not necessarily imply functional or pathological changes. However, it is important to realize that under some circumstances such alterations in protein synthesis may cause pathology. For example, administration of physiological replacement doses of glucocorticoid to individuals with cirrhosis of the liver may cause florid Cushing syndrome because free hormone levels will be high in the face of a combination of reduced protein binding and decreased steroid catabolism, as the liver is a major source of steroid metabolism.

Resistance to Hormone Action Hormone resistance is defined as a defect in the capacity of normal target tissues to respond to a hormone. The condition was first described in 1942 and, since then, resistance to the effect of many hormones has been described. Resistance can be hereditary, as in androgen resistance leading to manifestation of a female external genital appearance in a person with a normal male genotype (46,XY). The main feature of resistance is the presence of a normal or elevated level of the hormone in the circulation that arises because of the loss of regulatory feedback control from the target tissue/hormone. As partial defects can be compensated for by an increase in hormone concentration of little clinical consequence, hormone resistance may go unrecognized.

Multiple Hormone Abnormalities Multiple hormone abnormalities are now well documented and have several etiologies. The most serious are those multiple problems associated with abnormalities in families with multiple endocrine neoplasia syndrome. Several of these syndromes have now been described and may involve tumor development in glands such as the pituitary, parathyroids, pancreas, and adrenals. In these situations, the clinical manifestations tend to be hyperfunction of the glands in question. The polyglandular endocrinopathies consist of three subgroups in which autoimmune destruction of the endocrine organ is the most common component. In these polyglandular autoimmune conditions, a constellation of features involving the pancreas, parathyroid glands, adrenals, and thyroid may be manifest but with the clinical features that arise representing undersecretion of hormone. These multiple problems may manifest as single entities in the first instance, which necessitates a careful analysis of the family history and the need for constant monitoring of the individual for the evolution of hormonal problems in the longer term. A similar situation also pertains to medical interventions used to manage conditions that initially do not have an

Endocrine Diseases: Overview endocrine basis. Cranial irradiation is used in the management of brain tumors and in the past has been used to prevent secondary relapse of acute lymphoblastic leukemia in the central nervous system. The radiation doses applied impacted upon hypothalamo-pituitary function. High doses of radiation used to manage brain tumors produced undersecretion of hormones from the anterior pituitary with time. The most sensitive and the first lost was growth hormone, followed by the sex hormones, luteinizing hormone, and follicle-stimulating hormone, thyrotrophin-stimulating hormone, and adrenocorticotrophic hormone. In contrast, the lower doses of irradiation used in the management of acute lymphoblastic leukemia resulted in a milder degree of growth hormone loss but often an early activation of the hypothalamo-pituitary-gonadal axis, resulting in an early onset of puberty. These observations point to the differential effect of radiation on the endocrine axis and also serve to illustrate that disease may manifest over a prolonged period of time, necessitating long-term surveillance for the patients surviving these interventions.

Associated Factors Involved in Hormone Production The biosynthesis of a number of hormones often requires the presence of a number of substances to allow for full biological efficacy of the hormone in question. These factors may range from energy transfer through electron transfer chains to the presence of dietary agents such as iodine. The production of the two biologically active thyroid hormones, thyroxine and triiodothyronine, requires the presence of iodine. Because iodine is rapidly excreted in the urine, a regular daily intake of approximately 70 mg of iodine in adults is required. Iodine can come only from external sources, mostly food, but also water. It is not widely distributed in nature and, as

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a result, many people on just about every continent were at one stage iodine-deficient. Figure 4 gives an indication of the extent of the problem worldwide. Major attempts have been undertaken to increase the iodine dietary intake, but this is only the first step in the management of iodine deficiency, as this increase must be sustained. Traditional methods to increase the iodine intake of the population has been to fortify salt with iodine, but with trends toward lower addition of salt to food products, paradoxically there has been a decline in iodine intake in many countries that at one stage were replete. Severe iodine deficiency in the mother and fetus results in pregnancy loss and irreversible mental retardation, neurological dysfunction, and growth retardation in the fetus. Mild iodine deficiency results in learning disability, poor growth, and a mild enlargement of the thyroid gland (goiter) in school-age children. Overall, the small risks of chronic iodine excess are outweighed by the substantial hazards of iodine deficiency, which is still widespread. From a public health standpoint, iodine intake needs to be increased in many countries, not only those with iodine deficiency but also in those whose iodine intake is marginal.

Testing the Endocrine Axis The principles of endocrine testing depend on the condition that is being evaluated. In general, different tests will be required to dissect the underlying pathology. This may be separated into two broad categories: first, tests to define the actual biochemical problem, and, second, tests to confirm the diagnosis and to explore likely etiology such as genetic testing, or imaging of the organ in question. General considerations that need to be given to endocrine testing are portrayed in Table 2.

_200 µg/liter) Optimal (> Marginal (100–199 µg/liter) Deficient (56
C), chlorination, and formaldehyde are effective in inactivating the EVs.

Table 1 Species and serotypes within the Enterovirus genus affecting humans Enterovirus A Coxsackievirus A2–8, A10, A12, A14, A16 Enterovirus A71, A76, A89–A92, A114, A119, A120, A121 Enterovirus B Coxsackievirus A9 Coxsackievirus B1–B6 Echovirus 1–7, 9, 11–21, 24–27, 29–33 Enterovirus B69, B73–B75, B77–B88, B93, B97, B98, B100, B101, B106, B107, B110–112 Enterovirus C Coxsackievirus A1, A11, A13, A17, A19–A22, A24 Enterovirus C95, C96, C99, C102, C104, C105, C109, C113, C116–C118 Poliovirus 1–3 Enterovirus D Enterovirus D68, D70, D94, D111, D120

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Structurally, the EVs are nonenveloped icosahedral-shaped viruses containing a positive sense, single-stranded RNA genome (Stellrecht et al., 2015). The genome is approximately 7.4 kilobases in length consisting of a long 50 nontranslated region (NTR), a single open reading frame (ORF), and a short 30 NTR followed by a polyadenylated tail. The 50 and 30 NTRs contain regulatory elements for translation, replication, and virulence. Conserved sequences within the 50 NTR have permitted the design of oligonucleotide primers for detection of EVs in clinical specimens. The ORF is divided into three regions: P1–3. The P1 region contains sequences that code for the four structural proteins (VP1–4) that make up the capsid, while the P2 and P3 regions contain the sequences for seven nonstructural proteins and their three intermediates are required for viral replication (Stellrecht et al., 2015).

Epidemiology The NPEV exists worldwide and causes an estimated 1 billion infections annually (Stellrecht et al., 2015). In the United States, an estimated 30–50 million NPEV infections occur annually. The highest incidence of infection is in infants and children 5–10 years of age. While many NPEV serotypes exist, only a few are responsible for illness each year. Worldwide, the serotypes and prevalence of NPEVs isolated from infected patients vary both geographically and annually. Humans are the only known hosts for the NPEVs, although they have been isolated from primates. In temperate climates, enteroviral infections occur primarily in the summer and early fall. However, NPEVs can be isolated from patients during the winter months, albeit, far less frequently. In tropical regions, the EVs are isolated year round with an increased incidence during the rainy season. The most common mode of transmission for the NPEV is the fecal–oral route. Other documented modes are vertical, foodborne, waterborne, self-inoculation, respiratory, and, rarely, via breastfeeding and organ transplantation. They can be shed from the throat for short periods and in the stool for several weeks, thereby facilitating their transmission. Clinically, NPEVs are the principal cause of viral meningitis where an etiologic agent can be identified. In this group of meningitides, they are responsible for more than 90% of cases. Members of the B species of EVs, in particular the Group B CVs and the echoviruses, are the most frequently isolated NPEVs in this syndrome (Stellrecht et al., 2015). Among the causes of viral encephalitides, EVs are identified in approximately 10–20% of cases of proven viral etiology. The serotypes most commonly identified belong to the group A CVs within the EV A species. Some strains of EV-A71, also a member of the A species, can result in severe life-threatening rhombencephalitis (Huang et al., 1999; Ooi et al., 2010).

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Enteroviruses The paralytic potential of the polioviruses is well recognized. In regions of the world where they have been eradicated, the NPEVs and circulating vaccine-derived polioviruses are now the principal causes of EV-associated acute flaccid paralysis (AFP). NPEV serotypes that are associated with AFP include CVs A4, A7, A21, A24, B2, B3, B5; echoviruses 3, 7, 9, 18, 19, 33; and EVs D68 and A71 (Huang et al., 1999; Messacar et al., 2015; Ooi et al., 2010). However, the link is far from ironclad, in that many of the serotypes have been isolated only from the stool of patients with AFP and not from the central nervous system (CNS). During a recent national outbreak of EV-D68 respiratory illness in the United States, over 100 cases of AFP were reported to the Centers for Disease Control and Prevention. However, in no case was the virus identified from the cerebrospinal fluid (CSF). The species B EVs are known to cause myocarditis with the group B CVs among the most common etiologies of viral myocarditis (Stellrecht et al., 2015). The echoviruses have also been identified as a cause of myocarditis, though far less frequently. Males, physically active adolescents, and young adults are at greatest risk. Nonspecific mild respiratory signs and symptoms accompany many EV infections (Stellrecht et al., 2015). The EVs have been associated with the summer cold, pharyngitis, tonsillitis, and less commonly croup, bronchiolitis, and influenza-like illness. Molecular techniques for their detection have documented the EVs, including several of the newly identified EV C serotypes, as etiologic causes of pneumonia. A recent epidemic of EV-D68 severe respiratory tract disease attests to the potential for rarely encountered serotypes to cause a widespread epidemic disease (Midgley et al., 2015). Vertically transmitted species B enterovirus infections in neonates can result in potentially life-threatening illnesses (Abzug, 2004; Jenista et al., 1984). The group B CVs and echoviruses, in particular echovirus (Miyamoto et al., 2014), are most commonly associated with severe disease. Significant morbidity and mortality occur in these infections; neonates who develop hepatitis and coagulopathy are at greatest risk for adverse outcomes. The clearance of EV infection is dependent upon humoral (antibody-based) immunity, rather than cell-mediated immunity, as is the case in the majority of viral infections. Thus individuals with B cell defects that result in certain humoral immunodeficiencies are susceptible to chronic NPEV infections of the CNS that take the form of chronic meningoencephalitis (McKinney et al., 1987). Echoviruses are most commonly isolated from these cases. Similarly, individuals receiving immunotherapies that target B cells (i.e., rituximab and obinutuzumab) are also prone to severe or life-threatening EV infections.

Pathogenesis After the EVs are ingested, they infect the cells of the oropharynx and intestine. The EVs enter and replicate in the regional lymph nodes (e.g., tonsils, Peyer’s patches) and are subsequently released into the bloodstream (primary or minor viremic stage). By way of the blood, the EVs may infect the CNS, liver, heart, pancreas, respiratory tract, skin, and/or

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mucous membranes. Vertical transmission to the fetus may occur at this stage of maternal infection. Replication occurs in these organs with subsequent virus release into the bloodstream, resulting in a secondary or major viremic phase. During this stage, the EV may invade the CNS if it was spared during the initial viremic phase of the illness. Clinical and experimental data suggest the polioviruses may enter the CNS via retrograde axonal transport. Whether the NPEV uses a similar method is unknown. Viremia and viral replication in organs ceases once the host produces a type-specific antibody response.

Clinical Manifestations The NPEVs cause a wide range of clinical syndromes ranging from asymptomatic infection to life-threatening diseases such as myocarditis and neonatal sepsis. Given the myriad of clinical syndromes resulting from NPEV infection, it is not possible to cover them in their entirety in this article. The most prominent and recently identified NPEV syndromes will be discussed below. No single NPEV serotype is associated with a unique clinical presentation. The overwhelming majority of NPEV infections do not result in clinical symptoms and cause only subclinical infection. Additionally, many of those infected experience only fever without additional signs and symptoms. Importantly, the majority of EV infections are self-limiting.

Meningitis The illness is heralded by the acute onset of fever that may range from 38 to 40
C. In some, the fever may be biphasic, initially occurring in association with nonspecific constitutional symptoms followed by complete or near-complete resolution, and reappearance with the onset of signs and symptoms of CNS disease, such as headache, photophobia, vomiting, and neck stiffness. Headache is the most common symptom in adults and children capable of reporting it. Other constitutional symptoms include abdominal pain, anorexia, cough, rhinorrhea, and myalgias. Physical examination reveals signs of meningeal irritation: nuchal rigidity, Brudzinski sign, or Kernig sign. A rash may be present. The definitive diagnostic procedure is the lumbar puncture. Examination of the CSF commonly reveals a predominantly lymphocytic pleocytosis with typically 100–500 white blood cells mm3. A polymorphonuclear cell predominance may be present early in the course of the illness. In a small percentage of patients pleocytosis may be absent even though NPEV is present in the CSF. The protein concentration is normal to mildly elevated, and the glucose concentration is normal in most cases. The typical clinical course is relatively benign. Most children and adults resolve their illness within 1 week. However, adults may experience headaches for several weeks. Neurological complications may occasionally occur and take the form of seizures, increased intracranial pressure, and coma. Additionally, some patients may release excessive quantities of antidiuretic hormone.

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Encephalitis Most patients experiencing NPEV encephalitis present with mental status changes. Focal neurological findings such as partial motor seizures, hemichorea, and cerebellar ataxia may occur (Modlin et al., 1991). These neurologic findings can mimic those seen in cases of herpes simplex virus encephalitis. In contrast to NPEV meningitis, evidence of meningeal irritation is often absent. The CSF cytochemical analysis is typically normal, although the protein concentration may be mildly elevated. Neuroimaging studies have demonstrated diffuse and focal lesions, but this is the exception rather than the rule. Most patients recover without neurological sequelae. Rhombencephalitis, a brain stem encephalitis, has been observed as a result of infection with some strains of EVA71 (Huang et al., 1999; Ooi et al., 2010). This association is of greater prevalence in countries of the Asian-Pacific rim. Patients present with myoclonic jerks, tremors, and/or ataxia. Some progress rapidly to develop respiratory distress, shock, loss of doll’s eye response, and apnea. Magnetic resonance imaging of the CNS may reveal lesions within the brain stem. A high mortality rate has been associated with this syndrome.

Acute Flaccid Paralysis AFP may occur as a result of NPEV infections. As with the polioviruses, NPEV AFP may present as a biphasic illness. Initially, patients experience a nonspecific febrile illness that may be accompanied by upper respiratory or gastrointestinal (GI) complaints that resolve. Shortly thereafter, an acute onset of fever, muscle pain, and hyporeflexia occurs. Rapid development of weakness and paralysis ensues, which typically involves proximal limb muscles. The paralysis is asymmetric, flaccid, and without involvement of the sensory branch of the CNS. The NPEV-associated AFP is made to be less severe than that seen with poliovirus and rarely affects the brain stem. Cases of AFP associated with EV-D68 infection differ from those of the polioviruses and other NPEV (Messacar et al., 2015). The upper extremities, either alone or in combination with the lower extremities, are more frequently involved. Pain associated with the paralysis is more common. Cranial nerve (CN) involvement is observed in the majority of patients and, most frequently, manifests as hypophonia, dysarthria, dysphagia (CN IX and X), diplopia (CN VI), or facial droop (CN VII).

Oral lesions (i.e., enanthema) are found on the tongue and buccal mucosa and typically ulcerate. The cutaneous lesions of HFMD are described as papules or vesicles on an erythematous base that can be found on the hands, feet, wrists, ankles, buttocks, and genitalia. A low-grade fever and sore throat appear coincident with the skin lesions. The disease is self-limited and generally lasts 7 days. EV-A71 may be associated with severe neurologic complications (Huang et al., 1999). Herpangina, an enanthem, is characterized by the acute onset of fever and severe sore throat (Romero, 2016). It is most commonly associated with infections due to CVs A1– A6, A8, A10, and A22. The pharynx is hyperemic and in contrast to HFMD, the oral lesions (discrete vesicles) are located on the palate, uvula, posterior pharynx, anterior faucial pillars, and tonsils. The lesions evolve into painful ulcers. Typically, the fever resolves within 4 days, but the oral lesions may persist for a week. An atypical form of HFMD due to CV-A6 has been observed since 2008. The lesions associated with it are more widespread and the illness is associated with higher fever and with a high rate of hospitalization. Patients with eczema may develop concentrations of lesions at sites of active or dormant disease called eczema coxsackium. Although patients invariably recover, some may develop desquamation of palms and soles or onychomadesis (loss of fingernails) 1–3 weeks and 1–2 months later, respectively.

Myocarditis Myocarditis is a potentially life-threatening complication of NPEV infection. The onset of cardiovascular signs and symptoms may be preceded by an upper respiratory tract infection. Patients may present with fever, chest pain, shortness of breath, and exertional dyspnea. A gallop heart rhythm and/or pericardial friction rub may be present on auscultation of the heart. Echocardiographic findings may include a decreased ejection fraction or ventricular dilatation. Electrocardiographic findings vary and include low-voltage QRS complexes, ST-segment depression, and T-wave inversion. Cardiac enzymes are commonly elevated. In severe cases, acute congestive heart failure or lifethreatening arrhythmias may occur and contribute to mortality. While the majority of patients survive, long-term sequelae in the form of chronic, dilated cardiomyopathy may occur.

Enteroviral Exanthems and Enanthems Many different exanthems have been described with NPEV infections. These rashes are generally nondescript and nonpathognomonic. They may resemble those seen with infections due to other viruses or bacteria, such as measles or meningococcus or may even appear urticarial, suggesting an allergic reaction. A commonly encountered NPEV-associated exanthem in children is hand, foot, and mouth disease (HFMD) (Romero, 2016). HFMD is most frequently caused by CV-A16. EV-A71 is a common cause of HFMD in countries of the Asian-Pacific.

Respiratory Illnesses The clinical manifestations of the upper and lower respiratory tract syndromes associated with the EV vary little for the respiratory viruses typically associated with them. A notable exception is that of severe respiratory disease caused by EV-D68 (Midgley et al., 2015). Approximately half of children affected have a history of asthma or reactive airway disease. Dyspnea, cough, and wheezing are the predominant findings in 70% or greater of cases. Notably, fever is present in only half of children. Greater than half of children require

Enteroviruses intensive care management, including mechanical ventilation. Fatalities have been reported.

Severe Neonatal Enteroviral Infections Neonates are at risk of developing severe disease as a result of maternal NPEV infection at the time of delivery. In these cases, transplacental or perinatal transfer of virus may occur (Abzug, 2004). If the infant is delivered before maternal antibodies are transferred to the fetus, the newborn is at risk for overwhelming NPEV infection. Typically, severe neonatal NPEV infections present during the first 1–2 weeks of life (Abzug, 2004). Frequently, maternal symptoms such as severe abdominal pain or pleurodynia are present at the time of delivery. The liver, heart, or brain may be involved individually or in combination. The most severe presentation, neonatal enteroviral sepsis, is characterized by multisystem organ involvement. Clinically, the newborn may have a combination of the following conditions: myocarditis, meningoencephalitis, hepatitis, and/or pneumonia. The presentation may be subtle, at first consisting of poor feeding, apnea, lethargy, hypotonia, and abdominal distention. Fever may be absent. As the illness progresses, obvious evidence of multiple organ involvement becomes apparent. With neonatal NPEV, hepatitis, jaundice, and hepatomegaly occur. Extensive hepatic necrosis results in extreme elevations of liver transaminases along with prolonged prothrombin and partial thromboplastin times, leading to disseminated intravascular coagulopathy (DIC). Mortality is high in these patients. Neonates with NPEV myocarditis have evidence of myocardial dysfunction: tachycardia, respiratory distress, cyanosis, and decreased cardiac output. Pneumonia and meningoencephalitis are frequent manifestations of neonatal infection. The meningoencephalitis may be manifested by generalized seizures, lethargy, or coma.

NPEV Infections in Immunocompromised Hosts Individuals with B cell immunodeficiencies are at risk for chronic NPEV infections. Due to their lack of antibody production, the virus cannot be cleared by the host, resulting in chronic infection. In children with X-linked agammaglobulinemia, hyperIgM syndrome, severe combined immunodeficiency syndrome, and common variable immunodeficiency, NPEV infection can result in chronic EV meningoencephalitis. Children with these forms of humoral immunodeficiency should receive lifelong intravenous immunoglobulin (IVIG) replacement therapy in an attempt to prevent chronic infection. Reports exist of immunodeficient patients developing chronic EV meningoencephalitis despite immunoglobulin therapy. Chronic NPEV meningoencephalitis has a subtle presentation (McKinney et al., 1987). Patients initially complain of persistent headaches and lethargy. As the syndrome progresses, a constellation of neurologic symptoms develops, which includes ataxia, loss of cognitive skills, paresthesias, weakness, and seizures. Nonneurologic manifestations, including a dermatomyositis-like syndrome, edema, exanthems, and hepatitis,

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may occur. The CSF demonstrates a persistently elevated protein concentration and pleocytosis. Viral culture and polymerase chain reaction (PCR) from the CSF are repeatedly positive for EV. Patients who have undergone bone marrow transplantation are also at risk for serious EV infections (Biggs et al., 1990) as are those receiving rituximab and obinutuzumab. Meningoencephalitis, pulmonary infections, and severe gastroenteritis have been reported. These infections can be severe and may result in poor outcomes.

Diagnosis The current diagnostic method of choice for the NPEVs is nucleic acid amplification–based detection using either reverse transcription–PCR (RT-PCR) or nucleic acid sequence–based amplification (Rotbart et al., 1997; Stellrecht et al., 2015). Prior to the advent of RT-PCR, NPEV detection using cell culture was the standard. Cell culture techniques have several limitations for the detection of the EVs. The time required to determine a positive result is too long to be of clinical utility in the acute management of the patient. Not all NPEV serotypes replicate in cell culture. Most importantly, cell culture lacks sensitivity. The utilization of RT-PCR has been an important advancement in the diagnosis of EV infections (Nix et al., 2006; Rotbart et al., 1997; Stellrecht et al., 2015). The use of RT-PCR provides the clinician with the ability to diagnose the overwhelming majority, if not all, NPEV serotypes using a single test. It provides a rapid detection method that is clinically useful and has excellent sensitivity and specificity (Ramers et al., 2000). The result is generally available in a matter of hours. This results in decreased length of hospitalizations and allows for reduction in the use of antibiotics in individuals with NPEV meningitis. RT-PCR has been shown to reduce overall hospital cost associated with EV meningitis. The flexibility of this assay allows for the detection of NPEVs in different clinical specimens: CSF, serum, urine, stool, nasopharyngeal secretions, and tissues. Recent advances in RT-PCR methodologies permit both detection and determination of the infecting NPEV serotype. Because nucleic acid amplification–based detection of NPEV is not routinely available to all clinical laboratories, many continue to utilize cell culture for detection. When cell culture is employed, it is important that multiple cell lines be used in order to have the highest possible sensitivity (Stellrecht et al., 2015). Shell vial techniques combined with the use of monoclonal antibodies shorten the detection time, but the technique has poorer sensitivity than traditional cell culture methods. The interpretation of the results of cell culture and nucleic acid amplification–based assays requires that the clinician to take into account the specimen source from which the NPEV was detected. Because the NPEVs are shed from the oropharynx and GI tract for weeks to months after infection, the significance of detection from these sites must be cautiously interpreted (Stellrecht et al., 2015). The presence of NPEVs in specimens from these sites does not conclusively establish causality of the syndrome being evaluated. Stated more clearly,

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an NPEV isolated from a throat or GI specimen of a patient with meningitis, encephalitis, myocarditis, or febrile illness may represent viral shedding as a result of infection weeks earlier and may have no relationship with the current medical problem. In contrast, the identification of an NPEV from the CSF, blood, tissue, or urine is strongly supportive of an invasive infection and carries a high probability of being the causal agent of the illness being investigated. Samples from these sites represent the ideal sources from which to diagnose NPEV infections. A final caveat relates to the diagnosis of neonatal NPEV infections occurring within the first 2 weeks of life. Because the incubation period for the NPEV is 3–6 days, their identification in the stool or oropharynx from patients in this age group with NPEV-compatible syndromes is highly supportive of their role in disease.

Treatment No approved therapy exists for NPEV disease. IVIG has been used in the therapy of patients with severe EV infections, since antibody is critical to immunity to EVs. This approach has been employed in neonates with severe disease, but it remains unclear whether it provides a clinical benefit. Similarly, its use in the treatment of children suspected of having EV myocarditis has gained widespread acceptance without strong evidence for its benefit. Due to a lack of a proven therapeutic agent, supportive care is the cornerstone of management of individuals with NPEV infections. For patients with meningitis, analgesics for pain control of headaches and monitoring of fluid and electrolytes are essential. Respiratory and cardiovascular support and administration of blood products are essential in the neonate with severe disease and associated DIC. In cases of NPEV myocarditis, cardiovascular support in the form of inotropes, afterload reducers and, for those with life-threatening myocardial involvement, bridging with extracorporeal membrane oxygenation, may be indicated.

Prevention EVs are spread primarily by the lack of good hygiene. Handwashing is a key personal measure for the prevention of NPEV infection. Community-wide prevention of NPEV outbreaks requires adequate potable water, well-designed sewage systems, and waste treatment plants. During nursery outbreaks of NPEV infections, cohorting neonates is effective in limiting the outbreak. If a pregnant woman has an illness consistent with an NPEV disease and the fetus is doing well, attempts should be made to not deliver the baby. Waiting allows the fetus to acquire protective maternal antibodies. Recently, phase III trials of inactivated EV-A71 vaccines have demonstrated efficacy in preventing disease due to strains of the C4 genotype in China (Li et al., 2014; Zhu et al., 2014).

Further clinical trials are necessary, but this could represent a major step forward in the prevention of rhombencephalitis due to EV-A71.

See also: Childhood Infectious Diseases: Overview; Herpesviruses; Poliomyelitis; Viral Infections, an Overview with a Focus on Prevention of Transmission.

References Abzug, M.J., 2004. Presentation, diagnosis and management of enterovirus infections in neonates. Pediatr. Drugs 6, 1–10. Biggs, D.D., Toorkey, B.C., Carrigan, D.R., et al., 1990. Disseminated echovirus infection complicating bone marrow transplantation. Am. J. Med. 88, 421–425. Cabrerizo, M., De Miguel, T., Armada, A., et al., 2010. Onychomadesis after a hand, foot, and mouth disease outbreak in Spain, 2009. Epidemiol. Infect. 138, 1775–1778. Huang, C.C., Liu, C.C., Chang, Y.C., et al., 1999. Neurologic complications in children with enterovirus 71 infection. N. Engl. J. Med. 341, 936–942. Jenista, J.A., Powell, K.R., Menegus, M.A., 1984. Epidemiology of neonatal enterovirus infection. J. Pediatr. 104, 685–690. Li, R., Liu, L., Mo, Z., et al., 2014. An inactivated enterovirus 71 vaccine in healthy children. N. Engl. J. Med. 370, 829–837. Lott, J.P., Liu, K., Landry, M.L., et al., 2013. Atypical hand-foot-and-mouth disease associated with coxsackievirus A6 infection. J. Am. Acad. Dermatol. 69, 736–741. McKinney, R.E., Katz, S.L., Wilfert, C.M., 1987. Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev. Infect. Dis. 9, 334–356. Messacar, K., Schreiner, T.L., Maloney, J.A., et al., 2015. A cluster of acute flaccid paralysis and cranial nerve dysfunction temporally associated with an outbreak of enterovirus D68 in children in Colorado, USA. Lancet 385 (9978), 1662–1671. Midgley, C.M., Watson, J.T., Nix, W.A., et al., 2015. Severe respiratory illness associated with a nationwide outbreak of enterovirus D68 in the USA (2014): a descriptive epidemiological investigation. Lancet Respir. Med. 3, 879–887. Miyamoto, A., Hirata, R., Ishimoto, K., et al., 2014. An outbreak of hand-foot-andmouth disease mimicking chicken pox, with a frequent association of onychomadesis in Japan in 2009: a new phenotype caused by coxsackievirus A6. Eur. J. Dermatol. 24, 103–104. Modlin, J., Dagan, R., Berlin, L.D., et al., 1991. Focal encephalitis with enterovirus infections. Pediatrics 88, 841–845. Nix, W.A., Oberste, S.M., Pallansch, M.A., 2006. Sensitive, seminested PCR amplification of VP1 sequence for direct identification of all enterovirus serotypes from original clinical specimens. J. Clin. Microbiol. 44, 2698–2704. Ooi, M.H., Wong, S.C., Lewthwaite, P., et al., 2010. Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol. 9, 1097–1105. Ramers, C., Billman, G., Hartin, M., et al., 2000. Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. J. Am. Med. Assoc. 283, 2680–2685. Romero, J.R., 2016. Hand, foot, and mouth disease and herpangina: an overview. In: Edwards, M.S., Drutz, J.E. (Eds.), UpToDate. UpToDate, Waltham, MA (accessed on 24.07.16.). Rotbart, H.A., Ahmed, A., Hickey, S., et al., 1997. Diagnosis of enterovirus infection by polymerase chain reaction of multiple specimen types. Pediatr. Infect. Dis. J. 16, 409–411. Stellrecht, K.A., Lamson, D.A., Romero, J.R., 2015. Enteroviruses and parechoviruses. In: Jorgensen, J.H., Pfaller, M.A., Carroll, K.C., et al. (Eds.), Manual of Clinical Microbiology, eleventh ed. American Society for Microbiology, Washington, DC, pp. 1530–1536. The Pirbright Institute UK. Picornavirus.com. Enterovirus. http://www.picornaviridae. com/enterovirus/enterovirus.htm (accessed 14.07.16.). Zhu, F., Xu, W., Liang, Z., et al., 2014. Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China. N. Engl. J. Med. 370, 818–828.

Environmental and Occupational Epidemiology Neil Pearce and Jeroen Douwes, Massey University, Wellington, New Zealand Ó 2017 Elsevier Inc. All rights reserved.

In this article, we describe the key features of environmental and occupational epidemiology studies, the types of study designs, measurement of exposure, issues of bias, and interpretation of environmental and occupational epidemiology studies. We do not discuss methods of data analysis, and readers are referred to more detailed epidemiologic texts for more information (Rothman and Greenland, 1998). Environmental epidemiology and occupational epidemiology are separate fields that are usually covered by separate textbooks (Steenland and Savitz, 1997, Checkoway et al., 2004). However, the two fields often involve common exposures and there is therefore inevitably some overlap in the epidemiological methods that are used. For example, exposure to pesticides can be studied in the context of community exposures or exposures to pesticide production workers or commercial sprayers. These two different contexts of exposure provide the basis for the difference between environmental and occupational epidemiology. Each context has its own advantages and disadvantages in terms of conducting research, although in most instances studying such an exposure in the occupational context is easier and more valid scientifically than studying it in the environmental context.

Environmental Epidemiology Environmental epidemiology is the use of epidemiology to investigate causes of disease that are found in the environment (Pearce and Woodward, 2004). A recent World Health Report estimated that 24% of the global disease burden and 23% of all deaths can be attributed to environmental factors (World Health Organization, 2006). Among children 0–14 years of age, the proportion of deaths attributed to the environment was estimated to be as high as 36%, with the largest proportion in developing countries. Diseases with the largest absolute burden included diarrhea, lower respiratory infections, other unintentional injuries including occupational injuries, and malaria. The most important risk factors contributing to disease and mortality are unsafe drinking water and poor sanitation and hygiene (diarrhea), and indoor air pollution related largely to household solid fuel use and possibly second-hand smoke as well as to outdoor air pollution (lower respiratory infections) (World Health Organization, 2006). In most developed countries, these risks are now largely controlled, with the exception of outdoor air pollution, through the provision of safe drinking water, adequate food, waste disposal, immunizations, and adequate health care. However, other diseases with suspected environmental causes such as cancer, cardiovascular disease, asthma, chronic obstructive pulmonary disease, and diabetes are still common and are in fact increasing in prevalence in many developed countries. The term environment is very broad and includes epidemiological studies at the molecular, individual, population, and ecosystem levels. Analyses at the ecosystem level are unique to environmental epidemiology and often require research

International Encyclopedia of Public Health, 2nd edition, Volume 2

methods that are quite different from those used in other areas of epidemiologic research, including systems-based approaches such as complexity theory. There are also some features of environmental epidemiology that provide particular challenges to researchers (Pearce and Woodward, 2004). Firstly, environmental epidemiology is concerned generally with exposures that are, by definition, characteristics of the environment, not the individuals who live in that environment. Examples include infectious organisms in the water supply, features of the legislative environment (restrictions on smoking in bars for example), and air pollutants both indoors and outdoors. This means that the exposures that are being studied are typically widespread and not readily controlled by the individuals who are directly affected. What are the consequences for epidemiology? The fact that the exposures are widespread means that it may be difficult to find individuals who can act as an unexposed comparison group (e.g., persons who are not exposed to air pollution). Sometimes the exposures are not only widespread, but also vary little within a given population (e.g., air pollution levels in a neighborhood) compared with the differences between populations. In these circumstances, ecological studies – in which the unit of comparison is the group rather than the individual – may be particularly useful. An example of an ecological study of air pollution would be a study that compared the frequency of respiratory illnesses in different neighborhoods with the average levels of nitrogen oxide and ozone in those locations. Secondly, environmental epidemiology often involves studying exposures at low levels. An example is environmental dioxin exposure. Exposures in the general environment from sources such as incinerators are usually orders of magnitude less than those that may be experienced in some occupational settings (such as workers in the incinerator, or workers producing chemicals contaminated with dioxin). One consequence is that environmental epidemiology is frequently searching for risks on the margin of detectability. However, this does not mean that the risks presented by low-level exposures in the general environment are necessarily unimportant. First, these exposures are typically involuntary (people who live close to incinerators, e.g., have little choice over whether they are exposed to dioxin from the sites), and the public is far more sensitive to potential dangers of this kind than exposures that are seen to have an element of discretion about them. Second, the increase in risk for an individual may be small, but if exposures affect large numbers of people, then the overall burden of illness attributable to the exposure will be substantial. Relatively few people are exposed to dioxin at work, so although this may be an important personal health issue, the impact on the health of the population overall will be relatively small. On the other hand, if low-level environmental dioxin exposures do have health effects, then this would be a significant public health issue since the number of people at risk would be very large.

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Thirdly, the measurement of exposure may be particularly difficult in environmental epidemiology studies. For example, if someone experiences spray drift from pesticides being sprayed on a farm near their home, it may be very difficult to determine how much exposure they received, if any. Finally, studies of environmental causes of disease and injury tend to involve dispersed, heterogeneous populations. This provides particular challenges in recruitment of study participants and in the analysis of findings. It may be difficult to define the exposed population, weakening the confidence with which results can be extrapolated to other groups. The very mixed nature of the general population (in terms of age, health status, and co-exposures) means that an overall average risk estimate may mask considerable variations in the strength of effect in different subgroups. Consider for example a study of hospitalization rates in relation to ambient levels of air pollution in a major city. The population of the city will include a number of groups that are likely to be more susceptible than the average city inhabitant to the effects of pollution (such as the elderly, people with preexisting chest disease, outdoor workers). Typically, the numbers of susceptible individuals and the exposures they receive are not known, and caution must be applied in interpreting the relation observed between pollution levels and health outcome (e.g., numbers of hospital admissions per day). Exposure guidelines based on studies of this kind may not provide adequate protection to the most sensitive groups in the population, and this must be taken into account when epidemiological results are translated into public health policy (Woodward et al., 1995).

Occupational Epidemiology The major occupational health problems include cancer, heart disease, respiratory disease, musculoskeletal disease, neurological disease, hearing loss, and injury. Worldwide, 6000 people die each day as a result of their job, and of these deaths 15% are due to accidents and 85% to work-related disease. The picture is quite different when occupational morbidity is considered, with accidents accounting for about 90% of cases and nonfatal disease only about 10% (Driscoll et al., 2004). Studying exposures in the occupational context has many scientific advantages in comparison to studies of environmental exposures (Checkoway et al., 2004). Firstly, the exposures are generally well defined in time and space, rather than being ubiquitous in the environment. For example, in a study of occupational dioxin exposure, the exposure may be restricted to just a few departments within a factory, and workers in the other departments may serve as a nonexposed comparison group. Even if all workers in a particular factory receive some exposure, it is relatively straightforward to find a nonexposed comparison group from another factory or industry. Secondly, as noted above, occupational exposures are typically at much higher levels than environmental exposures, and study power is therefore correspondingly greater. Thirdly, the estimation of exposure is generally more straightforward in occupational studies. For example, in a study of pesticide production workers, even if individual

exposure measurements were not available, it would be relatively straightforward to classify workers in categories of exposure on the basis of their work history (job titles and departments) and a Job-Exposure-Matrix (JEM) (Checkoway et al., 2004). Finally, occupational populations are generally less heterogeneous than the communities that are studied in environmental epidemiology. For example, in studies of blue collar workers, there are usually few differences in lifestyle between exposed and nonexposed workers, so confounding by factors such as tobacco smoking and alcohol is usually weak. In addition, occupational populations do not usually include children or the elderly, two groups that may be particularly susceptible to some exposures. Furthermore, for many occupational exposures, it may be rare that the workforce includes pregnant women. These differences between exposures in the occupational and environmental context mean that it is generally more straightforward, and more valid scientifically, to study the occupational context. On the other hand, there may be difficulties in extrapolating findings from occupational studies to more heterogeneous populations with lower levels of exposure. Furthermore, there are some environmental exposures (e.g., air pollution, pollen exposure) for which it is relatively difficult to find suitable occupational populations. Thus, for many exposures environmental studies provide a useful complement to occupational studies.

Types of Epidemiologic Studies All epidemiologic studies are (or should be) based on a particular population (the study population, source population, or base population) followed over a particular period of time (the study period or risk period). The different epidemiological study designs differ only in the manner in which the source population is defined, and the manner in which information is drawn from this population (Checkoway et al., 2004).

Incidence Studies The most complete approach involves utilizing all of the information from the source population in a cohort study (follow-up study, longitudinal study) of disease incidence. Follow-up may be prospective (which is more expensive and time-consuming but may enable better quality data to be collected), or it may be based on historical records. The most common measure of disease occurrence is the incidence rate, which is a measure of the disease occurrence per unit time, and is the number of new cases of the outcome under study divided by the total person-time at risk. The usual approach is to compare the incidence rate in those exposed and those not exposed to a particular factor (e.g., air pollution) and to estimate the rate ratio. This may involve comparing the disease incidence in the exposed group (e.g., people living next to a factory which emits high levels of air pollution) with some nonexposed external reference population, such as another geographic area or the national population. Alternatively, if the source population involves both exposed and nonexposed persons (e.g., if some people are exposed and some are not

Environmental and Occupational Epidemiology Table 1 Cohort study of the population in zones A and B combined exposed to dioxin after the 1976 accident in Seveso, Italy Years of follow-up All causes mortality 0–4 years 5–9 years 10–14 years 15–19 years Total (0–20 years) All cancer mortality 0–4 years 5–9 years 10–14 years 15–19 years Total (0–20 years)

Observed

Expected

Relative risk

95% CI

103 113 95 127 438

109.4 104.1 105.7 117.3 436.2

0.9 1.1 0.9 1.1 1.0

0.8–1.1 0.9–1.3 0.7–1.1 0.9–1.3 0.9–1.1

28 43 37 58 166

30.1 34.7 41.2 44.2 149.7

0.9 1.2 0.9 1.3 1.1

0.6–1.4 0.9–1.7 0.6–1.2 1.0–1.7 1.0–1.3

Modified from Bertazzi, P.A., Consonni, D., Bachetti, S., et al., 2001. Health effects of dioxin exposure: a 20-year mortality study. Am. J. Epidemiol. 153, 1031–1044.

exposed within the same geographical area), then a direct comparison can be made within this population. Table 1 shows an example of an environmental epidemiology cohort study of the population exposed to dioxin after the 1976 accident in Seveso, Italy (Bertazzi et al., 2001). The accident took place in summer 1976 and exposed several thousand people in the neighboring area to substantial quantities of tetrachlorodibenzo-p-diozin (TCDD). Three contaminated zones (A, B, and R) were defined based on dioxin soil measurements along the direction of the prevailing winds. The study included all people living in these three zones at the time of the accident, or entering in the 10-year period after the accident. Vital status over the following 20 years was determined by contacting the vital statistics offices of the 11 study towns and of thousands of municipalities throughout the country to reach those subjects who had migrated (Bertazzi et al., 2001). The expected numbers of deaths were estimated based on the age, calendar period, and gender distribution of the population over the 20-year follow-up period. Table 1 shows the findings for all-cause mortality and cancer mortality in the two most heavily exposed zones (A and B) in the 20 years following the accident. It shows that there was little evidence of an elevation in all-cause mortality, but there was a significant increase in cancer mortality, particularly for the period 15 years or more after the accident.

Incidence Case–Control Studies Cohort studies are the most complete and definitive approaches to studying the occupational causes of disease, since they utilize all of the information in the source population. However, they often require large numbers and may be very expensive in terms of time and resources. The same findings can often be achieved more efficiently by using a case– control design. The key feature of case–control studies is that they involve studying all of the cases from the source population over the defined risk period (e.g., all cases of lung cancer in Rome during 2002), but only a sample of the non-cases are studied (e.g., a general population sample of people who do not currently have lung cancer). Exposure information is then collected for both groups. The aim is to obtain the same

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findings that would have been obtained with a full cohort study, but in a more efficient manner, because exposure information is collected only on the cases and a sample of controls, rather than on the entire population. For example, the earliest studies of smoking and lung cancer used the case–control design and the findings were subsequently confirmed in cohort studies. In case–control studies, the relative risk measure is the odds ratio, which is the ratio of the odds of exposure in the cases (i.e., the number exposed divided by the number not exposed) and the odds of exposure in the controls. Gaertner et al. (2004) conducted a case–control study of occupational risk factors for bladder cancer in Canada. They identified incident cases of histological confirmed bladder cancer in adults aged 20– 74 years identified through the provincial cancer registries in seven Canadian provinces, and selected 2847 controls from the general population of these provinces matched for age and gender. Cases and controls were sent postal questionnaires with telephone follow-up when necessary. Table 2 shows the findings for auto mechanics, an occupation which involves exposure to exhaust fumes and lubricating oils, both of which can contribute to bladder cancer risk (Gaertner et al., 2004). A higher proportion of cases than controls had worked as an auto mechanic (OR ¼ 1.69, 95% CI 1.02–2.82) and there was a statistically significant association with duration of employment (Table 2).

Prevalence Studies Incidence studies are usually conducted when studying fatal diseases such as cancer, since cases can be identified through death registrations or cancer registrations. However, when studying nonfatal chronic disease such as asthma, it is difficult to detect incident cases without very intensive follow-up. Thus, it is more common to study prevalence rather than incidence. This can be defined as point prevalence estimated at one point in time, or period prevalence which denotes the number of cases that existed at any time during some time interval (e.g., 1 year). Prevalence studies represent a considerable saving in resources compared with incidence studies, since it is only necessary to evaluate disease prevalence at one point in time, rather than continually searching for incident cases over an extended period of time. On the other hand, this gain in Table 2 Case–control study of occupational risk factors for bladder cancer in Canada Occupation

Cases

Controls

Odds ratioa

95% CI

Auto mechanic Never Ever 1–5 years 5–15 years >15 years

851 36 15 9 12

2799 48 25 14 9

1.00b 1.69 1.37 1.93 2.48

1.02–2.82 0.66–2.83 0.76–4.88 0.97–6.34 1.02–2.82

P-value for trend ¼ 0.01. a Adjusted for age, province, race, smoking, ex-smoking, and consumption of fruit, fried food and coffee, as well as for employment in nine suspect occupations. b Reference category. Modified from Gaertner, R.R.W., Trpeski, L., Johnson, K.C., 2004. A case–control study of occupational risk factors for bladder cancer in Canada. Cancer Causes Control 15, 1007–1019.

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Table 3 Prevalence (%) of renal dysfunction in South African lead/ acid battery production workers Exposure Category

Serum creatinine 125 mmol l1 (%)

Current blood Lead (mg dl1) 23–50 2.5 51–60 7.8 61–110 9.9 Cumulative blood Lead (mg.y dl1) 7–520.0 4.1 520.1–2681 8.9

Serum uric acid 500 mmol l1 (%)

Urinary NAGa  5 u/g creatinine (%)

1.0 2.8 7.9

20.5 22.0 29.2

4.1 6.0

19.1 27.4

a N-acetyl-b-D-glucosaminidase. Modified from Ehrlich, R., Robins, T., Jordaan, E., et al., 1998. Lead absorption and renal dysfunction in a South African battery factory. Occup. Environ. Med. 55, 453– 460; Checkoway, H., Pearce, N., Kriebel, D., 2004. Research Methods in Occupational Epidemiology. Oxford University Press, New York.

efficiency is achieved at the cost of some loss of information, since it may be much more difficult to understand the temporal relationship between various exposures and the occurrence of respiratory disease. In particular, it is usually difficult to ascertain, in a prevalence study, at what age disease first occurred, and it is therefore difficult to determine which exposures preceded the development of disease, even when accurate historical exposure information is available. Table 3 shows an example of a prevalence study. Ehrlich et al. (1998) conducted a cross-sectional study of kidney function abnormalities among 382 South African lead battery factory workers. Data on current and historical blood lead concentrations were available to categorize workers by exposure level. There were increasing prevalence trends of abnormalities of serum creatinine, serum uric acid, urinary N-acetyl-b-D-glucosaminidase with both current and historical cumulative blood levels.

Prevalence Case–Control Studies Just as an incidence case–control study can be used to obtain the same findings as a full cohort study, a prevalence case– control study can be used to obtain the same findings as a full prevalence study in a more efficient manner. For example, if obtaining exposure information is difficult or costly (e.g., if it involves lengthy interviews or collection of serum samples), then it may be more efficient to conduct a prevalence case– control study by obtaining exposure information on all of the prevalent cases of disease and a sample of controls selected at random from the non-cases. Table 4 shows an example of a prevalence case–control study. Studies of congenital malformations usually involve estimating the prevalence of malformations at birth (i.e., this is a prevalence rather than an incidence measure). Garcia et al. (1999) conducted a (prevalence) case–control study of occupational exposure to pesticides and congenital malformations in Comunidad Valenciana, Spain. A total of 261 cases and 261 controls were selected from those infants born in eight public hospitals during 1993–94. For mothers who were involved in

Table 4 Case–control study of parental agricultural work and congenital malformations Agricultural work Mothers Never Nonrisk periods During risk period Father Never Nonrisk periods During risk period

Cases

Controls

Odds ratioa

95% CI

127 72 15

134 80 7

1.0b 1.1 3.2

0.7–1.7 1.1–9.0

90 66 26

93 78 23

1.0b 0.9 1.5

0.5–1.5 0.7–3.1

The risk period was defined as the month before conception and the first trimester of pregnancy. a Adjusted for maternal and paternal confounders: spontaneous abortion (month), twins (index pregnancy), drug use during pregnancy (mother), heavy smoking during pregnancy (mother), education (mother), industrial work (father), and age >40 years (father). b Reference category. Modified from Garcia, A.M., Fletcher, T., Benavides, F.G., et al., 1999. Parental agricultural work and selected congenital malformations. Am. J. Epidemiol. 149, 64–74.

agricultural activities in the risk period (the month before conception and the first trimester of pregnancy), the adjusted prevalence odds ratio for congenital malformations was 3.2 (95% CI 1.1–9.0). There was no such association with exposure outside of this period, or with paternal agricultural work.

Measurement of Exposure In studies of environmental and occupational causes of disease, the distinction must be made between exposure and dose. The term exposure refers to the presence of a substance (e.g., environmental pesticide exposure) in the external environment. The term dose refers to the amount of substance that reaches susceptible targets within the body (e.g., concentration of a specific pesticide metabolite in the liver) (Checkoway et al., 2004). Epidemiological studies rarely have optimal exposure/dose data and often rely on relatively crude measures of exposure. The key issue is that the exposure data need not be perfect, but that it must be of similar quality for the various groups being compared. Provided that this principle is followed, then any bias from misclassification of exposure will be nondifferential (see section Information Bias), and will tend to produce false-negative findings. Thus, if positive findings do occur, one can be confident that these are not due to inaccuracies in the exposure data; on the other hand, if no association (or only a weak association) is found between exposure and disease, then the possibility of nondifferential information bias should be considered. In general, the aim of exposure assessment is to: (1) ensure that the exposure data are of equal quality in the groups being compared and (2) ensure that the data are of the best possible quality given the former restriction.

Subjective Measures of Exposure More often than not exposure or dose cannot be measured directly; instead researchers have to rely on subjective methods

Environmental and Occupational Epidemiology of exposure assessment. This is particularly the case in historical cohort studies and in case–control studies focusing on diseases with a long latency period. Traditionally, exposure to risk factors such as environmental tobacco smoke has been measured with questionnaires, and this approach has a long history of successful use in epidemiology. More recently, it has been argued that the major problem in epidemiology is the lack of adequate exposure data, and that this situation can be rectified by increasing use of molecular markers of exposure (Schulte and Perera, 1993). In fact, there are a number of major limitations of currently available biomarkers of exposures such as cigarette smoking, particularly with regard to historical exposures. Questionnaires have good validity and reproducibility with regard to current exposures and are likely to be superior to biological markers with respect to historical exposures. In occupational epidemiology, exposure is often estimated simply on the basis of occupation and industry and is typically dichotomized as never/ever exposed. More recently there has been increased use of semi-quantitative exposure assessment covering the whole exposure period using the full work history, and applying quantitative job exposure matrices (JEM) and expert assessment (Checkoway et al., 2004). In the absence of more sophisticated methods, these approaches may provide an efficient and low-cost method of assessing exposure, but it may result in considerable (nondifferential) misclassification.

Exposure Monitoring In addition to questionnaires, JEMs, and biological measurements, personal or environmental monitoring is commonly used to measure environmental or occupational exposures. Although this has the potential to provide a more valid and accurate exposure assessment, this may not always be the case and is strongly dependent on the chosen sampling strategy, which in turn is dependent on a large number of factors, including: 1. type of exposure and disease or symptoms of interest; 2. acute versus chronic health outcomes (e.g., disease exacerbation versus disease development); 3. population versus patient-based approaches; 4. suspected exposure variation both in time and space, and between the diseased and reference populations; 5. available methods to measure exposure; 6. costs of sampling and analyses. Data collected for environmental or occupational monitoring purposes may be of limited value in epidemiological studies. For example, monitoring is often done in areas where exposures are likely to be highest, in order to ensure compliance with exposure limits. Epidemiological studies, by contrast, require information on average levels of exposure and it may therefore be necessary to conduct a special survey involving random sampling, rather than relying on data collected for monitoring purposes.

Personal versus Area Sampling In general, personal measurements best represent the etiologically relevant current exposures, and personal sampling is therefore preferred over area sampling. Modern sampling

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equipment is now sufficiently light and small to allow it to be used for personal sampling purposes, and several studies focusing on chemical air pollution, for example, have demonstrated its feasibility in both the indoor and outdoor environments (Checkoway et al., 2004). However, personal sampling may not always be possible due to practical constraints, that is, it is too cumbersome for the study subjects, or there is no portable equipment to make the desired measurements (measurements of viable microorganisms, for example). In situations where personal sampling is not possible, area sampling can be applied to reconstruct personal exposure using the microenvironmental model approach. In this model, exposure of an individual to an airborne agent is defined as the time-weighted average of agent concentrations encountered as the individual passes through a series of microenvironments. However, some exposures only occur episodically, and these patterns are not likely to be accurately captured by environmental area samplers. In addition, it is practically impossible to measure all the relevant microenvironments.

Sampling: When and How Often? To the extent to which this is possible, samples should be taken such that they represent the true exposure at the appropriate time window. In the case of acute effects, exposure measurements taken shortly before the effects occurred would be most useful. For chronic effects, the situation is more complicated since exposure should ideally be assessed prior to the occurrence of health effects and preferably in the time window that is biologically most relevant, that is, when the exposure is thought to be the most problematic or when subjects are most susceptible for these exposures. This is only possible in longitudinal cohort studies (or historical cohort studies where historical exposure information is available). Even then it is often not clear when people are most susceptible to the exposures of interest. In cross-sectional studies, exposure measurements can also be valuable in assessing retrospective exposures, particularly when the environment in which people live or work has not changed significantly. Measures of exposure should be sufficiently accurate and precise, so that the effect of exposure on disease can be estimated with minimal bias and maximum efficiency. Precision can be gained (i.e., measurement error can be reduced) by increasing the number of samples taken either by: (1) increasing the number of subjects in whom exposure is measured or (2) increasing the number of exposure measurements per subject. In population studies, repeated sampling within subjects is particularly effective with exposures that are known to vary largely over time within subjects relative to the variation observed between subjects with the same job title or in the same work force. If the within-subject variability is small compared to the variation between subjects, however, repeated measures will not significantly reduce measurement error. If within- and between-subject variation is known (from previous surveys or pilot studies, for example) the number of samples required to obtain a given reduction in bias of the risk estimate can be computed in the manner described by Boleij et al. (1995). For instance, in studies that involve airborne sampling of viable micro-organisms in the indoor environment a within-versus between-home variance ratio of three to four in

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concentration is not uncommon, due to high temporal variation in microbial concentrations, combined with very short sampling times. In this particular situation, 27–36 samples per home would be required to estimate the average exposure reliably for an epidemiological study with less than 10% bias in the relationship between some health endpoint and the exposure. For most other exposure situations, the within-versus between-subject variation is, however, substantially lower, and far fewer repeated samples are therefore required.

Exposure Grouping In occupational epidemiology, a significant increase in validity may be achieved by using group mean exposure levels rather than individual levels since group-based exposure levels often (but not always!) vary less within job titles than within individuals. Exposure groups may be based on occupational categories, job title, work area, etc. Intragroup and intergroup variances and the pooled standard error of the mean can be calculated to evaluate the relative efficiency for various grouping procedures. Provided that reasonably homogeneous exposure groups can be defined with sufficient contrast between them, these same groups can be used to predict exposure levels of subjects for whom no exposure measurements are available, making this a very attractive option when limited resources are available to assess exposure. A similar approach may be employed for environmental exposures, but defining exposure groups with sufficient contrast is often not feasible because exposures often vary little within a given population. Ecological analyses may in those circumstances be more efficient (see section Environmental Epidemiology).

Exposure Modeling If the main factors that explain the variation in personal exposure are known, then mathematical models can be developed to predict individual exposure levels for those subjects where no or only limited exposure measurements are available (provided that valid information on determinants of exposure is available). Multiple regression models are most commonly employed, and can include variables such as tasks performed, type of production, environmental or climate characteristics, use of personal protective equipment, personal behavior, time spent in exposed areas, etc. Although these models can be very useful, they have limitations. In particular, the prediction model is generalizable only for the particular situation in which the data were collected. Extrapolation to other environments with the same exposure, or to the same environment at a different time point, may not be valid, and collection of new exposure data to update and/or validate the old model may be necessary (Boleij et al., 1995). Although exposure models to predict individual exposures have been used in environmental epidemiology, their use is more widespread (and perhaps more successful) in occupational epidemiology. Some examples of empirical exposure modeling include models to assess cadmium levels in blood in the general population, inhalation exposure to hydrocarbons among commercial painters, exposure to inhalable dust in bakery workers, and chemical and mutagenic exposure in the rubber industry. These types of exposure models have been shown to explain 50–80%

of the variability in exposure, but models with poorer performance have also been described. For example, Van Strien et al. (1994) assessed the association between home characteristics and house dust mite allergen levels in mattress dust using multiple regression analyses, and this model explained ‘only’ 26% of the variance. Although presented as separate strategies, often exposure assessment in occupational and epidemiological studies involve combinations of different approaches, for example a combination of subjective and objective measurements, or a combination of current personal sampling and the use of historical exposures collected for monitoring purposes.

Bias Systematic error, or bias, occurs if there is a difference between what the study is actually estimating and what it is intended to estimate. Systematic error is thus distinguished from random error in that it would be present even with an infinitely large study, whereas random error can be reduced by increasing the study size. There are many different types of bias, but three general forms have been distinguished (Rothman and Greenland, 1998): Confounding, selection bias, and information bias. In general terms, these refer to biases inherent in the source population because of differences in disease risk between the groups being compared (confounding), biases resulting from the manner in which study subjects are selected from the source population (selection bias), and biases resulting from the misclassification of these study subjects with respect to exposure or disease (information bias).

Confounding Confounding occurs when the exposed and nonexposed groups (in the source population) are not comparable due to inherent differences in background disease risk, usually due to exposure to other risk factors. Similar problems can occur in randomized trials in that randomization is not always successful and the groups to be compared may have different characteristics (and different baseline disease risk) at the time that they enter the study. However, there is more concern about noncomparability in epidemiological studies because of the absence of randomization. Confounding can be controlled in the study design, or in the analysis, or both. Control in the analysis involves stratifying the data into subgroups according to the levels of the confounder(s) and calculating a summary effect estimate that summarizes the information across strata. For example, in a study of environmental tobacco smoke (ETS) exposure and lung cancer, we might compare the risk of lung cancer in people exposed and people not exposed to ETS. We might make this comparison within five different age groups and in men and women, yielding 10 (5  2) different comparisons; for each stratum, we would calculate the relative risk of lung cancer in those exposed to ETS, compared with those not exposed, and we would then average these relative risks across the strata, giving more weight to strata with larger numbers of people (and lung cancer cases).

Environmental and Occupational Epidemiology Selection Bias Whereas confounding generally involves biases inherent in the source population, selection bias involves biases arising from the procedures by which the study subjects are chosen from the source population. Thus, selection bias is not usually an issue in a cohort study involving an internal reference population and with complete follow-up, since this incorporates all of the available information from the source population. Selection bias is of more concern in case–control studies since these involve sampling from the source population. In particular, selection bias can occur in a case–control study if controls are chosen in a nonrepresentative manner, for example, if exposed people were more likely to be selected as controls than nonexposed people.

Information Bias Information bias involves misclassification of the study subjects with respect to disease or exposure status. Thus, the concept of information bias refers to those people actually included in the study (whereas selection bias refers to the selection of the study subjects from the source population, and confounding generally refers to noncomparability within the source population). Nondifferential information bias occurs when the likelihood of misclassification of exposure is the same for diseased and nondiseased persons (or when the likelihood of misclassification of disease is the same for exposed and nonexposed persons). Nondifferential misclassification of exposure generally biases the effect estimate toward the null value. Thus, it tends to produce false-negative findings and is of particular concern in studies that find no association between exposure and disease (although it should be emphasized that nondifferential misclassification of a confounder can lead to bias away from the null if the confounder produces confounding toward the null). Differential information bias occurs when the likelihood of misclassification of exposure is different in diseased and nondiseased persons (or the likelihood of misclassification of disease is different in exposed and nonexposed persons). This can bias the observed effect estimate in either direction, either toward or away from the null value. For example, in a lung cancer case–control study, the recall of exposures (such as pesticide exposure) in healthy controls might be different from that of cases with lung cancer. In this situation, differential information bias would occur, and it could bias the odds ratio toward or away from the null, depending on whether cases were more or less likely to recall previous exposures than controls. As a general principle, it is important to ensure that the misclassification is nondifferential, by ensuring that exposure information is collected in an identical manner in diseased and nondiseased (and that disease information is collected in an identical manner in the exposed and nonexposed groups). In this situation, the bias is in a known direction (toward the null), and although there may be concern that negative findings may be due to nondifferential information bias, at least one can be confident that any positive findings are not due to information bias.

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Interpretation of Environmental and Occupational Epidemiology Studies The first task in interpreting the findings of an epidemiological study is to assess the likelihood that the study findings represent a real association, or whether they may be due to various biases (confounding, selection bias, information bias) or chance. If it is concluded that the observed associations are likely to be real, then attention shifts to more general causal inference, which should be based on all available information, rather than on the findings of a single study. A systematic approach to causal inference was elaborated by Bradford Hill (1965) and has since been widely used and adapted. The temporal relationship is crucial; the cause must precede the effect. This is usually self-evident, but difficulties may arise in studies (usually case–control or cross-sectional studies) when measurements of exposure and effect are made at the same time (e.g., by questionnaire, blood tests, etc.). An association is plausible if it is consistent with other knowledge. For instance, laboratory experiments may have shown that a particular environmental exposure can cause cancer in laboratory animals, and this would make more plausible the hypothesis that this exposure could cause cancer in humans. However, biological plausibility is a relative concept; many epidemiological associations were considered implausible when they were first discovered but were subsequently confirmed in experimental studies. Lack of plausibility may simply reflect current lack of medical knowledge. Consistency is demonstrated by several studies giving the same result. This is particularly important when a variety of designs are used in different settings, since the likelihood that all studies are making the same mistake is thereby minimized. However, a lack of consistency does not exclude a causal association, because different exposure levels and other conditions may reduce the impact of exposure in certain studies. The strength of association is important in that a strongly elevated relative risk is more likely to be causal than a weak association, which could be influenced by confounding or other biases. However, the fact that an association is weak does not preclude it from being causal; rather it means that it is more difficult to exclude alternative explanations. A dose–response relationship occurs when changes in the level of exposure are associated with changes in the prevalence or incidence of the effect. The demonstration of a clear dose– response relationship provides strong evidence for a causal relationship, since it is unlikely that a consistent dose–response relationship would be produced by confounding. Reversibility is also relevant in that when the removal of a possible cause results in a reduced disease risk, the likelihood of the association being causal is strengthened. Of these criteria for causal inference, only the criterion of temporality is a necessary criterion for establishing causality, in that if the cause does not precede the effect then the association must not be causal. Furthermore, none of these criteria, either individually or collectively, is sufficient to establish causality with certainty, but causality may be assumed to have been established beyond reasonable doubt if these criteria are substantially met.

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Acknowledgments The Center for Public Health Research is supported by a Program Grant from the Health Research Council (HRC) of New Zealand. Jeroen Douwes is supported by an HRC-funded Sir Charles Hercus Fellowship.

See also: Demography, Epidemiology, and Public Health; Environmental Health: Overview; Human Exposure Science; Indoor Air Pollution: Developing Countries; Occupational Health: Overview; Social Epidemiology.

References Bertazzi, P.A., Consonni, D., Bachetti, S., et al., 2001. Health effects of dioxin exposure: a 20-year mortality study. Am. J. Epidemiol. 153, 1031–1044. Boleij, J.S.M., Buringh, E., Heederik, D., et al., 1995. Occupational Hygiene of Chemical and Biological Agents. Elsevier, Amsterdam, the Netherlands. Checkoway, H., Pearce, N., Kriebel, D., 2004. Research Methods in Occupational Epidemiology. Oxford University Press, New York. Driscoll, T., Mannetje, A., Dryson, E., et al., 2004. The Burden of Occupational Disease and Injury in New Zealand: Technical Report. NOHSAC, Wellington, New Zealand, p. 2004. Ehrlich, R., Robins, T., Jordaan, E., et al., 1998. Lead absorption and renal dysfunction in a South African battery factory. Occup. Environ. Med. 55, 453–460. Gaertner, R.R.W., Trpeski, L., Johnson, K.C., 2004. A case–control study of occupational risk factors for bladder cancer in Canada. Cancer Causes Control 15, 1007–1019. Garcia, A.M., Fletcher, T., Benavides, F.G., et al., 1999. Parental agricultural work and selected congenital malformations. Am. J. Epidemiol. 149, 64–74.

Hill, A.B., 1965. The environment and disease: association or Causation? Proc. R. Soc. Med. 58, 295–300. Pearce, N., Woodward, A., 2004. Environmental epidemiology. In: Cameron, S., Cromar, N., Fallowfield, H. (Eds.), Environmental Health in Australia and New Zealand. Oxford University Press, Sydney, Australia, pp. 3–19. Rothman, K.J., Greenland, S., 1998. Modern Epidemiology. Lippincott-Raven, Philadelphia, PA. Schulte, P., Perera, F., 1993. Molecular Epidemiology: Principles and Practices. Academic Press, New York. Steenland, K., Savitz, D.A. (Eds.), 1997. Topics in Environmental Epidemiology. Oxford University Press, New York. Van Strien, R.T., Verhoeff, A.P., Brunekreef, B., et al., 1994. Mite antigen in-house dust-relationship with different housing characteristics in the Netherlands. Clin. Exp. Allergy 24, 843–853. Woodward, A., Guest, C., Steer, K., et al., 1995. Tropospheric ozone: respiratory effects and Australian air quality goals. J. Epidemiol. Commun. Health 49, 401–407. World Health Organisation, 2006. Preventing Disease through Healthy Environments: Towards an Estimate of the Environmental Burden of Disease. WHO, Geneva, Switzerland.

Further Reading Armstrong, B., White, E., Saracci, R., 1992. Principles of Exposure Measurement in Epidemiology. Oxford University Press, New York, p. 1992. Pearce, N., Beasley, R., Burgess, C., et al., 1998. Asthma Epidemiology: Principles and Methods. Oxford University Press, New York. Steenland, K. (Ed.), 1993. Case Studies in Occupational Epidemiology. Oxford University Press, New York. Teschke, K., Olshan, A.F., Daniels, J.L., et al., 2002. Occupational exposure assessment in case–control studies: opportunities for improvement. Occup. Environ. Med. 59, 575–593.

Environmental Health: Overview Dale A Dickinson and Karen E Iles, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Daniel Krewski, Michelle C. Turner, Nicole Boom, Franco Momoli, volume 2, pp. 361–373, Ó 2008, Elsevier Inc.

Introduction The World Health Organization (WHO) defines health as “a state of complete physical, mental and social wellbeing and not merely the absence of disease or infirmity” (WHO, 1948). It is well recognized that the health of a population is influenced by a wide array of health determinants. Environmental and occupational determinants of health must not be considered in isolation, but rather in the broader context of genetic, biological, social, behavioral, and other health determinants, as interactions among them may produce synergistic or antagonistic effects. The environment as defined in relation to health status is quite broad in scope, encompassing the natural environment (air, food, water, and soil), the built environment (including housing and the urban environment), and consumer products (such as household products and children’s toys). Definitions of environment sometimes include social factors (such as violence and economics) but exclude cultural practices (such as limited food choices). Defining environmental health is more difficult, although the WHO’s 2011 definition, “Environmental health addresses all the physical, chemical, and biological factors external to a person, and all the related factors impacting behaviours. It encompasses the assessment and control of those environmental factors that can potentially affect health. It is targeted towards preventing disease and creating health-supportive environments. This definition excludes behaviour not related to environment, as well as behaviour related to the social and cultural environment, and genetics,” is broadly accepted. Although the influence of the environment on health status has long been recognized, it is often difficult to establish etiological connections between environmental exposures and specific adverse health outcomes for a number of reasons. These include the multifactorial nature of many diseases, long latency periods, and cumulative and multiple exposures to diverse environmental hazards. Small risks associated with low levels of exposure to environmental hazards can only be characterized with carefully designed studies of sufficient size. Despite these difficulties, a wide range of adverse environmental and occupational health effects have been described, as will be seen in this article. Even small increases in risk can pose a substantial concern when considered on a population scale. A variety of scientific methods are used to evaluate environment–health outcome associations, including analytic epidemiologic studies, toxicological studies, and surveillance and biomonitoring programs (see the section Identification of Environmental and Occupational Health Risks). Quantification of the burden of disease attributable to environmental factors allows for the prioritization of health intervention initiatives. Burden of disease estimates can vary considerably due to difficulties in quantification as well as uncertainties regarding causality. Worldwide, the WHO

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estimated that 23% of all deaths and 24% of the global disease burden are attributable to environmental factors. However, the environmental disease burden is not equally distributed, with 25% of all deaths in developing countries attributable to the environment, as compared to 17% in developed nations. Per capita, children in developing countries have an eight times greater loss of years of healthy life from environmental factors than children in developed countries. Clearly, low- and middle-income countries (LMIC) carry a disproportionate load of environmental disease burden. These differences are attributed to a number of factors including poor infrastructure, lack of sanitation programs, and vectorborne diseases in LMIC countries. These observations clearly indicate that the environment exerts an important influence on health status. Fortunately, many environmental and occupational exposures are amenable to intervention and prevention, but this must be done critically with attention to the differences between each unique situation. For example, when implementing environmental health risk management programs, consideration must be given to population subgroups that may be particularly vulnerable to adverse environmental health effects. Public perception of risk must also be considered, as the success of any risk mitigation strategy can be affected by the public’s beliefs about the nature of the risk and their reaction to the intervention.

A Framework for Environmental and Occupational Health Risk Assessment An integrated framework for population health risk assessment is presented in Figure 1 (Krewski et al., 2007). The framework integrates the concepts of population health and risk assessment/management within a common paradigm to facilitate the environmental health policy decision-making process. Prominent population health elements of this integrated framework are the determinants of health, which form its foundation. The influence of environmental and occupational factors is considered in the context of the broader array of determinants, including biology and genetic endowment as well as social and behavioral factors, and their interactions. Examining the broad range of determinants and their complex interactions is important to properly address critical population health risk issues by recognizing the full range of factors influencing health risk. A range of risk mitigation strategies are considered, ranging from regulatory to community action. Prominent risk assessment/management elements of the framework are health risk science and health risk policy analysis; the latter component includes the selection and implementation of a risk management strategy, as well as the communication of information about the risk issue under consideration and the decisionmaking process. The remainder of this article will highlight key components of the framework and provide an overview

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Population health

Regulatory

Economic

Community action

Advisory

Technological

Multiple interventions

Health risk policy analysis Evidence - based policy

Health risk science Determinants and interactions

Biology – environment interactions

Biology and genetics

Environment – social interactions

Environment and occupational

Social and behavioral

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Figure 1 An integrated framework for risk management and population health. Reproduced from Krewski, D., Hogan, V., Turner, M.C., et al., 2007. An integrated framework for risk management and population health. Human Ecol. Risk Assess. 13 (6), 1288–1312. Figure reprinted with permission of the copyright holder, Taylor and Francis Group.

of adverse health effects associated with selected environmental and occupational health hazards.

Identification of Environmental and Occupational Health Risks Toxicological and epidemiological investigations are two main approaches for identifying environmental and occupational health risks. Whereas epidemiological studies evaluate health risks in human populations, toxicological studies evaluate risks in the laboratory using a variety of in vitro or in vivo systems. Although epidemiological studies examine human health status directly, a variety of potential limitations can reduce the strength of population-based investigations. On the other hand, toxicological studies are conducted in carefully controlled laboratory conditions and can provide information on a range of health effects. However, results obtained in nonhuman test systems have inherent shortcomings as they must then be extrapolated to the human experience.

Epidemiology Epidemiological studies can range from simple case reports of adverse health outcomes in individual patients to highly complex analytic studies designed to assess specific associations

between a given environmental contaminant and an adverse health outcome. Epidemiology is typically defined as the study of the distribution and determinants of disease in human populations. Last’s (2001) definition goes one step further, explicitly stating that “epidemiology also involves the application of findings to health risk control.” Therefore, simply describing environmental/occupational health associations is insufficient; rather, knowledge gained must be used to design the most appropriate risk management strategies to reduce the burden of disease. Although case reports are a good starting point in determining the causes of adverse health outcomes, the findings from case reports require confirmation in carefully conducted analytic investigations. Typically, case–control studies, retrospectively, collect detailed information on exposures of interest among a defined group of affected cases and an unaffected group of controls. In contrast, cohort studies collect exposure information on healthy participants at a defined entry point (or baseline) and follow cohort members over time for the occurrence of health outcomes of interest. Variants of these traditional study designs are also employed. The methodological strengths and weaknesses of these study designs are well described. A major criticism with respect to environmental/occupational health for any epidemiological investigation is the availability of a precise and valid exposure metric.

Environmental Health: Overview Exposure may be defined using a variety of approaches including self-reports (questionnaires, interviews), measures in the environmental media (routinely collected environmental monitoring data, study-specific measures), and measures of personal exposure (e.g., personal air samplers). Each of these exposure metrics represents only a proxy measure for the more relevant internal dose at the target tissue, which is largely not often practically or possibly measured (see the section Surveillance/Biomonitoring). Exposure misclassification due to recall biases, difficulties in measuring exposure history in the distant past or in the most relevant etiologic period, and arbitrary decisions such as the choice of peak or cumulative exposures as the most relevant exposure metric can limit the strength of the investigation. Interindividual variability in exposure from differences in personal behavior and toxicokinetic factors are also key methodological concerns. Occupational studies are typically faced with the difficulty of assessing risk from exposure to complex mixtures of contaminants that may vary over time and are often forced to rely on job titles or records of employment as surrogate measures of exposure. Further, information on work behavior patterns including use of protective equipment is often difficult to obtain. A range of technological advancements are being applied to environmental/occupational health issues to attempt to more accurately assess exposure history and reduce potential misclassification. For example, in air pollution research, the use of satellite data, geographic information systems (GIS) methodologies, land-use regression models, and studies of source apportionment may provide improved estimates of pollutant concentrations in ambient air. The use of computerized methods to link high-quality administrative databases on health status, such as cancer registries, mortality records, and hospital discharges or prescription drug use has also become a powerful tool in environmental epidemiology. Other important analytic considerations include limited power to detect subtle low-dose effects, additivity, or synergism among mixtures of pollutants; a lack of information on potential confounders or effect modifiers; and the classical ‘healthy worker effect’ in occupational and proportionate mortality studies. Nevertheless, analytic epidemiological investigations have been instrumental in elucidating a number of environmental/occupational health relationships such as radon and lung cancer, air pollution and adverse cardiovascular effects, and childhood lead exposure and cognitive defects (see the section Environmental Health Risks).

Toxicology Although the applications of toxicological investigations conducted in nonhuman systems may be limited, they are of great importance in assessing potential environmental health risks and they can be performed in advance of the introduction of a substance into use, prior to any human exposure. Toxicity testing is a rapidly expanding field of scientific investigation, with the breadth of endpoints and sensitivity of tests available, particularly with the explosion of genomics, which is continually evolving. Toxicology and epidemiology are also interdependent disciplines, as the results of both are mutually considered when evaluating the weight of evidence for a specific

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environmental exposure/health outcome relationship. Such an integrated approach has been employed to advantage in the International Agency for Research on Cancer’s (IARC) monograph program (see the section Carcinogens in the Workplace). Toxicological studies can range from acute studies that assess the toxicity of high doses of a substance in a short time frame with severe consequences, to subchronic and chronic studies designed to assess the effects of repeated exposures administered over a period of months or even years. Acute studies can provide information regarding the lethality of the exposure, whereas subchronic and chronic studies can provide information on endpoints requiring extended exposure, such as cancer. Well-recognized limitations of toxicological approaches to health risk assessment include uncertainties associated with extrapolation from animals to humans, the lack of availability of appropriate animal models for certain human diseases, and differences in exposure levels (that is, human exposures are typically much lower than those evaluated in animal studies). Safety/uncertainty factors and mathematical risk models are typically applied to toxicological information for the purpose of establishing human exposure guidelines. A 100-fold safety factor has commonly been applied to the no-observed effect level for noncancer endpoints. This allows for a 10-fold difference in susceptibility between animal and human species, and a 10-fold difference in susceptibility among individuals in the human population. Additional safety factors may be applied to reflect the quality and completeness of the available scientific data. In the case of nonthreshold effects, mathematical modeling is sometimes used to determine a ‘virtually’ safe dose corresponding to a very low level of risk. The virtually safe dose is highly dependent on the slope of the dose– response curve, and is often estimated under strong assumptions, such as linearity of the dose–response curve at low doses. Recently, the benchmark dose (BMD) corresponding to a 5% or 10% increase in risk has been proposed as a point of departure (PoD) for extrapolation to lower doses, with application to threshold and nonthreshold effects. Toxicokinetic studies are used to describe the absorption, distribution, storage, biotransformation, elimination, and excretion of xenobiotics. Physiologically based pharmacokinetic models are being increasingly used in risk assessment to estimate the dose of the reactive metabolite reaching target tissues. Toxicokinetic information is of value in designing appropriate testing protocols for new or existing substances, in interpreting the results from various toxicity tests, and in comparing results in different species. In vitro testing procedures offer many advantages in terms of resource use. The Ames Salmonella/microsome assay, introduced in the 1970s, remains one of the most widely used in vitro test procedures. The assay assesses the mutagenic potential of a particular substance by evaluating rates of reverse mutation in mutant bacteria strains deficient in their ability to synthesize histidine. Looking to the future, the US National Research Council recently proposed a long-range vision for toxicity testing and assessment of environmental agents. Elements of the vision include mapping of major toxicity pathways, greater use of computational toxicology to predict the toxic properties of environmental agents, the use of mediumand high-throughput in vitro test procedures to permit the

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assessment of a much greater number of environmental agents, and more use of cellular and molecular information derived from population-based studies.

Surveillance/Biomonitoring The WHO defines surveillance as the “systematic ongoing collection, collation, and analysis of data and the timely dissemination of information to those who need to know so that action can be taken” (Last, 2001: p. 174). A wide variety of environmental/occupational health surveillance systems exist from the local/hospital level to national and international levels. Surveillance systems can range from disease- or outcome-focused to product- or risk factor–focused. Injury surveillance systems, primarily outcome-focused, have been established in many hospital systems throughout the world. Some focus on injuries in specific populations, such as children, whereas others seek to evaluate the injury profile among the whole population. Cancer registries provide another example of a well-established systematic, disease-focused, surveillance initiative. In contrast, surveillance systems related to adverse drug reactions or medical devices use a productfocused approach. Air quality–monitoring networks routinely collect data on the concentrations of specific air pollutants in certain geographic areas. Monitoring trends in disease or adverse outcome events over time can help to warn of emerging epidemics and provide clues about possible etiological relationships. In the context of environmental/occupational health, biomonitoring relates to the collection of biological samples, such as blood or urine, which are used to measure levels of contaminants directly or indirectly through indicators of their physiological effects. Biomonitoring can be performed as part of an epidemiological investigation or as part of a routine surveillance program. One advantage of biomonitoring is that it gives a direct indication of internal dose rather than relying on self-reported exposure measures, and it reflects cumulative exposure from all exposure routes. A range of contaminants has been examined in previous environmental health studies, including blood lead levels in relation to neurotoxic effects in children, and serum or plasma levels of PCBs (polychlorinated biphenyls) in relation to breast cancer risk. Recently, biomonitoring has revealed increasing levels of flame retardants in human breast milk. Limitations associated with biomonitoring include cost, the reflection of only recent exposures to nonpersistent chemical exposures, and the lack of information on the time course of past exposures. The identification and validation of biomarkers has been notoriously difficult and continues to be an area that needs a lot of research if routine and accurate biomonitoring is to become routine in determining exposure and predicting risk.

Environmental Health Risks Outdoor Air Pollution The association between outdoor air pollution and a variety of disease outcomes including asthma, cancer, and cardiovascular disease has been extensively investigated. Since mixtures of air pollutants are ubiquitous in the urban atmosphere, it has been

difficult to ascertain the specific pollutant(s) responsible for the observed effects. The WHO estimated that exposure to particulate air pollution is responsible for 800 000 (1.2%) of total premature deaths worldwide. Region-specific estimates illustrate that air pollution is a greater risk factor for adverse health outcomes in developing countries, with developing countries in Asia contributing approximately two-thirds of the global air pollution disease burden. Toxicological studies done with complex mixtures are seldom done and are desperately needed to advance the understanding or real-world exposures. Short-term studies based on time series and related methods have revealed acute health effects including increased rates of heart attack, stroke, emergency room visits for respiratory symptoms, and overall mortality associated with daily levels of ambient air pollution. Specific subpopulations including the elderly, infants, and individuals with underlying illness appear to be at particular risk. Atmospheric pollutants have also been associated, although less consistently so, with various immunological, hematological, and reproductive outcomes. Studies of the long-term health effects of elevated levels of air pollution have consistently reported positive correlative effects. One of the largest investigations of the relationship between long-term exposure to ambient air pollution and mortality is the study conducted by the American Cancer Society. From this study, Pope et al.’s (2002) analysis found that each 10 mg m 3 elevation in fine particulate air pollution was associated with an approximate 4, 6, and 8% increase in risk for all causes, cardiopulmonary, and lung cancer mortality, respectively. The ongoing need for understanding the relationships between air pollution and health continues to grow as links to diabetes and liver disease have emerged, while tools such as GIS, complex mixture analysis, and personal micromonitoring have potential to advance the field of exposure science and provide better data for risk analysis (West et al., 2016).

Indoor Air Pollutants Radon

Epidemiological studies have established radon as a leading cause of lung cancer. Natural decay of uranium-238, a component of the earths’ crust, results in the release of radon-222 gas. Concentrations of radon are typically low outdoors, but can accumulate in enclosed environments. Radon most commonly enters structures through cracks in foundations, construction joints, gaps around service pipes, and in the water supply. Radon in water is only a concern when ground water is being used; water from lakes, rivers, and reservoirs do not accumulate radon. When inhaled into the lung, the short-lived decay products of radon can interact with biological tissues specifically causing DNA damage. Although occupational case–control studies of uranium miners have consistently demonstrated a positive association between radon gas and lung cancer risk, the results of individual case–control studies of residential radon exposure have been less conclusive. To further evaluate the lung cancer risk associated with residential radon exposure, pooled analyses of case–control studies conducted both in Europe (13 studies) and North America (7 studies) were undertaken (Darby et al., 2005; Krewski et al., 2006). Overall, radon is now considered to be the leading cause of lung cancer among nonsmokers

Environmental Health: Overview in the United States. This recognition underlies the National Radon Action Plan sponsored by the EPA, which was released in November 2015. The goal of this plan is to reduce the risk from radon exposure in 5 million homes, which is projected to save 3200 lives between 2015 and its completion in 2020.

Other Indoor Air Pollutants

A range of other indoor air pollutants have also been associated with specific adverse health outcomes in studies around the world. Cooking and heating with solid fuels on open fires or traditional stoves can cause high levels of indoor air pollution. This is especially relevant in developing countries, as many depend on solid biomass fuels (wood, charcoal, crop residues, dung) and coal for their energy needs. Biomass and coal smoke contain a large number of pollutants including particulate matter, carbon monoxide, nitrogen dioxide, formaldehyde, and polycyclic aromatic hydrocarbons such as benzo[a]pyrene. These pollutants were associated with increased risk of acute respiratory infection, chronic obstructive pulmonary disease (COPD), lung cancer, asthma, and adverse reproductive outcomes. A substantial body of evidence, particularly from China, has shown that women are especially at risk of developing lung cancer as a result of exposure to smoke from cooking with coal in their homes. Other sources of indoor air pollutants include volatile organic compounds emitted from adhesives, carpeting, upholstery, pesticides, cleaning products, personal care products, as well as outdoor air pollutants that enter buildings through poorly located air intake vents and other openings, and moisture accumulation in building structures leading to high levels of bacteria and mold. Dampness in indoor environments may lead to various respiratory symptoms, asthma, and allergies (Laumbach and Kipen, 2005). Formaldehyde, used in many synthetic materials as an adhesive agent, was found in high levels in the FEMA trailers used in the US posthurricane Katrina (Murphy et al., 2013) and may have been responsible for many of the reported health issues.

Drinking Water Contaminants Safe and reliable drinking water is of paramount importance, as water is a basic biological necessity for life. A variety of biological pathogens can threaten the integrity of the public drinking water supply, including bacterial, viral, and parasitic organisms. Gastrointestinal illness is the health effect most commonly caused by waterborne pathogens. Infants and the elderly are particularly at risk of severe illness and mortality from gastrointestinal illness. Sophisticated water treatment plants can typically limit the concentrations of biological pathogens to levels that do not pose a population health risk. However, disruptions in the water treatment process or unusual environmental events can lead to the occurrence of gastrointestinal disease outbreaks. In developing countries, poor infrastructure often results in chronic exposure to water contaminated with biological pathogens. This can lead to endemic gastrointestinal illness resulting in malnutrition and premature mortality. Surveillance systems designed to provide early warning signs of impending water-quality issues are needed to implement risk mitigation strategies at the first indications of a problem, thereby preventing a large-scale outbreak.

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Drinking water can also become contaminated with industrial discharges, pesticide residues, and leaching of naturally occurring heavy metals due to acidification of the raw water source. The consequences of low-level chronic exposure to these compounds are not well established. Disinfection by-products in chlorinated drinking water are suspected in the development of several types of cancer, although the likely risks are low, particularly in comparison with the benefits of microbiologically mediated disease control. There is increasing concern surrounding the identification of excreted natural and pharmaceutical hormones in drinking water supplies, and most municipal drinking water supplies now contain trace amounts of antiepileptic, antidepressant medications. A recent concern over the past few years is the presence of nanoparticles in drinking water, as filtration systems cannot remove these. Plastic microspheres are now being banned in some areas of the United States due to their presence and accumulation in the Great Lakes, which then make their way into the food chain and in water taken for drinking purposes. Recent research is focusing on the relationship between pesticidecontaminated groundwater in California’s Central Valley and the rapidly growing incidence of some neurodegenerative diseases among long-term residents who use groundwater. Parkinson’s disease appears to have the strongest association, although Alzheimer’s is becoming reported at increasingly higher rates in this same area.

Dietary Contaminants Biological Hazards

Individuals are exposed to a wide range of infectious or toxic compounds through the ingestion of food. Microorganisms are the source of a large proportion of food-borne illness globally. Some of the most common pathogens included Salmonella, Campylobacter, Escherichia coli, and Shigella. Poultry, red meat, unpasteurized milk, and untreated water are common sources of these organisms. Fresh produce can also become infected through the use of contaminated seeds, irrigation with contaminated water, and flooding. Food-borne illnesses of pathogenic origin typically result in gastrointestinal symptoms. These symptoms are usually short-lived and selflimiting; however, in a subset of the exposed population, they can cause severe health complications and risk of death, especially in the very young and very old. Long-term complications are rare, but include reactive arthritis from exposure to Salmonella and Shigella, Guillain-Barré syndrome from Campylobacter exposure, and renal damage due to infection with pathogens such as E. coli O15H7. In industrialized countries, up to 30% of the population is affected by food-borne illness each year. The CDC estimates that approximately one in six Americans will get sick from food-borne illnesses each year. This translates into 48 million cases of food-borne disease, resulting in 128 000 hospitalizations and 3000 deaths. The global incidence of food-borne disease is more difficult to estimate due to a lack of surveillance and reporting systems in developing countries. However, over 2 million people are estimated to die from diarrheal disease each year, of which an appreciable proportion can be attributed to contamination of food and drinking water.

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Chemical Hazards

Toxic metals, PCBs, and dioxins can contaminate food through contact with polluted air, water, or soil. Pesticide residues and administration of pharmaceuticals to livestock can also result in chemical contamination of food. Persistent organic pollutants are fat soluble, and thus accumulate in the fatty tissue of fish and other animals over time. Residents in extreme northern climates are especially prone to highly persistent compounds that deposit in the region due to their long-range transport pattern through the atmosphere and subsequently bioaccumulate in the food chain. The health risks of persistent organic pollutants remain undefined, although certain types of cancer and adverse reproductive health outcomes are suspected. The accumulation of chemicals such as PCBs and some heavy metals in fish lead to poorly documented and research environmental justice issues among subsistence fisherpersons, who are often in poor, minority communities.

Urban Environments Densely populated areas present unique public health challenges. Crowded conditions combined with inadequate hygiene can result in the rapid spread of infectious disease. Increased infectious disease risk can also stem from inadequate solid waste collection resulting in an environment which favors the proliferation of vectors and reservoirs of communicable diseases. In tropical countries, these vectorborne diseases include malaria, dengue, and typhoid. In other climates, rodents and flies act both as mechanical and biological vectors of infectious diseases. Individuals in many urban environments are exposed to high levels of air pollution as a result of heavy-motor vehicle traffic and proximity to industrial complexes. Motor vehicle traffic also contributes to increased risk of injury from collisions and pedestrian accidents. It is estimated that 20–50 million people worldwide are injured or disabled each year due to motor vehicle accidents and that number is expected to rise, particularly in developing countries, due to rapid and unplanned urbanization (Peden, 2005). High levels of traffic noise have also been implicated in hypertension, sleep disturbances, and myocardial infarction. Despite these potential health risks associated with densely populated areas, there are several advantages of living in an urban environment with respect to health including proximity to health-care facilities, public health programs, and increased opportunity to form social support networks.

Occupational Health Risks Dangerous substances and conditions have always existed in the workplace. Historically, instead of improving such work conditions, there are accounts of ‘unhealthy’ work environments exploited as a form of punishment or of work relegated to lower classes. Since the effects of a toxic and unsafe work environment can manifest in a wide variety of diseases and injuries, establishing a safe workplace has been an important population health goal in recent decades.

Carcinogens in the Workplace From the first observations of Sir Percival Pott in 1775, associating scrotal cancer in chimney sweeps with deposits of soot, through to the modern era, carcinogens were first identified primarily in the workplace. Other historic examples include benzidine and vinyl chloride. Although this is no longer true, occupational cancer epidemiology remains essential to the discovery of cancer-causing agents in humans. The predominant source of evidence on human carcinogens has arisen from epidemiologic studies of highly exposed workers. Some early studies identified lung cancer risks in relation to suspicious occupational circumstances, such as nickel refineries, chromate manufacturing, and sheep-dip manufacturing. Concerted investigation of occupational agents came later, as exemplified by Sir Richard Doll’s 1955 quantitative assessment of the relationship between asbestos exposure and lung cancer risk. In recognition of the vast and growing body of evidence concerning environmental carcinogenesis, several programs were established in the 1970s to aid in governmental regulation, including the IARC monograph program and the Environmental Health Criteria monographs of the International Program on Chemical Safety within the WHO. A partial listing of occupational groups and their known, associated cancers can be found in Table 1. As of 2016, the IARC monograph program has identified 118 definite human occupational carcinogens (Category 1), 79 probable carcinogens, and 290 possible carcinogens (Categories 2A and 2B, respectively). A further 501 chemicals or mixtures are in Category 3, meaning that they cannot be classified as to their potential for carcinogenicity in humans; only 1 compound is in Category 4, probably not carcinogenic to humans. While some of the well-studied classic occupational exposures are practically nonexistent in modern times, others remain common in the global setting. Exposure to crystalline silica, for example, is particularly ubiquitous, as is exposure to the many varieties of polycyclic aromatic hydrocarbons and exposures among welders. Though the global burden of cancer attributable to occupational exposures is small, on the order of about 2%, Boffetta (2004) has argued that these cancers occur disproportionately among male blue-collar work populations, in whom occupational cancers may account for upwards of 20% of cancers. These continuing incidents should be studied from an occupational justice perspective, reminiscent of Gauley Creek in WV, which was also due to silica exposure.

Respiratory Health While the ‘dusty trades’ were linked to chronic bronchitis since the nineteenth century, it was recognized as early as the 1500s that lung disease was common in miners. The lung is particularly susceptible to occupational exposures such as airborne dusts and fumes. As shown in Figure 2, inhaled materials can increase the risk of virtually all of the major chronic lung diseases, with the exception of vascular illnesses. Allergens and irritants can cause sneezing and congestion. Particulate matter can be deposited to areas of the upper respiratory system, causing rhinitis and various bronchial illnesses. Exposure to chromic acid can cause nasal ulcerations. Irritants are commonly inhaled from common mixtures of bleaches and

Environmental Health: Overview Table 1 Listing of occupational carcinogens and circumstances with strong evidence linking them to particular cancer sites Cancer site

Agent or circumstance

Pharynx and nasopharynx Nasal cavities and paranasal sinuses

Formaldehyde

Liver and biliary tract Liver (angiosarcoma) Larynx Lung

Lung (oat cell) Bone Melanoma Skin

Mesothelioma Bladder

Thyroid Leukemia

Boot and shoe manufacture and repair; furniture and cabinet making; isopropanol manufacture, strong acid process; selected nickel compounds, including combinations of nickel oxides and sulfides in the nickelrefining industry; wood dust Aflatoxin; ionizing radiation Vinyl chloride Isopropanol manufacture, strong acid process; inorganic acid mists containing sulfuric acid; mustard gas Aluminum production; arsenic and arsenic compounds; asbestos; beryllium; cadmium and cadmium compounds; chromium compounds, hexavalent; coal gasification; coke production; hematite mining, underground, with radon exposure; involuntary (passive) smoking; ionizing radiation; iron and steel founding; selected nickel compounds, including combinations of nickel oxides and sulfides in the nickelrefining industry; painters; silica, crystalline; soots; talc containing asbestiform fibers Bis(chloromethyl) ether and chloromethyl methyl ether (technical grade) Ionizing radiation Solar radiation Arsenic and arsenic compounds; coal tars and pitches; coal gasification; coke production; dibenz[a,h]anthracene; mineral oils, untreated and mildly treated; shale oils or shale-derived lubricants; solar radiation; soots Asbestos; erionite; talc containing asbestiform fibers Aluminum production; 4-aminobiphenyl; auramine manufacture; benzidine; coal gasification; magenta manufacture; 2naphthylamine; rubber industry Ionizing radiation Benzene; boot and shoe manufacture and repair; ethylene oxide; ionizing radiation

Adapted from Siemiatycki, J., Richardson, L., Straif, K., et al., 2004. Listing occupational carcinogens. Environ. Health Persp. 112, 1447–1459 and Rousseau, M.C., Straif, K., Siemiatycki, J., 2005. IARC carcinogen update. Environ. Health Persp. 113, A580–A581.

phosphorus or detergents and ammonia. Although COPD is primarily caused by smoking, chronic airflow limitations were related to exposure to silica, beryllium, cadmium (particularly emphysema), and cotton dusts (specifically bronchitis or ‘brown lung’). Asthma has emerged as the principal occupational respiratory disease in industrialized countries. Hundreds of substances in the workplace are known to impact asthma, which can be categorized into occupational (new onset from workplace exposure) or work-aggravated (exacerbation of

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preexisting disease). The traditional definition of asthma referred to a reversible airflow limitation from sensitizing exposures. Recent consensus now also considers the existence of asthma from short-term, high-intensity exposure to irritants. The highest reported prevalence of occupational asthma has been found in the detergent industry, from exposure to platinum salts and proteolytic enzymes. Hollenbach and Cloutier (2015) list many of the major exposures that can induce asthma, such as various egg and animal proteins, grain dusts, flours, latex among health-care workers, proteases in the detergent industry, red wood dusts, and platinum salts; understanding the relationships between specific triggers and genetic background is an important area of study. Pneumoconiosis, a dust-related fibrotic lung disease, can be caused by inhalation of asbestos (asbestosis), silica (silicosis), iron filings (siderosis), and coal dust (black lung in coal miners). Silica exposure, in particular, is still a major concern among construction workers worldwide. Although there has been a decrease in the numbers of coal miners in Western Europe and North America, the numbers of miners remain large, particularly in Eastern Europe, India, China, Africa, Australia, and South America.

Occupational Radiation Exposures Since its discovery by Roentgen in 1895, ionizing radiation has been exploited in medicine for diagnostic and therapeutic purposes. Historically, medical staff were occasionally exposed to sufficiently high doses to lead to skin burns. Indeed, the first substantial epidemiological evidence for the carcinogenic effects of radiation was obtained from observations on radiologists. International groups such as the International Commission on Radiological Protection were formed to provide recommendations for radiation protection for both workers and the public. The discovery of nuclear fission in the 1930s led to the development of nuclear weapons, power industries, and subsequent occupational exposure to ionizing radiation. Underground rock miners can be exposed to high levels of naturally occurring radiation, from radon gas and its progeny, depending on surrounding uranium content. Other sources of exposure include workers involved with nuclear fuel production, reactor operation, irradiated fuel reprocessing, sterilization of medical products, luminizing, and radionuclide production. Studies of Japanese nuclear workers involved in weapon production during World War II, with high radiation exposure, were shown to be at excess risk of solid tumors in the lung, bone, and liver. Flight attendants can accrue high doses of cosmic radiation, and there are suggestions of excess melanoma and breast cancer. Griffiths and Powell (2012) have summarized various environmental health risk factors for flight attendants, of which radiation is one; exposure to pesticides is probably a greater health issue overall. Interestingly, the increased incidence of breast cancer among flight attendants may be due to shift work and not radiation per se (Kamdar et al., 2013). Fallout from the Chernobyl reactor failure in 1986 has been estimated to be associated with an additional 40 000 cases of cancer in Europe over the subsequent 80-year period (Cardis et al., 2006), although other researchers have calculated estimates between 245 000 to as

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Rhinitis and laryngitis Large particles are deposited in the nose, pharynx, and larynx. More soluble gases (e.g., sulfur dioxide) are absorbed by upper respiratory tract mucous membranes, causing edema and mucus hypersecretion.

Nasal cavity

Pharynx

Tracheitis, bronchitis, and bronchiolitis Large particles (more than 10 µm in diameter) are deposited and then cleared by cilia. Small particles and fine fibers are deposited in bronchioles and bifurcations of alveolar ducts. Less soluble gases penetrate to deeper, small airways.

Larynx Trachea Bronchus

Asthma and chronic obstructive pulmonary disease Allergens and irritants are deposited in large airways by turbulent flow, causing chronic inflammatory changes. Cancer Carcinogens (asbestos and polycyclic aromatic hydrocarbons) come into contact with bronchial epithelial cells, causing mutations in proto-oncogenes and tumor-suppressor genes. More than one such contact results in malignant transformation. Interstitial disease Small particles (less than 10 µm in diameter) and fibers are deposited in terminal bronchioles, alveolar ducts, and alveoli. Penetration to the interstitium results in fibrosis and the formation of granulomas.

Bronchiole Alveolus

Figure 2 Occupational respiratory diseases. Reproduced from Becket, W., 2000. Occupational respiratory diseases. N. Engl. J. Med. 342, 406–413. Copyright 2000 Massachusetts Medical Society. All rights reserved.

few as 10 000. These estimates continue to be debated as the true relationship between radiation and cancer is still not well defined, and different models can yield different results with the same inputs.

Pesticide Workers Pesticides are a diverse family of chemicals. Health concerns are driven largely by the relative high toxicity of insecticides, nematicides, and fungicides. Exposure can occur by way of ingestion, inhalation, and skin absorption, with the latter two being the primary routes of exposure in worker populations. Although direct use of pesticides entails the highest exposure levels, such as in orchard and farm workers, even office workers are exposed to some extent when exterminators are present. Nosocomial poisoning is possible in health-care workers when handling patients with acute pesticide poisoning. First used in chemical warfare, milder forms of organophosphates have since been formulated for use worldwide on agricultural crops and livestock. Used in preference to organochlorines, because of their safer environmental impact, many organophosphates have nevertheless been restricted by the Environmental Protection Agency (EPA). The WHO has estimated about 3 million cases yearly of acute pesticide poisoning, with the majority in developing countries in Africa, Asia, and Central and South America. With chronic exposure to low levels of organophosphates, a pesticide-related illness can develop, involving symptoms of nausea, headache, and vomiting. Additional long-term health problems were noted, including respiratory problems, memory disorders, neurological conditions, miscarriages, and birth defects. Pesticide

workers also possibly have an excess risk of non-Hodgkin’s lymphoma, particularly linked to phenoxyacetic acid, organochlorine, organophosphate, carbamate, and triazine pesticides. As with many occupational exposures, complex analyses are needed to disentangle the individual effects of pesticides when workers tend to be exposed to multiple agents (see, e.g., De Roos et al., 2003).

Injury and Safety in the Workplace The landmark US Worker’s Compensation Act of 1911 established the need for safe working conditions. Workplace safety is an essential requirement for the modern worker. However, even with measures to reduce work-related injuries and illness, safety concerns can still exist due to inadequate training and lack of compliance with safety regulations. Workplace safety can be achieved in a number of ways. Guidelines have been established to limit ambient air concentrations of many occupational agents. In the case of pesticide workers, safety measures might include frequent changes of clothing, avoidance of eating in the workplace, and regulations regarding the use of personal protective equipment. Similar measures were implemented with medical staff, who are at constant risk of exposure to various pathogens from handling of patients and medical supplies. With the development of ergonomic measures to prevent musculoskeletal disorders, the reduction of falls, trips, and slips in the workplace has become an important goal for workplace safety. Reducing chronic noise exposure will not only prevent hearing loss, but may also have an influence on hypertension. However, research has also shown that introducing newer and safer equipment

Environmental Health: Overview must also be accompanied by educational campaigns: improving risk awareness and compliance with safety measures, modifying work behavior, and reducing accidents by improvement of job skills.

Vulnerable Populations Children’s Environmental Health In contrast to the broader field of environmental health, children’s environmental health has come into prominence more recently. The National Research Council (1993) report, Pesticides in the Diets of Infants and Children, was a major stimulus in this regard. It reported that children may experience higher exposure levels to pesticide residues in food and a greater susceptibility, due to immature and rapidly developing systems, to their toxic effects as compared to adults. Regulatory changes embodied in the Food Quality Protection Act, including an additional 10-fold margin of safety, provided further protection for children against environmental exposures. Among the leading causes of morbidity and mortality among infants and children, many have an appreciable environmental component. The weight of the evidence with which to characterize children’s environmental health issues can range from cases in which the evidence is substantive to cases in which the scientific basis for an association is limited or inadequate. The economic and societal costs associated with children’s environmental health disorders are estimated to be substantial, in part, due to the disruption of normal development with the potential for serious and irreversible consequences. Seemingly subtle adverse children’s environmental health effects from low-level exposures can be associated with large lifetime or population consequences (as is the case for lead). Children may be exposed to potentially hazardous environmental agents through a number of pathways including ingestion, inhalation, and dermal; the developing fetus is exposed transplacentally to the mother’s body burden of environmental contaminants. Children’s exposures to environmental agents (adjusted for body weight) may exceed those of adults, thereby increasing the likelihood of adverse health effects, due to a combination of physiological and behavioral factors. Compared to adults, large differences in the consumption of certain foods and water per unit body weight are observed. Behaviors such as crawling, playing on the ground, and handto-mouth contact can increase the level of children’s exposure to environmental contaminants. Children may also be exposed to contaminants from parental occupational exposures from direct transfer from articles worn at work. Contaminants such as flame retardants, pesticides, plasticizers, metals, and therapeutic drugs were detected in the breast milk of women throughout the world, a food source unique to infants. Complex patterns of growth and development are observed from conception through to adulthood. Development does not occur uniformly across each organ system, but rather through a series of stages of rapid development that occur at precise time intervals. These differential rates of development create critical exposure time windows that are characterized by periods of enhanced susceptibility to environmental exposures.

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The fetal and infant life stages are thought to be particularly sensitive to chemical exposures. Immature organ and tissue systems contribute to differences in the uptake, distribution, metabolism, and elimination of environmental agents in children and may play important roles in increasing their susceptibility to the occurrence of an adverse health effect. Early life exposures also allow for an extended time period for the manifestation of delayed adverse health effects. A particular challenge in the field of children’s environmental health is that the majority of established relationships in population studies are those where high levels of exposure were observed. Considerably less is known regarding chronic low-dose exposures to which the majority of the pediatric population is exposed. The effects of such low exposures are particularly difficult to characterize in epidemiological studies, resulting in uncertainty about the nature and level of potential health risk. The WHO has developed a global plan to improve children’s environmental health, to regularly monitor and then report the findings, via the Global Plan of Action for Children’s Health and the Environment. Additionally, the Children’s Environmental Health Network (CEHN) is a national multidisciplinary organization whose mission is to protect the developing child from environmental health hazards and promote a healthier environment. As noted in the following section, genetic and socioeconomic factors may affect children’s susceptibility to exposure to environmental hazards.

Gene–Environment Interactions Many human diseases are believed to result from an interaction between genetic susceptibility and modifiable environmental factors. Gene–environment (GE) interactions reflect differences in the effects of environmental exposures among individuals with different genetic polymorphisms. Differences in genetic susceptibility can render some individuals in a population to be more or less likely to develop a particular disease following exposure to an environmental agent. Elucidating GE interactions has been particularly difficult, requiring considerable understanding of the biological underpinnings of human disease. Large-scale epidemiologic studies specifically designed to evaluate GE interactions are just beginning to be conducted. Xeroderma pigmentosum is an autosomal recessive disorder in which exposure to ultraviolet (UV) light results in a high incidence of skin cancers, due to defective DNA repair; although skin cancer can occur from UV light exposure without this genetic disorder, the risk of UV-induced skin cancer is much greater among individuals with this genetic condition. Simple GE interactions, where the exposure and the gene are both well understood, are rare in environmental/occupational health. Most diseases likely involve a complex profile of multiple genes, lifestyle factors, and environmental exposures. Studies have suggested several possibilities of potentially vulnerable populations, though they are yet to be fully understood. There is evidence that asthma has a number of environmental and occupational etiologies; several candidate genes were identified with suggestive evidence implicating interactions with isocyanate exposure, smoking, and ozone exposure with antioxidant supplementation. Parkinson’s disease is believed to have some association with agricultural pesticides, and, given that there are dramatic differences in the reported prevalence in

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different countries, a complex multigenic interaction has been suggested. Psychiatric disorders, such as depression and schizophrenia, have long been suspected of having genetic susceptibilities that moderate the effects of environmental determinants. Inflammatory diseases like rheumatoid arthritis have recently been studied, with conflicting results suggesting that smoking history is a trigger for the release of rheumatoid factors in the presence of certain alleles of the human leukocyte antigen. Squamous cell carcinomas of the oral cavity, pharynx, and larynx have also recently been studied to understand what, if any, interaction exists between tobacco smoke and polymorphisms of several carcinogen-metabolizing enzymes. Ongoing development of epigenetic tools and epigenome analysis continue to reveal additional mechanisms by which GE interactions may occur and help explain the emerging phenomenon known as ‘transgenerational exposure inheritance.’

risk control. Population-level factors are also related to risk perceptions, particularly the nature and type of media exposure and the credibility of the source. Specific characteristics of the hazard, particularly factors related to the degree to which it is dreaded and understood, also influence risk perceptions. A hazard, for example, will tend to be dreaded and thus, perceived as a greater threat, if the consequences are fatal, are globally distributed, affect future generations, or for which the individual may be involuntarily exposed. Concern surrounding a hazard will also be increased when the risk is new or unknown to science, or for which levels of exposure are difficult to quantify. Industrial sources of radiation, such as nuclear power plants, as well as environmental chemical contaminants, such as pesticides, are examples of such hazards that consistently appear in the risk perception literature. Understanding of public perception as risk issues evolve will aid in the development of effective risk mitigation programs.

Environmental Health Risk Issues A wide variety of environmental/occupational health risks have so far been described. The WHO has estimated that globally, diarrhea, lower respiratory infections, other unintentional injuries (a category distinct from road traffic injuries), and malaria represent the greatest opportunities for interventions to reduce the burden of environmentally mediated disease. A variety of policy options are available for managing such health risks. Policies aimed at directly improving environmental quality may be used alone or in combination with policies aimed at improving environmental health indirectly through social, behavioral, or other interventions.

Public Perception of Risk Public perception of risk is an important factor in environmental/occupational risk management decision making. Risk perception is a subjective or intuitive process by which individuals evaluate the probabilities and consequences of risks. As such, public perceptions of risk often differ from quantitative or expert determinations of health risk. Discrepancies in risk apprehension between the public and health authorities can lead to challenges in risk communication and undermine the effectiveness of risk mitigation strategies. Since zero risk from exposure to an environmental/occupational contaminant may often be unattainable due to reasons of feasibility or cost, the level of risk that society should be willing to assume or tolerate has been debated. Specification of a precise level of risk that might be considered acceptable in some sense is problematic (Hrudey and Krewski, 1995) although the EPA’s NexGen project to develop a new paradigm for risk science is already showing positive results and is beginning to be put into practice (Krewski et al., 2014). Public perceptions of risk and acceptable levels of risk are influenced by a wide range of factors. Studies of risk perception conducted throughout the world have identified a number of individual- and population-level characteristics related to level of risk perceived. Risk perceptions are influenced by demographic factors such as gender, age group, level of educational attainment, and income; personal values and beliefs; as well as personality traits such as locus of health

Risk Management A wide range of mitigation strategies are available for environmental/occupational health protection including regulatory, economic, advisory, community action, and technological approaches. Such mitigation strategies may be employed jointly or separately according to the nature of the environmental/occupational health scenario of concern. Evaluation of any strategy following its implementation is required to assess its impact on environmental/occupational health status. It is also important that any risk management strategy be equitable and responsive to the availability of new scientific data.

Emerging Issues Environmental/occupational health risk issues continue to evolve and emerge over time. Emerging pathogens, such as the virus responsible for avian flu in Europe and Asia, have had significant impacts on international trade. This initial experience with avian flu challenges us to find new ways of anticipating and preventing similar outbreaks in the future, including a possible outbreak of pandemic flu. The rapid emergence and spread of Zika virus in the Americas is similarly affecting travel, warnings about human pregnancy and the possible connection to microcephaly, and renewed discussions on the use of now-banned pesticides such as DDT to prevent further spread. The threat of terrorism has prompted major efforts to address the chemical, biological, radiological, and nuclear risks associated with such potential terrorist events. Endocrine toxicants were associated with adverse effects on the ecological environment and animal species and are suspected to play a role in a variety of human diseases. Human activity has also resulted in global change, including climate change, and impacts on biogeochemical cycles, which are expected to impact the biosphere far into the future. Population health risk issues related to climate change include the impact of extreme weather events, heat stress, health effects of particulate and gaseous copollutants associated with greenhouse gas emissions, increased cancer

Environmental Health: Overview risks due to increased exposure to UV radiation, and the migration of infectious disease-carrying insect vectors. Geologic issues including deep-well injection of wastes and fracking for natural gas threaten groundwater supplies; the latter has been related to microtremors in regions with extensive fracking. The full extent of such impacts is currently being evaluated by governments throughout the world and by international agencies with responsibilities for both population health and the environment. Current evidence clearly indicates that environmental/occupational factors impact population health status. Scientific investigations will continue to uncover new linkages between our environment and human health and refine current understanding of existing environmental health risks and their interactions with other health determinants, particularly social and genetic factors. Government, academia, industry, and nongovernmental organizations will need to work together to assess and manage known environmental and occupational health risks and respond to new risk issues as they emerge. International collaboration will be essential in addressing transboundary and global risk issues. The approaches to risk assessment and risk management outlined here may be of value in meeting this challenge.

See also: Cancer Epidemiology; Cancer: Global Burden, Trends, and Projections; Carcinogens, Environmental; Chronic Obstructive Pulmonary Disease; Contaminants Associated with Drinking Water; Environmental and Occupational Epidemiology; Foodborne Diseases; Genetic Epidemiology; Global Burden of Disease; Global Issues: Urban Health in Developing Countries; Human Exposure Science; Human Health Risk Assessment; Indoor Air Pollution: Developing Countries; Injury Epidemiology; Intestinal Infections: Overview; Lung Diseases, Occupational; Observational Epidemiology; Occupational Death/Injury Rates; Occupational Health: Overview; Occupational Injuries and Work Place Violence; Outdoor Air Pollution: Sources, Atmospheric Transport, and Human Health Effects; Pesticides; Populations at Special Health Risk: Workers; Respiratory Diseases: Overview; Road Traffic Injuries; Social Gradients and Child Health; Surveillance of Disease: Overview.

References Boffetta, P., 2004. Epidemiology of environmental and occupational cancer. Oncogene 23, 6392–6403. Cardis, E., Krewski, D., Boniol, M., et al., 2006. Estimates of the cancer burden in Europe from radioactive fallout from the Chernobyl accident. Int. J. Cancer 119, 1224–1235. Darby, S., Hill, P., Auvinen, M., et al., 2005. Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies. Br. Med. J. 330, 223. De Roos, A.J., Zahm, S.H., Cantor, K.P., et al., 2003. Integrative assessment of multiple pesticides as risk factors for non-Hodgkin’s lymphoma among men. Occup. Environ. Med. 60, E11. Griffiths, R.F., Powell, D.M., 2012. The occupational health and safety of flight attendants. Aviat. Space Environ. Med. 83, 421–514. Hollenbach, J.P., Cloutier, M.M., 2015. Childhood asthma management and environmental triggers. Pediatr. Clin. N. Am. 62, 1199–1214. Hrudey, S.E., Krewski, D., 1995. Is there a safe level of exposure to a carcinogen? Environ. Sci. Technol. 29, 370A–375A.

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Kamdar, B.B., Tergas, A.I., Mateen, F.J., et al., 2013. Night-shift work and risk of breast cancer: a systematic review and meta-analysis. Breast Cancer Res. Treat. 138, 291–301. Krewski, D., Lubin, J.H., Zielinski, J.M., et al., 2006. A combined analysis of North American case-control studies of residential radon and lung cancer. J. Toxicol. Environ. Health Part A 69, 535–597. Krewski, D., Hogan, V., Turner, M.C., et al., 2007. An integrated framework for risk management and population health. Hum. Ecol. Risk Assess. 13 (6), 1288–1312. Krewski, D., Westphal, M., Andersen, M.E., et al., 2014. A framework for the next generation of risk science. Environ. Health Perspect. 122, 796–805. Last, J.M. (Ed.), 2001. A Dictionary of Epidemiology. Oxford University Press, New York. Laumbach, R.J., Kipen, H.M., 2005. Bioaerosols and sick building syndrome: Particles, inflammation, and allergy. Curr. Opin. Allergy Clin. Immunol. 5, 135–139. Murphy, M.S., Lando, J.F., Kieszak, S.M., et al., 2013. Formaldehyde levels in FEMAsupplied travel trailers, park models, and mobile homes in Louisiana and Mississippi. Indoor Air 23, 134–141. Peden, M., 2005. Global collaboration on road traffic injury prevention. Int. J. Inj. Control Saf. Promot. 12, 85–91. Pope III, C.A., Burnett, R.T., Thun, M.J., et al., 2002. Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution. J. Am. Med. Assoc. 287, 1132–1141. West, J.J., Cohen, A., Dentener, F., et al., 2016. What we breathe impacts our health: improving understanding of the link between air pollution and health. Environ. Sci. Technol. 50, 4895–4904.

Further Reading Bakulski, K.M., Fallin, M.D., 2014. Epigenetic epidemiology: promises for public health research. Environ. Mol. Mutagen. 55, 171–183. Becket, W., 2000. Occupational respiratory diseases. N. Engl. J. Med. 342, 406–413. Cardis, E., Vrijheid, M., Blettner, M., et al., 2005. Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15 countries. Br. Med. J. 331, 77. Cohen, A.J., Anderson, H.R., Ostro, B., et al., 2005. The global burden of disease due to outdoor air pollution. J. Toxicol. Environ. Health Part A 68, 1301–1307. Frumkin, H., 2016. Environmental Health: From Global to Local, third ed. Jossey-Bass/ John Wiley & Sons, San Francisco, CA. Ladd-Acosta, C., 2015. Epigenetic signatures as biomarkers of exposure. Curr. Environ. Health Rep. 2, 117–125. Leiss, W., 2001. In the Chamber of Risks. Understanding Risk Controversies. Montreal and Kingston. McGill-Queen’s University Press, Quebec. National Research Council, 2006. Human Biomonitoring for Environmental Chemicals. National Academies Press, Washington, DC. National Research Council, 2007. Toxicity Testing in the Twenty-first Century: A Vision and a Strategy. National Academies Press, Washington, DC. Pinto, R.Q., Soares, I., Carvalho-Correia, E., Mesquita, A.R., 2015. Gene-environment interactions in psychopathology throughout early childhood: a systematic review. Psychiatr. Genet. 25, 223–233. Reddy, M.B., Yang, R.S.H., Clewell III, H.J., et al., 2005. Physiologically Based Pharmacokinetics: Science and Applications. Wiley, Hoboken, NJ. Ritz, B.R., Paul, K.C., Bronstein, J.M., 2016. Of pesticides and men: a California story of genes and environment in Parkinson’s disease. Curr. Environ. Health Rep. 3, 40–52. Rousseau, M.C., Straif, K., Siemiatycki, J., 2005. IARC carcinogen update. Environ. Health Perspect. 113, A580–A581. Rothman, K.J., Greenland, S., 1998. Modern Epidemiology, second ed. Lippincott, Williams and Wilkins, Philadelphia, PA. Siemiatycki, J., Richardson, L., Straif, K., et al., 2004. Listing occupational carcinogens. Environ. Health Perspect. 112, 1447–1459. Simonds, N., Ghazarian, A.A., Pimentel, C.B., et al., 2016. Review of the geneenvironment interaction literature in cancer: what do we know? Genet. Epidemiol. http://dx.doi.org/10.1002/gepi.21967. Wigle, D.T., 2003. Child Health and the Environment. Oxford University Press, New York. World Health Organization (WHO), 2006. Preventing Disease through Healthy Environments. WHO, Geneva, Switzerland. World Health Organization (WHO), 2014. WHO Indoor Air Quality Guidelines: Household Fuel Combustion. WHO, Geneva, Switzerland.

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Relevant Websites http://www.cdc.gov – Centers for Disease Control and Prevention (CDC) (last accessed 15.06.16.). http://www.cehn.org – Children’s Environmental Health Network (last accessed 15.06.16.). http://www.iarc.fr – International Agency for Research on Cancer (IARC) (last accessed 15.06.16.).

http://www.niehs.nih.gov/ – National Institutes of Environmental Health Sciences (last accessed 15.06.16.). http://www.ntp.niehs.nih.gov/ – National Toxicology Program (last accessed 15.06.16.). http://www.epa.gov – U.S. Environmental Protection Agency (EPA) (last accessed 15.06.16.). http://www.who.int – World Health Organization (WHO) (last accessed 15.06.16.).

Environmental Justice and Health Carolyn Stephens, UCL Institute of Health Equity, Universidad Nacional de Tucumán, Tucumán, Argentina; and London School of Hygiene & Tropical Medicine, London, UK Chris Church, Community Environment Associates, London, UK Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Carolyn Stephens, Ruth Willis, Chris Church, volume 2, pp. 373–382, Ó 2008, Elsevier Inc.

What Is Environmental Justice and How Does It Relate to Health? It is now commonly understood that much of the worldwide burden of environmental ill-health falls disproportionately on poorer peoples (United Nations Environment Programme, 2002; UNICEF, 2005; World Health Organisation (CSDOH), 2007; World Health Organization, 2012). There is also substantial evidence that much environmental damage internationally is the result of the actions of richer nations or richer groups within nations – with impacts on poorer nations and poorer groups within nations (World Resources Institute, 2002; World Health Organization, 2012). Environmental justice is a concept that links environmental health to rights debates around access to a healthy environment. It fundamentally deals with the distribution of environmental goods and harms – and looks at who bears those harms and who is responsible for creating these harms, in both a practical sense and also in terms of policy decisions. It is a radical environmental health movement that has evolved from civil society groups, angered at what they perceive as the ‘unjust’ distribution of environmental resources for health and, conversely, the ‘unjust’ distribution of environmental harms. The movement now includes a collaboration of nongovernmental organizations with environmental scientists, public health professionals, and lawyers, all working on the issue of the distributions of environmental harms and the rights of everyone to a healthy environment. This article describes the concept of environmental justice; it discusses examples of environmental justice internationally and concludes with a brief discussion on current policy frameworks.

Origins of Environmental Justice – Born in the USA Environmental justice originated in protests in the 1980s by community groups in the USA against the repeated siting of polluting factories and waste sites in predominantly black neighborhoods and indigenous peoples’ reservations. Civil rights protestors highlighted the disproportionate burden of negative environmental impacts these caused for the most vulnerable sectors of society. In 1994 the issue reached the White House when President Clinton issued Executive Order 12898: Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations. This order reinforced the Civil Rights Act of 1964 by requiring federal regulatory agencies to ‘make environmental justice a part of all they do’ (United States Environmental Protection Agency, 2003). During the 1990s the environmental justice movement developed in the United Kingdom and Europe. There, the focus became less centered around racial minorities and more

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specifically linked to social inequality, specifically the disparities between environmental conditions experienced by the richest and poorest sectors of society. In Latin America, Africa, and Asia, individuals, community groups, NGOs, and academics are also actively involved in tackling environmental health problems that would be described in Europe or the USA as environmental justice issues.

Defining Environmental Justice Environmental justice is generally defined as a set of rights – that should be aspired to, sought after, or demanded, in terms of both substantive conditions for environmental health, and of procedural rights – principally including access to information and decision-making. Two definitions provide examples. The US Environmental Protection Agency defines environmental justice as: . the fair treatment and meaningful involvement of all people regardless of race, color, national origin, or income with respect to the development, implementation, and enforcement of environmental laws, regulations, and policies. Fair treatment means that no group of people, including a racial, ethnic, or a socioeconomic group, should bear a disproportionate share of the negative environmental consequences resulting from industrial, municipal, and commercial operations or the execution of federal, state, local, and tribal programs and policies. Meaningful involvement means that: (1) potentially affected community residents have an appropriate opportunity to participate in decisions about a proposed activity that will affect their environment and/or health; (2) the public’s contribution can influence the regulatory agency’s decision; (3) the concerns of all participants involved will be considered in the decision making process; and (4) the decision makers seek out and facilitate the involvement of those potentially affected. US Environmental Protection Agency (USEPA) (1998).

In 2005 the Scottish Executive joined the movement (2005) and defined environmental justice in similar terms: The first is that deprived communities, which may be more vulnerable to the pressures of poor environmental conditions, should not bear a disproportionate burden of negative environmental impacts. The second is that all communities should have access to the information and to the means to participate in decisions which affect the quality of their local environment. Scottish Executive Social Research (2005).

Friends of the Earth Scotland, the UK NGO, that led the way on EJ in the UK summarized it simply as “No less than a decent environment for all: no more than a fair share of the Earth’s resources” (Friends of the Earth Scotland, 2003, p. 22), which highlighted the need for justice both locally and globally.

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Environmental justice has also been conceived in terms of rights and responsibilities. For example, Stephens et al. identified two key assertions of environmental justice as:

A number of different elements or interrelated component parts of environmental justice can be identified from the range of definitions that exist. l

that everyone should have the right and be able to live in a healthy environment, with access to enough environmental resources for a healthy life. that responsibilities are on this current generation to ensure a healthy environment exists for future generations, and on countries, organisations and individuals in this generation to ensure that development does not create environmental problems or distribute environmental resources in ways which damage other peoples health. Stephens et al. (2001).

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Environmental Justice and Health Inequality Environmental inequality is a key part of environmental justice. In effect it is a step back or precondition for injustice to occur. Inequality is a descriptive term. Conceptually, to observe or claim an environmental inequality is to point out that an aspect of the environment is distributed unevenly among different social groups (differentiated by social class, age, ethnicity, etc.). There can be different degrees of inequality depending upon how skewed the environmental parameter is toward or away from the social groups of concern. In addition, this can encompass: negative aspects of the environment such as exposure to pollution; l positive aspects such as access to green space; and l procedural aspects such as access to information or decision-making processes. l

However, the crucial point is that an inequality is different to an injustice or inequity. It does not necessarily follow that because a distribution of an environmental good or bad is unequal, it is also unjust or inequitable. An evaluation or judgment has to be made to progress from inequality to injustice and, as theories of justice make clear, substantially different perspectives can be taken. Factors that may be relevant in considering the case for an environmental injustice include: the degree of inequality that exists; the degree to which individuals have been able to exercise choice in their exposure to an environmental good or bad; l whether or not an inequality has been created through the exercising of power by a public or private body (e.g., in taking facility siting decisions); l whether or not a pattern of inequality is combined with other patterns of inequality (an accumulation of unequal impacts), or with a higher degree of vulnerability or need among a social group, when compared to others; and l the degree to which those exposed to an impact or risk also have a role (direct or indirect) in, or benefit from, its creation. l l

Broadening the Concept Since its development in the USA, the conceptual boundaries of environmental justice have extended beyond local-level issues.

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Distributive justice is concerned with how environmental ‘goods’ (e.g., access to green space) and environmental ‘bads’ (e.g., pollution and risk) are distributed among different groups and the fairness or equity of this distribution. Procedural justice is concerned with the fairness or equity of access to environmental decision-making processes and to rights and recourse in environmental law. Policy justice is concerned with the principles and outcomes of environmental policy decisions and how these have impacts on different social groups. Intranational justice is concerned with how these distributions and processes are experienced and operate within a country. International justice extends the breadth of concerns to include international and global issues such as climate change. Intergenerational justice encompasses issues of fairness and responsibility between generations, such as emerge in debates over the protection of biodiversity.

While some people may recognize all of these components within their working definition or framing of environmental justice, others take a more restricted or focused view. There are also differences in the extent to which environmental justice is seen as only encompassing core environmental issues or extending – within a broader sustainability perspective – to include quality of life and social issues that have environmental dimensions to them.

Environmental Justice and Health Health is a key component of environmental justice and is a key reason why the environmental justice movement developed. This section outlines some of the evidence of ways in which environmental justice and health are linked.

Negative Environmental Impacts

Negative environmental impacts are not randomly distributed. Generally, poorer people live in worse environments (World Health Organization, 2012). Environmental epidemiology provides evidence of direct causal relationships between exposure to environmental pollutants and negative health outcomes. Industrial or domestic processes on a local or international scale may produce pollutants, with health outcomes ranging from mild skin irritation to death. This exposure– outcome relationship is affected by many socioeconomic factors that are treated as possible confounding factors in epidemiological analysis. Within a population group some individuals or groups are more likely to be exposed than others due to the location and conditions they live and work in. There will be varying levels of awareness about the possible negative effects of exposure, and varying capacity to prevent it. People with existing illness or previous exposure may be more vulnerable. Some people will have good access to diagnosis and treatment facilities, others will have none. These inequalities, a complication for environmental exposure–health

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Box 1 The International Human Rights Framework and its application We now recognise that respect for human rights is at the core of sustainable development, and the links today between human development, human rights, and human security could not be clearer. Equally important, human rights are our shared international language and framework, and human rights instruments give our multi-lateral system its means of putting into practice our shared values. Can there be any problem today that requires this approach more than climate change? Article 1 of the Universal Declaration of human rights states our birthright: “All human beings are born free and equal in dignity and rights”. However it is here that an issue of justice is raised, as I will explain further: it is poor communities who are suffering most from the effects of climate change, and it is rich countries that are contributing most to the problem. The human rights approach, emphasising the equality of all people, is a direct challenge to the power imbalance that allow the perpetrators of climate change to continue unchecked. And the human rights framework gives us the legal and normative grounds for empowering the poor to seek redress. Robinson, M., December 11, 2006. Climate Change and Justice (Paragraph 7). Barbara Ward Lecture, Chatham House, London.

outcome analysis, contribute to unequal distribution of risk. An environmental justice perspective also considers who is responsible for creating environmental hazards, who benefits from the process which creates them, and who is most at risk. Even in wealthy regions such as Europe, routine environmental exposures affecting child health such as transportrelated pollution and housing occur without citizens being able to access environmental policy for justice. Further, despite advanced worker protection fought for over the last hundred years, conditions are deteriorating for low-income workers and increasing numbers are excluded from the workforce. In addition, internationally, past environmental crises such as Chernobyl and Bhopal have all occurred despite well-developed constitutional, environmental, and human rights legislative frameworks at national and international levels dating back in some cases to the middle of the twentieth century (Box 1).

Access to Environmental Resources: A Healthy Environment

Another key aspect of environmental justice is the right of all people to environmental resources for healthy living. People need access to a range of environmental and social resources to be healthy: physical needs: shelter, heat, food, clean air, and water; economic needs: transport infrastructure, work, shops; and l aesthetic, mental, and spiritual needs: green space, quiet, access to countryside. l l

Access to these resources is highly skewed, both internationally and within countries. Poorer groups are less likely to have reliable access to safe drinking water, healthy sources of food, and transport infrastructure necessary for education and employment – even within wealthy nations and regions. In addition, richer countries access important environmental resources of poorer nations while peoples in those nations do not benefit and are sometimes harmed. For example, the United Kingdom consumes large quantities of raw environmental resources – metals, wood, oil, and minerals – which are mostly imported. Oil is an important example – communities in oil-producing

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countries are increasingly complaining about environmental damage caused by resource exploitation, and there is considerable concern about the distribution of development benefits associated with this resource (San Sebastian and Hurtig, 2005). Another aspect of this debate is the global inequality in consumption of the world’s resources. For example, a report for the World Economic Forum highlighted that the United Kingdom’s ‘ecological footprint’ – the total amount of land a country is appropriating in order to support its economy, is equivalent to an area over 10 times the size of the United Kingdom, the 8th worst out of 122 countries surveyed. The United Kingdom has a net deficit of 4.5 ha per person (World Economic Forum, 2001).

Intergenerational Justice

Even if everyone today lived in a healthy environment, environmental justice would not be done if this were achieved at the expense of people in future generations. There are at least four types of actions contributing to injustices across generations including: activities that impose costs on future generations without any balancing of benefits: nuclear waste will have to be managed for thousands of years; toxic waste that impacts on health of future generations; l reduction in the ability of the environment to provide nonsubstitutable resources and services (what environmental economists call ‘critical natural capital’); l creation of ongoing negative environmental impacts: for example, climate change is predicted to become more severe in its disruptive effects over the coming centuries; and l use of technologies with unknown and unexplored potential long-term effects – for example, there is limited scientific understanding of the long-term health and environmental impacts of the vast range of chemicals we use daily. l

There is a significant tension within environmental justice – how do we reconcile these different aspects of environmental justice? There is no easy answer and the second thread of environmental justice theory – dealing with procedural justice, does not make the case any less complex.

Substantive and Procedural Environmental Justice

Substantive injustices are caused in part, by procedural injustices. Access to information can be a major barrier for individuals or communities tackling environmental justice issues. People seek information from scientists, industry, regulators, legal advisors – all of which may be complicated or expensive to acquire and difficult for nonexperts to interpret. For example, waste disposal policies are not designed to hurt poorer communities, but can through the decision-making process if wealthier groups can access decisions more easily and avoid perceived harm. This aspect of environmental justice is known as procedural justice. A recent debate within the United Kingdom is on location of fracking (Hill, 2014; Jaspal and Nerlich, 2014). Poorer communities and ethnic communities face worse social, economic, and environmental conditions, but this can be linked to their inability to access decision-making processes. There are gender differences in environmental exposures and

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impacts: for example, poor housing conditions affect women – particularly single mothers and their children. Children overall and elderly people are often more greatly affected by environmental policies than adults of working age. Within the working population, there are great differences in environmental exposures, with lower-income workers employed in occupations with higher exposure to hazards, on lower incomes, and in greater insecurity of employment. A substantial and fast developing part of work that defines itself as part of environmental justice is about ensuing access to legal systems. There are a growing number of national NGOs for whom environmental law is their main focus as well as international networks such as Justice and Environment and EarthJustice.

Environmental Justice – Some Current Examples Local Injustice At a local level – the original focus of the environmental justice movement – examples of environmental injustice are most frequently linked to industry and decisions made by local and national government. Siting and regulation of manufacturing industries, waste disposal sites, energy extraction, and production facilities can cause or contribute to environmental injustice with negative effects on local people’s health. These situations can arise quickly or over decades. A study in 2010 of longterm (from 1983 to 2010) siting of waste sites in Europe and the USA found consistent indications that waste facilities are often disproportionally more located in areas with more deprived residents, or from ethnical minorities. This applies to waste incinerators, landfills, and hazardous waste sites, legal and illegal (Martuzzi et al., 2010).

International and Intergenerational Environmental Justice – What Rich Countries Do to Poorer Ones and What We All Do to Future Generations? Perhaps the biggest environmental justice issue to emerge in the early twenty-first century is linked to our global development process and the sharp injustices of unequal consumption patterns and unequal impacts of the environmental burden of such patterns on both poorer peoples in poorer nations and on future generations. Climate change impacts have emerged as a key environmental justice issue for almost every international and national policy body. The situation is ever more urgent. In 2013 at the UN climate change negotiations in Warsaw, the meeting saw an unprecedented hunger strike by the Philippines’ representative Minister, following the massive environmental and social disaster caused in that country by extreme weather events in 2013. This was combined with a mass walkout by all the civil society and nongovernmental organizations (CSOs and NGOs) present. Speaking for the CSOs and NGOs, Friends of the Earth stated, “this Warsaw summit is achieving nothing to help protect vulnerable and poor communities or to reduce global carbon pollution – we must all do more in the months ahead to make the world wake up to the need for urgent action” (Friends of the Earth, 2013). Christiana Figueres, Executive Secretary of the UN Framework Convention on Climate

Change (UNFCCC), said, “We have seen essential progress. But let us again be clear that we are witnessing ever more frequent, extreme weather events, and the poor and vulnerable are already paying the price” (United Nations, 2013). Figure 1 shows graphically how our world looks when the proportional size of pollution impacts are scaled to a map of the world. Climatologists also anticipate that global climate change will increase overall climate variability. Evidence already suggests that we are experiencing increasingly severe weather events including more powerful storms and stronger winds, intensification of the El Niño cycle, and altered patterns of drought and rainfall. There is great stability in the climate system, and once it begins to change it will continue to change. Thus, even if the buildup in greenhouse gases is arrested in the next 20–30 years, it is highly likely that the seas would continue to expand as the extra heat permeates the oceans, rising by up to several meters over the coming centuries (IPCC, 2013). As UNEP points out “from space the Earth looks blue” (UNEP, 2014). More than 50% of the world’s population, and 75% of all major cities, are within 60 km of the sea. A rise in sea level will have widespread and catastrophic social, environmental, and health impacts. The latest estimates suggest that even the IPPC scientists have underestimated the potential sealevel rises we will experience (Horton et al., 2014). The regions most vulnerable to sea-level rise include some of the world’s poorest countries and regions: Bangladesh, Egypt, and eastern India with huge river delta farming populations; and Pakistan, Indonesia, and Thailand, with large coastal populations. Various low-lying small-island populations in the Pacific and Indian oceans, with few material resources, face the prospect of wholesale displacement. Some of the world’s coastal arable land and fish-nurturing mangroves will be damaged by sea-level rise. This and human damage to mangroves, coral reefs, and other coastal ecosystems will also lead to erosion and siltation and render coastlines more vulnerable to storms and natural disasters (UNEP, 2014).

Procedural Environmental Justice – Who Gets Access to Decision-Making and Who Is Blocked from It? A survey of access to information, participation, and justice in environmental decision-making was carried out in nine countries – Chile, Hungary, India, Indonesia, Mexico, South Africa, Thailand, Uganda, and the United States – in 2001–02 (Petkova et al., 2002). Researchers found that: access to justice is hampered by unclear laws; access to justice is constrained by limited mechanism for redress; and l high costs are an effective barrier to access to justice. l l

Even in countries where democracy is argued to have existed for centuries, many of the most disadvantaged groups feel a sense of alienation from their rights to information or decision-making. For example, local campaigner Joan Higginson describes her communities’ experiences in Scotland (Friends of the Earth Scotland, 2003): “There is very little redress as the system and structures that are in place do very little to support them. For instance there is an imbalance within

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Figure 1 Where carbon dioxide emissions are produced.. Territory size shows the proportion of carbon dioxide emissions worldwide emitted in 2002. Copyright 2006 SASI Group (University of Sheffield) and Mark Newman (University of Michigan). www.worldmapper.org.

the planning system that significantly favours the developer above the community. The developer has the right of appeal whilst the local community does not. Therefore the aggrieved party has no way to address the issue unless they can afford the exorbitant and unpredictable fees for a judicial review.”

Toward Environmental Justice – Emerging Policy Approaches The United States was the first country to recognize environmental justice as a term in national legislation. There are many other approaches to environmental justice at a national policy level, but few use the phrase directly. A sizable number of nations (such as newer post-Soviet ones) include a right to a safe and healthy environment within their constitutions, and it is these nations that have tended to support the principles of the most promising piece of environmental justice policy to emerge within the last few years.

The Aarhus Convention – The European Approach The Aarhus Convention on Access to Information, Public Participation in Decision-making and Access to Justice in Environmental Matters is the first international agreement that takes forward some but not all aspects of work on environmental justice. Figure 2 shows the substantive and procedural aspects of the agreement. As its title suggests, the convention contains three broad themes or ‘pillars’: access to information, public participation, and access to justice. It applies to all countries within the European Union. The United Nations Economic Commission for Europe (UNECE) describes the convention in the following terms: “The

Convention adopts a rights-based approach. Article 1, setting out the objective of the Convention, requires Parties to guarantee rights of access to information, public participation in decisionmaking and access to justice in environmental matters. It also refers to the goal of protecting the right of every person of present and future generations to live in an environment adequate to health and well-being, which represents a significant step forward in international law. These rights underlie the various procedural requirements in the Convention” (United Nations Economic Commission for Europe, 1999). The convention entered into force on the 30 October 2001 and was hailed as a milestone of environmental democracy. A secretariat body based at the UNECE office in Geneva is responsible for the implementation of the convention. The ‘Aarhus Convention Compliance Committee’ is now able to receive submissions from NGOs and the public who have challenged decision-making and nonavailability of information in their own nations (where these have ratified the convention) and been unsuccessful (United Nations Economic Commission for Europe (ENECE), 2007b). These are then considered and where appropriate discussed at the annual meeting of nations which are ‘parties to the convention.’ Some of the first appeals came through ‘Green Salvation,’ an NGO (in Almaty, Kazakhstan). One concerned the failure of the national atomic energy company, Kazatomprom, to disclose information regarding its project for the importation and burial of low-level radioactive waste from foreign countries on the territory of Kazakhstan. The second appeal concerns the illegal construction of a high-voltage (110 kV) power line through the residential district of Gornyi Gigant within Almaty. These and other cases provided the first tests of the Convention’s compliance mechanism which found in 2005 that three countries – Turkmenistan, Ukraine, and Kazakhstan – had

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The Aarhus Convention.

failed to comply with certain provisions of the Convention. Moves toward compliance continue, and the ‘Aarhus Clearing House’ set up by UNECE monitors activity and promotes good practice (United Nations Economic Commission for Europe (ENECE), 2007a). The Aarhus Convention is a new type of legislation – built on principles of environmental democracy. This makes it an interesting policy, but also a highly controversial one. UNECE describes the convention in aspirational terms: “The Aarhus Convention is a new kind of environmental agreement. It links environmental rights and human rights. It acknowledges that we owe an obligation to future generations. It establishes that sustainable development can be achieved only through the involvement of all stakeholders. It links government accountability and environmental protection. It focuses on interactions between the public and public authorities in a democratic context and it is forging a new process for public participation in the negotiation and implementation of international agreements” (United Nations Economic Commission for Europe (ENECE), 2007a). By 2015, the Aarhus Convention had become more international and is being used to fight climate change and put pressure on governments to comply with their agreed targets (see Relevant Websites). As of January 2015, there were 47 Parties to the Convention, 33 Parties to the Protocol on Pollutant Release and Transfer Registers (PRTRs), and 28 Parties to the amendment on public participation in decisions on the deliberate release into the environment and placing on the market of genetically modified organisms (GMOs).

Linking Environmental Justice and Sustainable Development There is a growing concern to create stronger links of the environmental justice movement with the global sustainable development community. Every country who signed the

1992 UN Rio Declaration committed to develop a strategy toward sustainable development and most have done so with varying degrees of commitment. The 2012 UN World Summit on Sustainable Development in Rio saw calls from NGOs for a global right to a safe and healthy environment to be a central part of work on sustainable development but this, once again, failed to get agreement from governments. There are promising moves by many governments, but we are yet to see environmental justice as an explicit policy goal within sustainable development strategies at international level. The most promising work continues to take place at local level.

Conclusions Environmental justice is still low on international and national policy agendas. This may be due to a lack of capacity among those worst affected to engage on policy issues, but it is also linked to the overall global economic crisis – which emerged in 2009 in richer countries of Europe and the USA and still dominates government policies internationally. Building capacity to engage is likely to be central to any long-term change in this area, and this is likely to help develop increasing links between those working on environmental issues and those engaged with social justice. Environmental justice may also become an increasingly important issue as the impacts of global climate change are felt. Many likely ‘climate refugees’ are coming from poorer nations such as Bangladesh that have low carbon emissions themselves yet suffer disproportionately from the policies and practice of richer nations. Even within such poorer nations there are likely to be environmental injustices since poorer communities are often on more marginal land and may be more vulnerable to flooding and droughts. At the same time, there is an emerging tool kit for governments, individuals, and communities to use to implement

Environmental Justice and Health environmental justice. New assessment techniques, policies, and laws now allow the more transparent establishment of rights and responsibilities, and this in turn brings new legal, reputational, and financial risks for those acting in an irresponsible way. Environmental justice is not a panacea for all social injustices or all health inequalities. But overall, environmental justice offers a fresh perspective. Environmental justice’s two basic premises are first, that everyone should have the right and be able to live in a healthy environment, with access to enough environmental resources for a healthy life, and second, that it is predominantly the poorest and least powerful people who are missing these conditions. Taking these two premises together suggests that a priority is to ensure that the adverse conditions faced by the least powerful people are tackled first. In addition to implying environmental rights, it implies environmental responsibilities. These responsibilities are on this current generation to ensure a healthy environment exists for future generations and on countries, organizations, and individuals in this generation to ensure that development does not create environmental problems or distribute environmental resources in ways which damage other people’s health. This is a view that reframes environmental issues as a critical and core element of achieving social justice goals, rather than as a set of priorities that conflict with social goals. If social justice can be thought of ensuring that all people have at least a basic set of minimum conditions to achieve a healthy life, then having a healthy, safe environment and access to enough environmental resources for all people is a central part of this social justice goal. We are yet to grasp fully the impacts of our current development trajectory on either our local environment or our global one. Environmental justice asks us to think about rights and responsibilities toward our environment and our health. It asks us to think about others and about future generations. It is not a simple environmental health policy – it is a complex approach for our complex twenty-first century environmental health challenges. Environmental justice offers a new frame for public health professionals interested in the traditional public field of social equity, but also is a new lens on public health within the context of global environmental change.

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Further Reading Broughton, E., 2005. The Bhopal disaster and its aftermath: a review. Environ. Health 4 (1), 6. Faber, D.R., Krieg, E.J., 2002. Unequal exposure to ecological hazards: environmental injustices in the Commonwealth of Massachusetts. Environ. Health Perspect. 110 (Suppl. 2), 277–288.

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Liu, F., 2001. Environmental Justice Analysis: Theories, Methods and Practice. Lewis Publishers, Boca Raton, Florida. Navarro, V., 1999. Health and equity in the world in the era of “Globalization”. Int. J. Health Serv. 29 (2), 215–226. O’Neill, M.S., Jerrett, M., et al., 2003. Health, wealth, and air pollution: advancing theory and methods. Environ. Health Perspect. 111 (16), 1861–1870. http://www. ehponline.org/members/2003/6334/6334.pdf. Powell, D.L., Stewart, V., 2001. Children. The unwitting target of environmental injustices. Pediatr. Clin. North Am. 48 (5), 1291–1305. Rajeev Gowda, M.V., Easterling, D., 2000. Voluntary siting and equity: the MRS facility experience in Native America. Risk Anal. 20 (6), 917–929. Stephens, C., Bullock, S., 2000. Environmental justice: an issue for the health for the children of Europe and the world. In: Tamburlini, G. (Ed.), The Environment and Children’s Health in Europe. World Health Organisation, Rome. United Church of Christ, Commission for Racial Justice, 1987. Toxic wastes and race in the United States: A National Report on the Racial and Socioeconomic Characteristics of Communities with Hazardous Waste Sites. New York. Wilson, S.M., Howell, F., et al., 2002. Environmental injustice and the Mississippi hog industry. Environ. Health Perspect. 110 (Suppl. 2), 195–201. Wing, S., Cole, D., et al., 2000. Environmental injustice in North Carolina’s hog industry. Environ. Health Perspect. 108 (3), 225–231. Young, H.P., 1994. Equity in Theory and Practice. Princeton University Press, Princeton, NJ.

Relevant Websites http://www.unece.org/environmental-policy/conventions/public-participation/aarhusconvention/news/envppaarhusaarhusweek.html – Aarhus Convention (last accessed on 28.06.16.). Non-Governmental Organisations campaigning for Environmental Justice: Many organisations ranging from small community groups to international charities campaign about EJ issues and health. Examples include: www.ejustice.lk – Centre for Environmental Justice, Sri Lanka (last accessed on 28.06.16.). www.foei.org – Friends of the Earth (last accessed on 28.06.16.). www.greenpeace.org/international – Greenpeace (last accessed on 28.06.16.). www.weact.org – West Harlem Environmental Action (last accessed on 28.06.16.). Film Resource: www.element-tv.net/news/2007/03/episode-2/ – Short film ‘Ilfie and Tina’ about oil and gas extraction in the Niger Delta produced by the Element Partnership (last accessed on 28.06.16.). UK/US Resources: http://www.geography.lancs.ac.uk/envjustice/envjusticelinkslancs.htm – Environmental Justice Lancaster University (last accessed on 28.06.16.). www.ejrc.cau.edu – Environmental Justice Resource Centre at Clark Atlanta University (last accessed on 28.06.16.).

Environmental Protection Laws Nicholas A Ashford and Charles C Caldart, Massachusetts Institute of Technology, Cambridge, MA, USA Ó 2017 Elsevier Inc. All rights reserved.

Introduction The manufacturing, processing, and use of chemicals, materials, tools, machinery, and equipment in industrial, construction, mining, and agricultural workplaces often cause environmental, health, and safety hazards and risks. Occupational and environmental factors cause or exacerbate major diseases of the respiratory, cardiovascular, reproductive, and nervous systems and cause systemic poisoning and some cancers and birth defects. Occupational and environmental disease and injury place heavy economic and social burdens on workers, employers, community residents, and taxpayers. Because voluntary efforts in the unregulated market have not proven sufficiently successful in reducing the incidence of these diseases and injuries, the public has demanded government intervention into the activities of the private sector. This intervention takes the form of legislation aimed at reducing or eliminating environmental health and safety hazards through standard setting, information disclosure requirements, and/or other governmental directives. This article addresses the major regulatory systems (or regimes) designed to protect public and worker health from chemicals discharged from sources that pollute the air, water, ground, and/or workplace. The establishment of standards and other legal requirements in these regulatory regimes has occurred over a more than 40-year period that has seen changes in the use of scientific and technical information in regulatory initiatives and in legal doctrine, including the manner in which science, economics, and technological capability are viewed by the courts. The concepts of risk assessment, cost–benefit analysis, and technology forcing have evolved, both through the development of case law and through changes in the political environment. Often, change in one of the regulatory regimes has affected the other regulatory regimes as well. Finally, the focus and stringency of all of these regulatory regimes have been influenced by the participation of environmental groups, labor unions, and the affected industries themselves; public input into the setting (and, in many cases, the enforcement) of regulatory standards is specifically encouraged by all of these statutes. Standards can be classified in a number of ways. A performance standard is one that specifies a particular outcome – such as a specified emission level above which it is illegal to emit a specified air pollutant – but does not specify how that outcome is to be achieved. A design or specification standard, on the other hand, specifies a particular technology – such as a catalytic converter – that must be used. In either case, the standard can be based on (1) a desired level of protection for human health or environmental quality, (2) some level of presumed technological feasibility, (3) some level of presumed economic feasibility, or (4) some balancing of social costs and social benefits. Within each of these options, there is a wide spectrum of possible approaches. A human health-based standard, for example, might choose to protect only the average member of the population, or it might choose to protect the most sensitive individual. A technology-based standard might

International Encyclopedia of Public Health, 2nd edition, Volume 2

be based on what is deemed feasible for an entire industry, or on what is deemed feasible for each firm within the industry. Moreover, some standards might be based on a combination of these factors. Many standards based on technological feasibility, for example, are also based on some concept of economic feasibility. Other regulatory controls include (1) information-based obligations, such as the disclosure of (and retention of, or provision of access to) exposure, toxicity, chemical content, and production data and (2) requirements to conduct testing or screening of chemical products. In the United States, toxic substances in the industrial workplace have been regulated primarily through the Occupational Safety and Health Act (OSHAct) of 1970 and the Toxic Substances Control Act (TSCA) of 1976. These federal laws have remained essentially unchanged since their passage, although serious attempts at reform have been made from time to time. The evolution of regulatory law under the OSHAct has profoundly influenced other environmental legislation, including the regulation of air, water, and waste, but especially the evolution of TSCA. Since 1990, sudden and accidental releases of chemicals (chemical accidents), which may affect both workers and community residents, have been regulated under both the Clean Air Act and the OSHAct. The OSHAct established the Occupational Safety and Health Administration (OSHA) in the Department of Labor to implement and enforce compliance with the act, the National Institute for Occupational Safety and Health (NIOSH) in the Department of Health and Human Services (under the Centers for Disease Control and Prevention) to perform research and conduct health hazard evaluations, and the independent, quasi-judicial Occupational Safety and Health Review Commission to hear employer contests of OSHA citations. The Office of Pollution Prevention and Toxic Substances in the Environmental Protection Agency (EPA) administers TSCA. EPA’s Office of Air, Water, and Solid Waste, regulates media-based pollution generally, while the agency’s Office of Chemical Preparedness and Emergency Response is responsible for the chemical safety provisions of the Clean Air Act. Increasingly, the health and environmental hazards associated with energy-related activities such as the emission of greenhouse gases (GHGs) and the extraction of oil and gas through hydraulic fracturing (fracking) are receiving regulatory attention.

Standard Setting and Obligations of the Employer and the Manufacturer or User of Toxic Substances The Occupational Safety and Health Act of 1970 The OSHAct requires OSHA to (1) encourage employers and employees to reduce hazards in the workplace and to implement new or improved safety and health programs, (2) develop mandatory job safety and health standards and enforce them effectively, (3) establish “separate but dependent responsibilities

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and rights” for employers and employees for the achievement of better safety and health conditions, (4) establish reporting and record-keeping procedures to monitor job-related injuries and illnesses, and (5) encourage states to assume the fullest responsibility for establishing and administering their own occupational safety and health programs, which must be at least as effective as the federal program. OSHA can begin standard-setting procedures either on its own or on petitions from other parties, including the Secretary of Health and Human Services, NIOSH, state and local governments, any nationally recognized standards-producing organization, employer or labor representatives, or any other interested person. The standard-setting process involves input from advisory committees and from NIOSH. When OSHA develops plans to propose, amend, or delete a standard, it publishes these intentions in the Federal Register. Subsequently, interested parties have opportunities to present arguments and pertinent evidence in writing or at public hearings. Under certain conditions, OSHA is authorized to set emergency temporary standards, which take effect immediately, but which are to be followed by the establishment of permanent standards within 6 months. To set an emergency temporary standard, OSHA must first determine that workers are in grave danger from exposure to toxic substances or new hazards and are not adequately protected by existing standards. Both emergency temporary and permanent standards can be appealed through the federal courts, but filing an appeals petition does not delay the enforcement of the standard unless a court of appeals specifically orders it. Employers may make application to OSHA for a temporary variance from a standard or regulation if they lack the means to comply readily with it, or for a permanent variance if they can prove that their facilities or methods of operation provide employee protection that is at least as effective as that required by OSHA.

Key OSHA Standards The OSHAct provides two general means of protection for workers: (1) a general statutory duty to provide a safe and healthful workplace and (2) promulgation of specific standards to which specified categories of employers must adhere. The act imposes on virtually every employer in the private sector a general duty “to furnish to each of his employees employment and a place of employment which are free from recognized hazards that are causing or are likely to cause death or serious physical harm .” A recognized hazard may be a substance for which the likelihood of harm has been the subject of research, giving rise to reasonable suspicion, or a substance for which an OSHA standard may or may not have been promulgated. The burden of proving that a particular substance is a recognized hazard and that industrial exposure to it results in a significant degree of exposure is placed on OSHA. Because standard setting is a slow process, protection of workers through the employer’s general duty obligation could be especially important, but it is crucially dependent on the existence of reliable health effects data, as well as on the willingness of a particular OSHA to use this as a vehicle for protection. The OSHAct specifically addresses the subject of toxic materials. It states, in Section 6(b)(5) of the act, that the Secretary of

Labor (through OSHA), in promulgating standards dealing with toxic materials or harmful physical agents, shall set the standard that “most adequately assures, to the extent feasible, on the basis of the best available evidence that no employee will suffer material impairment of health or functional capacity, even if such employee has a regular exposure to the hazard dealt with by such standard for the period of his working life.” These words indicate that the issue of exposure to toxic chemicals or carcinogens that have long latency periods, as well as to reproductive hazards, is covered by the act in specific terms. In 1971, under Section 6(a) of the act, which allowed for their adoption without critical review, OSHA initially adopted as standards the so-called permissible exposure limits (PELs): 450 threshold limit values (TLVs) recommended by the American Conference of Governmental Industrial Hygienists (ACGIH) as guidelines for protection against the toxic effects of these materials. Thereafter, in the 1970s, OSHA proceeded to set updated standards for asbestos, vinyl chloride, arsenic, dibromochloropropane, coke oven emissions, acrylonitrile, lead, cotton dust, and a group of 14 carcinogens under Section 6(b). In the 1980s, OSHA set Section 6(b) standards for benzene, ethylene oxide, and formaldehyde as carcinogens and regulated asbestos more rigidly as a carcinogen at 0.2 fibers cm 3. In the early 1990s, OSHA regulated cadmium, bloodborne pathogens, glycol ethers, and confined spaces. OSHA also lowered the PEL for formaldehyde from 1 to 0.75 parts per million (ppm; averaged over an 8-h period) and issued a process safety management (PSM) rule (see the discussion in the section The Chemical Safety Provisions of the Clean Air Act: Obligations Imposed by EPA and OSHA to Prevent the Sudden and Accidental Releases of Chemicals). In 2013, after decades of delay, OSHA proposed a new PEL of 50 mg m 3 (averaged over an 8-h period) for silica dust, which would replace the 1971 PEL and provide further protection against silicosis, lung cancer, other respiratory diseases, and kidney disease. The burden of proving the hazardous nature of a substance is placed on OSHA, as is the burden of proving that the proposed controls are technologically feasible. The necessarily slow and arduous task of setting standards, substance by substance, makes it impossible for OSHA to deal realistically with 13 000 toxic substances or approximately 250 suspect carcinogens on NIOSH lists. Efforts were made to streamline the process by (1) proposing generic standards for carcinogens and (2) proposing a generic standard updating the TLVs (PELs). Neither of these efforts was successful. The inadequacy of the 450 TLVs adopted under Section 6(a) of the act is widely known. The TLVs originated as guidelines recommended by the ACGIH in 1969 to protect the average worker from either recognized acute effects or easily recognized chronic effects. The standards were based on animal toxicity data or the limited epidemiologic evidence available at the time. They do not address sensitive populations within the workforce or those with prior exposure or existing disease; nor do they address carcinogenicity, mutagenicity, or teratogenicity. An example of the inadequacy of protection offered by the TLVs is the 1971 TLV for vinyl chloride, which was set at 250 ppm, whereas the latter, more protective standard

Environmental Protection Laws (see below) recommended no greater exposure than 1 ppm (averaged over 8 h), a level still recognized as unsafe, but the limit that the technology could detect. Another example is the TLV for lead, which was established at 200 mg m 3, whereas the latter lead standard was established at 50 mg m 3, also recognizing that that level was not safe for all populations, such as pregnant women or those with prior lead exposure. In 1997, OSHA promulgated a new PEL for methylene chloride of 25 ppm, replacing the prior TLV of 500 ppm. The ACGIH updates its TLV list every 2 years. Although useful, an updated list would have unclear legal significance unless formally adopted by OSHA. OSHA did try, unsuccessfully, to adopt an updated and new list of PELs in its Air Contaminants Standard in 1989 (see later discussion). However, OSHA continues to maintain that it is intent on revising the list. The fact that the official OSHA TLVs are more than 40 years out of date compared with industry’s own voluntary consensus standards is not welcomed, especially by the more modern firms in industry. Under Section 6(b) of the OSHAct, new health standards dealing with toxic substances were to be established using the mechanism of an open hearing and subject to review by the U.S. Circuit Courts of Appeals. The evolution of case law associated with the handful of standards that OSHA promulgated through this section of the OSHAct is worth considering in detail. The courts addressed the difficult issue of what is adequate scientific information necessary to sustain the requirement that the standards be supported by “substantial evidence on the record as a whole.” The cases also addressed the extent to which economic factors were permitted or required to be considered in the setting of the standards, the meaning of feasibility, OSHA’s technology-forcing authority, the question of whether a cost–benefit analysis was required or permitted, and, finally, the extent of the jurisdiction of OSHAct in addressing different degrees of risk.

Emergency Temporary Standards

In Section 6(c), the OSHAct authorizes OSHA to set, on publication in the Federal Register and without recourse to a formal hearing, emergency temporary (6-month) standards (ETSs) for toxic exposures constituting a grave danger. Before OSHA lowered its permanent standard for asbestos from 2.0 to 0.2 fibers cm 3, it attempted to protect workers by promulgating an ETS at 0.5 fibers cm 3. In 1984, the Fifth Circuit Court of Appeals denied OSHA the ETS, arguing that the cost involved defeated the requirement that the ETS be necessary to protect workers. Attempts by OSHA to establish an ETS for hexavalent chromium likewise failed court review. OSHA has issued nine emergency temporary standards under the OSHAct. Standards for vinyl chloride, dibromo3-chloropropane (DBCP), and the first ETS on asbestos were not challenged in court and remained in effect until superseded by permanent standards. An ETS for acrylonitrile survived court challenge. ETSs on benzene, commercial diving, pesticides, 14 carcinogens, and asbestos were stayed or vacated by the courts. Over the past two decades, OSHA has avoided setting ETSs and instead has proceeded directly – but slowly – to establishing permanent standards for toxic substances under Section 6(b). Thus, OSHA denied a 1993 request from Public Citizen for a temporary emergency hexavalent chromium standard

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but promised an advanced notice of rule making for 1995. After a successful court challenge, the agency issued a proposed revision of its 8-h exposure limit in 2004, 9 years after it had promised action. The proposed revision lowered the standard to 1 mg m 3 from the previous 33-year-old standard of 52 mg m 3. However, in 2006 OSHA set a permanent standard of 5 mg m 3.

Short-Term Exposure Limits

Short-term exposures to higher levels of carcinogens are in general considered more hazardous than longer exposures to lower levels. OSHA issued a new standard for exposure to ethylene oxide in 1984 but excluded a short-term exposure limit (STEL) that had originally been prepared, in deference to objections from the Office of Management and Budget. Ralph Nader’s Health Research Group sued the Secretary of Labor in 1986 over OSHA’s continuing failure to issue the STEL. In 1987, the District of Columbia Circuit Court of Appeals ordered OSHA to establish an STEL for ethylene oxide by March 1988. OSHA complied by setting an STEL of 5 ppm over a 15-min period.

The Air Contaminants Standard

It is obvious that the slow, arduous process of promulgating individual health standards under Section 6(b)(5) of the OSHAct could never catch up with advances in scientific knowledge concerning the toxicity of chemicals. The ACGIH has updated its TLV list every 2 years, and although not as protective as workers and their unions would have liked, the recent updated lists did advance protection over the 1969 list that OSHA adopted into law in 1971. In 1989, OSHA decided to update the original list in a single rule-making effort through the 6(b) standard revision route. The agency issued more protective limits for 212 substances and established limits for 164 chemicals that were previously unregulated. Neither industry nor labor was satisfied with all of the standards. Industry, although giving general support, objected to the stringency of some of the PELs. Labor objected to their laxity, citing NIOSH recommendations not adopted, and generally objected to the rush-it-through process. The Eleventh Circuit Court of Appeals vacated the standard in 1992, ruling that OSHA failed to establish that a significant risk of material health impairment existed for each regulated substance (required by the benzene decision) and that the new exposure limit for each substance was feasible for the affected industry. OSHA decided not to appeal the decision to what it perceived as a conservative Supreme Court. Thus, the original and inadequate TLV list remains in effect, and 164 new substances remain unregulated. OSHA periodically expresses its intent to update the list through new rule making, but no new action has been forthcoming. In the meantime, OSHA could argue that those 164 substances are recognized hazards and enforceable through OSHA’s general duty clause, but OSHA administrations have not been willing to emphasize this approach in the case of the TLVs, although OSHA has used the general duty obligation to force compliance with good ergonomic practices in nursing homes. In 40 years, OSHA has issued only about a dozen general duty citations for substances covered by the original TLV list. Recently, OSHA’s reluctance to use the general duty obligation in the case of the outdated TLVs was in part due

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to the many congressional attempts to pass legislation prohibiting such use.

The Toxic Substances Control Act TSCA enables EPA to require data from industry on the production, use, and health and environmental effects of chemicals. TSCA also requires the manufacturer of new chemicals, or of existing chemicals put to a significant new use, to file a premarket notification (PMN) with EPA. EPA may regulate chemicals under TSCA – by requiring labeling, setting tolerances, or banning completely and requiring repurchase or recall – where the chemicals present “an unreasonable risk of injury to human health or the environment.” EPA may also order a specific change in chemical process technology. In addition, TSCA gives aggrieved parties, including consumers and workers, specific rights to sue to enforce under the act, with the possibility of awards for attorneys’ fees, a feature not found in the OSHAct. Under TSCA, EPA must regulate “unreasonable risks of injury to human health or the environment.” EPA has issued a regulation for worker protection from asbestos that extends the OSHA limit of 0.2 fibers cm 3 to state and local government asbestos abatement workers not covered by OSHA. Although the potential exists for broader regulation of workplace chemicals under TSCA, EPA has not been aggressive in this area. Between 1977 and 1990, of the 22 regulatory actions under TSCA directed at existing chemicals, 15 addressed polychlorinated biphenyls (PCBs), which EPA has a specific statutory directive to address under TSCA. Only regulations pertaining to asbestos, hexavalent chromium, and metalworking fluids had a strong occupational exposure component. Although EPA declared formaldehyde a probable carcinogen and the International Agency for Research on Cancer classified it as a confirmed human carcinogen, EPA initially chose not to take regulatory action on this substance, opting instead to defer to OSHA workplace regulations. However, Congress ultimately intervened, probably influenced by the government’s reluctance to house Hurricane Katrina refugees in trailers containing formaldehyde particle-board. In 2010 President Obama signed the Formaldehyde Standards for Composite-Wood Products Act, which added a new Title VI to TSCA establishing limits for formaldehyde emissions from composite wood products, mirroring standards previously established by the California Air Resources Board for products sold, used, or manufactured for sale in California. EPA is expected to promulgate final regulations under these provisions that will minimize formaldehyde exposure for both workers and the public. EPA has also taken action to address hazards posed by nanotechnology materials by requiring premarket notification for these materials under its Significant New Use Rules. Used together, the OSHAct and TSCA provide potentially comprehensive and effective information-generation and standard-setting authority to protect workers. In particular, the information-generation activities under TSCA can be the necessary data to have a substance qualify as a recognized hazard that, even in the absence of specific OSHA standards, must be controlled in some way by the employer to meet the general duty obligation under the OSHAct to provide a safe and healthful workplace.

The potentially powerful role of TSCA regulation was seriously challenged by the Fifth Circuit Court of Appeals in 1991, when it overturned the omnibus asbestos phase-out rule that EPA had issued in 1989. The court held that, under TSCA, EPA should not have issued a ban without having first considered alternatives that would have been less burdensome to industry. This would require the agency to perform a more comprehensive, detailed, and resource-intensive analysis. Rightly or wrongly, EPA has viewed this case (which was not appealed to the U.S. Supreme Court) as a significant impediment to future TSCA regulations, and the agency generally regards standard setting for chemicals other than PCBs to be a nearly impossible task under TSCA for now. There have been many (thus far unsuccessful) attempts by Congress to reform TSCA since the asbestos decision. Nonetheless, TSCA continues to be important for its surviving authority to require the testing of chemicals and for its information reporting and retaining requirements. Since 2012 EPA has turned its attention to (1) chemical assessments carried out under TSCA by the National Toxicology Program and the Agency for Toxic Substances and Disease Registry (in CDC), and (2) prioritization of needed chemical controls based on those assessments, in anticipation of revised or renewed regulatory authority resulting from future successful congressional reauthorization of TSCA. As of late 2016, only eight of 90 such assessments had been completed. Both the House and the Senate have bills currently in place to reform TSCA, but it remains to be seen whether they will get congressional reauthorization, or whether a final bill will strengthen protection from toxic substances.

Control of Gradual Pollution in Air, Water, and Waste The Clean Air Act

The modern Clean Air Act (CAA) came into being in 1970, and although significant changes were made in 1977 and 1990, the basic structure of the act has remained the same, with the addition of provisions for authority over acid rain, chlorofluorocarbons (CFCs), indoor air, and chemical safety, the last of which is discussed in the penultimate section of this article. The CAA regulates both stationary and mobile sources of pollution, taking into account the relative contributions of each to specific air pollution problems, and the relative capacity of different kinds of sources within each category to reduce their emissions. The recognition that sources using newer technology might be able to achieve greater emission reductions than older sources with older technology led to the act’s distinction – both in the stationary and mobile source provisions – between new and existing sources. Driven by equity considerations regarding the relative financial and technical burdens of pollution reduction, this approach unwittingly discouraged modernization or replacement of facilities and resulted in the operation of older (especially energy) facilities beyond their expected useful life. For new sources within each industrial sector, there was a recognition of the need for uniformity and also for encouraging technological innovation through technology-forcing inherent in stringent standards. The court decisions recognizing EPA’s technology-forcing authority were greatly influenced by OSHA’s early technology-forcing approach to worker protection. The 1970 CAA directed EPA to establish primary ambient air quality standards for certain ‘criteria’ air pollutants

Environmental Protection Laws Table 1 Carbon monoxide

National ambient air quality standards Primary (1970): 35 ppm averaged over 1 h and 9.0 ppm averaged over 8 h; neither to be exceeded more than once per year Secondary: None

Particulate mattera PM10 Primary (1970): 150 mg m 3 averaged over 24 h, with no more than one expected exceedance per calendar year; also, 50 mg m 3 or less for the expected annual arithmetic mean concentration Secondary: Same as primary PM2.5 Prior primary (1997): 65 mg m 3 averaged over 24 h; 15 mg m 3 annual maximum Revised primary (2006): 35 mg m 3 averaged over 24 h Further revised primary (2012) 12 mg m 3 annual maximum Ozone Prior primary (1979): 235 mg m 3 (0.12 ppm) averaged over 1 h, no more than one expected exceedance per calendar year (multiple violations in a day count as one violation). Revoked June 2005. Codified August 2005 Prior secondary: Same as primary Revised primary and secondary (1997/2008): 0.075 ppm averaged over 8 h Proposed new primary & secondary standards: 0.070 ppm (2015) averaged over 8 h Nitrogen dioxide Primary (1970): 100 mg m 3 (0.053 ppm) as an annual arithmetic mean concentration Secondary: Same as primary Sulfur oxides Prior primary (1970): 365 mg m 3 (0.14 ppm) averaged over 24 h, not to be exceeded more than once per year; 80 mg m 3 (0.03 ppm) annual arithmetic mean Revised primary (2010): Hourly standard of 75 parts per billion; prior daily and annual standards revoked Secondary: 1300 mg m 3 averaged over a 3-h period, not to be exceeded more than once per year Lead Primary (1977): 1.5 mg m 3 arithmetic average over a calendar quarter Secondary: Same as primary a

Note that PMxy below refers to particles equal or less than xy microns in diameter.

(see Table 1). These primary standards were to protect public health with “an adequate margin of safety” (see Section 109(b)(1)). As interpreted by the courts and supported by congressional history, these standards were to be established without consideration of economic or technological feasibility. In addition, secondary ambient air quality standards for the same pollutants were to be established to protect “the public welfare . within a reasonable time” (see Section 109(b)(2)). Both federal and state government were to be involved in protecting the ambient air. While the ambient air quality (concentration) standards for the criteria pollutants were to be established by the federal government, these were to be attained through (1) emission limitations placed on individual existing polluters through permits issued by state government as a part of their State Implementation Plans (SIPs) (Section 110); (2) emission limitations for new sources, established not by the states but rather by EPA as New Source Performance Standards (Section 111); and (3) by a combination of federal and state

511

restrictions on mobile sources. In specifying compliance with federal emission standards, Congress expressed concern with possible hot spots of localized intense pollution and also with intermittent versus continuous versus sudden and accidental releases of harmful substances. Emission standards, in contrast with ambient concentration standards, are expressed as an emissions rate (milligrams emitted per 100 kg of product, per hour, per day, per week, per quarter, per year, per BTU, per passenger mile, or other unit of measurement). The 1970 CAA also made a distinction between the control of criteria pollutants through federal ambient air standards and the control of hazardous air pollutants by means of federal emission limitations. Hazardous air pollutants were those recognized as extraordinarily toxic and eventually regarded as non- or low-threshold pollutants. Initially, these were to be regulated to protect public health with “an ample margin of safety” (Section 112) and, as with the primary ambient standards for criteria pollutants, standards were to be established without consideration of economic burden. These pollutants, Congress determined, were sufficiently dangerous to preclude any reliance on atmospheric dispersion and mixing as a means of reducing their ambient concentrations. Because of their extraordinary toxicity, ‘hot spots’ of these pollutants were to be avoided, and because ambient standards were considered impractical and of little relevance for sporadic and idiosyncratic sources, uniform federal emission standards were considered necessary. (Note, however, that California did establish an ambient standard as a complement to the federal emission limitation on vinyl chloride.) In the early stages of the implementation of the stationary source provisions of the Clean Air Act (approximately 1970–1975), EPA focused on (1) the primary and secondary ambient air quality standards and (2) emission standards for new sources of criteria pollutants and for all sources emitting seven regulated hazardous air pollutants (discussed below). Prior advisory standards for five criteria pollutants – carbon monoxide (CO), sulfur dioxide (SO2), oxides of nitrogen (NOX), large particulate matter, and photochemical oxidants – were made mandatory. In 1979, the standard for photochemical oxidants was narrowed to cover only ground-level ozone, and the standard was relaxed from 0.08 to 0.12 ppm averaged over a 1-h period. A revised standard for coarse particulate matter (PM10) – ‘inhalable’ particulates up to 10 mm in diameter – was adopted in 1987. In 1997, the ozone standard was returned to 0.08 ppm. At the same time, the particulate standard was expanded to place more stringent requirements on smaller (50

1971–74 1971–74 1981–85

1992 1992 1989

Average Average, good dietary data Cancer-free, 1st year

Lifestyle and dietary interview and exam with blood samples Mailed dietary questionnaire

34–59

1980

1988

Cancer-free

Mailed dietary questionnaire

40–59

1982

1987

Cancer-free

Lifestyle and dietary questionnaire: nested case– control analysis

Kvale et al. (1983) Long de and Hammond (1985) Enstrom et al. (1986) Gey et al. (1987) Eichholzer et al. (1996) Kromhout (1987) Ocke et al. (1997) Heilbrun et al. (1989) Knekt et al. (1991) Jarvinen et al. (1997) Chow et al. (1992) Enstrom et al. (1992) Enstrom (1999) Yong et al. (1997) Shibata et al. (1992) Hunter et al. (1993) Rohan et al. (1993)

Epidemiology of Vitamin C

Table 1

Pandey et al. (1995) Zheng et al. (1995) Gale et al. (1995) Hertog et al. (1996) Losonczy et al. (1996) Sahyoun et al. (1996) Bandera et al. (1997) Botterweck et al. (2000) Loria et al. (2000) Kwaw et al. (2001) Jacobs et al. (2002) Fletcher et al. (2003) Genkinger et al. (2004)

40–55

1958–59

1983

No history of CHD, cancer, or other serious illness

Lifestyle and dietary interview and numerous exams

55–69

1986

1992

no history of cancer

Mailed dietary questionnaire

65þ

1973

1993

45–69

1979–83

1995

No history of CHD, stroke, or arteriosclerosis Average

Detailed dietary interview, health exam, blood sample Baseline and follow-up exams with lifestyle and dietary questionnaire

67–105

1984–86

1993

Average

Medical history, lifestyle and dietary interview

60–101

1981–84

1992

Physical, medical, dietary, and biochemical exam

40–80

1980

1987

Free of terminal disease and severe disorders

55–69

1986

1990

Average

30–75

1976–80

1992

45–79

1993–97

1999

No history of CHD, stroke, or cancer No history of CHD, stroke, or cancer

Mailed dietary questionnaire: nested case–control analysis Lifestyle and dietary interview and exam with blood samples Lifestyle and dietary interview and exam with blood samples

30þ

1982

1998

No history of cancer

Lifestyle and dietary questionnaire

75–84

1995

1999

Average

Health and nutrition interview and exam with blood samples

Mean 55

1974–89

2001

Average

Lifestyle and dietary interview and 1989 exam with blood samples

45–79

1992–98

2001

Average

Lifestyle and dietary interview and exam with blood samples

Mailed dietary questionnaire: nested case–control analysis

Data from Enstrom, J.E., 1997. Vitamin C in prospective epidemiologic studies. In: Packer, L., Fuchs, J. (Eds.), Vitamin C in Health and Disease. Marcel Dekker, New York, pp. 381–398; Enstrom, J.E., 2001. Epidemiology and clinical aspects of ascorbate and cancer. In: Cadenas, E., Packer, L. (Eds.), Handbook of Antioxidants, second ed. Marcel Dekker, New York, pp. 167–188.

Epidemiology of Vitamin C

Jenab et al. (2006)

1556 Male employees of Western Electric Company in Chicago, IL (Western Electric Study) 34 691 Females recruited from a random DMV sample in Iowa 359 Males, 307 females; stratified random sample from 8 areas in the UK 2112 Males recruited from all residents of Caerphilly, South Wales, UK (Caerphilly Study) 4095 Males, 7083 females; free living persons from communities in MA, IA, CT and NC 254 Males, 471 females; noninstitutionalized recruited from MA community groups 27 544 Males, 20 456 females in New York State selected from DMV file (New York State Cohort) 58 279 Males, 62 573 females in Netherlands Cohort Study 3347 Males, 3724 females; national sample (NHANES II Mortality Follow-up Study) 8860 Males, 10 636 females; general practices sample in Norfolk, UK (EPIC Study) 460 737 Males, 585 186 females in 50 U.S. states enrolled by ACS (Cancer Prevention Study II) 552 Males, 662 females; randomly selected patients of 51British family practitioners (MRC Study) 2299 Males, 3852 females; Washington County, MD, population sample (CLUE Study) 153 451 Males, 368 032 females in 10 European countries (EPIC-EURGAST Study)

561

562

Epidemiology of Vitamin C

The majority of these studies show an inverse relationship between vitamin C intake and risk of death from all causes, cancer, and cardiovascular disease. Many of these studies have focused on tobacco-related cancers, such as oral cavity, esophagus, and lung cancer. The observational studies have failed to find any consistent adverse effects associated with increased vitamin C intake. In addition, data from in vitro and animal carcinogenesis studies have been generally consistent with the observational studies. This review focuses on prospective epidemiologic studies that involve vitamin C intake, an index of vitamin C intake, or serum vitamin C (plasma ascorbic acid). Most of these studies have been published during the past 20 years. These studies are generally methodologically superior to case–control studies since they obtain information about vitamin C and other characteristics before cancer or other diseases develop and are less subject to selection bias. Although not the focus of this review, there are several prospective studies that show an inverse relationship between fruit and/or vegetable intake and mortality. Many of these studies are relevant because citrus fruit intake is a reasonable measure of dietary vitamin C intake. This review incorporates findings from our previous reviews (Enstrom, 1997, 2001), other recent reviews (Block, 1991; Byers and Guerrero, 1995; Carr and Frei, 1999; Levine et al., 1999; Asplund, 2002; Knekt et al., 2004; Stanner et al., 2004; Coulter et al., 2006; Bjelakovic et al., 2007), and recent randomized controlled trials (De Lorgeril et al., 1998; Hercberg et al., 2004; Jaxa-Chamiec et al., 2005).

Methods A complete presentation of all results on the relationship of vitamin C intake and mortality and incidence from all diseases is beyond the scope of this review. To provide information on the most important epidemiologic evidence, the essential characteristics are given for 26 major prospective studies that measured vitamin C intake in the diet or in blood samples and had mortality from all causes, cancer, and/or cardiovascular disease as an outcome (Bjelke, 1982; Kvale et al., 1983; Long de and Hammond, 1985; Enstrom et al., 1986, 1992; Gey et al., 1987; Kromhout, 1987; Heilbrun et al., 1989; Knekt et al., 1991; Chow et al., 1992; Shibata et al., 1992; Hunter et al., 1993; Rohan et al., 1993; Pandey et al., 1995; Zheng et al., 1995; Eichholzer et al., 1996; Hertog et al., 1996; Losonczy et al., 1996; Sahyoun et al., 1996; Bandera et al., 1997; Ocke et al., 1997; Jarvinen et al., 1997; Yong et al., 1997; Enstrom, 1999; Botterweck et al., 2000; Loria et al., 2000; Khaw et al., 2001; Jacobs et al., 2002; Fletcher et al., 2003; Genkinger et al., 2004; Cho et al., 2006; Jenab et al., 2006). Vitamin C intake was determined for each subject based on their consumption of fruits and other foods containing vitamin C and/or supplements containing vitamin C. In addition, serum vitamin C (plasma ascorbic acid) was measured for the subjects in several cohorts. Table 1 describes the study population, number of subjects, geographic location, age range, follow-up period, health status, and type of data collected for these 26 population cohorts cited in the previous paragraph. The studies are shown in chronological order, citing the first and/or most important publication

associated with each cohort. Several small cohorts that examined vitamin C intake and total mortality during 1950–80 are described in a former review (Enstrom, 1997). Table 2 describes the results of those studies that give all-cause mortality for males, females, and/or both sexes. The number of years of follow-up, the high and low vitamin C intake groups, and the variables controlled for are presented along with the total number of deaths in the cohort, relative risk (RR) of the high-intake group versus the low-intake group, and 95% confidence interval (CI) or statistical significance level (p-value) for the relative risk. Table 3 describes the results of these same studies where results are presented for mortality or incidence from all cancer for males, females, and/or both sexes. Table 4 describes the results of these same studies where results are presented for mortality from all cardiovascular disease or coronary heart disease for males, females, and/or both sexes. The mortality or incidence results for the specific cancer sites of lung, breast, stomach, colorectum, and prostate are described in a former review (Enstrom, 2001). Finally, a summary is given regarding recent randomized controlled trials that have assessed the impact of vitamin C intake on subsequent cancer and/or cardiovascular disease (De Lorgeril et al., 1998; Hercberg et al., 2004; Jaxa-Chamiec et al., 2005).

Results Among the 26 prospective cohorts described in Table 1, the relative risk (RR) for all-cause mortality as a function of vitamin C intake is presented in Table 2 for eight cohorts. Results based on dietary vitamin C and serum vitamin C are presented in separate parts of the table. Each relative risk is based on comparing persons with the highest and lowest vitamin C intake, generally values close to the RDA. The 12 RRs for males from five cohorts range between 0.48 and 0.95: All 12 are less than 1.00 and 10 are significantly less than 1.0 (p < 0.05). The nine RRs for females from four cohorts range between 0.77 and 1.03: Seven are less than 1.0 and four are significantly less than 1.0. The 18 RRs for both sexes from seven cohorts range between 0.43 and 0.97: 18 are less than 1.0 and 13 are significantly less. Of the RRs that control for confounding variables, five of six for males, one of three for females, and six of ten for both sexes are significantly less than 1.00. Table 3 shows the RRs for mortality or incidence from all cancer sites: 27 of 27 RRs are less than 1.0, and 11 are significantly less than 1.0. Table 4 shows the RRs for mortality for cardiovascular disease mortality: 24 of 27 are less than 1.0 and 12 are significantly less than 1.0. The reviews by Block (1991) and Byers and Guerrero (1995) of the results of case– control studies for stomach, colorectal, lung, breast, and prostate cancer showed RRs that were less than 1.0. Of the studies in the Block review, 25 of 44 (57%) of the RRs are significantly (p < 0.05) less than 1.0; of the studies in the Byers review, 38 of 49 (78%) of the RRs are less than 1.0. These results are consistent with the cohort results for specific cancer sites presented in our previous reviews (Enstrom, 1997, 2001). Thus, the vast majority of observational results from both case–control and cohort studies indicate a beneficial effect of increased vitamin C intake with respect to cancer and coronary heart disease.

Table 2

Results for prospective vitamin C studies: all-cause mortality Males

Author (year)

Low vitamin C (group L)

Results based on dietary vitamin C Enstrom et al. VC < 250 mg day
1 (1986) Enstrom et al. VC < 50 mg day
1 (1992) Enstrom et al. VC < 50 mg day
1 (1992) Enstrom et al. VC < 50 mg day
1 (1992) Enstrom et al. VC < 50 mg day
1 (1992) Enstrom (1999) VC < 50 mg day
1

Both sexes

High vitamin C (group H)

Control variables

Years of FU

Total deaths

RR (H vs L) CI of RR

Total deaths

RR (H vs L) CI of RR

Total deaths

RR (H vs L) CI of RR

VC > 250 mg day
1

Age

10

134

0.95

0.61–1.42

130

1.03

0.68–1.51

264

0.97

0.67–1.38

VC > 50 mg day
1 and reg supps VC > 50 mg day
1 and reg supps VC > 50 mg day
1 and reg supps VC > 50 mg day
1 and reg supps VC > 50 mg day
1 and reg supps VC > 50 mg day
1 and VC ¼ 113–393 mg day
1 VC > 388 mg day
1

Age

5

473

0.52

0.35–0.73

276

0.77

0.53–1.06

749

0.66

0.53–0.82

Age, 10 confounders 5

473

0.61

0.43–0.86

749

0.68

0.52–0.89

Mean 10 1069

0.59

0.47–0.72

1809

0.74

0.64–0.85

Age, 10 confounders Mean 10 1069

0.78

0.62–0.97

1809

0.86

0.73–1.02

Age

Mean 19 2132

0.67

0.57–0.77

1876

0.86

0.76–0.98

4008

0.79

0.72–0.87

Age, 10 confounders Mean 19 1883 Age, 11 confounders Mean 24 667 Age, sex Mean 10

0.90 0.73

0.78–1.04 0.58–0.91

1652

1.01

0.88–1.17

3535

0.95

0.85–1.05

217

0.53

0.33–0.84

Mean 10

217

0.55

0.34–0.88

4.4

258 910

0.88 0.88

0.54–1.39 0.72–1.07

Mean 10

217

0.56

0.34–0.91

Enstrom (1999) VC < 50 mg day
1 Pandey et al. (1995) VC ¼ 21–82 mg day
1 Sahyoun et al. VC < 90 mg day
1 (1996) Sahyoun et al. VC < 90 mg day
1 VC > 388 mg day
1 (1996) Fletcher et al. (2003) Med VC ¼ 52.1 mg day
1 Med VC ¼ 103.5 mg day
1 Genkinger et al. Med VC ¼ 39.4 mg day
1 Med VC ¼ 175.6 mg day
1 (2004) Results based on serum vitamin C (plasma ascorbic acid) Sahyoun et al. PAA < 0.91 mg dl
1 PAA > 1.56 mg dl
1 (1996) Loria et al. (2000) PAA < 0.50 mg dla PAA > 1.30 mg dla PAA < 0.70 mg dlb PAA > 1.50 mg dlb Loria et al. (2000) PAA < 0.50 mg dla PAA > 1.30 mg dla PAA > 1.50 mg dlb Mean PPA ¼ 1.28a Mean PPA ¼ 1.50b Mean PPA ¼ 1.28a

Mean PPA ¼ 0.53b Fletcher et al. (2003) PAA < 0.19 mg dl
1 Fletcher et al. (2003) PAA < 0.19 mg dl
1

Mean PPA ¼ 1.50b PAA > 1.40 mg dl
1 PAA > 1.40 mg dl
1

Age

Age, sex, 3 confounders Age, sex Age, sex, energy Age, sex, 3 confounders Age, sex

740

0.90

0.74–1.09

Mean 14 242

0.52

0.41–0.67

127

0.68

0.51–0.92

369

0.58

0.48–0.70

Age, sex, 8 confounders

Mean 14 242

0.64

0.49–0.83

127

0.84

0.60–1.16

369

0.71

0.58–0.87

Age, sex

Mean 4

309

0.48

0.33–0.70

187

0.50

0.32–0.81

496

0.49

0.36–0.65

Age, sex, 6 confounders

Mean 4

309

0.50 0.34–0.72

187

0.58 0.37–0.94

496

0.53 0.39–0.71

Age, sex Age, sex, 11 confounders

4.4 4.4

258 258

0.43 0.54

0.29–0.64 0.34–0.84

563

Male values. Female values; VC, vitamin C intake in mg day
1; reg supps, daily use of vitamin C and/or multivitamin supplements; PAA, plasma ascorbic acid in mg dl
1 (1.0 mg dl
1 ¼ 0.568 mmol dL
1 ¼ 56.8 mmol l
1). Data from Enstrom, J.E., 1997. Vitamin C in prospective epidemiologic studies. In: Packer, L., Fuchs, J. (Eds.), Vitamin C in Health and Disease. Marcel Dekker, New York, pp. 381–398; Enstrom, J.E., 2001. Epidemiology and clinical aspects of ascorbate and cancer. In: Cadenas, E., Packer, L. (Eds.), Handbook of Antioxidants, second ed. Marcel Dekker, New York, pp. 167–188. b

Epidemiology of Vitamin C

PAA < 0.70 mg dlb Khaw et al. (2001) Mean PPA ¼ 0.37a Mean PPA ¼ 0.53b Khaw et al. (2001) Mean PPA ¼ 0.37a

a

Females

564

Results for prospective vitamin C studies: all-cancer mortality or incidence Males

Author (year)

Low vitamin C (group L)

High vitamin C (group H)

Results based on dietary vitamin C VC ¼ 83–103 mg day
1 Kromhout (1987) VC < 63 mg day
1 Enstrom et al. VC < 50 mg day
1 VC > 50 mg day
1 and reg (1992) supps Enstrom et al. VC < 50 mg day
1 VC > 50 mg day
1 and reg (1994) supps Shibata et al. (1992) VC < 145 mg day
1 VC > 210 mg day
1 Pandey et al. (1995) VC ¼ 21–82 mg day
1 VC ¼ 113–393 mg day
1 Sahyoun et al. VC < 90 mg day
1 VC > 388 mg day
1 (1996) Genkinger et al. Med VC ¼ 39.4 mg day
1 Med VC ¼ 175.6 mg day
1 (2004) Results based on serum vitamin C (plasma ascorbic acid) Eichholzer et al. PAA < 0.4 mg dl
1 PAA > 0.4 mg dl
1 (1996) Sahyoun et al. PAA < 0.91 mg dl
1 PAA > 1.56 mg dl
1 (1996) Loria et al. (2000) PAA < 0.50 mg dla PAA > 1.30 mg dla PAA < 0.70 mg dlb PAA > 1.50 mg dlb Loria et al. (2000) PAA < 0.50 mg dla PAA > 1.30 mg dla b PAA > 1.50 mg dlb PAA < 0.70 mg dl Khaw et al. (2001) Mean PPA ¼ 0.37a Mean PPA ¼ 1.28a b Mean PPA ¼ 0.53 Mean PPA ¼ 1.50b Khaw et al. (2001) Mean PPA ¼ 0.37a Mean PPA ¼ 1.28a b Mean PPA ¼ 0.53 Mean PPA ¼ 1.50b a

Control variables

Years of FU

Age, smoking Age

Both sexes

RR (H vs L) CI of RR

Total deaths

RR (H vs L) CI of RR

Total deaths

RR (H vs L) CI of RR

25 155 Mean, 10 228

0.05 0.79 0.51–1.18

169

0.93

0.60–1.40

397

0.85

0.63–1.14

Age

Mean, 14 346

0.69

0.47–.97

269

0.92

0.65–1.27

615

0.78

0.60–0.98

Age, smoking Age, 11 Age, sex, 2 confounders Age, sex

Mean, 7 645c Mean, 24 155 Mean, 10

0.90 0.61

0.74–1.09 0.40–0.94

690c

0.76

0.63–0.91

1335c

0.83

0.71–0.95

57

0.94

0.36–2.44

307

0.82

0.58–1.15

57

0.68

0.25–1.83

2.5

Age, smoking, lipids 17 Age, sex, 3 confounders Age, sex Age, sex, 8 confounders Age, sex Age, sex, 6 confounders

Total deaths

Females

290

0.81

0.59–1.12

Mean, 10 Mean, 14 228

0.49

0.31–0.76

155

0.83

0.51–1.35

383

0.62

0.45–0.87

Mean, 14 228

0.62

0.39–0.99

155

0.94

0.53–1.67

383

0.73

0.51–1.05

Mean, 4 116

0.47

0.26–0.88

84

0.73

0.38–1.40

200

0.58

0.37–0.90

Mean, 4 116

0.43 0.25–.80

84

0.85 0.44–1.64

200

0.58 0.38–0.90

Males values. Female values. c Cancer incidence was measured in Shibata et al. (1992) and cancer mortality was measured in all other studies. VC, vitamin C intake in mg day
1; reg supps, daily use of vitamin C and/or multivitamin supplements; PAA, plasma ascorbic acid in mg dl
1 (1.0 mg dl
1 ¼ 0.568 mmol dL
1 ¼ 56.8 mmol l
1). Data from Enstrom, J.E., 1997. Vitamin C in prospective epidemiologic studies. In: Packer, L., Fuchs, J. (Eds.), Vitamin C in Health and Disease. Marcel Dekker, New York, pp. 381–398; Enstrom, J.E., 2001. Epidemiology and clinical aspects of ascorbate and cancer. In: Cadenas, E., Packer, L. (Eds.), Handbook of Antioxidants, second ed. Marcel Dekker, New York, pp. 167–188. b

Epidemiology of Vitamin C

Table 3

Table 4

Results for prospective vitamin C studies: Cardiovascular disease mortality Males

Author (year)

Low vitamin C (group L)

High vitamin C (group H)

Results based on dietary vitamin C VC > 50 mg day
1 and reg Enstrom et al. VC < 50 mg day
1 supps (1992) Knekt et al. VC < 61 mg day
1 VC > 85 mg day
1 (1994) Gale et al. (1995) VC < 27.9 mg day
1 VC > 44.9 mg day
1 VC > 196 mg day
1 Kushi et al. (1996) VC < 87 mg day
1
1 Sahyoun et al. VC < 90 mg day VC > 388 mg day
1 (1996) Fletcher et al. Med VC ¼ 52.1 mg day Med VC ¼ 103.5 mg day
1
1 (2003) Genkinger et al. Med VC ¼ 39.4 mg day Med VC ¼ 175.6 mg day
1
1 (2004) Studies based on serum vitamin C (plasma ascorbic acid) Gey et al. (1993) PAA < 0.4 mg dl
1 PAA > 0.4 mg dl
1
1 Sahyoun et al. PAA < 0.91 mg dl PAA > 1.56 mg dl
1 (1996) Loria et al. (2000) PAA < 0.50 mg dla PAA > 1.30 mg dla PAA < 0.70 mg dlb PAA > 1.50 mg dlb a Loria et al. (2000) PAA < 0.50 mg dl PAA > 1.30 mg dla

a

PAA > 1.50 mg dlb Mean PPA ¼ 1.28a Mean PPA ¼ 1.50b Mean PPA ¼ 1.28a Mean PPA ¼ 1.50b PAA > 1.40 mg dl
1 PAA > 1.40 mg dl
1

Control variables

Years of FU

Age

Mean, 10 588

0.55

0.39–0.74 371

0.75

0.55–0.99 929

0.64

0.51–0.80

Age, sex, 5 confounders Age, sex Age, 12 confounders Age, sex, 2 confounders Age, sex

16

1.00

0.68–1.45 58

0.49

0.24–0.98 244

0.85

0.61–1.19

20 7 Mean, 10

1.43

0.75–2.70

182

0.80

0.60–1.20

101

0.38

0.19–0.75

4.4

113

0.91

0.54–1.57

Age, sex, energy

2.5

378

1.05

0.76–1.50

Age, smoking Age, sex, 3 confounders Age, sex

Mean, 7 132 Mean, 10

0.80

0.50–1.30

75

0.53

0.27–1.06

Mean, 14 293

0.58

0.36–0.91 213

0.82

0.52–1.30 506

0.69

0.50–0.96

Age, sex, 8 confounders

Mean, 14 293

0.69

0.43–1.11 213

1.08

0.65–1.75 506

0.85

0.61–1.20

Age, sex

Mean, 4

123

0.29

0.15–0.59 57

0.41

0.20–1.00 180

0.34

0.20–0.56

Age, sex, 6 confounders Age, sex

Mean, 4

123

0.31

0.16–0.64 57

0.46

0.23–1.13 180

0.37

0.22–0.62

4.4

113

0.46

0.26–0.83

Age, sex, 11 confounders

4.4

113

0.57

0.29–1.12

186

RR (H vs L) CI of RR

Total deaths

Both sexes

122

RR (H vs L) CI of RR

Total deaths

RR (H vs L) CI of RR

Males values. Female values; VC, vitamin C intake in mg day
1; reg supps, daily use of vitamin C and/or multivitamin supplements; PAA, plasma ascorbic acid in mg dl
1 (1.0 mg dl
1 ¼ 0.568 mmol dL
1 ¼ 56.8 mmol l
1). Data from Enstrom, J.E., 1997. Vitamin C in prospective epidemiologic studies. In: Packer, L., Fuchs, J. (Eds.), Vitamin C in Health and Disease. Marcel Dekker, New York, pp. 381–398; Enstrom, J.E., 2001. Epidemiology and clinical aspects of ascorbate and cancer. In: Cadenas, E., Packer, L. (Eds.), Handbook of Antioxidants, second ed. Marcel Dekker, New York, pp. 167–188. b

Epidemiology of Vitamin C

PAA < 0.70 mg dlb Khaw et al. (2001) Mean PPA ¼ 0.37a Mean PPA ¼ 0.53b Khaw et al. (2001) Mean PPA ¼ 0.37a Mean PPA ¼ 0.53b Fletcher et al. PAA < 0.19 mg dl
1 (2003) Fletcher et al. PAA < 0.19 mg dl
1 (2003)

Total deaths

Females

565

566

Epidemiology of Vitamin C

Also, it is obvious that the results in Tables 2–4 represent only a small fraction of the potential results that would be available if the cohorts in Table 1 were fully analyzed with respect to vitamin C intake and mortality. Other compilations have yielded somewhat different findings. A recent study pooled nine prospective cohort studies with information on intakes of vitamin E, carotenoids, and vitamin C and coronary heart disease (CHD) incidence (Knekt et al., 2004). During a 10-year follow-up of 293 172 subjects who were free of CHD at baseline, dietary intake of antioxidant vitamins was only weakly related to a reduced CHD risk after adjustment for potential nondietary and dietary confounding factors. Compared with subjects in the lowest dietary intake quintile for vitamin C, those in the highest intake quintile had a relative risk of CHD incidence of 1.23 (1.04–1.45). However, compared with subjects who did not take vitamin C supplements, those who took at least 700 mg per day of supplemental vitamin C had a relative risk of CHD incidence of 0.75 (0.60–0.93). However, this compilation is based on well-nourished cohorts and deals with CHD incidence and not the CVD mortality, making a direct comparison with results in Table 4 difficult. Overall, there is substantial epidemiologic evidence that dietary vitamin C intake is consistently associated with moderately lower death rates from all causes, cardiovascular disease, and cancer, and particularly some types of tobacco-related cancer. This reduced mortality appears to be associated with diets rich in vitamin C, particularly the intake of citrus fruits, and with increased blood levels of ascorbic acid. The antioxidant hypothesis proposes that vitamin C and other antioxidant nutrients afford protection against chronic diseases by decreasing oxidative damage. Although scientific rationale and observational studies have been convincing, randomized primary and secondary intervention trials involving vitamin C have failed to show consistent benefit from the use of supplements on cardiovascular disease or cancer risk. Most of the major antioxidant trials have involved vitamin E and/or vitamin A given at relatively high doses and several of these trials suggest possible harm in certain subgroups. The definitive trial investigating the effect of a dietary level of vitamin C has not been done. A recent review of 68 randomized controlled trials of antioxidants assessed their safety and efficacy (Bjelakovic et al., 2007). Very few trials have involved vitamin C supplements. There were no consistent adverse effects of multivitamin and mineral supplements. The evidence thus far shows that vitamin C supplements have had no significant effect on mortality from any cause. The evidence is insufficient to prove the presence or absence of benefits from use of multivitamin and mineral supplements to prevent cancer and chronic disease. Thus, there is a need for further evaluation of this issue. Three recent trials involving a vitamin C intervention are noteworthy. One intervention trial among acute myocardial infarction (AMI) patients in France showed that a Mediterranean-type diet with vitamin C intake of about 130 mg per day resulted in a lower cancer death rate (De Lorgeril et al., 1998). In a randomized, double-blind, multicenter trial, 800 Polish patients (mean age, 62) with acute myocardial infarction (AMI) were randomly allocated to receive, on top of routine medication, one of two treatments:

Vitamin C (1000 mg/12 h infusion followed by 1200 mg/ 24 h orally) and vitamin E (600 mg/24 h) or matching placebo for 30 days (Jaxa-Chamiec et al., 2005). This randomized pilot trial shows that supplementation with antioxidant vitamins is safe and seems to positively influence the clinical outcome of patients with AMI. The Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study is a randomized, double-blind, placebo-controlled primary prevention trial of nutritional doses of supplementation among 13 017 French adults (7876 women aged 35–60 years and 5141 men aged 45–60 years) (Hercberg et al., 2004). All participants took a single daily capsule of a combination of 120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta carotene, 100 mug of selenium, and 20 mg of zinc, or a placebo. Median follow-up time was 7.5 years. The outcome of intervention versus placebo for total cancer incidence showed RR ¼ 0.69 (0.53–0.91) in men and RR ¼ 1.04 (0.85–1.29) in women. The outcome for total mortality showed RR ¼ 0.63 (0.42–0.93) in men and 1.03 (0.64–1.63) in women. Recently, the evidence of vitamin C supplements for treatment and prevention of cancer has been reviewed (Coulter et al., 2006). Results for intervention studies involving vitamin C supplements and cancer have been inconclusive. There have been two small randomized controlled trials of terminal cancer patients (median survival of 7 weeks) and neither of these showed any benefit from 10 g of vitamin C supplements. However, one small trial of bladder cancer patients showed a significant benefit for 2 g of vitamin C. In general, the potential role of vitamin C supplements in the treatment of human cancer has not been fully investigated. Systematic review of the literature does not support the hypothesis that the use of supplements of vitamin C in the doses tested helps prevent and/or treat cancer in the populations tested. The isolated findings of benefit require confirmation. Further details about these trials are presented in a former review (Enstrom, 2001) and a number of other studies (Creagan et al., 1979; Moertel et al., 1985; Blot et al., 1993; Lamm et al., 1994; Hercberg et al., 1998).

Conclusions A large majority of epidemiologic studies show a modest decrease in mortality from all causes, cancer, and cardiovascular disease with an increase of vitamin C intake, particularly for levels of vitamin C intake around the current U.S. RDA of 75–90 mg per day for adults. This inverse relationship is strongest for males, next strongest for both sexes combined, and weakest for females. However, several studies show no significant relationship after controlling for confounding variables and others do not properly control for confounding variables. Indices of varying quality have been used and they have usually been based on dietary sources alone. There does not appear to be a relationship between mortality and vitamin C supplement intake per se. The strongest inverse relationship has been observed in those studies that have analyzed serum vitamin C and total mortality. The vast majority of available prospective data remain unanalyzed and there is a need for comprehensive analysis in this area.

Epidemiology of Vitamin C There have been relatively few intervention trials involving dietary vitamin C and vitamin C supplements. However, there are suggestions from the trials summarized above that there are benefits associated with interventions involving dietary levels of vitamin C. The beneficial results thus far should not be overinterpreted and probably apply only to populations with similar baseline nutritional status and risk factors and to the specific intervention used. But the potential benefit of vitamin C may have been minimized in these trials if the intervention was given too late in the disease process, given for an inadequate duration, or given to an already well-nourished population. Although the specific antioxidant mechanism by which vitamin C may be causally related to reduced mortality has not yet been clearly established, the available epidemiologic evidence indicates there is continuing value in understanding this mechanism. This relationship can be substantially refined by complete analysis of the available prospective cohort data. Additional well-designed trials can measure the impact of specific vitamin C interventions, particularly in populations with poor nutrition. It is important to further examine the role of vitamin C in reducing mortality, because it is a component of the diet that can be easily and inexpensively changed and one where even a small benefit can have a large population impact. While the existing epidemiologic evidence is not conclusive, it strongly suggests that increased levels of dietary vitamin C and serum vitamin C are associated with reduced mortality. Further studies are certainly warranted in order to conclusively determine the health benefits of vitamin C.

Acknowledgment This article has been supported in part by the Wallace Genetic Foundation.

See also: Diet and Heart Disease; Functions and Deficiencies of B-Vitamins (and Their Prevention); Vitamin A Deficiency and Its Prevention; Vitamin D.

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Mayne, S.T., 1997. Antioxidant nutrients and cancer incidence and mortality: an epidemiologic perspective. Adv. Pharmacol. 38, 657–675. Moertel, C.G., Fleming, T.R., Creagan, E.T., Rubin, J., O’Connell, M.J., Ames, M.M., 1985. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy: a randomized double-blind comparison. N. Engl. J. Med. 312, 137–141. Ocke, M.C., Bueno-de-Mesquita, H.B., Feskens, E.J., van Staveren, W.A., Kromhout, D., 1997. Repeated measurements of vegetables, fruits, beta-carotene, and vitamins C and E in relation to lung cancer: the Zutphen Study. Am. J. Epidemiol. 145, 358–365. Otten, J.J., Hellwig, J.P., Meyers, L.D. (Eds.), 2006. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. National Academy Press, Washington, DC. Pandey, D., Shekelle, R., Tangney, C., Stamler, J., 1995. Dietary vitamin C and beta carotene and risk of death in middle-aged men: the Western Electric Study. Am. J. Epidemiol. 142, 1269–1278. Patterson, R.E., White, E., Kristal, A.R., Neuhouser, M.L., Potter, J.D., 1997. Vitamin supplements and cancer risk: the epidemiologic evidence. Cancer Causes Control 8, 786–802. Prasad, K.N., Kumar, A., Kochupillai, V., Cole, W.C., 1999. High doses of multiple antioxidant vitamins: essential ingredients in improving the efficacy of standard cancer therapy. J. Am. Coll. Nutr. 18, 13–25. Rohan, T.E., Howe, G.R., Friedenreich, C.M., Jain, M., Miller, A.B., 1993. Dietary fiber, vitamins A, C, and E, and risk of breast cancer: a cohort study. Cancer Causes Control 4, 29–37. Sahyoun, N.R., Jacques, P.F., Russell, R.M., 1996. Carotenoids, vitamins C and E, and mortality in the elderly population. Am. J. Epidemiol. 144, 501–511. Shibata, A., Paganini-Hill, A., Ross, R.K., Henderson, B.E., 1992. Intake of vegetables, fruits, beta-carotene, vitamin C and vitamin supplements and cancer incidence among the elderly: a prospective study. Br. J. Cancer 66, 673–679. Stanner, S.A., Hughes, J., Kelly, C.N., Buttriss, J., 2004. A review of the epidemiological evidence for the ‘antioxidant hypothesis’. Public Health Nutr. 7, 407–422. Vivekananthan, D.P., Penn, M.S., Sapp, S.K., Hsu, A., Topol, E.J., 2003. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 361, 2017–2023. Yong, L.C., Brown, C.C., Schatzkin, A., et al., 1997. Intake of vitamins E, C, and A and risk of lung cancer. The NHANES I epidemiologic followup study. First National Health and Nutrition Examination Survey. Am. J. Epidemiol. 146, 231–243. Zheng, W., Sellers, T.A., Doyle, T.J., Kushi, L.H., Potter, J.D., Folsom, A.R., 1995. Retinol, antioxidant vitamins, and cancers of the upper digestive tract in a prospective cohort study of postmenopausal women. Am. J. Epidemiol. 142, 955–960.

Relevant Websites http://www.iom.edu/Object.File/Master/7/296/webtablevitamins.pdf – Health Benefits, Food Sources, Side Effects, and Recommended Daily Intakes of Vitamin C. http://www.nlm.nih.gov/medlineplus/ency/article/002404.htm – MedlinePlus Medical Encyclopedia: Vitamin C.

Equity in Health Financing Diana De Graeve, Universiteit Antwerpen, Antwerp, Belgium Ke Xu, World Health Organization, Manila, Philippines Raf Van Gestel, Universiteit Antwerpen, Antwerp, Belgium Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Diana De Graeve, Ke Xu, volume 3, pp. 180–189, Ó 2008, Elsevier Inc.

Concept of Equity in Health Financing What is Equity in Health Financing? The question what constitutes equity is a normative one; it has to do with what a person ought to have, as of right. Philosophers and also economists have reflected on the issue and have formulated various theories of distributional justice in general. Equity in health financing is about fairness in the distribution of health-care payments across the population. Who pays how much for health care is the central question in any discussion of equity in health financing. During the past decades the equity issue has been of growing importance to policy makers, health workers, and researchers. Since the beginning of the 1990s, the European Union (EU) has financed cross-EU country comparative research measuring equity in the finance of health care (Van Doorslaer et al., 199). In the 2000 World Health Report the World Health Organization (WHO) suggested a framework for evaluation of health system performance in which fairness is one of the three goals of the health system along with health and responsiveness. In the 2010 World Health Report, equity in health financing is seen as an important means to achieve universal coverage. A system of risk pooling with subsidies for the poorest part of the population, compulsory contributions, and a large pool decreases the risk for financial hardship and can therefore achieve the long-term objective of universal coverage. Work has been done to specify what could constitute equity in the finance of medical care. There seems to be broad consensus on the normative assumption that health-care payments should be linked to ability to pay with use related to need and that all households should be protected against catastrophic financial losses related to ill-health (Van Doorslaer et al., 1993; WHO, 2000; Murray et al., 2003). This implies a disconnection between the payment and the use of services. Given equal access to needed care, people with high capacity to pay should contribute more to a health system than those with lower capacity to pay. Furthermore, people with the same capacity contribute the same amount. The former is vertical equity or progressivity and the latter is horizontal equity. The contribution to a health system includes all payments made by a household through general taxation (direct tax and indirect tax), social health insurance premiums (payroll tax), voluntary prepayment schemes, and out-of-pocket payments. In such prepayment systems “the rich subsidize the poor and the healthy subsidize the sick” (WHO, 2010).

What Do We Care? Following the principle that payment for health care should correspond to capacity to pay, the equity concern nevertheless

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is perceived differently in societies with different economic, political, cultural, and historical contexts. For example, most OECD countries have reached universal coverage of essential health care through a tax-based system, social health insurance, or some mixed mechanisms. Few households face severe financial hardship or impoverishment by paying for health care. These societies focus more on whether health payments worsen the overall equity of income (Wagstaff, 2002). In middle- and low-income countries, health-care financing relies heavily on out-of-pocket payments. As a result, some portions of the population, particularly the poor, are unable to access needed care as they cannot afford it. For those who do get needed care, catastrophic expenditure and impoverishment are a frequent result. In this context, the reduction of financial burden and prevention of impoverishment are the primary equity concerns.

Methodologies in Measuring Equity in Health Financing In short, to measure equity in health financing is to assess the variation in health payments across the population. However, not all variations are regarded as inequitable. Equity implies some social judgments. Many indicators are applicable to measuring equity in health financing among which two main approaches are widely used, namely, the income approach and the financial burden approach. Both of them require microlevel (household) data. The income approach is derived from the equity measure of public finance where progressivity is the main concern. This approach has been used mostly for OECD countries. The financial burden approach argues that the burden of paying for health care should be equally distributed across all households. It puts more emphasis on catastrophic health spending and is more applicable to developing countries. Both approaches are in fact complementary and accept the fundamental principle that funds for health care should be collected according to capacity to pay.

Household’s Capacity to Pay Defining capacity to pay is essential in measuring equity in health care financing. Theoretically, a household’s capacity to pay is equal to the total resources that a household can mobilize for purchasing health services, including savings, selling assets, and borrowing from financial institutions, relatives and friends. Practically, different variables have been used as a proxy for household capacity to pay because the information required is not always available from a cross-section household survey.

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Gross Income or Net Income?

In the taxation literature, pretax gross equivalent income is used as a proxy for capacity to pay, and one is essentially interested in the move from the pretax to the posttax income distribution. Taxes (and social security contributions) are regressive (the poor pay a higher percentage of their income than the rich), neutral (proportional to income), or progressive (the poor pay a lower percentage of income than the rich) if they deteriorate equity in income, leave it unchanged, or improve it. Analogous, in most European countries, gross income has been used to examine the progressivity of health-care payments. Health-care payments, however, include public (taxes and compulsory insurance) as well as private sources (voluntary prepayment and out-of-pocket payments). Van Ourti (2004) argues to use disposable income instead of gross income for the private payments since it is a more adequate indicator of a household’s ‘ability to pay’ and redistribution is not a purpose of these payments.

Household Income or Expenditure?

The choice between income and expenditure often depends on the accuracy of available data. In most OECD countries, income data often are linked to the registration system and they are more reliable than reported expenditure from a household survey. By contrast, in most developing countries where registered income data are not available, reported expenditures in household surveys are considered more reliable than reported income. But also for developed countries, there is an argument to use expenditures instead of current income because expenditures are less liable to short-term fluctuations, and therefore better approximate ability to pay.

Household Nonfood Expenditure or Nonsubsistence Spending?

In the WHO World Health Report 2000, household nonfood expenditure was used as a proxy for capacity to pay and this variable has been adopted in various subsequent studies. The argument for using nonfood expenditure is that a household should first meet its basic food requirement (although other basic needs such as shelter and clothing also need to be fulfilled) before considering its potential contribution to a health system. Although food is considered as a household’s basic need, empirical data show that a rich household spends much more money on food than a poor household. So the same subsistence spending for all households with adjustment for household size should be defined. The 1.25 dollar a day poverty line, revisited by the World Bank in 2008, and a national poverty line have been used as subsistence spending (Ravallion et al., 2008). In order to reduce unnecessary bias and improve the comparability across countries, WHO has proposed to use the food expenditure of the household whose food share of total household expenditure is at the middle of all households in the country (Xu et al., 2005).

Summary Indices Income Approach

The commonly used indexes are the concentration index (CI), Kakwani index (KI), and redistributive effect (RE) (van Doorslaer et al., 1999). For the explanation we refer to Figure 1. The horizontal axis of the figure represents the

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cumulative percentage of the population ranked according to gross income (the poorest first). The vertical axis measures the cumulative share of health-care payments (X) and gross income (Y). The curve LX,Y(p) is the concentration curve of health-care payments. When all individuals have exactly the same amount of health-care payments, LX,Y(p) will coincide with the diagonal. When the surface of the rectangle is standardized to one, the CI is defined as twice the area below LX,Y(p) 1 and thus is a measure of inequality in health-care payments. The CI ranges from 1 to 1. The distribution of health payments is progressive when the CI is positive, regressive when CI is negative, and neutral when CI is 0. Analogously, the Lorenz curve LY(p) and the Gini coefficient measure inequality in gross income. By comparing LX,Y(p) with LY(p), we can see whether health-care payments increase income inequity. This will be the case when LX,Y(p) lies below LY(p). The KI is defined as the difference between the CI and the Gini coefficient; it coincides with twice the area between the two curves. The KI ranges from 2 to 1. A positive value indicates that health payments reduce income inequality, a negative value indicates that health payments increase income inequality, and 0 indicates that health payments do not change equity in income. The RE is defined as the difference between two income Gini coefficients: income prehealth payments and income posthealth payments. The RE takes into consideration both vertical and horizontal equity and is dependent on the share of health-care payments in income. It ranges from 1 to 1 with the same interpretation of the KI. The RE can be decomposed in three components: (1) vertical equity, (2) horizontal equity, and (3) reranking in the income distribution (Wagstaff and van Doorslaer, 1997). As such the effects relate equity in health financing to the treatment of unequals and the differential treatment of equals. The three components can again be decomposed in effects from a tax rate and a tax structure change (Zhong, 2009). All three indexes have the property of scale invariance which means when every household doubled their payments, the indexes do not change (Jenkins, 1991). Also, these indexes

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Financial Burden Approach

The financial burden approach argues that although progressivity is desirable for a health financing system, most societies do not seek to redistribute income through financing health care but do expect health payments to be arranged in a fair way (WHO, 2000). At any given level of total revenue from health-care services, each individual should carry the same burden. The burden is measured as a share of total household spending on health to a household capacity to pay (nonsubsistence spending). The fairness in financial contribution (FFC) index is used to summarize the distribution of the burden across the population. The FFC index is between 0 and 1 with 1 indicating the perfect situation that the share of the total health spending of household capacity to pay is identical for all household. The index will be less than 1 in case shares differ. All deviations are treated alike; no distinction is made between inequities due to progressivity or regressivity of payments. 0 represents the maximum unfairness. The FFC index has the property of constant invariance which means that by adding or subtracting the same amount of burden to all households the index remains the same. The FFC index is more sensitive to health payments made by households at the tail of the distribution (Xu et al., 2003). According to the financial burden approach, a fairly financed health system collects its revenue in a progressive manner since payment of an equal share of nonsubsistence spending by all households implies that a high-income household pays a higher share of its total expenditure than a lowincome household. It also implies that no household should face financial catastrophe. The most commonly used measure in the financial burden approach is the percentage of households facing catastrophic health expenditure. The percentage of households with catastrophic expenditure also gives the flexibility in setting different thresholds according to different country situations. The WHO has used 40% of the out-of-pocket payment in a household’s nonsubsistence spending as a threshold for its cross-country studies.

The Limitation of the Indices Equity or fairness in health financing is defined under the condition that every person can access services when needed. None of the measures take into consideration the actual use of health services. It has been argued that equity in health payments and equity in access to care imply separate policies (Smith, 2010). While it may not be necessary or desirable to combine the two into one index, a further analysis of the distribution of access to health care should provide a more comprehensive picture of equity. Related to this discussion is the issue of the ‘origin’ of health-care payments. Health-care payments can be the result of characteristics for which the individual can be held responsible or not. Think about the health expenditure following a skiing accident versus that resulting from a genetic defect (Le Clainche and Wittwer, 2015). High payments may also be associated with the individual’s choice of a very expensive, but not more effective physician. Furthermore, each equity index has it its own focus. The choice among the indexes depends on the purpose of the study. For example, the income approach gives more an overall picture while the burden approach focuses on vulnerable groups. Apart from the methodological concern, the characteristics of data used in measuring equity or fairness are critical. Most measures use sampled household survey data. The quality of data, the recall period of total household expenditures and expenditures for health care, and the questions phrased in the survey may all have an impact on the results.

Empirical Results on Equity in Health Financing Global Inequity Despite continuous efforts made at the global and national levels, equity in health-care financing is still far below expectation. Statistics in the World Health Report (2005) show that in the year 2002, about 85% of the global population spent only 20% of total health expenditure (Figure 2). According to the Global Health Expenditure Atlas, the per capita total health spending in 2011 was less than $20 in 6 countries and less than $44 in 26 countries (WHO, 2014). Furthermore, every year 44 million households, or more than 150 million individuals, throughout the world face catastrophic expenditure, about 25 million households or more than 100 million individuals are pushed into poverty by the need to pay for services, and 1.3 billion people do not have

A wide range of equity measures can also be used to analyze the distribution of households’ health payments, such as the entropy measures, Atkinson’s index, and variance. The entropy measures, including Theil and mean logarithmic deviation (MLD), are derived from the notion of entropy in information theory. The Theil and MLD give more weight to the individuals at the tail of the distribution. Atkinson’s index has its origins in the social welfare literature. Through changing levels of inequality aversion, Atkinson’s index allows one to explore the consequence of different weighting systems. A higher inequality aversion implies higher weights on the households at the tail of the distribution.

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access to effective and affordable health care (Preker et al., 2002; Xu et al., 2005).

Cross-country Comparison There is a rich literature on equity of health financing, among which two groups of studies have made great effort to undertake cross-country comparisons. The first group was started in the late 1980s in the OECD countries by Wagstaff and van Doorslaer, who used income approach indexes to examine the progressivity of different means of health financing (Murray et al., 2003; Wagstaff et al., 1999; De Graeve and Van Ourti, 2003). Later on in the early 2000s the same methodology was applied to a group of countries in the Asia Pacific region (O’Donnell et al., 2008, 2006; Wagstaff and Van Doorslaer, 2003). The overall progressivity of a health financing system depends on the progressivity of health payments from various sources (general government tax revenue, social health insurance, etc.) and their share in total health payments. The study by Wagstaff and van Doorslaer in OECD countries (Murray et al., 2003; Wagstaff et al., 1999; De Graeve and Van Ourti, 2003) found that the overall health payments were regressive in 7 out of the 14 countries (Table 1). The United States and Switzerland were the worst in terms of equity while the United Kingdom was the best. The variability across countries in the KI of total payments is small, however (range 0.045 to 0.051), with the exception of the United States and Switzerland being outliers. Payments made through direct taxes, such as income Table 1

Progressivity of health-care financing by components (Kakwani index) Direct taxes

Early study in OECD countries Belgium (1997) Denmark (1987) Finland (1990) France (1989) Germany (1989) Ireland (1987) Italy (1991) The Netherlands (1992) Portugal (1990) Spain (1990) Sweden (1990) Switzerland (1992) The United Kingdom (1993) The United States (1987) Asia Pacific region Bangladesh (1999–2000) China mainland (2000) Hong Kong (1999–2000) Indonesia (2001) Japan (1998) Korea Rep. (2000) Kyrgyzstan (2000) Nepal (1995–96) Philippines (1999) Sri Lanka (1996–97) Taiwan (2000) Thailand (2002) (14;15).

tax and property tax, were progressive in all countries while payments made through indirect taxes, such as value-added tax (VAT), sales tax, and excise duties, were regressive. Social health insurance contributions through payroll tax were progressive except in Germany and the Netherlands, where until recent reforms high-income earners could opt out or are excluded from social insurance. Private health insurance varied across countries, due to the variety of roles and market shares. The out-of-pocket payments were the most regressive financing source in all countries included in this study (except for Italy and the Netherlands). Out-of-pocket payments are related to demand for health-care consumption, which is higher in low-income groups who incur more illnesses. The Asia Pacific region study included 10 territories, most of which belong to the developing world. Compared to OECD countries, the results from the Asia Pacific region were somewhat surprising except for health payments financed via direct taxes. Among the 10 territories included in the study, only Taiwan had a regressive health financing system (Table 1). Health payments financed via direct taxes were generally progressive as with the OECD countries. Unlike the OECD countries, the health payments financed via indirect taxes in Asia Pacific were all progressive except in Sri Lanka. Out-ofpocket payments were progressive except in China mainland, Kyrgyzstan, and Taiwan. Social health insurance was prevalent in eight territories in this study, but most on a small scale except in Taiwan, Japan, and Republic of Korea where it covered nearly the entire population. Surprisingly, social health

Indirect taxes

0.180 0.0624 0.1272

0.180 0.1126 0.0969

0.2488 0.2666 0.1554 0.2003 0.2180 0.2125 0.0529 0.2055 0.2843 0.2104

0.0922 0.1135 0.0885 0.0347 0.1533 0.0827 0.0722 0.1522 0.0674

0.5523 0.1521 0.3940 0.1962 0.0950 0.2683 0.2395 0.1436 0.3809 0.5693 0.2438 0.5101

0.1110 0.0398 0.1102 0.0741 0.2232 0.0379 0.0508 0.1143 0.0024 0.0100 0.0404 0.1819

Social insurance

Private insurance

0.102

0.0210 0.0313 0.000 0.1956 0.1219 0.0210 0.1705 0.0833 0.1371 0.0224

0.0937 0.1112 0.0977 0.1263 0.1072 0.1286 0.1845 0.0615 0.0100 0.0551 0.1867 0.0181 0.2348 0.3057 0.0415 0.1634 0.1422

0.2548 0.0766 0.2374

0.0403

0.2048

0.1199

0.0749 0.1803

0.2053 0.0039

Out-of-pocket payments

Total financing

0.260 0.2654 0.2419 0.3396 0.0963 0.1472 0.0807 0.0377 0.2424 0.1801 0.2402 0.3619 0.2229 0.3874

0.000 0.0047 0.0181 0.0012 0.0452 0.0413 0.0703 0.0445 0.0004 0.0158 0.1402 0.051 0.1303

0.2192 0.0168 0.0113 0.1761 0.2691 0.0124 0.0520 0.0533 0.1391 0.0687 0.0780 0.0907

0.2142 0.0404 0.1663 0.1737 0.0688 0.0239 0.0087 0.0625 0.1631 0.0850 0.0292 0.1972

Equity in Health Financing

insurance contributions were progressive in all territories except the three that nearly reached universal coverage. The second group of comparative studies were conducted within the framework of health system performance assessment proposed by WHO. The studies focused on fairness and catastrophic health expenditure and used the burden approach measures. Data for 59 countries have so far been analyzed (WHO, 2000). Results from the second group of studies found significant variations in the FFC index across countries. It ranged from 0.74 in Brazil to 0.94 in Slovakia (Table 2). The percentage of households with catastrophic expenditure ranged from less than 0.1% in Belgium, Canada, Czech Republic, France, Germany, Romania, Slovakia, Slovenia, South Africa, and the United Kingdom to over 10% in Brazil and Vietnam. In general the high-income OECD countries scored high in FFC and a low percentage of households were facing catastrophic expenditure, but there was considerable variation even among OECD countries. For example, the United States and Switzerland were far behind most of the other OECD countries. Catastrophic expenditure were highest in some countries in transition and in certain Latin-American countries. A further study has explored the link between catastrophic expenditure and health system indicators (Xu et al., 2003). The study identified three key preconditions for catastrophic payments: the availability of health services requiring out-ofpocket payment, low capacity to pay, and the lack of prepayment mechanism. The results showed that the higher the percentage of out-of-pocket payment in total health-care spending and the larger the population below the poverty line, the higher the percentage of households with catastrophic expenditure. Holding these two factors constant, a higher ratio of total health spending to gross domestic product (GDP) led to a higher percentage of catastrophic expenditure; GDP is a proxy for availability of services. Out-of-pocket payments were specifically highlighted in causing catastrophic expenditure. Figure 3 shows the relationship between the percentage

Fairness in financial contribution and catastrophic

Table 2 payments Country

FFC index

% Of households a Country

Argentina Azerbaijan Bangladesh Belgium Brazil Bulgaria Cambodia Canada Colombia Costa Rica Croatia Czech Denmark Djibouti Egypt Estonia Finland France Germany Ghana Greece Guyana Hungary Iceland Indonesia Israel Jamaica Korea Kyrgyz Latvia

0.785 5.77 0.748 7.15 0.868 1.21 0.903 0.09 0.740 10.27 0.862 2.00 0.805 5.02 0.913 0.09 0.809 6.26 0.861 0.12 0.865 0.20 0.904 0.00 0.920 0.07 0.853 0.32 0.835 2.80 0.872 0.31 0.901 0.44 0.889 0.01 0.913 0.03 0.862 1.30 0.858 2.17 0.887 0.60 0.905 0.20 0.891 0.30 0.859 1.26 0.897 0.35 0.787 1.86 0.847 1.73 0.875 0.62 0.828 2.75

FFC index

Lebanon Lithuania Mauritius Mexico Morocco Namibia Nicaragua Norway Panama Paraguay Peru Philippines Portugal Romania Senegal Slovakia Slovenia South Africa Spain Sri Lanka Sweden Switzerland Thailand UK Ukraine USA Vietnam Yemen Zambia

% Of households a

0.844 5.17 0.875 1.34 0.861 1.28 0.857 1.54 0.913 0.17 0.877 0.11 0.829 2.05 0.888 0.28 0.801 2.35 0.815 3.51 0.813 3.21 0.886 0.78 0.845 2.71 0.901 0.09 0.892 0.55 0.941 0.00 0.890 0.06 0.894 0.03 0.899 0.48 0.865 1.25 0.920 0.18 0.875 0.57 0.888 0.80 0.921 0.04 0.788 3.87 0.860 0.55 0.762 10.45 0.853 1.66 0.816 2.29

% of households with catastrophic expenditure (logarithm)

(2). a Only out-of-pocket payments are included.

Figure 3

15 8 3 1 0.3 0.1 0.03 0.01 3

5

8

573

14

22

37

61

100

Out-of-pocket payment in total health expenditure % (logarithm) OECD

Others

Proportion of households with catastrophic expenditures versus share of out-of-pocket payment in total health expenditure. (18).

574

Equity in Health Financing

of catastrophic expenditure and the percentage of out-of-pocket payments in total health spending.

Within-Country Difference There are also country case studies exploring the differences in health payments across socioeconomic groups and their impact on households’ financial situation. Many studies related to developing countries find that the poor carry a larger burden than the rest of the population. The poor also use fewer services. Furthermore, households with senior members, disabled members, lowly educated members, and those with a chronic disease or living in rural areas are more likely to face financial catastrophe (Kronenberg and Pita Barros, 2014; Özgen Narci et al., 2015; Choi et al., 2015; Moziful Islam et al., 2014). Using public facilities does not protect households against financial loss because of user charges. Health insurance schemes frequently play a limited role in financial risk protection because of its insufficient population coverage and the inappropriate benefit package (Su et al., 2006; Xu et al., 2006; Fabricant et al., 1999; Falkingham, 2004; Gotsadze et al., 2005). The information from those studies is useful for identifying and targeting disadvantaged population groups. Vulnerable groups benefit more from a bottom-up approach, where the poor are covered first, with generous benefit schemes and transparent rules on reimbursement levels and service provision (Somkotra and Lagrada, 2008; Axelson et al., 2009; Kwon, 2011). In federal states, the variation in health financing equity within countries can be equally large as between countries (Crivelli and Salari, 2014). However, this variation does not seem to be strongly driven by decentralization of health responsibilities to regions (Costa-Font and Gil, 2009).

Policy Implications in Improving Equity in Health Financing Different Policy Focuses in Different Settings Equity in health financing is a common concern of many countries. Diverse socioeconomic and political settings have produced different perspectives on how to address the equity issue. For example, in Africa, user fees, the official fees charged by public facilities, have been a central focus during the past decades. Some studies found that user fees reduced the level of equity not only in health-care financing but also in access to basic care, such as in Burkina Faso, Burundi, Ghana, Tanzania, and Kenya (Ridde, 2003; Bate and Witter, 2003; Hussein and Mujinja, 1997; Nyonator and Kutzin, 1999; Chuma and Okungu, 2011; Macha et al., 2012). Other studies, for example, in Cameroon, Mauritania, Benin, and Guinea, found that the quality of services had improved after introducing user fees and that with an effective exemption mechanism the poor can also benefit from high-quality services (Litvack and Bodart, 1993; Audibert and Mathonnat, 2000; Soucat and Gandaho, 1997). Obviously, there is no final conclusion on the impact of user fees. Through debate, people realize that user fees do not constitute the sole cause of inequity in health-care financing and access to services. Alternative financing mechanisms aiming to reduce the overall out-of-pocket payments

are key in improving equity. Recent papers focus on reforms to achieve universal coverage. The main message is that this can be attained through further reductions in OOP payments, a move toward more tax-based financing and attention for the informal sector (Chuma and Okungu, 2011; Mills et al., 2012). Equity in health financing has been on the agenda of recent reforms in many Latin-American countries where social health insurance has a long history. To achieve universal coverage, also Latin-American countries face a challenge to further reduce OOP payments (Titelman et al., 2015). However, the main challenge for those countries is to reduce the gap between the insured (often formal workers) and the uninsured (mostly informal workers). In this respect, most countries have used supply-side (higher coverage, more services, fixed benefits) and demand-side (budget transfers to improve insurance coverage for the uninsured) initiatives (Atun et al., 2015). Most Asian countries face similar difficulties in coping with both the formal and informal sector (Tangcharoensathien et al., 2011; Kwon, 2011). Cambodia and Laos have supported on health equity funds financed by donors and governments. Countries previously under centralized planned economic regime had enjoyed nearly free health-care service from public facilities financed by government. Following market-oriented economic reform, these health systems solely funded by government could not be maintained, however. In order to make up for the shortage in government funding, user charges became a common practice in public facilities and equity decreased (Ensor and Savelyeva, 1998; Gao et al., 2002; Makinen et al., 2000). In these circumstances, many countries have considered social health insurance as an attractive alternative financing mechanism (Saltman et al., 2004). However, the risk is that social health insurance would start with formal sector employees leaving behind the self-employed and the poor. Furthermore, the lack of experience in organizing social health insurance adds more challenges to current reform efforts. Wagstaff and Moreno-Serra (2009) show that in the transition from a socialist regime to a system financed by social health insurance, overall expenditure increased while no effects were found on health. Finally the most developed OECD countries face the challenge to maintain their relatively equitable public health financing systems. Most of these countries have reached nearly universal coverage, but now need to cope with tight government budgets having to finance increasing health-care costs. Therefore, some have decreased the public financing share in total health expenditure and shifted financing to out-of-pocket payments and private insurance. Differential user charges, exemptions, and deductibles are also being explored to avoid catastrophic expenditures of some (unfortunate) households.

Is One Method Better than Another in Revenue Collection? Funds used for health care are mainly from government general taxation, payroll taxes, private insurance premiums, out-ofpocket payments, and external resources (especially for low-income countries). There is strong evidence that out-ofpocket payment is the most inequitable way to finance health care although some modest level of out-of-pocket payments can be maintained to stimulate the rational use of health

Equity in Health Financing services. However, out-of-pocket payments should remain affordable, which is not the case for a large proportion of the population in developing countries. Reducing out-of-pocket payments and increasing the role of prepayment schemes in overall revenue collection is still the main task for most developing countries. There are two broad types of public prepayment schemes: the tax-based financing system and the social health insurance system. In the former, funds collected are used to provide basic health services to the general population through public health facilities. Whether a tax-based system is the most equitable way to collect funds depends on the equity of the overall taxation system. Income taxes are usually more progressive than indirect taxes such as VATs, sales taxes, and excise duties. In many developing countries, government taxation mainly relies on indirect taxes so that progressivity is not guaranteed. In a social health insurance system, funds are collected from payroll taxes that are generally proportional to income. In most cases a ceiling is applied reducing the potential contribution of the high-wage population. On the other hand, there can be exemptions for the lower-wage population. In recent health financing reforms, many countries have been struggling to choose between tax-based and social health insurance mechanisms (William, 2004). In practice, we also see mixes of the two systems. For example governments may subsidize social health insurance by paying the premiums for the poor or unemployed or by providing services through public facilities at a low cost for the uninsured population (e.g., Atun et al., 2015). The choice between a tax-based system, social health insurance, or some mixed system depends on a country’s specific situation. Private health insurance, which is important in the United States, is problematic from an equity point of view. While more limited in the rest of the world, its market share is growing in some highly developed countries. These increased resources for health care can make health care more responsive to the insured, but vulnerable groups can be refused cover or priced out the market by risk-rated premiums. Policy makers should be aware of this and regulate the role of private health insurance (e.g., specify rules of access). Community-based schemes or mutual fund programs have found favor in some African countries, such as Rwanda and Senegal (Schneider and Hanson, 2006). External resources are very important in financing health care for some low-income countries. For example, in Malawi and Haiti, respectively 70% and 66% of total health expenditure comes from external resources. In Mozambique external funding accounts for 59% and in Congo 50.8%. External resources accounted for more than 11% of total health expenditure in the African region in 2012 (World Health Organization, 2015). External funding can both offset shortages of public resources and also improve equity if they are used properly in these countries.

How to Improve Equity in Health Financing? In 2005, the World Health Assembly adopted a resolution Sustainable Health Financing, Universal Coverage, and Social Health Insurance (WHO, 2005b). This resolution encourages countries to increase the extent of prepayment and reduce the reliance on out-of-pocket payments in order to improve equity in health financing. This message has remained the same for

575

the last decade (WHO, 2010, 2013) with an emphasis on universal coverage. Such reforms on revenue collection should run parallel with modifications to the other two functions of health financing, namely pooling and purchasing (World Health Organization, 2000). An appropriate pooling system allows for cross-subsidies from the healthy to the ill and from the rich to the poor (Kawabata et al., 2002). The more people are covered by a prepayment scheme, the more efficient the pooling function is. The purchasing function contributes to equity through carefully choosing a benefit package and setting a cost-sharing scale. A too small benefit package (Zhang et al., 2010) or a too high cost sharing rate will not be able to improve equity, while a too generous benefit package or a too low cost sharing rate can make the program unsustainable and compromise equity in the long run. The ideal situation of universal coverage cannot be reached within a short period of time. In most developed countries, the transitional period has lasted several decades, and this is likely also to be the case for developing countries. During the transition, various kinds of prepayment schemes should be encouraged, not only taxation and social health insurance, but also community-, cooperative-, and enterprise-based health insurance and other forms of private health insurance. There is no golden standard or universal path which can be applied to all countries. The choices have to be made within the social, economic, historical, and cultural context in each country. Above all, governments’ political will and good leadership are critical to ensure that the equity component is taken into consideration in any reform process. Once reached, there should be a continuing concern to keep the system equitable and to guarantee access to the basic benefit package to all income groups, including the poor.

See also: Cost-Influenced Treatment Decisions and CostEffectiveness Analysis; Economic Models of Hospital Behavior; Measurement and Valuation of Health for Economic Evaluation.

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Ergonomics and Musculoskeletal Issues Jack T Dennerlein, Northeastern University, Boston, MA, USA Ó 2017 Elsevier Inc. All rights reserved.

Defining Ergonomics in Public Health Ergonomics is commonly known as ʻfitting the job to the human.ʼ This definition, albeit simple, provides the fundamental directive for ergonomics of matching the requirements of a task/job with the capabilities of the worker. Other definitions describe balancing or matching the capabilities of the human and the demands of the work. As the third millennium began in 2000, the International Ergonomics Association (IEA) provided the following new and modern definition of ergonomics. “Ergonomics (or human factors) is the scientific discipline concerned with the understanding of interactions among humans and other elements of a system, and the profession that applies theory, principles, data and methods to design in order to optimize human well-being and overall system performance.” This definition sets out the idea that ergonomics is a scientific discipline utilizing applied sciences to determine relationships between work and human capability. In addition, it asserts that the practice of ergonomics includes “the design and evaluation of tasks, jobs, products, environments and systems in order to make them compatible with the needs, abilities and limitations of people.” The modern definition from the IEA identifies ergonomics as a transdisciplinary field, created in the space of many traditional disciplines such as engineering, medical, clinical, business, and social sciences. As a result ergonomics includes these disciplines and individuals working in the field come with these various backgrounds. Because the ergonomics goal of optimizing human well-being is within the broad goals of public health, many public health schools and programs incorporate ergonomics and injury prevention in their research and teaching curricula. This modern definition can be considered a foundation for public and environmental health. The IEA defines three major domains in ergonomics – physical ergonomics, cognitive ergonomics and organizational ergonomics. These domains are inclusive of traditional ergonomics fields of human factors (cognitive) and macro-ergonomics (organizational). These traditional fields have often been treated separately and for which there has been great discussion. The new IEA definition provides a single and inclusive definition.

The Burden of Musculoskeletal Disorders (MSDs) and Injury The promotion of human well-being is a broad goal; however, the focus of many ergonomics programs within public health is the prevention of work-related musculoskeletal disorders and injury. As well, the goal of optimizing system performance also meets the public health goal of improving overall well-being: increasing a worker’s productivity can increase their social and economical status and thus provide them with other opportunities to improve their overall health and wellbeing. Musculoskeletal disorders (MSDs) span a range of aliments affecting the soft tissues of the musculoskeletal systems,

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including tendons, ligaments, cartilage, muscles, and nerves. MSDs can include the bones as well (e.g., fractures), and the joints (e.g., arthritis). Work-related MSDs are deemed as any MSD that may be related to an exposure at work, exacerbated by exposure to work, or that inhibits a worker’s capability in performing their duties of employment. Chief among work-related MSDs is low back pain. Low back pain is a common and difficult problem – common in that life-time prevalence of low back pain is over 70% and difficult in that 87% of low back pain is non-specific with no known pathology. Known pathologies include failure of the intervertebral discs (yet, herniated discs have been observed in many individuals who are asymptomatic) and sciatica, referring to pain associated with the innervations of the sciatic nerve that can radiate down the whole leg. Its high prevalence and lack of a specific pathology has made treating and preventing low back pain difficult; however, there are effective primary and secondary prevention treatments available (Snook, 2004). The other major grouping of work-related MSDs is those of the upper extremities including the hand, wrist, elbow, arm, shoulder and neck. These are often subdivided into those affecting either the neck and shoulder, or those affecting the hand, wrist and arm. These disorders include many musculoskeletal aliments, but the most commonly reported are tendonitis (pain and inflammation of tendons) and generalized muscle pain. Tendonitis affects several parts of the upper extremity and is usually given a specific name based on its location. These include lateral and medial epicondilitis (tennis and golfer’s elbow, respectively), de Quervain’s (tendonitis of the thumb extensor tendon near the base of the thumb on the radial/dorsal side of the wrist) and rotator cuff injuries in the shoulder. Muscle pain also affects different parts of the extremity, mainly the shoulder trapezius muscles and the wrist and finger extensor muscles located in the forearm. Other upper extremity disorders include nerve entrapments. The most known entrapment is carpal tunnel syndrome, entrapment of the median nerve at the wrist as it passes through the small tunnel formed by the carpal bones of the wrist and the transverse ligament. Work-related MSDs encompass several different names, such as Repetitive Stress Injuries (RSIs), cumulative trauma disorders (CTDs), repetitive motion disorders, and overexertion injuries. These common names are widely used in many parts of the world; however, there is a general shift among scientists and practitioners to use the more general term musculoskeletal disorders. The chief reason is that the terminology of musculoskeletal disorders emphasizes the disorder and its specific pathology rather than the suspected etiology or exposure that led to the disorder. Work-related MSDs are a large public health burden (NCR/ IOM, 2001). MSDs are the second leading cause of absenteeism from work behind the common cold. The most recent national report about costs in the United States was in 2001. That report stated that in 1999 over one million people in the United States took time off from work to recover and treat an MSD.

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In addition, the estimated costs of MSDs to the United States economy range between $45–54 billion annually. These estimates do not include indirect costs, such as loss in productivity due to a worker’s reduced functionality or the cost of training a new employee. When estimates of indirect costs are included, cost estimates soar above $200 billion annually (NCR/IOM, 2001). As a result of this large public health burden, government agencies around the world have defined work-related MSDs as a research priority. In the United States, the National Occupational Research Agenda (NORA) defined by the National Institute for Occupational Safety and Health (NIOSH) defined MSDs as one of their 21 cross-sector research agenda items (NIOSH, see Relevant Websites).

Historical Perspective

While recent attention has been paid to work-related MSDs and ergonomics, research and treatment of MSDs are not new. The seventeenth century writings of Bernardino Ramazzini (1633– 1714) include descriptions of musculoskeletal ailments of porters who carried large loads on their shoulders, fatigue of office workers (clerks at that time worked standing up), and sciatica in potting wheel operators. In the mid-nineteenth century the industrial revolution with the advent of new manufacturing technology and processes was in full force. It was during this time that the word ergonomics was coined by a Polish engineer, Wojciech Jastrzebowski, from the Greek words ergo (work) and nomos (laws). As the twentieth century began there was an emphasis on increasing work-productivity. Frederick Taylor and Frank and Lillian Gilbreth studied the performance of humans through task, motion and time analysis with the goal of reducing cycle times for repetitive tasks such as brick layers and manual materials handling. As the twentieth century progressed technology continued to advance at faster and faster rates. The skill needed to operate these advancing technologies such as airplanes also increased. Operations of power plants, especially nuclear power plants, required even more sophistication to monitor and operate the multiple power generation, cooling, and containment systems. Since the results of error in operating these advanced technologies can and have had catastrophic results, engineers and psychologists worked together to understand how to design the human–machine interface. The end of the twentieth century brought the personal computer to the forefront of ergonomics in the areas of human computer interface (HCI) and in workstation design. In addition, awareness of work-related MSDs increased, and the reported incident rates increased substantially. Thus labor organizations in the United States rallied behind the creation of ergonomic work-place standards to ensure protection against work-related MSDs. Both California and the State of Washington put forth ergonomic standards and on 14 November 2000, the US Department of Labor introduced an ergonomics standard as part of the Occupational Safety and Health Administration (OSHA). In the first decade of the twenty-first century, the adoption of ergonomics standards experienced a few political setbacks. While many industries have successful ergonomics programs, others lobbied the US Government to repeal the ergonomics

standard. In 2001, Congress passed and the President signed into law the repeal of the OSHA ergonomic standard. Through a ballot initiative, the State of Washington repealed their ergonomics standard, which was developed involving industry and many of the specific stakeholders. In Sweden, a conservative government disbanded their National Institute for Working Life, a global leader in researching work-related MSDs in 2007. Despite these political set backs, ergonomics remains a priority for industry, research, education and public health practitioners. The California standard has successfully weathered several court challenges and is still protecting workers in California. In industry, ergonomic best practices have been identified with decreases in workers’ compensation costs as well as increases productivity providing an economical motivation for establishing and maintaining prevention efforts in the work-place. As we move further into the twenty-first century, the globalization of the world economy drives many countries to adapt and incorporate ergonomic practices and standards. Globalization has transferred many ergonomic risks to developing nations. Nations such as Brazil and Vietnam are facing challenges associated with growing production needs while dealing with health and safety issues; however, such countries understand that to be competitive their work force needs safe work and need to be healthy in order to be productive. According to the World Health Organization work-related injuries are grossly underreported (1–4%) making it difficult to even begin to establish prevention efforts. Many of these countries are developing surveillance systems in order to track and direct interventions and safety programs. In the United States, ergonomics is a key component of integrated approaches to worker health and safety that is part of the National Institute for Occupational Safety and Health (NIOSH’s) Total Worker HealthÔ initiative. These integrated approaches combine workplace occupational health and safety interventions with health promotion activities. The result is an increased effectiveness. The common example is when a worker is exposed at work to respiratory hazards they are less likely to quit smoking; however, when an occupational health intervention that reduces the respiratory hazard is implemented with a quit smoking program, smoking quit rates double. Since MSDs and many health behaviors have similar work organizational risk factors, ergonomic programs provide an opportunity for a work environment intervention that can address both the MSD and the health behavior. As a result in 2014 all four of the NIOSH Total Worker Health Centers have strong ergonomic initiatives as part of their integrated approaches to workplace health and safety interventions.

Evidence and Identified Risk Factors for Work-Related MSDs

Since many MSDs have unknown pathology and etiology, opponents to workplace standards believe that MSDs are not work-related and are more related to genetics and behavioral factors. However, major reviews of the literature by the National Research Council and the Institute of Medicine, one reported in 1998 and one in 2001, have both concluded that there is strong evidence linking work and MSDs (NRC/IOM, 2001). Specifically, their reviews identified both physical and psychosocial characteristics linked with the occurrence of MSDs in the work place (Table 1). The report acknowledges

Ergonomics and Musculoskeletal Issues Table 1 Work-related risk factors for musculoskeletal disorders identified by the NRC/IOM (2001) report Body part

Physical

Low back

l

l l l l

Upper extremity

l l l l l

Psychosocial

Lifting and or carrying of loads (manual materials handling) Load moment Whole–body vibration Frequent bending and twisting Heavy physical work Repetitive tasks Forceful tasks Combination of repetition and force Combination of repetition and cold Vibration

Rapid work pace Monotonous work l Low job satisfaction l Low decision latitude l Job stress l l

l l

High job demands High job stress

the complex interaction of an individual worker within the context of the social and organizational work environment (Figure 1). Since the reviews, there have been several animal-based studies confirming that the physical demands of repetitive work do create injuries to nerves, muscles and tendons. Low back pain is associated with jobs that involve a great deal of manual materials handling. Specifically, larger load moments have been identified as risk factors. The load moment is defined as the torque at the bottom of the lumbar region of the back by the external weight (Figure 2). The load moment supports both the weight of the object being lifted as well as the weight of the bent over torso. Hence, simply supporting the weight of the torso can add stress to the low back and frequent bending and twisting have also been identified risk as factors for low back pain. For the upper extremity, the combination of repetition and force are important factors, more significantly than simply force or repetition alone. This combination effect is demonstrated effectively by Silverstein et al. (1987). They report that the relative risk of carpal tunnel syndrome for jobs with both high force

W o r k

External load

Biomechanical loading P e r s o n

Internal loads

Physiologic response

and high frequency repetitions is 15 times compared to jobs with low force and low frequency repetition. The relative risk for high force and low repetition jobs is three times and the relative risk for high repetition and low force is five times larger compared to jobs with low force and low frequency repetitions. The NCR/IOM review concludes that psychosocial factors in the work place are also linked with the occurrence of MSDs. Psychosocial factors are broad in definition and several models have been used to define them. The Karasek model (Karasek et al., 1998) uses two fundamental axes – job demands and decision latitude – to describe work stress. Karasek also includes social support from family, co-workers and management as influencing job stress. Siegrist et al. (1997) uses two variables as well, effort and reward, to model work-related psychosocial factors. When there are in equalities either between reward and stress or demand and decision latitude, jobs are considered stressful and have been associated with increased prevalence and incidents of MSDs. In addition to these observational studies, workplace interventions addressing these risk factors further demonstrate the relationship between work and musculoskeletal health outcomes. Through these interventions, exposures to specific factors are changed, often through randomized controlled trials.

Physical Ergonomics The heart of many ergonomics programs lies in the design of physical work, and in matching the designs with the physical capabilities of human worker. The design of physical work addresses specific requirements of task and workstation design. The physical capabilities of the human worker include strength, tissue tolerances and motor capability. In general, the goal of physical ergonomics is to reduce physical loading on the musculoskeletal system through the design of work, without sacrificing performance.

Manual Materials Handling and the NIOSH Lifting Equations One of the most extensive efforts to provide a tool to match the capabilities of the humans with the specific task requirements is

Organizational factors

Internal tolerances Mechanical strain

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Fatigue

Social context

Outcomes Pain discomfort

Impairment disability

Individual factors

Figure 1 Conceptual model of injury mechanisms and risk factors for musculoskeletal disorders. The model highlights the interaction between the work-environment and the individual, showing many different pathways for the multiple work factors to affect the hypothesized injury mechanisms. Modified from NRC/IOM, 2001. Musculoskeletal Disorders and the Workplaces: Low Back and Upper Extremities. National Academy Press, Washington, DC. www.nap.edu.

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d

DM Load moment W VM

Figure 2 The load moment is created at the low back by the torque generated by the weight of the load (W) times the horizontal distance between the low back and the load. Hence load moment ¼ W d. For a given mass, an increase in the horizontal distance increases the load moment. Biomechanically, the muscles of the low back have to counteract the load moment and hence increase their forces as the load moment increases, which in turn increases the spinal compression.

the NIOSH Lifting Equation for manual materials handling (Waters et al., 1993). The lifting equation predicts a recommended weight limit for a given lifting task incorporating for different lift locations and distances relative to the body (Figures 2 and 3). The equation integrates three measures of human capabilities: (1) spinal compression forces; (2) physiological capabilities of the human; and (3) self-perceived physical capabilities (psychophysics). The spinal compression force limit is 3.4 kN (760 pounds). The 3.4 kN value is based on data from cadaver studies demonstrating that the lumbar fails between 2.1 and 9.6 kN of compression. The 3.4 kN value provides conservative estimate while allowing for uncertainty and the variability associated with cadaver studies (Waters et al., 1993). The physiological capability limit is 9.5 kcal min
1. This limit establishes a maximum aerobic lifting capacity for repetitive lifting, which is scaled down for longer exposure to lifting per day and increased frequency of lifting. The psychophysical limit is 23 Kg (51 lbs) based on the experiments conducted by Snook and Ciriello (1991). In these experiments, individuals determined their maximum lifting weight for repetitive lifting tasks given specific instructions to work without straining themselves. The 23 Kg limit matches what 75% of the women and 99% of men chose as acceptable weight, which corresponds to approximately 90% of the total population. Many airlines have 23 Kg weight limits for baggage. The NIOSH equation incorporates the specific task requirements through a set of distance measurements and assessment of the asymmetry (twisting of the torso) to complete the tasks (Figure 3). The horizontal distance and to a lesser extent the

HM Figure 3 Lifting task parameters used in the NIOSH lifting equations. HM is the parameter associated with the Horizontal distance from the midpoint of the ankles to the location of the grip; VM is the parameter associated with the vertical distance between the floor and the grip; and DM is the parameter associated with the vertical distance the load is moved.

vertical multiplier is related to the task load moment described in Figure 2. The vertical multiplier and the distance multiplier deal with the physiological limits associated with bending over or working overhead. The NIOSH lifting equation has limitations, especially when applied to real jobs. Since the human worker is flexible and can adapt to diverse jobs, workers often complete lifts (63% of lifts) that go out of the scope of the lifting equations. However, the lifting equation does identify high risk jobs and the relative risk of low back pain does increase with the equation score.

Guidelines for Lifting

From the NIOSH lifting equation and other intervention studies, general recommendations for job redesign for lifting include using lifting assistive technology, elevating the initial height of the lift (that is keeping material off the floor), and keep items close as possible to the body during lifting tasks (Marras et al., 1999; Snook, 2004). These approaches reduce bending, twisting and reaching – the specific work-related risk factors for low back pain. There are two important notes about lifting technique and back belts as interventions. First, the recommendation to ʻlift with your legsʼ is not well supported by biomechanics and interventions studies. Mechanically, lifting with one’s legs often increases the load moment about the low back by increasing the distance between the low back and the load (Chaffin et al., 2006). Unless the load can be placed between the knees during a squat lift, the load moment will be greater for squat

Ergonomics and Musculoskeletal Issues compared to stoop. In addition, a randomized control trial intervention study that used teaching ʻproperʼ lifting techniques showed no effect in reducing low back pain (Daltroy et al., 1997). The use of back belts at the work place has shown little effect. There is some biomechanical evidence that using a stiff belt, similar to heavy-weight lifters’ leather belts reduces the compressive load (Kingma et al., 2006).

Upper Extremity Tasks and Workstation Designs

The dexterity of upper extremities allows for a large range of task capabilities spanning from overhead work to interfacing with computer equipment. As a result the development of a single comprehensive tool to evaluate tasks has been lacking. The Rapid Upper Limb Assessment (RULA) provides a measure of non-neutral postures with some modifiers for force, repetition or duration (McAtamney and Corlett, 1993). The Strain index is a bit broader, including force, repetition and duration of the task within its index (Moore and Garg, 1995). Finally, the hand activity level (HAL) provides a measure of force, frequency and duration (Franzblau et al., 2005). Overall these tools are useful in identifying specific tasks that may be a risk and evaluating how redesigns and interventions can reduce the relative risk; however, their specificity is sometime lacking. In general, these tools can be summarized by five fundamental guidelines for task and workstation design: 1. 2. 3. 4. 5.

Keep the required forces low; Keep postures neutral and natural; Provide good visual access; Keep items close; Support the body and its limbs when possible.

Neutral postures reduce unnecessary strain on the body and often improve productivity. When wrists have to extend, for example, both the pressure in the carpal tunnel increases and finger and wrist muscles are stretched. Since our bodies follow our eyes, visual access, or lack thereof, directly affects the body posture assumed by a worker. Workers usually have to see clearly what they are doing and we will move their bodies to gain visual access. Visual access depends on the task and often sets the location of the work objects and point of operation of the manual work. Supporting the body decreases the load on the musculoskeletal system increasing the margin for tissue tolerances. In addition, good support allows for the body to rest and heal from any damage it may have incurred during the unsupported portions of work. These support scenarios are important for micro breaks during work as well as continuous support.

Other Physical Ergonomic Domains: From Slips and Trips to Lighting

There are several other domains of physical ergonomics, including slips, trips and falls, vibration, noise, heat stress and illumination. Injuries from falls to the same level rank number 2 for cost among workers’ compensation claims (Liberty Mutual, 2013). The environment often provides many challenges to successful locomotion. Humans are quite successful in navigating slippery surfaces and cluttered work spaces, yet they fall from time to time. Improving the design of work floor surfaces to maximize friction can reduce the risk for slips. Better housekeeping that removes lubricating

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contaminants from floors and clutter in a workspace is also an effective intervention. Lighting workspace adequately increases the visibility of potential trip and slip hazards and improves worker performance when doing other non-locomotive tasks. Vibration, both whole body (WBV) and hand arm vibration (HAV) fall in the general domain of ergonomics as well. The association between whole body vibration and low back pain as well as health outcomes in professional drivers is well documented. Similarly, the association between exposure to hand arm vibration with neurological and vascular disorders in the hands and arm is also well documents. Approaches to reduce the exposures to vibration are to attenuate the exposure through seat suspension systems in drivers and through tool handle redesign and gloves. Glare is another common light problem. When lighting is less than optimal, workers have to strain the muscles of the eyes. Simple interventions that balance the light so that the brightest area in the field of view is the point of operation for the task can provide low-cost solutions. The use of indirect lighting for general illumination and specific task lighting at the workstation is ideal, and has become popular in the workplace. Also having properly design corrective lenses help reduce eye strain.

Cognitive Ergonomics Cognitive ergonomics encompasses what is traditionally known as human factors. The goal of cognitive ergonomics is to understand the capabilities of humans to observe information (either static or dynamic) decipher the information, and act upon the given information. An example is roadway signage. Operating a motor vehicle in traffic requires the driver to observe information about road patterns while safely maneuvering a vehicle through traffic. Signage ideally provides the user with information before encountering the specific pattern. This allows for the driver to take the information and anticipate the upcoming pattern in a manner that improves the performance of the vehicle’s excursion through the pattern. The design of the signage should portray information concisely and efficiently to the driver. Another traffic example is the third center-located brake light in automobiles, which allows for cars further back to view a car’s brake light, increasing the time a driver has to decipher and act upon the information provided by the light. The design has reduced rear-end collisions. Other examples of information display and control design range from the cockpits of jumbo-jet airliners to the remote controls for home entertainment systems. Paul Fitts used specific information theory to define the capabilities of a human to comprehend information and act upon this information during the control of human movement. He applied information theory to a tapping task exploring speed versus accuracy tradeoffs (Figure 4; Fitts, 1954). Fitts proposed that as the required accuracy of the tapping task increased so did the amount of information contained in the task. As a result, the time to complete the tapping task also increased. Fitts proposed an Index of Performance as bits/second and demonstrated that for the tapping experiment for various accuracies the index

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Target width

6 inches

Target amplitude

Figure 4 The one dimensional reciprocal tapping paradigm of Fitts (1954) testing the idea of speed versus accuracy in human movement. The accuracy of the movement increases as the target width decreases and/or the amplitude of the movement increases. The movement time increases as the accuracy increases in a log-linear fashion. Reprinted from Fitts, P.M., 1954. The information capacity of human motor systems in controlling the amplitude of a movement. J. Exp. Psychol. 47, 381–391 with permission.

remained constant supporting the idea that information flow has a maximum throughput. Fitts’ law has been used for the design and location of control devices, especially with input devices for personal computers and mobile information technology.

Designing for Human Error Humans have a specific capability of processing information and making decisions. When technology has increased rapidly, the human component in the design and control of technology is important. When the capabilities of the human are exceeded in terms of these process systems can fail and the outcomes are usually blamed on human error. “Human error is defined as the failure of a planned action to be completed as intended (error of execution) or the use of a wrong plan to achieve an aim (error of planning). An error may be an act of commission or an act of omission” (IOM, 2007). Systems can be designed to mitigate the effects of human error. A study by Rigby (1973) demonstrates well this concept. In this study Rigby describes that an electronics assembly plant was losing a large number of its product components due to employees dropping them during the assembly process. Telling the employees not to drop the devices had little to no affect. It was realized that, throughout the manufacturing process, the items were hand carried numerous times, each time being exposed to the risk of being dropped. The actual rate that employees were dropping the assemblies was normal if not better. Decreasing the number of times the items were carried reduced the number of units lost due to damage caused from a dropped device. The solution was to realize that people do drop items and that the design of the process should be to mitigate the consequences of these simple and expected human errors. The aerospace industry has excelled in understanding human error and has incorporated many redundant systems to mitigate the consequences of humans error. The fundamental concept of co-pilots provides a redundant system to act both as a system checker and a backup to the main pilot.

In the new century there is emphasis on human error in health care situations. According to the Institute of Medicine report (IOM, 2000), the number of deaths due to medical error could be as high as 98 000 per year in the United States alone. While the professionals in the health care industry are among the most trained, they work in systems that need to better incorporate the human element. For example, simple prevention strategies for medication errors include having a pharmacist participate in hospital rounds, and more effective labeling. For surgical approaches, simply using a procedural check list in the operating room can reduce medical errors.

Organizational Ergonomics Organizational Ergonomics, traditional denoted as macro ergonomics, deals with how the policies, programs, and practices of an organization affect a workers wellbeing and performance within the context of the organization at large. The structure of an organization can directly determine the exposure to physical factors for individual workers and indirectly affect the individual through social structures. In addition these policies, programs, and practices can determine the organization’s flexibility needed to deal with changing ergonomic (and economic) challenges within the workplace. The manufacturing of products consists of processes that include both automated and manual tasks; hence, it follows that the design of the production process influences the workers’ exposure to specific risk factors for MSDs. The organization of the production process determines the worker performance and hence the worker’s exposure to potential risk factors for work-related MSDs. Therefore, many opportunities for ergonomic interventions exist at several levels of the process development ranging from the community, the company and the individual worker. Figure 5 depicts a simple example of how the production process can influence ergonomics of manual materials handling. The figure has two boxes that have the same dimensions and contain the same item; however the boxes are oriented differently creating different biomechanical load when the boxes are manually lifted. The difference in orientation can be attributed to the manufacturing process, where the box on the left is design for automatic materials handling via conveyor belt and vacuum lift assisting systems. The horizontal configuration provides stability and larger surface area for moving the material within these automated systems. While most of the process is automated, the end user and delivery person will lift the box in this configuration due to the orientation of the printed material and the location of the handles. The box on the right could still be moved through automatic handling systems in the horizontal configuration; however, the labels and the location of the handles suggest a different biomechanical interface that reduces the load. Participatory ergonomics addresses the organizational factors surrounding an individual’s decision latitude by empowering individual workers to make specific changes in their work that improve process productivity and reduce exposure to MSD risk factors. Overall participatory approaches

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Figure 5 Here, two boxes with the same dimensions and the same contents are oriented differently creating different biomechanical load for the worker. The box on the left is oriented horizontally, which may increase its stability during automatic materials handling via conveyer belts and vacuum lifts; however, this horizontal configuration increases the load moment when the box is handled after it has left the production facility.

articulate aspects of successful health and safety programs through employee involvement. Wilson (1995) define participatory ergonomics as the involvement of people in planning and controlling a significant amount of their own work activities, with sufficient knowledge and power to influence both processes and outcomes in order to achieve desirable goals.

To achieve a participatory approach the culture of the organization has to be integrated well with the workers, their knowledge, and their control. There are many success stories of participatory ergonomics in industries ranging from the military to service industries (see Hignett et al., 2005 for a review). In the construction industry, Hess et al. (2004) describe improvements in the physical ergonomic parameters during manual materials handling tasks of a concrete supply hose due to a new skid plate developed through a participatory ergonomics program. Within the Total Worker Health efforts, participatory approaches further emphasize the importance of participatory approaches for work place health promotion activities. The attitudes and beliefs of the work environment and society as a whole can affect the outcomes of MSD, specifically a worker not returning to work due to an MSD (disability). Changing the attitudes about low back pain among supervisors can change the rates of disability associated with MSDs. Shaw et al. (2006) has demonstrated that simply training the supervisor about communication skills and ergonomic accommodation for workers reporting injuries reduces disability within the

workplace. Changing the beliefs of management, workers and physicians within society can also reduce work disability. In Australia, Buchbinder et al. (2001) documented that media campaigns can assist physicians by helping them prescribe changes to work rather than requiring avoiding work or any physical activity as a treatment for low back pain. The literature is quite convincing that for non-specific low back pain, remaining active prevents disability.

The Effectiveness of Ergonomic Interventions Ergonomic interventions do work. Comprehensive approaches that integrate all three areas of ergonomics (i.e., physical, cognitive, and organizational) appear to be the most effective. The Institute for Work and Health in Ontario, Canada (http://www.iwh. on.ca/) has completed many systematic reviews documenting the effects of workplace health and safety intervention studies aimed at reducing work-related musculoskeletal disorders. These reviews point toward these comprehensive approaches. These reviews also demonstrate the effectiveness of changing the physical environment through products designed to reduce exposure to physical factors that can be employed at a workplace. Often however, the introduction of the product or tool is necessary but not always sufficient. Several studies have shown that training and usability of the tool is also necessary for their successful integration. In addition, improvements are more frequently observed when the physical intervention is derived from a participatory ergonomic intervention. The big component in a successful

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safety program for any work-place is management’s commitment to allow for all three areas of ergonomics to improve the wellbeing of the worker. Again, all of these reviews point toward comprehensive approaches that contain the essential elements of an ergonomics program aimed ad injury and illness prevention. These include management commitment, employee involvement, hazard identification and control, training, and program evaluation.

Conclusions The beauty of the human work force is its versatile capabilities to perform a vast range of manual tasks from heavy lifting to fine assembly; however, when the duration of work is long and its tasks are repetitive the capabilities of the human are limited and the overall wellbeing of the human worker can be harmed. The public health burden of work-related musculoskeletal disorders and injury are large, accounting for the majority of employee compensation costs. Ergonomic through a systems approach can mitigate this public health burden of MSDs through identifying and understanding the capabilities of the human and the demands of the work via multidisciplinary approaches to work place design and management. These approaches have proven to be successful in reducing the burden of injury among workers.

References Buchbinder, R., Jolley, D., Wyatt, M., 2001. 2001 Volvo Award winner in clinical studies: effects of a media campaign on back pain beliefs and its potential influence on management of low back pain in general practice. Spine 26, 2535–2542. Chaffin, D.B., Andersson, G., Martin, B.J., 2006. Occupational Biomechanics. Wiley-Interscience, New York, NY. Daltroy, L.H., Iversen, M.D., Larson, M.G., Lew, R., Wright, E., Ryan, J., Zwerling, C., Fossel, A.H., Liang, M.H., 1997. A controlled trial of an educational program to prevent low back injuries. N. Engl. J. Med. 337, 322–328. Fitts, P.M., 1954. The information capacity of human motor systems in controlling the amplitude of a movement. J. Exp. Psychol. 47, 381–391. Franzblau, A., Armstrong, T.J., Werner, R.A., Ulin, S.S., 2005. A cross-sectional assessment of the ACGIH TLV for hand activity level. J. Occup. Rehabil. 15, 57–67. Hess, J.A., Hecker, S., Weinstein, M., Lunger, M., 2004. A participatory ergonomics intervention to reduce risk factors for low-back disorders in concrete laborers. Appl. Ergon. 35, 427–441.

Hignett, S., Wilson, J.R., Morris, W., 2005. Finding ergonomic solutions–participatory approaches. Occup. Med. (Lond.) 55, 200–207. IOM, Institute of Medicine, 2000. To Err Is Human: Building a Safer Health System. National Academy of Sciences, Washington, DC. IOM, Institute of Medicine, 2007. Preventing Medication Errors: Quality Chasm Series. National Academy Press, Washington, DC. Karasek, R., Brisson, C., Kawakami, N., Houtman, I., Bongers, P., Amick, B., 1998. The Job Content Questionnaire (JCQ): an instrument for internationally comparative assessments of psychosocial job characteristics. J. Occup. Health Psychol. 3, 322–355. Kingma, I., Faber, G.S., Suwarganda, E.K., Bruijnen, T.B., Peters, R.J., van Dieen, J.H., 2006. Effect of a stiff lifting belt on spine compression during lifting. Spine 31, E833–E839. Liberty Mutual, 2013. Liberty Mutual Workplace Safety Index. Liberty Mutual Inc., Boston, MA. Marras, W.S., Fine, L.J., Ferguson, S.A., Waters, T.R., 1999. The effectiveness of commonly used lifting assessment methods to identify industrial jobs associated with elevated risk of low-back disorders. Ergonomics 42, 229–245. McAtamney, L., Corlett, N.E., 1993. RULA: a survey method for the investigation of work-related upper limb disorders. Appl. Ergon. 24, 91–99. Moore, J.S., Garg, A., 1995. The Strain Index: a proposed method to analyze jobs for risk of distal upper extremity disorders. Am. Ind. Hyg. Assoc. J. 56, 443–458. NRC/IOM, 2001. Musculoskeletal Disorders and the Workplaces: Low Back and Upper Extremities. National Academy Press, Washington, DC. www.nap.edu. Rigby, L.V., 1973. Why do people drop things? Qual. Prog. 16–19. Shaw, W.S., Robertson, M.M., McLellan, R.K., Verma, S., Pransky, G., 2006. A controlled case study of supervisor training to optimize response to injury in the food processing industry. Work 26, 107–114. Siegrist, J., Klein, D., Voigt, K.H., 1997. Linking sociological with physiological data: the model of effort-reward imbalance at work. Acta Physiol. Scand. Suppl. 640, 112–116. Silverstein, B.A., Fine, L.J., Armstrong, T.J., 1987. Occupational factors and carpal tunnel syndrome. Am. J. Ind. Med. 11, 343–358. Snook, S.H., 2004. Work-related low back pain: secondary intervention. J. Electromyogr. Kinesiol. 14, 153–160. Snook, S.H., Ciriello, V.M., 1991. The design of manual handling tasks: revised tables of maximum acceptable weights and forces. Ergonomics 34, 1197–1213. Waters, T.R., Putz-Anderson, V., Garg, A., Fine, L.J., 1993. Revised NIOSH equation for the design and evaluation of manual lifting tasks. Ergonomics 36, 749–776. Wilson, J.R., 1995. Ergonomics and participation. In: Wilson, J.R., Corlett, N. (Eds.), Evaluation of Human Work: A Practical Ergonomics Methodology, pp. 1071–1096.

Relevant Websites www.ergonomics.org.uk – Ergonomics Society (UK). www.hfes.org – The Human Factors and Ergonomics Society. http://www.iwh.on.ca/ – Institute for Work and Health (CA). www.iea.cc – The International Ergonomics Association. http://www.cdc.gov/niosh/docs/2006-121/pdfs/2006-121.pdf – Niosh.

Escherichia coli Jan T Poolman, Bacterial Vaccine Discovery & Early Development, Janssen, Leiden, The Netherlands Ó 2017 Elsevier Inc. All rights reserved.

Introduction Escherichia coli is a gram-negative rod-shaped bacterium and a member of the family of Enterobacteriaceae, a large family which also includes Salmonella, Klebsiella, Proteus, and Enterobacter spp. Escherichia coli are facultative anaerobes and display a wide diversity in phenotype and genotype. The E. coli genome undergoes constant change due to a continual flux of genetic insertions and deletions. The genome size, which can vary by up to 1.9 Mb, encodes approximately 4000–6500 proteins. The core genome comprises only 2000 genes, and the rest of the genome determines commensalism, species specificity, pathotype, and antibiotic susceptibility profile. The core genome contains mostly nonmobile elements, while strainspecific genes are more likely to be located on pathogenicity islands, which are large regions of the genome that contain virulence-related genes found in pathogenic strains but not commensal strains, and mobile elements including plasmids, bacteriophages, insertion sequence elements, transposons, integrons, and prophages. Many of these mobile genetic elements are found in other pathogenic bacterial species suggesting a history of genetic transfer and exchange. Escherichia coli strains can be broadly grouped into three families: (1) commensal organisms that are normal residents of the gastrointestinal tract that do not cause disease, (2) strains that cause diarrheal intestinal disease (enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), enterohemorrhagic E. coli (EHEC), enteroaggregative E. coli (EAEC), enteroinvasive E. coli (EIEC), and diffusely adherent E. coli (DAEC)), and (3) strains that usually cause disease outside of the intestinal tract (grouped together under the term extraintestinal pathogenic E. coli or ExPEC) (Kaper et al., 2004). Among representative strains from each of these families, only around 20% of coding sequences are shared among all strains, with
64% of sequences shared between commensal and ExPEC strains. It has been generally held that many, or even most E. coli pathotypes, cause a limited range of clinical symptoms and can be readily classified according to the presence or absence of key virulence factors. However, distinctions between pathotypes are not clear-cut and there is considerable overlap in the spectrum of infections caused by some pathotypes (Figure 1). More recently, comparative genomics demonstrate substantial genetic diversity within pathovars, indicating that the distinction between pathovars is substantially more complex than originally thought.

Escherichia coli Pathotypes Causing Intestinal Disease Enterotoxigenic Escherichia coli ETEC are frequent causes of watery, dehydrating diarrheal disease in children in the resource-limited world and in international travelers (Table 1). These organisms have also been identified as the source of food-borne outbreaks in the

International Encyclopedia of Public Health, 2nd edition, Volume 2

resource-sufficient world. ETEC also cause significant morbidity and mortality in young animals, especially piglets and calves. ETEC produce secretory diarrhea and must first colonize the small bowel where the secretory toxins will act. This is achieved by encoding for the production of colonizing fimbriae (colonizing fimbrial antigens, or CFA) that bind to receptors on the small bowel enterocytes or within the small bowel mucin. Escherichia coli that produce CFA but no toxins are able to colonize the small bowel but are less likely to produce diarrheal disease. ETEC produce two major classes of secretory toxins (the heat-labile (LT) cholera-like enterotoxin and heat-stable enterotoxin (ST)), which are encoded on plasmids and which are used for identification of ETEC strains (Table 2). ST may be the more important toxin, and ST-producing ETEC, but not ETEC producing only LT, have been implicated in moderate-to-severe diarrhea in children living in resource-limited countries. There are two STs that produce diarrheal disease, STa and STb, but only STa is associated with human disease. STb produces diarrheal disease in piglets. ST activates cyclic GMP which also results in the secretion of chloride and the inhibition of sodium chloride absorption with the secretion of water into the small bowel. LT is actually a family of toxins that are related in structure and

ExPEC

AIEC

UPEC DAEC

NMEC EAEC

aEPEC

EPEC

EHEC

tEPEC

STEC

O104:H4

O157:H7 S.dysenteriae

ETEC

EIEC Shigella

Figure 1 The complex relationship between Escherichia coli pathotypes causing intestinal and extraintestinal disease. aEPEC, atypical EPEC; tEPEC, typical EPEC; ETEC, enterotoxigenic E. coli; EAEC, enteroaggregative E. coli; EPEC, enteropathogenic E. coli; STEC, Shiga toxin– producing E. coli; EHEC, enterohemorrhagic E. coli; EIEC, enteroinvasive E. coli (Shigella); DAEC, diffusely adherent E. coli; ExPEC, extraintestinal E. coli; UPEC, uropathogenic E. coli; MNEC, meningitis-associated E. coli; AIEC, adherent invasive E. coli; O157:H7, major virulent foodborne pathogen with reservoir in cattle and other ruminants; O104:H4, caused an outbreak of diarrhea in Europe in 2011 with high fatality due to a Shiga toxin–producing variant. Adapted with permission from Donnenberg, Michael (Ed.), 2013. Escherichia coli: Pathotypes and Principles of Pathogenesis, second ed. Academic Press.

http://dx.doi.org/10.1016/B978-0-12-803678-5.00504-X

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586 Table 1

Escherichia coli Pathogenic Escherichia coli Site of infection

E. coli causing intestinal disease ETEC: enterotoxigenic E. coli Small intestine

Disease

Phylogroup

Epidemiology

Complications

Watery diarrhea

B1, B2

Endemic in resource-limited countries, traveler’s diarrhea, food-borne Sporadic, endemic in resourcelimited countries, travelers, individuals with HIV Sporadic or endemic disease, institutional outbreaks

Dehydration

EAEC: enteroaggregative E. coli

Small and large intestine

Watery diarrhea

B1, A

EPEC: enteropathogenic E. coli

Small intestine

Watery diarrhea

B1

EHEC: enterohemorrhagic E. coli EIEC: enteroinvasive E. coli (Shigella) DAEC: diffusely adherent E. coli

Large intestine

Hemorrhagic colitis

B1, E

Large intestine (intracellular) Small intestine

Watery or bloody A, B1 diarrhea Acute diarrhea, B2, D possibly plays a role in inflammatory bowel disease, pregnancy complications

E. coli causing extraintestinal infections ExPEC: Extra-intestinal E.coli Blood stream UPEC: uropathogenic E. coli

Urinary tract

NMEC: neonatal meningitisassociated E. coli

Meninges

AIEC: adherent invasive E. coli

Ileum

Bacteremia Pyelopnephritis Cystitis Meningitis

B2, D D, A, B1 B2, D

Thought to play a role B2 in Crohn’s disease

mechanism of action to the secretory toxin produced by Vibrio cholerae. LT acts by stimulating adenylate cyclase and increasing intracellular cyclic AMP which activates secretory processes in the small intestinal cell. The increased levels of cyclic AMP initiate secretion of chloride from the intestinal crypt cells and inhibit the absorption of sodium chloride in the cells at the tips of the intestinal villi. These alterations are followed by secretion of water.

Enteroaggregative Escherichia coli EAEC are associated with acute and persistent diarrheal illnesses in children in the resource-limited world and in patients with HIV; they have also been identified as a frequent cause of traveler’s diarrhea (Table 1). EAEC cause diarrheal disease through attachment to enterocytes; these organisms were originally recognized by their distinctive ‘cascading, brickwork’ adherence to cells in tissue culture that form a thick biofilm. This adherence pattern has also been noted in intestinal biopsies of children with EAEC disease and is not just an in vitro phenomenon. EAEC express aggregative adherence fimbriae 1 and 2 (AAF I and AAF II) that are associated with the Dr-family of adhesins (Table 2). These adherence fimbriae are present on many, but not all, of the EAEC associated with

Sporadic, outbreaks, food-borne Sporadic diarrhea

Persistent diarrhea, nutritional compromise Dehydration, nutritional compromise Hemolytic uremic syndrome Dehydration

All ages

Possible contribution to ulcerative colitis pathogenesis or relapse

All ages, particularly elderly, post-operative All ages All ages Neonates

Sepsis, abscess, death

Crohn’s disease

Renal scarring, sepsis Pyelonephritis, sepsis Long-term neurological sequelae, death Possible contribution to Crohn’s disease pathogenesis or relapse

diarrheal disease. The genes for these fimbriae are encoded on a virulence plasmid. EAEC are a heterogeneous group and some strains have been isolated from UTIs (Figure 1). It is believed that a package of virulence factors is necessary for the production of diarrheal disease by EAEC and that the expression of this package is under the control of AggR, a transcriptional regulator. Toxins linked to EAEC include E. coli aggregative secretory toxin 1 (EAST1), and the autotransporters Pic and Pet, but the association of these toxins with diarrheal disease is unclear. A unique EAEC strain expressing Shiga toxin (O104:H4; Figure 1) caused a major epidemic of hemorrhagic diarrhea in Germany in 2011. There were 3842 confirmed cases, 855 of which developed hemolytic uremic syndrome (HUS) and 54 deaths (Navarro-Garcia, 2014). Cases were subsequently reported from throughout Europe as well as the United States. This highly virulent strain combines characteristics of EAEC, such as Aggr transcription factor and a prophage encoding the stx2 gene found among STEC (see below).

Enteropathogenic Escherichia coli EPEC cause sporadic, usually self-limiting diarrheal illnesses in adults and children and are also responsible for outbreaks of

Escherichia coli Table 2

587

Representative virulence traits of Escherichia coli pathogenic to humans Key virulence factors

ETEC: enterotoxigenic E. coli

Site

Function Induces a secretory state resulting in watery diarrhea Induces a secretory state resulting in watery diarrhea Attachment Possibly interacts with epithelial receptors Adherence Homologue of STa of uncertain role Adherence Mucinase activity Enterotoxin Promotes bacterial spreading or mucus penetration Enterotoxin Intimin and translocated intimin receptor promotes protein delivery to enterocytes Inhibits lymphocyte activation Possibly adherence Intimin and translocated intimin receptor promotes protein delivery to enterocytes

Heat-labile enterotoxin

eltAB

Plasmid

Heat-stable enterotoxin

sta

Plasmid

Plasmid-encoded fimbriae Type 1 secretion system Aggregative adherence fimbriae Heat-stable enterotoxin EAST1 Aggregative adherence fimbriae Autotransporter toxin Autotransporter toxin Dispersin transporter protein

various eg cfa aat-cexT aggR, aggA astA aaf1-4 pic pet aatA

Plasmid Plasmid Plasmid Plasmid Plasmid Chromosome Plasmid Plasmid

Shigella enterotoxin 1 Type III secretion system

Set TTSS

Chromosome LEE pathogenicity island

Lymphostatin Bundle-forming pilus Type III secretion system

lifA bfp TTSS

Chromosome EAF plasmid LEE pathogenicity island

Shiga toxin

Stx

Bacteriophage

a-Hemolysin

hlyCABD

Type III secretion system

mxi/spa

Plasmid or chromosome Plasmid

Invasion plasmid pINV Shigella enterotoxin 1 Shigella enterotoxin 2 Shiga toxin (Shigella dysenteriae serotype 1)

Ial Set1A Sen Stx

Plasmid Chromosome Plasmid Bacteriophage

DAEC: diffusely adherent E. coli

Dr-binding adhesins a-Hemolysin

Afa/draBC hlyCABD

Plasmid Plasmid

UPEC: uropathogenic E. coli

Invasion of brain endothelium

ibeA

Type 1 pili a-Hemolysin

fimA/F/G/H hlyCABD

GimaA Pathogenicity island Chromosome Chromosome

P fimbriae Dr-binding adhesins Vacuolating autotransporter toxin O-antigen lipopolysaccharide

pap afa/draBC vat

Chromosome Plasmid Pathogenicity island

Between galF and gnd kpsM fliC kpsM pap

Chromosome

Invasion of brain endothelium (putative) Type 1 pili

ibeA fimA/F/G/H

GimaA pathogenicity island Chromosome

Long polar fimbriae (putative)

lpfA2

Chromosome

Invasion of brain endothelium (putative)

ibeB

Chromosome

EAEC: enteroaggregative E. coli

EPEC: enteropathogenic E. coli

STEC/EHEC: Shiga-toxin producing/ enterohemorrhagic E. coli

EIEC: enteroinvasive E. coli (Shigella)

NMEC: neonatal meningitis-associated E. coli AIEC: adherent invasive E. coli

K1 capsule H-antigen K1 capsule P fimbriae (putative)

Chromosome Chromosome Chromosome Chromosome

Systemic toxin responsible for hemorrhagic colitis and hemolytic uremic syndrome Impairs intestinal barrier function and tight junctions Intimin and translocated intimin receptor promotes protein delivery to enterocytes Influences invasiveness and virulence Induces intestinal fluid secretion Induces intestinal fluid secretion Systemic toxin responsible for hemorrhagic colitis and hemolytic uremic syndrome Adherence, potentially proinflammatory Impairs intestinal barrier function and tight junctions Invasion protein Adherence and invasion Invasion of brain microvascular endothelial cells Adherence Adherence Toxin, may improve fitness during infection Resists opsonophagocytosis and complement-mediated killing Antiphagocytic Bacterial motility Shown to traverse the blood–brain barrier Binding to human brain microvascular endothelial cells Contributes to invasion of the blood–brain barrier Adhesion, invasion, intracellular replication Possibly enhances attachment and microcolony formation Invasion protein

588

Escherichia coli

diarrheal illnesses in young children in hospital settings (Table 1). Occasionally EPEC diarrhea may be prolonged and lead to serious nutritional compromise in young children. EPEC are identified based on the presence of the LEE (locus of enterocyte effacement) pathogenicity island and the absence of stx genes that encode the Shiga toxin (Table 2). EPEC produce diarrheal disease by initiating a three-step process in which the organisms adhere to the intestine in a specific, localized fashion to initiate disease. The genes encoding these attaching factors are on the LEE pathogenicity island within the EPEC organism. EPEC use a Type III secretion system (TTSS), a structure that injects virulence factors into the host cell to disrupt the host epithelium. EPEC secrete a protein–ligand pair: Tir (translocated intimin receptor), which becomes incorporated in the host cell membrane and serves as the receptor for the more intimate attachment of EPEC organisms (via the receptor ‘intimin’) to the enterocyte. This more intimate attachment allows for protein delivery to the enterocyte, with the initiation of enterocyte signal transduction, including the mobilization of intracellular calcium, the activation of protein kinase C, and myosin light chain kinase, as well as the induction of the tyrosine phosphorylation of proteins. The result of this signal transduction pathway activation cascade is the classic attaching and effacing lesion associated with EPEC. These lesions, combined with the organism’s ability to induce submucosal inflammation and increase tight junction permeability, results in the secretion of water and electrolytes. EPEC do not produce proteins defined as classic toxins, namely, molecules acting at a distance from their source. However, EPEC do secrete proteins into culture supernatants as well as directly into the enterocyte. These proteins do not have any demonstrated impact on the enterocyte when exposed externally to the protein, but when the protein is delivered directly into the enterocyte, cell signaling is initiated. For example, one secreted protein, EspF, disrupts intestinal barrier function by increasing intestinal permeability; two other secreted proteins, EspG and EspG2, inhibit luminal chloride absorption by disruption of microtubules. EPEC are typically divided into two lineages: strains with the EPEC adherence factor plasmid (EAF)–encoded bundleforming pilus (BFP) are referred to as typical EPEC (tEPEC), whereas atypical EPEC (aEPEC) refers to strains without the EAF (Figure 1). However, sequencing studies of multiple EPEC isolates indicate that differences between EPEC lineages are substantially more complex and that different EPEC use multiple molecular mechanisms to induce a similar clinical picture.

Shiga Toxin–Producing Escherichia coli The Shiga toxin (or verocytotoxin)–producing E. coli (STEC/ VTEC) are capable of producing the Shiga toxin. Enterohemorrhagic E. coli (EHEC) refers to the subset of STEC that contain the LEE pathogenicity island including a TTSS. Classification, however, is not straightforward because STEC lacking the LEE have also been identified in cases of severe diarrhea, pointing to the presence of other virulence factors and highlighting the limitations of classifying E. coli according to the presence or absence of mobile genetic units. EHEC cause a spectrum of diseases from watery diarrhea to bloody diarrhea which may

be complicated by HUS in up to 15% of affected children, and in a lower proportion of affected adults (Table 1). EHEC have been isolated in a number of large food-borne outbreaks of diarrhea through contamination of apple cider, spinach, lettuce, and walnuts, as well as in the ground meat outbreaks that led to the original recognition of the organisms in the 1980s. The first strain of EHEC to be identified was O157:H7 which has since been implicated in numerous foodborne outbreaks and is thought to be responsible for around 50% of reported cases of EHEC diarrhea. Non-O157 EHEC strains may be equally virulent. The pathogenesis of diarrhea by EHEC requires a series of adherence events which are initially similar to those induced by EPEC, with the formation of attaching and effacing lesions requiring the TTSS. Similar to EPEC, EHEC secrete proteins (such as Tir) which enter the cell to which the bacteria are attached. The toxin produced by the EHEC organisms also upregulates the production of another receptor for the organism on the surface of the enterocyte. EHEC may also utilize other mechanisms to attach to the enterocyte membrane. After becoming established on the enterocyte surface, EHEC are distinguished from EPEC by their production of one or more Shiga toxins (STx1 and/or STx2; these toxins are key contributors to disease). These Shiga toxins are closely related to the Shiga toxin produced by Shigella dysenteriae. The toxin has an A subunit which is enzymatically active and five B subunits which promote binding of the toxin to the enterocyte. The A subunit, an N-glycosidase, enters the cytosol of the enterocyte where it cleaves a single adenine residue from the 28s rRNA component of eukaryotic ribosomes leading to cell death by disruption of protein synthesis. The Shiga toxins also appear to translocate across the intestinal epithelial cell barrier without killing these cells, stimulate an inflammatory response, and enter the systemic circulation where they target select endothelial cells (intestinal, renal, central nervous system) bearing STx receptors. The resulting vascular damage and inflammation may lead to the most severe expression of EHEC disease, namely, bloody diarrhea and HUS. HUS occurs, at least in part, due to renal endothelial damage and is defined as a clinical triad consisting of renal failure, microangiopathic hemolytic anemia, and thrombocytopenia that can be severe enough to cause death.

Enteroinvasive Escherichia coli and Shigella EIEC cause a diarrheal illness that is indistinguishable from shigellosis and appear to be a less common cause of diarrheal disease than the other E. coli pathogens, although this may be related to the methods that are used to detect these organisms. EIEC appear to cause predominantly sporadic cases of diarrheal disease. The EIEC are closely related to Shigella spp. and use genetic material similar to that of Shigella to encode virulence factors such as the TTSS. Using virulence proteins termed ‘invasins,’ the EIEC enter the intestinal cell, multiply intracellularly, and extend into adjacent intestinal cells leading to cell death and occasionally bloody diarrhea. Most EIEC disease presents clinically as watery diarrhea and cannot be distinguished at the bedside from the numerous other etiologies of diarrhea.

Escherichia coli Diffusely Adherent Escherichia coli DAEC are so-called because of their diffuse adherence to HEp-2 cell monolayers. DAEC strains have been implicated in intestinal infections as well as UTIs (Figure 1) and may also be implicated in the pathogenesis and/or relapse of ulcerative colitis. DAEC adhere to the intestinal mucosa and use a-hemolysin to promote the release of proinflammatory cytokines, and induce loss of microvilli and changes in tight junctions that lead to increased cell permeability (Mirsepasi-Lauridsen et al., 2016). It has been proposed that strains expressing higher levels of a-hemolysin might contribute to epithelial barrier dysfunction which could influence the pathophysiology of ulcerative colitis.

Extraintestinal Pathogenic Escherichia coli ExPEC encompass a varied group of E. coli capable of causing disease usually outside of the gastrointestinal tract. The primary pathotype is the uropathogenic E. coli (UPEC) that cause, but are not limited, to infections of the urinary tract (Figure 1). ExPEC also cause neonatal meningitis (NMEC), soft tissue, respiratory and skin infections, postoperative infections, prostatitis, and intra-abdominal infections, any of which can lead to bacteremia and sepsis. Escherichia coli is the most common cause of UTI, implicated in up to 95% of cases of uncomplicated cystitis, 90% of pyelonephritis, and approximately one-third of catheter-associated UTIs. Although the treatment of uncomplicated cystitis is usually straightforward, both the frequency of infection and the increasing prevalence of multidrug-resistant strains contribute to the public health significance of UPEC infections. The lifetime risk for UTI among women is estimated to be 60%, and 50% of women who experience UTI will have a recurrence. The primary care burden of E. coli UTI diagnosis and treatment is therefore substantial. The prevalence of UPEC strains that are resistant to first-line oral agents used to treat UTI, such as trimethoprim-sulphamethoxazole, ampicillin, and fluoroquinolones is increasing worldwide. Escherichia coli is the leading cause of bacteremia and E.coli bacteremia is increasing in incidence. Escherichia coli bacteremia is most common in the elderly in whom the incidence exceeds that due to other causes of bacteremia, such as Streptococcus pneumoniae. Escherichia coli bacteremia results in death in 13– 19% of cases, but the mortality rate can reach 60% in elderly individuals. No single virulence trait is associated with ExPEC infections. The O, K, and H surface antigens are well-known virulence factors but display marked variability. The O (lipopolysaccharide) and K (capsule) antigens inhibit phagocytosis and complementmediated killing, and H-antigen (flagella) contributes to motility (Orskov and Orskov, 1992). To date, more than 180 O-antigens, more than 80 K-antigens, and more than 50 types of H-antigen have been recognized, resulting in an almost limitless number of O–K–H combinations that potentially differ in their virulence phenotype. While there are many genes that encode for extraintestinal virulence factors, none appear to be linked to specific clinical syndromes, and multiple gene combinations can cause the

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same clinical profile. In addition to virulence factors, the clinical outcome of an ExPEC infection is also strongly influenced by host factors, such as age, underlying pathology (particularly immunosuppression), recent surgery, and the presence of an indwelling catheter. Thus, the individual virulence profile of a specific pathovar may not accurately predict its pathogenicity in the human host.

Uropathogenic Escherichia coli UPEC are able to live and survive in the gastrointestinal tract but cause disease when they gain entry to the urinary tract. UPEC are highly genetically and phylogenically diverse. However, UPEC that cause cystitis tend to resemble fecal commensal strains, sharing around 52% of their genome, more closely than strains that cause pyelonephritis. UPEC virulence factors are found on pathogenicity-associated islands acquired via horizontal gene transfer. UPEC urovirulence is determined by multiple genes and a range of virulence mechanisms, including adhesins, toxins, systems for iron capture, metabolic pathways, and protectins, none of which is pathognomonic (Flores-Mireles et al., 2015). The urinary tract is protected from infection by the physical barrier of a glycoprotein plaque made up of uroplakin and a hydrated mucus layer (Abraham and Miao, 2015). The host immune response to UPEC infection begins with encapsulation of bacteria within RAB27bþ fusiform vesicles that are recognized by Toll-like receptor 4 (TLR4) which initiates expulsion of the vesicles back into the urinary space. Intracellular UPEC outside of RAB27bþ vacuoles are targeted by autophagy which also results in their expulsion into the bladder lumen. TLR4 initiates signaling release of soluble factors from uroepithelial cells including chemokines, antimicrobial peptides, and proteins, leading to recruitment of neutrophils which have an important role in bacterial clearance. The products of activated neutrophils, such as reactive oxygen species, can also result in inflammation and damage to uroepithelium. The number of neutrophils and the bacterial load appear to increase and decrease in parallel, and clearance of neutrophils and their toxic by-products is facilitated by urination. Shedding of the outer epithelial layer may also occur, which effectively reduces the bacterial load and the proinflammatory response. The immune response to uncomplicated cystitis is characterized by a robust innate response which does not stimulate downstream adaptive immunity or antibody production. By contrast, pathogen-specific antibodies are produced during pyelonephritis. The reasons for the bladder’s limited response to infection are not clear, but the absence of adaptive immunity after a UTI could contribute to the high frequency of UTI recurrence. UPEC use flagellae (the H-antigen) to move up through the urinary tract, and a range of fimbrial and nonfimbrial adherence mechanisms (such as fimbrillae and autotransporters), to colonize the urinary tract epithelium and evade host defense mechanisms. Chaperone–usher pathway pili facilitate adhesion and invasion of epithelial cells, and individual UPEC can code for multiple CUP pili types. Type 1 pili are made up multiple copies of the FimA subunit that forms a pilus rod and FimF/G/H subunits that form the distal tip. The terminal FimH adhesion protein binds to integrins and

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uroepithelial barrier proteins known as uroplakins, initiating the processes of colonization, cellular invasion, and formation of intracellular bacterial communities within superficial umbrella cells. Bacterial attachment via FimH is an important initial step in colonization, and FimH is a potential candidate for drugs/vaccines for the treatment or prevention of UTIs. UPEC expressing the P pilus are capable of causing pyelonephritis as the P pilus adhesion (PapG) binds to glycolipids located on kidney cells. P pili also act to prevent secretion of immunoglobulin A into the urinary space. Secretion of virulence factors promotes UPEC survival within the urinary tract. These can include the production of toxins (vacuolating autotransporter toxin which is thought to contribute to UPEC fitness during infection, a-hemolysin which promotes iron and nutrient release through host cell lysis, and cytotoxic necrotizing factor which disrupts the epithelial barrier and promotes access to deeper tissue), siderophores that facilitate iron uptake, and factors to facilitate host cell disruption and remodeling. Bacteria within intracellular bacterial communities are shielded from host defense mechanisms and antibiotics and can disperse to invade other cells. Small reservoirs of bacteria residing in underlying transitional cells within membrane-bound compartments are capable of remaining viable for long periods. If reactivated, these bacteria are believed to contribute to recurrent infection.

Neonatal Meningitis-Associated Escherichia coli NMEC is the second most comment cause of neonatal meningitis globally, but their virulence factors and genomic trials are not well explored. NMEC appear to resemble fecal commensal strains in terms of phylotype and serotype but contain the RS218 plasmid which harbors many sequences similar to those found in UPEC. The plasmid encodes for multiple virulence factors, but the functional significance of these in causing meningitis remains unknown. NMEC expressing the K1 polysaccharide capsule predominate among meningitis isolates. NMEC are able to traverse the blood–brain barrier by transcellular penetration in settings of high levels of bacteremia (Table 2). NMEC express virulence factors that promote adhesion and invasion, as well as factors that rearrange the cytoskeleton of human brain microvascular endothelial cells allowing successful transport of live bacteria across the blood–brain barrier.

Adherent Invasive Escherichia coli AIEC are a recently described pathotype first proposed in 1999 after isolation of a strain from a patient with Crohn’s disease (LF82) (Boudeau et al., 1999). The LF82 strain lacked virulence factors typically associated with EIEC, EPEC, or ETEC, but showed high invasive potential and the ability to replicate intracellularly. Diverse AIEC strains have since been identified from ileal lesions in other patients with Crohn’s disease. AIEC appear to be genomically related to UPEC and NMEC strains, and thus to belong to the ExPEC subset of pathogenic E. coli, but contain distinct genomic islands and unique genes which may contribute to their specific pathogenicity. Currently the virulence features specific to AIEC are not well characterized. AIEC use the type 1 pilus and FimH adhesion to adhere

to the intestinal mucosa before entering and replicating. Polymorphisms have been observed in FimH from E. coli isolated from patients with inflammatory bowel disease, although it is not known if these changes translate into functional differences in FimH. AIEC are thought to promote a proinflammatory granulomatous immune response which could influence the course of Crohn’s disease.

Public Health Importance of Escherichia coli Infections Epidemiology of Diarrheal Escherichia coli Infections In recent decades there have been substantial gains in reducing global deaths due to diarrhea. Between 2000 and 2013, the number of children under 5 years of age who died due to a diarrheal illness reduced by 54%. Nevertheless, diarrheal disease remains the second most common cause of death in children under 5 years worldwide and is a leading cause of malnutrition. Diarrhea accounts for
9% of annual worldwide child deaths. The most significant burden of diarrheal disease is in children between the ages of 6 months (the time of weaning) and 3 years of age. While bacterial, viral, and parasitic pathogens are all causative agents of these diarrheal illnesses, the various kinds of diarrheagenic E. coli are responsible for a significant proportion of the diarrheal illnesses caused by bacteria. The ability to document the precise involvement of E. coli in diarrheal disease in any setting depends on when and how the study was conducted and what means were used to identify pathogens; variations in the methods used result in a wide variation of the estimates of the burden of diarrhea attributable to E. coli. It has been suggested that 70–80% of the bacterial diarrheal illnesses in the resource-limited world may be caused by the diarrheagenic E. coli. Diarrheal disease caused by E. coli remains highly endemic throughout much of the world where sanitation and availability of clean water remain public health issues of concern. Malnutrition, particularly in children at the time of weaning (growth faltering), in these regions of the world may either be a result of the diarrheal illness or predispose the child to more frequent, more severe, or more prolonged episodes of diarrhea when they occur. Escherichia coli diarrhea is endemic at low rates or occurs sporadically or as outbreaks in the rest of the world. In some countries, such as Thailand or Brazil, which have become ‘transitional’ between the resourcelimited and resource-sufficient worlds for the majority of public health issues, the incidence, prevalence, and severity of diarrhea has decreased over the past decades. The emergence of the HIV epidemic has been profound in reversing many of these advances in the control of diarrheal disease. In countries highly endemic for HIV, diarrhea is a frequent complication of HIV infection and may be related to an increased risk of developing disease when exposed to enteric pathogens because of the reduction in immune function that occurs with advancing HIV disease. HIV has also contributed to dramatically increased rates of malnutrition in children and adults in the resourcelimited world, which may provide another avenue by which HIV may impact the rates of diarrhea, as malnourished individuals are at increased risk of diarrheal disease. While opportunistic pathogens have contributed to diarrheal disease in

Escherichia coli HIV-infected populations, the greatest risk in much of the world is exposure to the pathogens that typically cause diarrheal disease in the region, which certainly includes the diarrheagenic E. coli. EAEC in particular have been described as a cause of prolonged diarrhea in HIV-infected adults and children with more advanced disease in the United States and Europe as well as Africa. Adults in the resource-limited world are generally less prone to illness from the diarrheagenic E. coli due to repeated exposure over time, likely with the development of at least partial protective immunity. However, HIV disease seems able to increase the susceptibility of HIV-infected adults to symptomatic disease with at least some pathogenic types of E. coli, although further studies investigating the impact of HIV infection on E. coli diarrhea are needed.

Transmission

Escherichia coli are transmitted primarily through the fecal–oral route; any individual, food or liquid that becomes contaminated with E. coli that are able to cause diarrhea will be capable of transmitting the organisms to a susceptible host. The size of the inoculum of E. coli required to cause diarrheal disease depends again on the type of E. coli that is being transmitted as some of the diarrheagenic E. coli are more virulent than others. ETEC, which cause diarrheal disease similar to that caused by V. cholerae, require a fairly high inoculum (
103) similar to the inoculum of vibrios required to evade the intestinal defense mechanisms, colonize the small bowel, and, hence, cause diarrheal disease. In contrast, STEC or EIEC, which behave much more like Shigella, may require an inoculum of only 102 organisms to cause illness, as do Shigella. In a human volunteer study, EIEC required 108 cfu as a minimum dose to yield diarrhea in volunteers, and this was also the dose leading to diarrhea in at least 50% of the volunteers. So, although it has at least some similar virulence factors to Shigella, it is far less virulent. In the endemic setting in the resource-limited world, the lack of access to a sufficient and regular supply of clean drinking, cooking, and washing water may be the most significant risk for diarrheal illness caused by E. coli; lack of appropriate means to store food before and after cooking and contact with animals, whether in the household or on the farm, also contribute to the risk. Mothers may inadvertently transmit E. coli to their children. Studies done in Bangladesh suggest that mothers who wiped their hands on their saris were more likely to transmit diarrheal pathogens to their children than mothers who had access to water for washing hands. These studies looked primarily at transmission of organisms that require a small inoculum, such as Shigella. Hand washing with soap has been shown to be particularly effective in decreasing transmission of diarrheal pathogens in this setting. Alcohol-based hand hygiene gels are expected to similarly decrease the risk of transmission. Escherichia coli such as ETEC may exist as contaminants in room-temperature cooked rice, serving utensils, and water in the resource-limited world. While ETEC are often thought of as predominantly pathogens in children in the resource-limited world and in travelers, these organisms have also been implicated in a number of significant outbreaks of diarrhea in the resource-sufficient world. In the setting of outbreaks of E. coli diarrheas, contamination of food is the most likely means of transmission, and

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this is most often due to lack of hand hygiene, stressing again the fecal–oral route of transmission. Contact with mammals, whether these animals are at home, on the farm, in the wild, or in a zoo (particularly petting zoos), may facilitate transmission of diarrheagenic E. coli and may contribute to outbreaks of E. coli diarrhea. The transmission of STEC organisms in particular has been noted to occur in settings where animal (such as deer or cow) droppings contaminate windfall apples that are used to make apple cider, as well as in petting zoos of farm animals. Contamination of freshwater lakes with STEC has also been documented. Outbreaks of E. coli diarrhea may also occur after natural disasters such as flooding, which may spread fecal contamination from one region to another. Refugee situations, whether from natural disaster or war, may also lead to increased numbers of outbreaks of diarrheal disease caused by E. coli, as crowding and lack of adequate water supply and sanitation provide ideal conditions for the transmission of E. coli pathogens.

Prevention/Control of Diarrheal Disease While there is intriguing potential for vaccines to control many of the diarrheal syndromes caused by the diarrheagenic E. coli, currently there is no E. coli vaccine targeting diarrheal disease that is imminently ready for global testing or widespread use (O’Ryan et al., 2015). The strategy currently being explored for the majority of the diarrheal vaccines under development is the oral route, which promotes a direct immune response by the lymphoid tissue in the intestine, as well as providing the most direct access to the site of the pathogen–host interface. The development of resistance to ETEC disease with increasing exposure and age and the protection of breast-fed infants by maternal antibody (in humans and animals) suggest that ETEC are a group of E. coli that are amenable to control by vaccination. Because the global burden of ETEC diarrhea is so large, ETEC are an important target for vaccine development (Bourgeois et al., 2016). Effective vaccine development is hampered by serotype specificity of immunity to ETEC colonization antigens and the nonimmunogenicity of the STa toxin. Thus, vaccine efforts focus on development of immunogenic vaccines comprised of the LT toxin (or its b subunit), on colonization factors of greatest epidemiologic importance in developing countries, and on the potential limited immunogenicity of vaccines in very young children (Table 3). Although the development of vaccines against the STEC, especially the EHEC, is also desirable, and although studies have demonstrated immunogenicity of STx in animal models, initial efforts have been directed at Shigella – especially S. dysenteriae that express Shiga toxin (Table 3; Mani et al., 2016); Shigella infections are far more common globally than EHEC infections. Vaccination of cattle to prevent carriage of STEC is a potential alternative to diminish the transmission of EHEC. Plans to prevent or control diarrheal illnesses caused by E. coli must be multidisciplinary. Socioeconomic status, availability of freshwater, adequate food, hand washing, safe storage of water, food storage to prevent bacterial contamination of food, and education of parents or care providers for the children are all key elements in preventing these diarrheal diseases. Socioeconomic status of the family is important, but the economic status of the country or region where the family lives

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Table 3

Escherichia coli vaccines in clinical development

Pathotype

Administration route

Vaccine component

Clinical development stage

ETEC

Transcutaneous

LT patch

Shigella

Oral Oral Intradermal Oral Oral Oral Oral Oral Oral Oral Intramuscular Intramuscular Intramuscular

EHEC ExPEC

Intramuscular Intramuscular

Inactivated 4-valent whole cell (ETVAX  dmLT) Live-attenuated (Typhetec® Prokarium) Anti-adhesin subunit LTR192G Live-attenuated Shigella (CVD 1208S) Live-attenuated (ACE527) Double-mutant heat-labile toxin (dmLT) Live-attenuated (CVD 1208) Live-attenuated (SC599) Live-attenuated (WRSS1, WRSs3, WRSf3) Inactivated trivalent whole cell O-antigen conjugate (chemical conjugation) Recombinant O-antigen bioconjugate (GVXN SD133) Generalized module for membrane antigen (GMMA) protein vesicle O157:H7 conjugate vaccines Recombinant O-antigen bioconjugate (EcoXyn-4V)

Phase III (efficacy not demonstrated) Phase I Phase I Phase II Phase II Phase II Phase I Phase I Phase II Phase II Phase I Phase III Phase II Phase I

is also crucial, as the status of sanitation and the availability of water depend not only on the individual but also on the environment in which they live. Measures to control diarrheal diseases caused by E. coli will also assist in the control of multiple other diarrheal disease pathogens. Achieving these major steps forward in public health globally requires enhanced political and economic will that can and must be promoted by public health practitioners. The WHO Global Action Plan for Pneumonia and Diarrhoea (GAPPD) aims to end preventable childhood deaths due to pneumonia and diarrhea by 2025 (WHO, 2013). GAPPD provides a roadmap for governments and partners to work toward an integrated approach for the prevention and treatment of diarrhea, using well-accepted strategies such as promoting breast-feeding, development of standard guidelines for illness identification and treatment, promoting the use of oral hydration salts and zinc supplementation, hygiene interventions, and improving access to clean water. Implementing GAPPD initiatives in the countries with the highest incidence of child death due to diarrhea has proved challenging. In addition, settings of war and intense human migration in recent years have slowed progress.

ExPEC Multidrug Resistance Mechanisms of antibiotic resistance exist among all E. coli strains, and like other virulence factors, these mechanisms are diverse, readily transferrable, and evolving. For example, the production of extended-spectrum beta-lactamases (ESBLs) can occur using TEM, SHV, CMY, and CTX-M types. Currently, CTX-M-15 is the most prevalent ESBL among ExPEC. Resistance to carbapenems occurs via NDM-1 and OXA-48-type carbapenemases. Fluoroquinolone and aminoglycoside resistance is conferred by plasmid-encoded or chromosomally encoded transferases, or mechanisms that reduce antimicrobial uptake into the cell (O’Neill, 2014). Multidrug resistance is defined as resistance to two or three or more antibiotic classes. The prevalence of multidrugresistant E. coli strains is increasing in many countries and is

Phase II Phase II

recognized as a major hazard to human health and development. This position was reflected in the conclusions of a United Kingdom Prime Ministerial review committee which estimated that antibiotic-resistant E. coli infections account for one-half of the estimated global burden caused by antibiotic-resistant infections each year. Infections with multidrug-resistant bacteria are less likely to respond to treatment, are more likely to require additional and more costly antibiotics, are more likely to result in hospitalization or to prolong hospitalization, and are more likely to result in death. The health-care and societal costs associated with multidrug-resistant infections are therefore substantial. Multidrug-resistant ExPEC infections have been associated with increased hospitalization rates for UTI, increases in infectious complications after prostatic biopsy and other urogenital and abdominal surgical procedures, and poor clinical outcome in patients with bacteremia. Escherichia coli bacteremia is a potentially lethal, costly, and escalating problem (Poolman and Wacker, 2015). The incidence of bacteremia is increasing along with the aging population, and multidrug-resistant E. coli account for a disproportionate increase in infections. Escherichia coli are capable of rapid evolution through exchange of genetic material and new pathovars may arise, such as the O104:H7 strain that caused an epidemic of bloody diarrhea and HUS in Germany in 2011. The ST131 clonal complex (mostly linked to O25B) is another highly successful, virulent, antibiotic-resistant, and relatively new E. coli which has spread globally. ST131 has been identified in community, health-care, and environmental settings. Within the ST131 clonal complex are sublineages with specific virulence traits and antibiotic resistance profiles. The clonal subtype, known as ST131-H30 (an allele of FimH), is a virulent, fluoroquinolone-resistant clone that expanded rapidly from 2000. ST131-H30 has a distinct set of virulence factors including point mutations in gyrA and parC genes that confer fluoroquinolone resistance. ST131 is prevalent among patients with recurrent or persistent UTI, and in patients with bacteremia. Around 70% of fluoroquinolone-resistant E. coli and more

Escherichia coli than 50% of multidrug-resistant E. coli in the United States were ST131 in 2007. ST131 currently dominates multidrug-resistant ExPEC worldwide, posing significant challenges for treatment.

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See also: Antimicrobial Resistance in a One Health and One World Perspective – Mechanisms and Solutions; Bacterial Infections: Overview; Foodborne Diseases; Intestinal Infections: Overview; Shigellosis.

Prevention/Control of ExPEC Infections An effective vaccine to prevent ExPEC infections could have a profound impact on human health and the control of multidrug-resistant infections. Although several vaccines and bacterial suspensions are licensed for use for prevention of ExPEC infections, they are not widely available. These include a wholecell intravaginal vaccine containing 10 heat-killed ExPEC strains, which showed efficacy in reducing recurrent UTI, and suspensions of inactivated bacteria or bacterial extract that include E. coli. A subunit vaccine candidate based on FimH and the chaperone FimC that showed reduced bladder and kidney colonization in mice and nonhuman primates progressed to clinical trials, but was canceled due to insufficient efficacy. Other past and current vaccine attempts have focused on the O-antigen, a well-described virulence factor that contributes to E. coli survival through evasion of host defenses and serum resistance. The antibody response to ExPEC infection is largely directed at the O-antigen, and O-specific antibodies promote phagocytosis and have been shown to confer protection against homologous lethal challenge in animal models. The challenge for manufacturers attempting to develop an O-antigen-based vaccine is the large diversity in O-serotypes. There are over 180 O-serotypes identified, although the majority of ExPEC infections in humans are caused by 10–12 of these. During the 1990s, a 12-valent Opolysaccharide vaccine chemically conjugated to Pseudomonas aeruginosa exoprotein A was developed. The vaccine was immunogenic and well tolerated in human volunteers, with increases in antibody titers that were as high as fourfold for some serotypes (Cross et al., 1994). A correlation between antibody levels measured by ELISA and functional activity measured by opsonophagocytic assay was noted. This vaccine candidate was not pursued further, despite promising results, possibly because of technical issues with production. More recently, a multivalent vaccine using O-antigen has been developed using bioconjugation, a method of in vivo conjugation of multiple O-polysaccharides to specific sites of a carrier protein (Table 3; Poolman and Wacker, 2015). Initial results from a Phase I study of a 4-valent bioconjugated vaccine evaluated in healthy women with recurrent UTI indicate that the vaccine induced functional antibody responses and decreased the number of single-pathogen E. coli UTI episodes, warranting further investigation. Challenges facing ExPEC vaccine development include selection of the correct number and combination of O-serotypes to maximize coverage and identification of the target infection (for example, prevention of UTIs in young women, prevention of bacteremia in the elderly, prevention postoperative infections, or prevention of neonatal meningitis) and selection of appropriate study endpoints (immunogenicity, identification of serological correlate of protection, efficacy). An ExPEC vaccine is one of very few means capable of reversing current upward trends in antibiotic resistance.

References Abraham, S.N., Miao, Y., 2015. The nature of immune responses to urinary tract infections. Nat. Rev. Immunol. 15, 655–663. Boudeau, J., Glasser, A.L., Masseret, E., et al., 1999. Invasive ability of an Escherichia coli strain isolated from the ileal mucosa of a patient with Crohn’s disease. Infect. Immun. 67, 4499–4509. Bourgeois, A.L., Wierzba, T.F., Walker, R.I., March 15, 2016. Status of vaccine research and development for enterotoxigenic Escherichia coli. Vaccine. http:// dx.doi.org/10.1016/j.vaccine.2016.02.076. Cross, A., Artenstein, A., Que, J., et al., 1994. Safety and immunogenicity of a polyvalent Escherichia coli vaccine in human volunteers. J. Infect. Dis. 170, 834–840. Flores-Mireles, A.L., Walker, J.N., Caparon, M., et al., 2015. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat. Rev. Microbiol. 13, 269–284. Kaper, J.B., Nataro, J.P., Mobley, H.L., 2004. Pathogenic Escherichia coli. Nat. Rev. Microbiol. 2, 123–140. Mani, S., Wierzba, T., Walker, R.I., March 12, 2016. Status of vaccine research and development for Shigella prepared for WHO PD-VAC. Vaccine. http://dx.doi.org/ 10.1016/j.vaccine.2016.02.075. Mirsepasi-Lauridsen, H.C., Du, Z., Struve, C., Charbon, G., et al., 2016. Secretion of alpha-hemolysin by Escherichia coli disrupts tight junctions in ulcerative colitis patients. Clin. Transl. Gastroenterol. 7, e149. Navarro-Garcia, F., December 2, 2014. Escherichia coli O104:H4 pathogenesis: an enteroaggregative E. coli/Shiga toxin-producing E. coli explosive cocktail of high virulence. Microbiol. Spectr. 2. O’Neill, J., 2014. Antimicrobial resistance: tackling a crisis for the health and wealth of nations. Rev. Antimicrob. Resist. Available at: http://www.his.org.uk/files/4514/ 1829/6668/AMR_Review_Paper_-_Tackling_a_crisis_for_the_health_and_wealth_ of_nations_1.pdf. Orskov, F., Orskov, I., 1992. Escherichia coli serotyping and disease in man and animals. Can. J. Microbiol. 38, 699–704. O’Ryan, M., Vidal, R., del Canto, F., et al., 2015. Vaccines for viral and bacterial pathogens causing acute gastroenteritis: Part II: vaccines for Shigella, Salmonella, enterotoxigenic E. coli (ETEC) enterohemorrhagic E. coli (EHEC) and Campylobacter jejuni. Hum. Vaccines Immunother. 11, 601–619. Poolman, J.T., Wacker, M., 2015. Extraintestinal pathogenic Escherichia coli, a common human pathogen: challenges for vaccine development and progress in the field. J. Infect. Dis. 213, 6–13. WHO, 2013. World Health Organization. Ending Preventable Child Deaths from Pneumonia and Diarrhoea by 2025. WHO. Available at: http://www.who.int/ maternal_child_adolescent/documents/global_action_plan_pneumonia_diarrhoea/ en/ (accessed 23.08.14.).

Further Reading Donnenberg, Michael (Ed.), 2013. Escherichia coli: Pathotypes and Principles of Pathogenesis, second ed. Academic Press. Hénock Blaise, N.Y., Dovie, D.B.K., 2007. Diarrheal diseases in the history of public health. Arch. Med. Res. 38, 159–163. Kalita, A., Hu, J., Torres, A.G., 2014. Recent advances in adherence and invasion of pathogenic Escherichia coli. Curr. Opin. Infect. Dis. 27, 459–464. Lorntz, B., Soares, A.M., Moore, S.R., et al., 2006. Early childhood diarrhea predicts impaired school performance. Pediatr. Infect. Dis. J. 25, 513–520. Tourret, J., Denamur, E., February 2016. Population phylogenomics of extraintestinal pathogenic Escherichia coli. Microbiol. Spectr. 4. Vila, J., Sáez-López, E., Johnson, J.R., et al., March 8, 2016. Escherichia coli: an old friend with new tidings. FEMS Microbiol. Rev. http://dx.doi.org/10.1093/femsre/ fuw005.

Esophageal Cancer Linda M Brown, RTI International, Rockville, MD, USA David P Check and Susan S Devesa, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Ó 2017 Elsevier Inc. All rights reserved.

Introduction Esophageal cancer is a malignant tumor that develops in the inner layers of the mucosal lining of the esophagus, the hollow, muscular tube that transports food and liquid from the pharynx to the stomach (Figure 1). The length of the esophagus in a normal adult is approximately 25 cm or about 10 inches. There are two major types of esophageal cancer, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), which share a poor prognosis but have rather distinct histopathologic and epidemiologic profiles. ESCC, which can arise in any part of the esophagus, arises from thin, flat, squamous cells that line the esophagus. EAC, usually found in the lower part of the esophagus near the stomach, forms in glandular cells (not normally present in the lining of the esophagus) that replace a section of squamous cells, a condition called Barrett’s esophagus. Although the risk of EAC in patients with Barrett’s is small (less than 1% per year), people with Barrett’s esophagus are estimated to be at

30 to 125 times the risk of developing EAC than people who do not have this condition.

Demographic Features Incidence and Mortality Rates Esophageal cancer is known for its marked variation by geographic region, ethnicity, and gender. The most recent estimates of global cancer incidence indicate that esophageal cancer is the eighth most frequent cancer in the world (some 323 000 new cases a year in men and 133 000 in women), but because of its poor prognosis, it is the sixth most common cause of cancer death (281 000 deaths a year among men and 119 000 among women) (Ferlay et al., 2013). There are large differences in incidence between the different regions of the world with rates per 100 000 ranging from 0.8 in Western Africa to 17.0 in Eastern Asia in men, and 0.2 in Micronesia/ Polynesia to 7.8 in Eastern Africa in women. Fatality rates are so high (88%) that age-standardized rates per 100 000 are generally comparable for incidence (9.0 for men, 3.1 for women) and mortality (7.7 for men, 2.1 for women). Some of the highest mortality rates in both men (Figure 2(a)) and women (Figure 2(b)) occur in the ‘Asian esophageal cancer belt,’ which stretches from northern Iran and central Asia (including Turkmenistan and Kazakhstan) into northern and western China. However, no population-based tumor registries operate in this region, so true incidence rates are unknown. Other areas of high mortality are found in southern and eastern Africa. Malawi has the highest mortality rates per 100 000 for both men and women, 26.9 and 19.5, respectively.

Incidence Patterns and Trends

Figure 1 Illustration of the digestive tract including the esophagus. Illustration from the National Cancer Institute, Bethesda, MD.

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International differences in esophageal cancer incidence rates are striking. Recent (2003–07) esophageal cancer rates among selected registries with long-term rate information varied by over eightfold among males, from 15.0 cases per 100 000 population per year in Miyagi, Japan to 1.8 in Israel. Rates were greater than 10.0 per 100 000 among men in Scotland (11.8), England (10.8), and Calvados France (10.8). Recent rates among females varied over sevenfold, from 4.6 in Scotland to 0.6 in Costa Rica, Italy, Spain, and Singapore. Rates were greater than 3.0 per 100 000 in England (4.2) and India (3.5). Rates in all areas were higher in males than in females. Male:female rate ratios varied from less than two in India to more than seven in Calvados France, Spain, and Slovakia. Rates in all populations rose consistently with age (Forman et al., 2013). Among men, incidence rates declined by 50% or move over most of the period 1978–82 to 2003–07 in US blacks, Bas-Rhin France, India, China, and Singapore; rates increased by 50% or

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Figure 2 International variation in estimated esophageal cancer mortality rates during 2012 (per 100 000 person-years, age-standardized to the world population) among males (a) and females (b). Figure generated from Ferlay, J., Soerjomataram, I., Ervik, M., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F., 2013. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. [Internet]. International Agency for Research on Cancer, Lyon, France. Available from: http://www.globocan.iarc.fr (accessed on 05.08.14.).

more in Denmark and Slovakia (Figure 3; Muir et al., 1987; Parkin et al., 1992; Parkin et al., 1997; Parkin et al., 2002; Curado et al., 2007; Forman et al., 2013; SEER, 2014a; see Relevant Websites). Although rates among females tended to fluctuate more over time due to the smaller number of cases, the trends were broadly similar to those in males. Incidence rates fell by 50% or more in US blacks, Finland, India, China, and Singapore, whereas they rose 50% or more in Denmark, Bas-Rhin France, and Slovakia. These divergent incidence patterns and trends reflect the changing frequencies of ESCC and EAC. Incidence of ESCC, which tends to be higher in developing countries and US blacks, has been falling, whereas the incidence of EAC, which tends to be higher in more developed countries and in US whites, has been steadily increasing. Examples of these trends

are presented in Figure 4, which demonstrates the impact of changing rates of ESCC and EAC on total esophageal cancer rates among US black and white men and women over the time period 1978–82 to 2008–11 (SEER, 2014a). The rates for cancers with a poorly specified cell type (approximately 9% of all esophageal cancers) were allocated proportionally to ESCC and EAC by race, gender, and time period. Total esophageal cancer rates per 100 000 among US black men peaked at 16.5 in 1978–87 and then began a marked decline, reaching 4.5 in 2008–11. Rates per 100 000 among white men, however, increased steadily from 3.8 in 1978–82 to 5.5 in 2003–07 and 5.4 in 2008–11. The dramatic decrease in total esophageal cancer rates for black men was driven by the 77.5% drop in the incidence of ESCC (from 16.0 in 1978–87 to 3.6 in 2008–11), which is more than four times

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Figure 3 International trends in esophageal cancer incidence rates (per 100 000 person-years, age-standardized to the world population) by geographic area, registry, and sex, c.1978–82 to 2003–07. Adapted from CI5 I-X Tables by Volume Online Analysis found at this link (see Relevant Websites). References for volumes V to X included at this link (see Relevant Websites) and in the References section. U.S. trends based on data from the Surveillance, Epidemiology, and End Results (SEER) Program. (www.seer.cancer.gov) SEER*Stat Database: Incidence – SEER 9 Regs Research Data, November 2013 Sub (1973–2011)
Linked To County Attributes – Total U.S., 1969–2012 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, Released April 2014, Based on the November 2013 submission.

Esophageal Cancer

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Figure 4 Trends in esophageal cancer incidence rates (per 100 000 person-years, age-standardized to the world population) in nine Surveillance, Epidemiology, and End Results (SEER) areas in the United States by race, sex, and type from 1978–82 to 2008–11. Based on data from Surveillance, Epidemiology, and End Results (SEER) Program. (www.seer.cancer.gov) SEER*Stat Database: Incidence – SEER 9 Regs Research Data, November 2013 Sub (1973–2011)
Linked To County Attributes – Total U.S., 1969–2012 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, Released April 2014, Based on the November 2013 submission.

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as common as EAC in black men. The incidence of ESCC also decreased 64.3% among white males (from 2.8 in 1978–82 to 1.0 in 2008–11). In contrast, among white males, the incidence of EAC more than quadrupled from 0.9 in 1978–82 to 4.3 in 2008–11. With the decrease in ESCC and the increase in EAC, the rates for EAC among white men surpassed those for ESCC during the period 1988–92. Similar decreases in ESCC and increases in EAC were seen for black and white women.

Etiologic Factors The established or suspected risk or protective factors for ESCC and EAC are listed in Table 1 and explained in greater detail below.

frequently consumed by the population is the one most strongly associated with the risk of ESCC. The formerly widespread habit of drinking hot alcoholic beverages, particularly hot calvados in France, probably contributed both to the higher rates of ESCC there than among men in other European countries and to the recent downward trends in incidence depicted in Figure 3. Although alcohol is strongly related to the risk of ESCC, the mechanisms responsible for its carcinogenicity have not been identified but may include acting as a local chronic irritant, promoting dietary deficiencies, enhancing susceptibility to the effects of tobacco or other carcinogens, and a role of acetaldehyde (a metabolite of alcohol and a recognized animal carcinogen). Alcoholic beverage consumption appears to play at most a minor role in the etiology of EAC.

Tobacco Use

Alcohol Use There is strong epidemiologic evidence that excessive consumption of alcoholic beverages is a major cause of ESCC, especially in Western populations (Kamangar et al., 2009). In some developing countries with exceptionally high rates of ESCC, including parts of Africa, Iran, and China, alcohol drinking historically had not been shown to be a risk factor. However, more recently alcohol has been identified as a risk factor in southern India, Hong Kong, and Shanghai, China. Although only a few studies have investigated esophageal cancer risk associated with alcohol use among nonsmokers, the dose–response gradient for alcohol consumption remains strong when analyses are restricted to lifelong nonsmokers. Variability in risk by type of alcoholic beverage is thought to reflect drinking habits that are culturally or economically determined. Generally, the beverage most

Table 1 Risk and protective factors for esophageal cancers by type Factors

ESCC

EAC

Alcohol use Tobacco use Dietary deficiencies High fruit and vegetable intake Hot food and beverages Other high-risk foods Barrett’s esophagus Gastro-esophageal reflux disease Obesity/high body mass index (BMI) Helicobacter pylori prevalence Humanpapilloma virus Other medical conditions Aspirin/NSAID use Radiotherapy Poverty/low socioeconomic status

þþþ þþþ þþ þþ þþ þ 0 0

þ/
þ/
þþ

þþ þþ

þ þþ 0 þ 0 0 þþþ þþþ þþþ
0 0

þþ þ

ESCC, Esophageal squamous cell carcinoma; EAC, Esophageal adenocarcinoma; NSAID, Non-steroidal anti-inflammatory drug. Risk factor: þþþ (strong and well documented); þþ (medium); þ (weak/not well documented). Protective factor:


(strong and well documented);

(medium);
(weak/not well documented). No documented relationship: 0.

Tobacco use, regardless of form, is a major risk factor for ESCC in most parts of the world (Kamangar et al., 2009). Significant positive trends in risk have been associated with both the intensity and the duration of cigarette smoking. Reductions in risk in the neighborhood of 50% have been seen for ex-smokers compared to current smokers, along with an inverse effect with time since cessation of smoking. In addition to traditional cigarettes, cigars, pipes, snuff, and chewing tobacco, elevated risks have also been found in India associated with smoking bidi (native cigarettes of coarse tobacco in a dry termburni leaf) and the chewing of pan (a mixture of betel leaf, sliced areca nut, and aqueous shell lime) and pan-tobacco. In South America and Europe, lower risks of ESCC have been reported among smokers of blond rather than black tobacco; the smoke of black tobacco contains higher levels of carcinogens and mutagens. A number of known or suspected carcinogens such as nitrosamines, benzo[a]pyrene, and benzene have been identified in tobacco smoke, but the specific agents responsible for ESCC and their mechanisms of action are not clear. It is likely that declines in the prevalence of smoking since the 1960s, especially among men in the United States, may have contributed to the downward trends of ESCC (Brown and Devesa, 2002). In Western Europe and North America, 80–90% of the risk of ESCC has been attributed to use of alcohol and tobacco. Alcohol and tobacco appear to act independently, with the importance of each factor depending on characteristics of the population. Alcohol seems to be more important in a population of heavy drinkers, whereas tobacco appears to be more important in a population of heavy smokers. In most studies, the highest risk of ESCC is seen in heavy consumers of both alcohol and tobacco, often consistent with a multiplicative interaction. From a public health standpoint, it is clear that reduction in alcohol and tobacco use would markedly lower the incidence of ESCC (Brown et al., 2001). Although smoking is a less potent cause of EAC than ESCC, elevated risks of EAC have been documented, especially among heavy smokers. Contrary to the findings for ESCC, smoking cessation does not appear to diminish risk; EAC risk remains elevated 30 or more years after stopping smoking.

Esophageal Cancer Dietary Factors Deficiencies

The variations in ESCC incidence around the world have been linked to dietary insufficiencies. Historically, ESCC has been linked to Plummer–Vinson syndrome, which is associated with vitamin and iron deficiencies, and to celiac disease, a malabsorption syndrome often characterized by malnutrition. However, in some populations it has been difficult to disentangle the influence of dietary factors from the more potent effects of alcohol and tobacco. Consumption of alcoholic beverages and tobacco products can interfere with the intake and metabolism of a variety of nutrients and can also be sources of N-nitroso compounds that may increase the risk of ESCC.

Fruit and Vegetable Intake

The most consistent dietary finding for ESCC has been the protective effect of consumption of fruits and vegetables, especially those eaten raw, which contain a variety of micronutrients and dietary components. Studies have suggested a protective effect of vitamin C, which blocks the endogenous formation of N-nitroso compounds. Other nutrients which may be protective include alpha- and beta-carotene, lycopene, folate, vitamin E, vitamin B6, vitamin B12, zinc, selenium, and flavonoids. Various foods, food groups, and nutrients have also been related to the risk of EAC, but the most consistent finding is a protective effect of fruits, vegetables, and fiber. Nutrients that may be protective against EAC include vitamin C, vitamin E, beta-carotene, vitamin B6, vitamin B12, and folate.

Other Foods and Beverages

A number of studies have suggested that excess risks of ESCC may be associated with consumption of burning hot soup, gruel, porridge, tea (especially mate), and other beverages in various populations around the world. Suspected risk factors for ESCC include foods that are sources of heterocyclic amines formed during cooking (e.g., barbecued or fried meats, especially red meat) or N-nitroso compounds or their precursors nitrates and amines (e.g., cured or processed meat, moldy breads and cereals, pickled vegetables, and salted fish).

Medical Conditions and Treatments Gastroesophageal Reflux Disease

The reflux of gastric acid into the esophagus, which commonly presents as chronic heartburn, in gastroesophageal reflux disease (GERD) may stimulate the esophageal mucosa to develop metaplastic columnar epithelium, which is characteristic of the EAC precursor lesion, Barrett’s esophagus, found in almost all patients with EAC. No clear association has been found between drugs used to treat GERD and the risk of EAC (Blot et al., 2006).

Obesity

Populations at high risk for ESCC tend to be poorly nourished. Within a population, risk tends to increase as body mass index (BMI) (weight in kg/height in meters2) decreases.

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In contrast, risk of EAC tends to increase as BMI rises, with clinically obese individuals (BMI  30) having a substantially higher risk of EAC than individuals of normal or lower weight (BMI < 25). Data emerging from recent studies suggest that the relationship with obesity may account for part of the upward trend in EAC incidence (Kubo and Corley, 2006). Although the exact mechanism is unclear, it may be related to the higher prevalence of GERD in obese individuals.

Helicobacter pylori

Infection with Helicobacter pylori, a risk factor for stomach cancer, appears to be associated with a reduced risk of EAC. Whether H. pylori infection is related to risk of or protection from ESCC is unclear. Further investigations are needed to determine whether the decreasing prevalence of H. pylori infection may be related to the upward trend for EAC (Blot et al., 2006).

Other Medical Conditions and Treatments

The possible role of humanpapilloma virus (HPV) infection in the etiology of ESCC has been controversial. It appears to be related to ESCC risk in areas with exceptionally high incidence of esophageal cancer such as China, Iran, South Africa, and South America, but not in the United Kingdom or North America. Increased ESCC risks have been reported with chemical injuries to the esophagus and with medical conditions such as pernicious anemia, achalasia, some autoimmune diseases, and following gastrectomy. Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) appears to be related to a reduced risk of both ESCC and EAC. Exposure to ionizing radiation, particularly among women who received radiotherapy for breast cancer, has been linked to excess risks of both ESCC and EAC (Kamangar et al., 2009).

Poverty/Low Socioeconomic Status (SES) The highest rates of ESCC are generally found in impoverished areas of the world. Within a population, the risk of ESCC is greatest among those with the lowest SES. Low SES, whether measured by education, income, or occupation, is a surrogate for a set of complex lifestyle and environmental factors (e.g., poor living conditions, exposure to infectious or chemical agents, workplace hazards, poor nutrition, cigarette smoking, excessive alcohol consumption, and limited access to medical care). Low SES has also been related to excess risk of EAC, but the effect is less pronounced than for ESCC.

Diagnosis Signs and Symptoms Symptoms of esophageal cancer generally do not appear until the tumor has grown large enough to obstruct part of the esophagus. The most common sign of esophageal cancer is dysphagia or difficulty swallowing solids or liquids. As the tumor grows and becomes locally invasive, additional symptoms may include: l l

Odynophagia (painful swallowing) Regurgitation of food

600 l l l l l l

Esophageal Cancer

Indigestion and heartburn Weight loss Chest pain behind the breastbone Hoarseness Coughing Vomiting/coughing up blood.

Diagnosis and Staging Tests Tests to rule out esophageal cancer include: A barium-swallow examination (also called an upper GI series or esophagogram): the patient drinks a barium solution, which coats the surface of the esophagus so that any irregularities on the lining of the esophagus show up when a series of X-rays are taken. l Upper endoscopy (also called esophagoscopy): a thin, flexible, lighted tube (called an endoscope or esophagoscope) with a camera on the end is passed through the mouth or nose and down the esophagus to look for abnormal areas. If an abnormal area is found, a biopsy specimen will be taken and examined for signs of cancer. l

Once a diagnosis of esophageal cancer has been confirmed, the doctor will need to perform staging tests, important in determining treatment, to ascertain whether cancer cells have spread within the esophagus or metastasized outside the esophagus to nearby organs and lymph nodes. Common staging tests and procedures may include: l

l

l

l

l

Computed tomography (CT) or computerized axial tomography (CAT): a series of detailed X-ray pictures are taken at different angles inside the body and integrated by a computer to produce three-dimensional images. Endoscopic ultrasound (EUS) (also called endosonography): an endoscope with a small ultrasound probe on the tip that bounces sound waves off the walls of the esophagus is passed through the mouth and into the esophagus. This procedure is very good at determining the depth of the tumor in the esophageal wall and whether adjacent lymph nodes are involved. Positron emission tomography (PET) scan: a small amount of radioactive glucose is injected into a vein. The scanner makes detailed pictures of where the glucose is used in the body. Since the glucose is taken up more rapidly by cancer cells than normal cells in the body, it can be used to pinpoint cancer cells. Magnetic resonance imaging (MRI): intense magnetic fields and radio-frequency waves are used to provide real-time, three-dimensional views of the human body. Other procedures sometimes used for staging include thoracoscopy, laparoscopy, ultrasonography, and bone scan.

Treatment Treatment for esophageal cancer is determined by: l

The stage of the cancer, which ranges from Stage 0 (carcinoma in situ), in which cancer is confined to the innermost lining of the esophagus, to Stage IV (metastatic cancer), in which the cancer has spread to distant organs.

l l

The size of the tumor. The general health of the patient.

Cure is possible if the cancer is diagnosed at an early stage and the patient is healthy enough to undergo surgery. Unfortunately, symptoms usually do not occur until the tumor is large; therefore, most patients present with advanced or metastatic disease. For these patients, cure is unlikely; the goal of treatment is generally to relieve or palliate symptoms and prolong survival. The treatments used to treat early esophageal cancer are surgery, radiation, and chemotherapy or some combination thereof. These treatments can also be used to relieve symptoms and reduce pain.

Surgery The most common treatment for esophageal cancer is the surgical removal or resection of the cancerous part of the esophagus and the nearby lymph nodes, a procedure called esophagectomy. Major esophageal resections are associated with significant morbidity and mortality.

Chemotherapy Chemotherapy for esophageal cancer usually involves the intravenous use of drugs to kill or inhibit the growth of esophageal cancer. Chemotherapy is often used in combination with surgery and/or radiation. It can be given before or after surgery.

Radiation Therapy Radiation therapy is commonly used to treat esophageal cancer by using beams of high-energy to shrink the tumor and kill the cancer cells. External radiation therapy comes from a large machine outside the body; whereas internal radiation therapy (brachytherapy) comes from a tube inserted into the esophagus near the tumor. Radiation therapy is often combined with surgery and/or chemotherapy.

Survival

Five-year relative survival is an estimate of the chance of surviving the effects of cancer 5 years after diagnosis. It is calculated by adjusting the survival rate to remove all causes of death except cancer. Although survival among patients diagnosed with esophageal cancer is poor, significant improvements in 5-year relative survival in the United States and Europe have occurred over the past three decades (Table 2 (SEER, 2014b; Berrino et al., 1995; Berrino et al., 1999; Coleman et al., 2003; Berrino et al., 2007)). Five-year relative survival for those diagnosed during 2000–07 was substantially higher for US whites than for US blacks (20.1% vs 12.9%). Survival is similar for patients with ESCC and EAC. There is a strong decreasing gradient in survival with increasing extent of disease at diagnosis for all esophageal cancer patients. Recent 5-year survival rates for US patients diagnosed with esophageal cancer ranged from 40% for those with localized disease to 21% for regional disease to 4% for distant disease (Howlader et al., 2014). Pooled estimates of 5-year relative survival from up to 24 European countries have generally been similar to the 5-year

Esophageal Cancer Table 2 Five-year relative survival among patients diagnosed with esophageal cancer in the United States and Europe Year of diagnosis

US White a

US Black a

Europe b

1978–84 1985–89 1990–94 1995–99 2000–07

7.0% 10.2% 13.0% 14.9% 20.1%

4.6% 8.1% 9.1% 9.2% 12.9%

5% 9% 9% 9.8% 12.3%

a

Based on data from the Surveillance, Epidemiology, and End Results (SEER) Program. (www.seer.cancer.gov) SEER*Stat Database: Incidence – SEER 18 Registries, November 2013 Sub (1973–2011 Varying) – Linked to County Attributes – Total U.S., 1969–2011 Counties. National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, Bethesda, MD, Released April 2014. Rates are based on follow-up of patients through 2011. b 1978–84 data based on data from Berrino, F., Sant, M., Verdecchia, A., et al. (Eds.), 1995. Survival of Cancer Patients in Europe: The EUROCARE Study. IARC Scientific Publications No. 132. IARC, Lyon, France; 1985–89 data from Berrino, F., Capocaccia, R., Coleman, M.P., et al. (Eds.), 1999. 1990–94 data based on data from Coleman, M.P., Gatta, G., Verdecchia, A., et al., 2003. EUROCARE-3 summary: Cancer survival in Europe at the end of the 20th century. Ann. Oncol. 14 (Suppl. 5), 128–149; 1995–99 data based on data from Gavin, A.T., Franceschi, S., Foschi, R., Donnelly, D.W., Lemmens, V., Brenner, H., Anderson, L.A., 2012. The EUROCARE-4 Working Group. Oesophageal cancer survival in Europe: a EUROCARE-4 study. Cancer Epidemiol. 36, 505–512. 2000–07 data based on data from De Angelis, R., Sant, M., Coleman M.P., et al., 2014. Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE-5 – a population-based study. Lancet Oncol. 15, 23–34.

relative survival among US blacks (Table 2). There appears to be substantial variation in the 5-year relative survival among residents of developing countries when compared to US rates during the same time periods (Sankaranarayanan et al., 1998). For example, survival rates of 4% among residents of Quidong, China and Chiang Mai, Thailand diagnosed during 1982–91 and 1983–92, respectively, were lower than comparable rates among US blacks; survival rates of 7% among residents of Madras, India diagnosed during 1984–89 were similar to survival rates among US blacks; survival rates of 11% among residents of Shanghai, China diagnosed during 1988–91 resembled survival rates in US whites; however, survival rates of 30.5% (ESCC) and 28.3% (EAC) among residents of Linzhou City, China as extracted from the Linzhou Cancer Registry were substantially higher than survival rates in US whites (Liu et al., 2013).

Public Health Significance and Global Importance

Esophageal cancer is the eighth most common cancer worldwide and the sixth most common cause of cancer death. It is a highly fatal tumor if not detected early and treated aggressively with surgery, either alone or in combination with radiotherapy and/or chemotherapy. There is no cost-effective method for screening asymptomatic patients; however, it is recommended that patients with Barrett’s esophagus, the precursor condition for EAC, undergo surveillance with endoscopy and biopsy. Decreasing use of alcohol, tobacco, and very hot foods and beverages, and increasing intake of fresh fruits and vegetables may lead to lower incidence of ESCC in some populations. Reasons for the rapid rise in EAC, especially in several Western

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populations, remain elusive but may be related to epidemic increases in the prevalence of obesity and the subsequent increases in gastroesophageal reflux disease. Treatment is generally palliative rather than curative, because most esophageal cancers are not detected until the tumor has grown large enough to inhibit swallowing, at which point it is not usually amenable to radical surgery with curative intent. Reduction in the burden of esophageal cancer will only come from primary prevention by reducing exposure to known risk factors, especially tobacco and alcohol, and increasing exposure to protective factors, especially dietary fruit, vegetables, and fiber. This is because screening offers no prospect of reducing mortality except in the very small subpopulation with the premalignant condition Barrett’s esophagus, and the natural history of the disease precludes early clinical diagnosis in the vast majority of cases.

See also: Alcohol Consumption: An Overview of International Trends; Burden of Disease and Injury Caused by Alcohol; Environmental and Occupational Epidemiology; Global Issues: Urban Health in Developing Countries; Helicobacter pylori; Herpesviruses; Historical and Sociocultural Context of Psychoactive Substance Use; Race, Human Variation, and Health, the Interaction of; Smoking, The Burden of Mortality of; Social Epidemiology.

References Berrino, F., Sant, M., Verdecchia, A., et al. (Eds.), 1995. Survival of Cancer Patients in Europe: The EUROCARE Study. IARC, Lyon, France. IARC Scientific Publications No. 132. Berrino, F., Capocaccia, R., Coleman, M.P., et al. (Eds.), 1999. Survival of Cancer Patients in Europe: The EUROCARE-2 Study. IARC, Lyon, France. IARC Scientific Publications No. 151. Berrino, F., De Angelis, R., Sant, M., et al., 2007. Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995–99: results of the EUROCARE-4 study. Lancet Oncol. 8, 773–783. Blot, W.J., McLaughlin, J.K., Fraumeni Jr., J.F., 2006. Esophageal cancer. In: Schottenfeld, D., Fraumeni Jr., J.F. (Eds.), Cancer Epidemiology and Prevention, third ed. Oxford University Press, New York, pp. 697–706. Brown, L.M., Hoover, R., Silverman, D., et al., 2001. Excess incidence of squamous cell esophageal cancer among US black men: role of social class and other risk factors. Am. J. Epidemiol. 153, 114–122. Brown, L.M., Devesa, S.S., 2002. Epidemiologic trends in esophageal and gastric cancer in the United States. Surg. Oncol. Clin. North Am. 11, 235–256. Coleman, M.P., Gatta, G., Verdecchia, A., et al., 2003. EUROCARE-3 summary: cancer survival in Europe at the end of the 20th century. Ann. Oncol. 14 (Suppl. 5), 128–149. Curado, M.P., Edwards, B., Shin, H.R., Storm, H., Ferlay, J., Heanue, M., Boyle, P. (Eds.), 2007. Cancer Incidence in Five Continents, vol. IX. IARC, Lyon. IARC Scientific Publications, No. 160. De Angelis, R., Sant, M., Coleman, M.P., et al., 2014. Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE-5 – a population-based study. Lancet Oncol. 15, 23–34. Ferlay, J., Soerjomataram, I., Ervik, M., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F., 2013. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. International Agency for Research on Cancer, Lyon, France. Available from: http://www. globocan.iarc.fr (accessed on 05.08.14.). Forman, D., Bray, F., Brewster, D.H., Gombe Mbalawa, C., Kohler, B., Piñeros, M., Steliarova-Foucher, E., Swaminathan, R., Ferlay, J. (Eds.), 2013. Cancer Incidence in Five Continents, vol. X. IARC, Lyon (electronic version). http://www.ci5.iarc.fr (accessed on 05.08.14.). Gavin, A.T., Franceschi, S., Foschi, R., Donnelly, D.W., Lemmens, V., Brenner, H., Anderson, L.A., 2012. The EUROCARE-4 Working Group. Oesophageal cancer survival in Europe: a EUROCARE-4 study. Cancer Epidemiol. 36, 505–512.

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Howlader, N., Noone, A.M., Krapcho, M., et al. (Eds.). SEER Cancer Statistics Review, 1975–2011. National Cancer Institute, Bethesda, MD. http://www.seer.cancer. gov/csr/1975_2011/. Based on November 2013 SEER data submission, posted to the SEER website, April 2014. Kamangar, F., Chow, W.-H., Abnet, C., Dawsey, S., 2009. Environmental causes of esophageal cancer. Gastroenterol. Clin. North Am. 38, 27–57. Kubo, A., Corley, D.A., 2006. Body mass index and adenocarcinomas of the esophagus or gastric cardia: a systematic review and meta-analysis. Cancer Epidemiol. Biomarkers Prev. 15, 872–878. Liu, S.-Z., Wang, B., Zhang, F., et al., 2013. Incidence, survival and prevalence of esophageal and gastric cancer in Linzhous city from 2003 to 2009. Asian Pac. J. Cancer Prev. 14, 6031–6034. Muir, C.S., Waterhouse, J., Mack, T., Powell, J., Whelan, S.L. (Eds.), 1987. Cancer Incidence in Five Continents, vol. V. IARC, Lyon. IARC Scientific Publications, No. 88. Parkin, D.M., Muir, C.S., Whelan, S.L., Gao, Y.-T., Ferlay, J., Powell, J. (Eds.), 1992. Cancer Incidence in Five Continents, vol. VI. IARC, Lyon. IARC Scientific Publications, No. 120. Parkin, D.M., Whelan, S.L., Ferlay, J., Raymond, L., Young, J. (Eds.), 1997. Cancer Incidence in Five Continents, vol. VII. IARC, Lyon. IARC Scientific Publications, No. 143. Parkin, D.M., Whelan, S.L., Ferlay, J., Teppo, L., Thomas, D.B. (Eds.), 2002. Cancer Incidence in Five Continents, vol. VIII. IARC, Lyon. IARC Scientific Publications, No. 155. Sankaranarayanan, R., Black, R.J., Parkin, D.M., 1998. Cancer Survival in Developing Countries. IARC, Lyon, France. IARC Scientific Publications, No. 145. Surveillance, Epidemiology, and End Results (SEER) Program. (www.seer.cancer.gov) SEER*Stat Database: Incidence – SEER 9 Regs Research Data, November 2013 Sub (1973–2011) – Linked To County Attributes – Total U.S., 1969–2012 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, Released April 2014, Based on the November 2013 submission. Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence – SEER 18 Registries, November 2013 Sub (1973–2011 Varying). (2014) – Linked to Country Attributes – Total U.S., 1969–2011 Counties. National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, Bethesda, MD, Released April 2014.

Further Reading Ajani, J.A., Curley, S.A., Janjan, N.A., Lynch, P.M. (Eds.), 2005. Gastrointestinal Cancer. M.D. Anderson Cancer Care Series. Springer, New York. DHHS/PHS/NIH/NCI, 2000. What You Need to Know about Cancer of the Esophagus. NIH Publication No. 00–1557. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute, Bethesda, MD. Enzinger, P.C., Mayer, R.J., 2003. Esophageal cancer. N. Engl. J. Med. 349, 2241–2252. Posner, M.C. (Ed.), 2002. Surgical Oncology Clinics of North America. Contemporary Management of Esophageal and Gastric Carcinoma, vol. 11 (2). Posner, M.C., Vokes, E.E., Weichselbaum, R.R. (Eds.), 2002. American Cancer Society Atlas of Clinical Oncology. Cancer of the Upper Gastrointestinal Tract. BC Decker, Hamilton, ON. Posner, M.C., Forastiere, A.A., Minsky, B.C., 2005. Cancers of the gastrointestinal tract: cancer of the esophagus. In: DeVita, V.T., Hellman, S., Rosenberg, S.A. (Eds.), Cancer: Principles and Practice of Oncology, seventh ed. Lippincott Williams & Wilkins, Philadelphia, PA.

Relevant Websites http://www.cancer.org/ – American Cancer Society. http://www.ci5.iarc.fr/CI5I-X/Pages/table1_sel.aspx – CI5 I–X: Cancer Incidence in Five Continents Volumes I to X, Tables (last accessed on 01.08.16.). http://www.ci5.iarc.fr/CI5I-X/Pages/references.aspx – CI5 I–X: Cancer Incidence in Five Continents Volumes I to X, References (last accessed on 01.08.16.). http://www-dep.iarc.fr/ – International Agency for Research on Cancer (IARC). http://www.cancer.gov/ – National Cancer Institute, U.S. National Institutes of Health. http://www.seer.cancer.gov/ – SEER Surveillance Epidemiology and End Results.

Essential Drugs Policy H Haak, Consultants for Health and Development, Leiden, The Netherlands Ó 2017 Elsevier Inc. All rights reserved.

Pharmaceutical Policies Are an Integral Part of Health Policies

Introduction Governments around the world have always been concerned with securing and sustaining access to medicines for their populations (the terms medicines, drugs, and pharmaceuticals, are used here interchangeably, although preference is now given to the term medicines, to avoid confusion with the term hypnotics). This concern has often posed a challenge because medicines often represent significant monetary value and because numerous stakeholders are involved in their procurement, management, prescription, and use. Views about medicines are often strong and sometimes polemic. Even though pharmaceuticals play a key role in health care – and major resources are spent on them – according to the WHO (2000) they are often unavailable, unaffordable, unsafe, and/or improperly used. These problems are common around the world. Health systems are challenged by the rising costs of medicines, difficult choices regarding conventional and new therapies, and inequities in access (Govindaraj et al., 2000). Pharmaceutical expenditures in developing countries represent between 20 and 50% of total health-care expenditures (WHO, 1998). This figure is much higher than the average spent in industrialized countries. Access to pharmaceutical products is strikingly imbalanced between rich and poor countries and also within countries. The politics of pharmaceuticals are complex. Governments have many – sometimes contradictory – obligations to protect health, safeguard jobs, and ensure a strong economy (Almarsdottir and Traulsen, 2006). Balancing these different obligations requires skill and careful management of the political dimensions. Unfortunately, policy makers do not always seem to be aware of the distinct features of pharmaceuticals and pharmaceutical policies, which may explain the frequent failures in access to pharmaceuticals in countries around the world.

Pharmaceuticals Are Unique An issue that often complicates discussions on pharmaceutical policy is the mistaken belief that pharmaceuticals are like any other commodity. One study by Smith (1983: p. 112) identified 27 ‘latent functions’ of pharmaceuticals. These include symbolic and social functions in patient–doctor interactions as well as broad political functions (e.g., poor people claiming rights to health and pharmaceutical care) and economic functions (e.g., interests in strengthening pharmaceutical industries). The multifaceted nature of pharmaceuticals contributes to the complexity of pharmaceutical policy decision making. Assuming that pharmaceuticals can be viewed as any other commodity without considering their context may result in ineffective policy decisions. Discussions of pharmaceutical policy are often further complicated because it elicits debates about basic social values such as the roles of the market and the state, and the relative importance of efficiency and equity (Reich, 1995).

International Encyclopedia of Public Health, 2nd edition, Volume 2

Pharmaceutical policies cannot be isolated from broader health policies and need to fit within the framework of health-care systems. Most governments would see the goals of national pharmaceutical policy as having to be consistent with broader health objectives (WHO, 2001). Despite this intertwined role, pharmaceutical policy is fundamentally different from health policy and its development requires a different set of tools and knowledge (Traulsen and Almarsdottir, 2005a). Differences include the actors involved, their interests, the different power relations between them, and the influence of specific configurations of international forces. These differences have an impact on all aspects of pharmaceutical policy development and implementation.

Pharmaceutical Policy Literature Pharmaceutical policy means different things to different people (Traulsen and Almarsdottir, 2005a). Searching the literature on ‘pharmaceutical policies’ or ‘drug policies’ results in an avalanche of papers, as both phrases are added as keywords in almost any paper that refers to medicines. As well, the pressure of increasing prices of medicines has resulted in a narrowing of the discussion of pharmaceutical policy to one of cost. Much of the current literature is about pharmaceutical budgets, pricing of individual medicines, and whether inclusion of individual medicines in reimbursement schemes can be justified. The literature on the advantages and disadvantages of specific medicines in defined disease conditions is substantial. Much of this literature is considered relevant by the authors for ‘pharmaceutical policy development’ (i.e., policy content). As this literature generally does not discuss the pharmaceutical policy process, however, it will not be part of the analysis and conclusions of this article. A number of pharmaceutical policy papers describe specific experiences of policy implementation and change in particular countries. These papers are extremely useful, but they do not always compare the experiences of pharmaceutical policy implementation in different contexts. The relevance of these papers is therefore limited to policy development in comparable systems.

Actors in Pharmaceutical Policy Development In most settings, there are many actors involved in pharmaceutical sector regulation and policy making. These actors may include various ministries (health, finance, and industry), scientists, health professionals, nongovernmental organizations (NGOs), pharmacists, and consumers. In addition, activists, industry representatives, and drug wholesalers and retailers may claim a role in policy and regulation decisions. Some of these players are discussed here.

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Governments and Their National Drug Regulatory Agencies Governments are generally considered to hold the legal power to develop policies for production and delivery systems of pharmaceuticals. Most governments have also created national drug regulatory agencies, which ensure quality through national drug registration systems, and which – at least in theory – restrict the number of pharmaceuticals circulating within national borders. While not all countries have the capacity to actually enforce such registration schemes, registration status may nevertheless influence the procurement of medicines for public health-care systems. Stakeholders naturally lobby governments for pharmaceutical policies favorable to their interests.

Stringent Drug Regulatory Agencies Some drug regulatory agencies have gained an important transnational drug regulatory role. When such agencies have international relevance it is because their decisions have assumed an impact beyond their respective, national stakeholders. The countries included in this category are the regulatory authority member countries of the Pharmaceutical Inspection Cooperation Scheme (PIC/S) and/or the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The countries include all European Union member countries, the United States, Australia, Canada, Iceland, Japan, Liechtenstein, Malaysia, Norway, Singapore, and Switzerland. Although not a medicines registration agency, the European Medicines Agency (EMEA) has an increasingly important role in international pharmaceuticals registration decision making. The decisions of these ‘stringent’ drug regulatory agencies are important, as they have implications for the range of products that can be procured using the resources of some of the large international donors and financing mechanisms, include the Global Fund to Fight AIDS, TB, and Malaria (Global Fund), the President’s Emergency Plan for AIDS Relief (PEPFAR), and the President’s Malaria Initiative (PMI).

International Development Agencies Intergovernmental organizations such as the WHO and the World Bank have traditionally aspired to play a key role in guiding pharmaceutical policy development. Their input is noticeable in several of the documents quoted here. The WHO’s focus is on meeting the pharmaceutical needs of disadvantaged populations (WHO, 2004). The WHO’s framework for national pharmaceutical policy development was essentially the only comprehensive framework for national pharmaceutical policies until the late 1990s and is outlined later (see section The World Health Organization’s Perspectives on Pharmaceutical Policies). The World Bank has recently assumed a more active role in pharmaceutical sector development in member countries (Govindaraj et al., 2000). Until the late 1990s, the agency’s main focus in the sector was on ensuring adequate procurement practices and capable supplies systems. As Traulsen and Almarsdottir (2005b) stated, software components of pharmaceuticals supplies – such as pharmaceutical policy development

and correct (i.e., rational) use of medicines – was often only an afterthought. The revision of the World Bank’s strategies was stimulated by the continuing challenge of rising costs, new pharmaceutical therapies, and persistent inequities in access to pharmaceuticals (see the World Bank’s conceptual thinking outlined in a later section The World Bank’s Perspectives on Pharmaceutical Policies).

International Pharmaceutical Industry In 2006 the world pharmaceutical market was worth an estimated $608 000 million at ex-factory prices. The North American market (the United States and Canada) was the world’s largest market with a 47.7% share, with Europe at 29.9%, and Japan at 9.3%. Shareholder value tends to be the decisive factor in its decisions at the corporate, national, or international levels, more than public health considerations about the populations served. The pharmaceutical industry has a strong interest in pharmaceutical policies that are favorable to increased sales of its products. The application of the principles underlying ‘essential medicines’ approaches (see section The World Health Organization’s Perspectives on Pharmaceutical Policies) is generally not in the pharmaceutical industry’s interest, and it has traditionally opposed policies restrictive to the introduction of the latest and more expensive pharmaceutical solutions. Its powerful lobby, especially in the United States, has often succeeded in influencing national- and international-level pharmaceutical policy decisions, while its considerable financial and legal power has often led to the defeat of its opponents. Its power is, however, by no means a guarantee for victory. In 1997, for example, 39 pharmaceutical companies unsuccessfully sued the South African government for perceived violation of international property rights. Support of the internationally operating AIDS advocacy movement and worldwide press coverage resulted in the industry’s admission of defeat (The Economist, 2001).

International Nongovernmental Organizations and Activist Groups International NGOs and activist groups have gained an increasingly strong role in influencing decision making on pharmaceutical regulations and policy. Groups in this category include organizations such as Health Action International, Social Audit, Healthy Skepticism, and others (see section Relevant Websites). Some special initiatives by international NGOs have also had important repercussions for national pharmaceutical regulations and policy frameworks. Such initiatives include the Médecins Sans Frontières Access Initiative, the Clinton Foundation HIV/AIDS Initiative, and the Consumer Project on Technology (see section Relevant Websites). Assisted by rapid, Internet-based information sharing, these groups not only gained an increasingly authoritative voice in pharmaceutical policy debates, but also managed to have an impact on some national and international pharmaceutical policy discussions and thereby affected their content. AIDS activists pressured the World Trade Organization (WTO) to consider public health needs in the adoption of intellectual property rights and also successfully pressured the WHO to include

Essential Drugs Policy patented AIDS medicines in its Model List of Essential Drugs – this was unheard of until that time. Activist pressure has led to remarkable battles in the pharmaceutical arena.

Patient Organizations Patient organizations have traditionally tried to influence decisions on treatment policies, thereby also affecting pharmaceutical policy decisions. Until recently most patient organizations were independent, but more recently a new set of patient organizations has emerged with pharmaceutical industry funding. The independence of these industryfunded ‘patient organizations’ has been questioned, and some consider them to be marketing mechanisms in disguise (Herxheimer, 2003).

Health Insurance Industry Health insurance companies are not expected to make national pharmaceutical policy, but their influence on policy making may be large, because of their reimbursement policies and the size of the populations they insure. Especially in countries in which the private sector has large responsibilities in health insurance, their influence may be significant.

Information Networks A set of internet-based pharmaceutical policy discussion forums emerged with the growth of the Internet during the 1990s. The best known of these is the E-drug discussion forum (see section Relevant Websites). Established in 1994, E-drug membership now also includes staff from international agencies and the multinational pharmaceutical industry. It is not uncommon for highly controversial issues to be discussed in the E-drug forum. Novartis, for example, justified its decision to sue the Indian government in an open letter found at the website E-drug for what Novartis considered patent infringements of its profitable product Glivec (Novartis International, 2007). Similarly, an industry-sponsored effort led to a lengthy debate on whether expensive, patented antiretrovirals (ARVs) had an impact on access to these products in developing countries (Attaran, 2003). Information networks have clearly come to play a key role in rapidly circulating information to selected groups of opinion and decisions makers.

World Trade Organization The WTO is not an actor in the pharmaceutical sector in the strict sense of the word. The WTO has, however, worked on strengthening patent protection of costly pharmaceutical products, so it has often been perceived as such. Patent issues have played a controversial role in securing access to and cost containment of modern pharmaceuticals in both developing and developed countries. The pharmaceutical industry has tried to defend its position that patents ultimately improve access of populations to high-quality pharmaceutical care, an argument that has been met with skepticism by many health-care professionals and activists. The WTO’s meeting in Doha, Qatar, in 2001 reached agreement to allow developing countries to override certain patent laws and facilitate the use of less expensive

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generic drugs. In Article 31(f) of the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), the WTO allowed countries to issue licenses to manufacturers other than the patent holder to produce patented medicine (so-called ‘compulsory licensing’). The article also allowed the import of patented pharmaceuticals if they were less costly in another country (‘parallel importing’). The key principle of the TRIPS agreement was that trade agreements should be interpreted and implemented to protect public health and promote access to medicines for all. The United States refused to support a more detailed plan saying that it failed to protect patents on drugs for noninfectious diseases and that it would undermine research and development (Laing, 2003). Given the (research-based) pharmaceutical industry’s strong influence on U.S. foreign policy, the United States has started to establish bilateral free trade agreements (FTAs) to enforce patent protection in individual countries after failing to work out the details of the TRIPS agreement. These FTAs are often dubbed ‘TRIPS-Plus’ agreements, as their patent protection arrangements go well beyond the original TRIPS agreement. Some countries (e.g., Australia) had to accept the decision to provide a seat to brand-name industry representatives in the medicine selection committee of its pharmaceutical benefit scheme (PBS) (Hughes, 2004). These players (and others) influence drug regulatory and policy decisions to varying degrees, and the dynamics are rarely static. The balance of power tends to shift continuously. In studying the literature it becomes clear that pharmaceutical policies can and should be different, and that a one-size-fits-all approach for all pharmaceutical policies, and in all countries and health systems, is not recommended.

Key Concepts in Pharmaceutical Policy Development Since the mid-1970s, the WHO has urged countries to establish national pharmaceutical policies (WHO, 2001). Initially considered appropriate only for countries with limited health resources, more recently pharmaceutical policy development has been seen as relevant in industrialized nations as well. The increased cost of pharmaceuticals has played an important role in changing this perception.

The World Health Organization’s Perspectives on Pharmaceutical Policies The WHO, in its role as technical assistance agency to governments, considers a national pharmaceutical policy as presenting

a commitment to a goal and a guide for action. It expresses and prioritizes the medium- to long-term goals set out by a government for the pharmaceutical sector, and identifies the main strategies for attaining them. It provides the framework within which the activities of the pharmaceutical sector can be coordinated. It covers both the public and the private sectors, and involves the main actors in the pharmaceutical field. It includes drug legislation and regulation, essential drugs selection, drug registration, pricing policy, and public sector procurement. WHO (2001: p. 7).

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WHO literature (Quick et al., 1997; WHO, 1998; WHO, 2000; WHO, 2001; WHO, 2004) prioritizes a number of problems that in its view determine poor access to medicines: l

l

l

l

l

l

Unaffordable medicine prices, especially for newer products, such as ARVs, artemisinin-based antimalarial medicines, and other recently launched products. Irrational use of medicines, for example, the WHO estimates half of all medicines are inappropriately prescribed, dispensed, or sold and that half of all patients fail to take their medicine properly. Unfair health financing mechanisms, leaving poor households to cover the cost of essential medicines they need, placing the heaviest burden on those least able to pay. Persistence of unreliable medicine supply systems, causing irregular and unsustainable supply of medicines. Inefficient procurement systems pay up to twice the global market price for pharmaceuticals and lead to waste of resources. Greatly varying quality of medicines, especially in low- and middle-income countries. Counterfeit and substandard medicines are circulating globally. An estimated 50–90% of samples of antimalarial medicines in WHO-member countries failed quality control tests and more than half of sampled ARVs did not meet international standards. Lack of new medicines for diseases that typically affect the poor, especially ‘neglected’ diseases. Most research and development of medicines is focused on medical conditions of the richest 20% of the global population.

To achieve major improvements, the WHO notes that a pharmaceutical policy should be based on the essential medicines concept. This concept is believed to be the most cost-effective way of guaranteeing access to the majority of the global population (WHO, 2004). Key features of the essential medicines concept are: Selection of products as ‘essential’ based on national health priorities, and proven therapeutic effectiveness; l Careful quantification of needs; l Efficiency in procurement and supply mechanisms; l Promotion of rational drug use. l

Key components of a national pharmaceutical policy are summarized in Table 1. The WHO’s priority is to expand access to essential medicines, particularly for low-income and disadvantaged populations and for the priority diseases of HIV/AIDS, tuberculosis, and malaria. More recently, the WHO also started to place greater focus on financing, supply systems, and quality assurance. It is currently broadly agreed that the WHO’s essential medicines concept is potentially applicable in any country, in public and private sectors, and in rural or urban settings. The large-scale application of essential medicines selection and the use of generic medicines by health maintenance organizations (HMOs) in the United States exemplify this. The WHO claims that efforts of its own organization, countries, and other actors to update national pharmaceutical policies have increased access to essential medicines for people in countries from roughly US$2.1 billion in 1977 to an estimated US$3.8 billion in 1999 (WHO, 2000).

Table 1

Key components of a national pharmaceutical policy

Legislative and regulatory framework l l

Legislation and regulations Drug registration and licensing

Pharmaceutical quality assurance l Regulation of prescription and distribution l Pharmaceutical promotional activities Selection of medicines

Financing strategies l l

Roles of government Medicines financing mechanisms (public financing, user charges, health insurance)

l

Principles of medicines selection l Selection process, criteria, and levels of use l Application of traditional medicines in allopathic health systems Supply systems l Programming and budgeting needs l Procurement mechanisms l Supply system strategies and alternatives l Storage and distribution functions l

Rational use of medicines l

Medicines information systems

Rational prescribing by health personnel l Rational use by consumers l

Human resources in pharmaceutical sector l Human resources development

l l

Training strategies Motivation and continuing education

Reproduced from Quick, J.D., Rankin, J.R., Laing, R.O., O’Connor, R.W., Hogerzeil, H.V., Dukes, M.N.G., Garnett, A.(Eds.), 1997. Managing Drug Supply, second ed. Kumarian Press, West Hartford, CT.

The World Bank’s Perspectives on Pharmaceutical Policies The World Bank’s view on pharmaceutical policies is congruent with that of the WHO, but there are differences that have important implications for pharmaceutical policy making. A recent World Bank discussion paper presented the following reasons for the agency becoming more involved in pharmaceutical policy debates (Govindaraj et al., 2000): Significant public and private expenditures: Pharmaceuticals represent a significant proportion of government and private, out-of-pocket expenditures in many developing countries. The policy implications of these large public and out-of-pocket expenditures are many. l Inadequate regulatory capacity: Governments in developing countries often lack adequate institutional capacity to regulate pharmaceutical activities effectively and have difficulty in assuring the quality of pharmaceuticals in the public sector and on the private market. l Inadequate access to essential medicines: Inefficient use of pharmaceutical resources in many developing countries has substantially reduced access to essential medicines and potential health benefits. A significant portion of pharmaceutical expenditures in developing countries is wasted due to inefficiencies associated with the procurement and management of supplies. Problems in some countries are compounded by widespread corruption in public sector procurement and distribution systems, including the health sector. l

Essential Drugs Policy Limited access to new medicines: There is limited funding for new pharmaceutical products in developing countries, resulting in limited access for groups who might benefit therapeutically. The limited access is compounded by the tendency of pharmaceutical companies to set prices close to those of industrialized countries. l Globalized product patents affecting developing countries’ purchasing power: Patent protection is believed to provide an impetus to research and development investments, but globalized patent protection may also reduce access if those products are marketed at high monopoly prices in developing countries. l Limited incentives for research and development of new medicines: Developing countries represent a relatively small proportion of the global pharmaceutical market, providing limited market incentives for the development of new medicines specific to diseases of those countries (including many tropical diseases). l

The World Bank believes that these pharmaceutical policy issues have created market failures and failures in good governance, resulting in poor access to pharmaceutical products and, consequently, in poorly functioning health systems. In line with this analysis, the World Bank proposed a number of directions for pharmaceuticals in its lending and advisory activities (Govindaraj et al., 2000). Of key importance is that the World Bank should become more involved in pharmaceutical policy dialogues with client governments on sustainable pharmaceutical reform. Such policy dialogues may target comprehensive national drug policy reform, or focus on specific subcomponents, such as drug financing, management of drug supplies, pharmaceutical pricing, or selection of drugs to be included in national essential drug lists and/or reimbursement packages. Moreover, pharmaceutical sector assessments should become an integral part of World Bank lending activities, especially when pharmaceutical procurement is involved, and outcomes help to determine the poverty focus as well as the institutional and political context of reforms. In addition, the following propositions were made: Restrict World Bank support for pharmaceutical procurement to projects that promote policy and systems development and target the poor: Drug procurement should only be financed in situations in which the lending is linked to institutional development, capacity building, and specific poverty alleviation initiatives. Sufficient attention should be paid to the careful selection of pharmaceuticals, appropriate delivery to and storage within the recipient health system, and stringent monitoring and assurance of quality through inspection and product testing, as well as to the cost-effective management of the purchasing of goods. l Control corruption and increase transparency and accountability in all World Bank pharmaceutical lending activities: As pharmaceutical procurement and handling typically involve significant amounts of money, there is a high potential for corruption in the pharmaceutical management chain, from selection of drugs to be procured, to nontransparent contracts, or illegally selling publicly procured drugs. Corruption in the pharmaceutical sector not only means inefficiencies and waste in the health l

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system, but may also result in health risks for the population. l Create incentives for pharmaceutical research and development targeted at critical diseases of the poor: As the World Bank has financed initiatives such as the UNDP/ World Bank/WHO Special Program for Research and Training in Tropical Diseases (TDR), the Medicines for Malaria Venture (MMV), and the International AIDS Vaccine Initiative (IAVI), collaboration with the private sector is recommended, to stimulate the development of medicines for critical diseases of the poor. l Expand access to drugs through public-private partnerships and encourage the use of the private sector as a technical resource: A number of public-private interactions aim at increasing access of populations to needed drugs, such as single-drug donation programs of the private sector, efforts to create incentives for the pharmaceutical industry to enter underserved markets (e.g., The GAVI Alliance), and strategies to implement tiered pricing for new drugs. These efforts are believed to offer opportunities to increase access of populations to drugs. In addition, it is believed that the private sector – both for-profit and nonprofit – may be used as a technical resource in defined areas.

Assessing Pharmaceutical Policy Sound pharmaceutical policy development needs a solid understanding of the problems at hand. This requires evaluations of past policies in a given country context and careful studies of the impacts of possible future policy options. Policy analysis as a discipline is considered as a multidisciplinary social science – drawing particularly from the fields of political science, economics, and sociology (Buse et al., 2005). Research into pharmaceutical policy has similarities with general policy analysis and evaluation. The knowledge base for good pharmaceutical policy making needs to be broad with varied approaches (Almarsdottir and Traulsen, 2006). Proper pharmaceutical policy making is guided by questions like, ‘What works?’ ‘What does not work?’ ‘Why?’ or ‘Why not?’ and ‘How does it work, and at what cost/benefit?’ In particular, users’ views on pharmaceutical policies should be studied. Answering these key questions requires using varied approaches ranging from highly quantitative and experimental methodologies to purely qualitative ones. International collaboration between policy makers and other stakeholders is of key importance in these efforts (Almarsdottir and Traulsen, 2006). Nevertheless, the concept of systematically using evidence in health and pharmaceutical policy making and implementation is relatively new, and its value is not always appreciated. As Traulsen and Almarsdottir (2005a) pointed out: Although evidence-based decision making has become routine in medicine and is taking its place in insurance benefit design, there is no comparable trend toward evidence-based policy. Despite rigorous research, numerous health policy publications in the peer-reviewed literature, timely conferences, and methodological advances through professional societies, appeals to evidence as the basis for legislators’ decisions are uncommon.

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This important conclusion highlights the current challenges of using evidence in pharmaceutical policy making and implementation. Pharmaceutical policy evaluation and analysis is not necessarily difficult, but there are several potential problems (Almarsdottir and Traulsen, 2006): l

l

l

l

l l

Choosing inappropriate or poor assessment methodologies. Inappropriate or poor methods and designs are often selected based on the experience of the researcher (or the lack thereof) rather than on the most appropriate for the study in question. Qualitative research often does not have a place in pharmaceutical policy research and evaluation. Not being transparent about assessment designs. Given the sensitive nature of pharmaceutical policy, full openness about methods is a precondition to using assessment results to develop new policies. Using evaluation questions and policy options that are too narrow. Pharmaceutical policy analysis and evaluation should be broad and include the full spectrum of options available for policy. Using bias and self-censorship. Bias and self-censorship may distort study outcomes and be caused by preconceived ideas or financial obligations with funders. Special care must be taken to avoid industrial or political bias. Failing to estimate the effectiveness of pharmaceutical policy interventions outside of clinical settings. Not applying social science methods in pharmaceutical policy development.

Although pharmaceutical policy research is slowly gaining ground, it continues to be one of the lower priorities in formulating and evaluating policy. More research data is needed on policy making and on how research data is used. Almarsdottir’s and Traulsen’s study (2006) joins other calls for putting a stronger focus on using research in analysis, as opposed to basing policies on opinion-based approaches.

Strategies to Develop and Change Pharmaceutical Policies Pharmaceutical policy development may address the formulation of comprehensive national policies or be limited to specific subcomponents. According to Mossialos et al. (2004), common objectives of pharmaceutical policies have been to: Enhance quality of care; Improve access to pharmaceuticals; l Improve efficiency in the sector; l Define roles and responsibilities in the sector; l Contain expenditures. l l

These objectives sometimes conflict and policy changes may be difficult to implement. The focus of policy change in developing countries has often been on improving access and quality of care. In industrialized countries the focus has frequently been on containing costs while maintaining access and quality. These different objectives make it difficult to compare policy change processes between developing and industrialized countries.

A recurrent theme of many pharmaceutical policy papers is that effective change strategies include carefully designed mixes of interventions by governments, health delivery systems, health training institutions, professional societies, pharmaceutical companies, and consumers. Such interventions include strengthening regulation, educating medical or pharmaceutical professionals or the general public, and economic interventions to make adequate practices also financially attractive. Available intervention theory appears to agree that multifaceted interventions (e.g., implementing changes in drug reimbursement schemes, accompanied by dissemination of well-tested manuals and broad information campaigns to the medical profession and the general public) are more likely to succeed than small-scale, narrowly focused actions (e.g., mailing printed educational materials only) (Govindaraj et al., 2000; Quick et al., 1997). Another common theme is that professional education is often expected to bring about substantial change. It is now generally recognized, however, that strategies relying heavily on training do not always result in major improvements (Quick et al., 1997; Radyowijati and Haak, 2003). Pharmaceutical policies are most successful when they include an implementation plan that involves all stakeholders, a human resource development plan, and a monitoring and evaluation plan. A pharmaceutical policy implementation plan will also need sufficient resources to achieve effective change.

Political Management of Change Designing policies on the basis of careful study of current realities and examples of comparable systems is of major importance. Equally, if not more important, is careful management of the change process. Health and pharmaceutical policy development reform teams tend to focus on the technical rather than the political change process (Reich, 2003). Authoritative policy content–oriented literature is often believed to play a key role in generating changes in pharmaceutical policies. International agencies regularly publish technical literature that they expect governments and technical assistance agencies to consider in their policy development work. As Haak and Claeson argued (1996), however, providing scientific information to change policy may have limited impact. Pharmaceutical policy reforms are often contested because they may change the costs and benefits of different stakeholders, including domestic and international pharmaceutical producers, physician groups, and governments. Some of these stakeholders (e.g., the pharmaceutical industry) are relatively well organized, while others (e.g., patients) may be less able to use political influence. A few patient organizations are well organized and may be able to make their voices well heard in the policy process. The political change process may, in fact, be far more important than the power of individual players, and this process should, therefore, be handled skillfully. A number of factors are important in the policy change process: l

Policy making is characterized by debate, disagreement, and conflict (Traulsen and Almarsdottir, 2005a). Such

Essential Drugs Policy disagreements should not be considered a complication but a natural occurrence that can, and should be, managed. Negotiation and interaction should take place among all key players in the pharmaceutical sector (Grund, 1996). Such negotiations may be complex and time-consuming. l Shared values among various interest groups may be used to make policy development successful. The interests of a politically weak group (e.g., consumers) can often be protected if their goals coincide, at least partially, with those of more powerful interest groups (e.g., pharmacists). l Winner-takes-all approaches should be resisted. The perspective of various interest groups (government, health-care system, providers, patients, public) should be incorporated in pharmaceutical policy making and create a situation in which no one party simply wins or loses. Politics are bound to be played in all stages of the development policy cycle, including defining problems, defining solutions to be considered, shaping proposals for policy, policy adoption, and policy implementation. There are political limits to trying to implement radical changes in any policy (Reich, 1994), so it is important that these limitations are understood early. Evidence suggests that major policy reform in the health sector is feasible provided it is well defined and well timed. Evidence also suggests that political conditions for policy reform can be shaped by skilled leaders (Reich, 1995). Explicit political strategies may be employed to enhance the political feasibility of reform (Reich, 2003). Strategies may include helping supporters, weakening arguments of opponents, increasing the commitment of allies or nonmobilized players, decreasing commitment of opponents, and changing the nature of the issue. Support from domestic and international interest groups can be solicited. It may be necessary to enter into bargains and negotiate trade-offs to obtain this support. The consequences of each trade-off in the formulation and implementation of pharmaceutical policies should be carefully considered. Many pharmaceutical policies are usually, not surprisingly, the result of long and painstaking negotiation processes in which several concessions are made by all parties. Reich (1995) proposed to analyze relevant political conditions so as to shape political factors to achieve policy reform. A method known as political mapping was proposed to help policy makers manage the political dimensions of pharmaceutical policy reform and improve its political feasibility. Reich further argued that health sector reform is a profoundly political process so applied political analysis is required to determine feasibility and enhance the probability of success (1995). An important benefit of political analysis is that it acknowledges that politics are part of policy making, and that it cannot be ignored. Good timing and careful political maneuvering may allow policy change to occur as was shown by the adoption of a major pharmaceutical policy overhaul in Bangladesh (Reich, 1994). On the other hand, poor timing and failing to take a gradual approach may create social turmoil. In Korea, for example, poor timing and swift radical change in prescribing and dispensing regulations resulted in social tensions (Kim et al., 2004).

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Monitoring Pharmaceutical Policy Change The impact of pharmaceutical policies must be monitored as they evolve. Progress toward achieving targets should be assessed in each policy area and strategies adjusted accordingly. Indicators for monitoring national pharmaceutical policies have been developed by the WHO (Brudon-Jakobowicz et al., 1999), although they may need to be adapted to match particular contexts. Monitoring needs to be carried out using both quantitative and qualitative research methodology. Obviously the actors responsible for policy implementation have a key role in monitoring progress, but independent oversight of the process cannot be left behind.

Policy Enforcement Although less popular in pharmaceutical policy discussions, pharmaceutical regulation without active enforcement assures neither quality of health care nor of pharmaceutical products. Enforcement of regulations is a problem in many countries, in particular in low-income countries. Many problems in pharmaceutical sectors have their root in financial incentives in their manufacture, importation, supply, prescription, and sales. Sometimes these financial incentives become barriers to evidence-informed policy making, for example, generics of ARV drugs not being registered to protect the interests of the brand-name industry, or mono-component artemisinin medicines not being de-registered, despite the WHO advice to do so. In other cases, regulations are adopted, while enforcement is left behind (e.g., not monitoring the sales of banned pharmaceutical products in pharmacies). Voluntary guidelines and self-regulation, often selected as an acceptable compromise, are rarely effective on their own.

Conclusions Pharmaceutical policy development is a challenge for governments and health-care systems. The issues are complex; there are many stakeholders with multiple social, economic, and political interests. Agencies, such as the WHO and the World Bank, have supported countries in the development of pharmaceutical policies, through provision of information and examples of ‘best practices.’ The expectation was that this would result in improved policy making. Evidence-based pharmaceutical policy making has not yet become sufficiently common, however, even though evidence-based decision making is common practice in many other fields of medicine. The evidence suggests that to stand a chance of being effective, pharmaceutical policy approaches must be based on clear, verifiable data and tailored to individual environments. Carefully designed mixes of actions by several stakeholders are more likely to result in effective system changes than a narrow range of activities. A clear implementation plan and a budget are also key factors in successful pharmaceutical policy development. Teams responsible for reforming health and pharmaceutical policy development tend to focus on the technical rather than on the political aspects of the change process. However, as politics play a role at all stages of the development and implementation of any policy, politics cannot be ignored. It is important

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to realize the necessity of managing, rather than ignoring, political factors. Negotiation and concession-making aimed at reaching agreements with all relevant stakeholders should be accepted as part of the whole developmental process. Furthermore, effective implementation relies on the presence of sound frameworks for monitoring and enforcement. These are especially important in the implementation of any newly designed policy. To summarize, pharmaceutical policy change is feasible. However, improved access to medicines and containment of their soaring costs – the goals of responsible pharmaceutical policy design – can only be achieved by applying the evidence-based, politically sensitive, new approaches described in this article. Without these, the impetus to improve pharmaceutical policy will remain mere words on paper.

See also: Agenda Setting in Public Health Policy; Global Health Law: International Law and Public Health Policy; Public Health Law and Public Health Policy.

References Almarsdottir, A.B., Traulsen, J.M., 2006. Studying and evaluating pharmaceutical policy – becoming a part of the policy and consultative process. Pharm. World Sci. 28, 6–12. Attaran, A., 2003. Reply to Dr. Srinivas from Dr. Attaran (cont’d). http:// www.essentialdrugs.org/edrug/archive/200304/msg00011.php (accessed November 2007). Brudon-Jakobowicz, P., Rainhorn, J.D., Reich, M.R., 1999. Indicators for Monitoring National Drug Policies. A Practical Manual, second ed. World Health Organization, Geneva, Switzerland. Buse, K., Mays, N., Walt, G., 2005. Making Health Policy. Open University Press, Milton Keynes, UK. The Economist, April 19, 2001. Drug-Induced Dilemma. The Economist (available in Google). Govindaraj, R., Reich, M.R., Cohen, J.C., 2000. World Bank Pharmaceuticals. Internal Discussion Paper (unpublished). Grund, J., 1996. The societal value of pharmaceuticals: balancing industrial and healthcare policy. Pharmacoeconomics 10, 14–22. Haak, H., Claeson, M.E., 1996. Regulatory actions to enhance appropriate drug use: the case of antidiarrhoeal drugs. Soc. Sci. Med. 42, 1011–1019. Herxheimer, A., 2003. Relationships between the pharmaceutical industry and patients’ organisations. Br. Med. J. 326, 1208–1210. Hughes, T., 2004. Big Pharma vs. Australian Pharmaceutical Benefits Scheme. http://www.bmj.com/cgi/eletters/329/7475/1169%2385148 (last accessed November 2007). Kim, H.J., Chung, W., Lee, S.G., 2004. Lessons from Korea’s pharmaceutical policy reform: the separation of medical institutions and pharmacies for outpatient care. Health Policy 68, 267–275. Laing, R., 2003. Whose interests does the World Trade Organization serve? Lancet 361 (9365), 1297. Mossialos, E., Walley, T., Mrazek, M., 2004. Regulating pharmaceuticals in Europe: an overview. In: Mossialos, E., Walley, T., Mrazek, M. (Eds.), Regulating Pharmaceuticals in Europe: Striving for Efficiency, Equity and Quality. Open University Press, Milton Keynes, UK. Novartis International, 2007. Perspectives from Novartis: An Open Letter. http:// www.essentialdrugs.org/edrug/archive/200702/msg00008.php (accessed November 2007). Quick, J.D., Rankin, J.R., Laing, R.O., O’Connor, R.W., Hogerzeil, H.V., Dukes, M.N.G., Garnett, A. (Eds.), 1997. Managing Drug Supply, second ed. Kumarian Press, West Hartford, CT. Radyowijati, A., Haak, H., 2003. Improving antibiotic use in low-income countries: an overview of evidence on determinants. Soc. Sci. Med. 57, 733–744. Reich, M.R., 1994. Bangladesh pharmaceutical policy and politics. Health Policy Planning 9, 130–143.

Reich, M.R., 1995. The politics of health sector reform in developing countries: three cases of pharmaceutical policy. Health Policy 32, 47–77. Reich, M.R., January 2003. Introduction to Political Analysis. Flagship Course on Health Sector Reform and Sustainable Financing. Boston, USA, pp. 13–31. Smith, M.C., 1983. Principles of Pharmaceutical Marketing. Lea and Febiger, Philadelphia, PA. Traulsen, J.M., Almarsdottir, A.B., 2005a. The argument for pharmaceutical policy. Pharm. World Sci. 27, 7–12. Traulsen, J.M., Almarsdottir, A.B., 2005b. Pharmaceutical policy and the lay public. Pharm. World Sci. 27, 273–277. WHO, 1998. Health Reform and Drug Financing: Selected Topics. World Health Organization, Geneva, Switzerland. WHO/DAP/98.3. WHO, 2000. Medicines Strategy 2000–2003: Framework for Action in Essential Drugs and Medicines Policy. World Health Organization, Geneva, Switzerland. WHO, 2001. How to Develop and Implement a National Drug Policy, second ed. World Health Organization, Geneva, Switzerland. WHO, 2004. Medicines Strategy 2004–2007: Countries at the Core. World Health Organization, Geneva, Switzerland.

Further Reading Abraham, J., 1995. Science, Politics and the Pharmaceutical Industry. Routledge, London. Avorn, J., 2005. Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs. Vintage Books, New York. Brody, H., 2007. Hooked: Ethics, the Medical Profession and the Pharmaceutical Industry. Rowman and Littlefield, Lanham. Cohen, J.C., Schuklenk, U., Illingsworth, P., 2006. The Power of Pills: Social, Ethical and Legal Issues in Drug Development, Marketing, and Pricing. Pluto Press, London. Davis, P. (Ed.), 1996. Contested Ground: Public Concern and Private Interest in the Regulation of Pharmaceuticals. Oxford University Press, Oxford, UK. European Federation of Pharmaceutical Industries and Associations, 2007. The Pharmaceutical Industry in Figures. Key Data update. http://212.3.246.100/ Objects/2/Files/infigures2007.pdf. Goozner, M., 2004. The $800 Million Pill: The Truth behind the Cost of New Drugs. University of California Press, Berkley, CA. Hansson, O., 1989. Inside Ciba Geigy. International Organization of Consumers Unions, Penang. LeCarre, J., 2001. The Constant Gardener. Hodder and Stoughton, London. Medawar, C., 1992. Power and Dependence: Social Audit on the Safety of Medicines. Social Audit, London. Moynihan, R., Cassels, A., 2005. Selling Sickness. Allen and Unwin, Sydney, Australian. Permanand, G., 2006. EU Pharmaceutical Regulation. Manchester University Press, Manchester, UK. Reynolds-Whyte, S., van der Geest, S., Hardon, A.P., 2002. Social Lives of Medicines. Cambridge University Press, Cambridge, UK. Silverman, M., Lydecker, M., Lee, P.R., 1992. Bad Medicine: The Prescription Drug Industry in the Third World. Stanford University Press, Stanford, CA.

Relevant Websites http://www.clintonfoundation.org – Clinton Foundation. http://www.cptech.org – Consumer Project on Technology. http://www.essentialdrugs.org – E-Drug Discussion Forum. http://www.efpia.org/Content/Default.asp – European Federation of Pharmaceutical Industries and Associations. http://www.haiweb.org – Health Action International – Europe. http://www.healthyskepticism.org – Healthy Skepticism – Countering Misleading Drug Promotion. http://www.accessmed.msf.org – Médecins Sans Frontières – Campaign for Access to Essential Medicines. http://www.socialaudit.org.uk – The Social Audit Website. http://www.worldbank.org – The World Bank. http://www.who.int/medicines – World Health Organization – Medicines. http://www.wto.org – The World Trade Organization (WTO).

INTERNATIONAL ENCYCLOPEDIA OF PUBLIC HEALTH SECOND EDITION VOLUME 3 ETHeHER

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INTERNATIONAL ENCYCLOPEDIA OF PUBLIC HEALTH SECOND EDITION EDITOR IN CHIEF STELLA R. QUAH Duke-NUS Medical School, Singapore

ASSOCIATE EDITOR IN CHIEF WILLIAM COCKERHAM University of Alabama at Birmingham, Birmingham, AL, USA

VOLUME 3

AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD PARIS • SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier

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To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-803678-5 For information on all publications visit our website at http://store.elsevier.com Printed and bound in Canada 17 18

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Publisher: Oliver Walter Associate Acquisition Editor: William Smaldon Content Project Manager: Justin Taylor Associate Content Project Manager: Katherine Finn Cover Designer: Matthew Limbert

EDITORIAL BOARD EDITOR IN CHIEF Stella R. Quah (PhD) is Adjunct Professor at the Duke-NUS Medical School, Singapore. She received her BA in Sociology from the Universidad Nacional de Colombia, her MSc in Sociology from Florida State University as a Fulbright-Hays Scholar, and her PhD in Sociology from the National University of Singapore (formerly University of Singapore). Prior to her current appointment she was Professor at the NUS Department of Sociology where she was a faculty member from 1977 to 2009. Before joining the Sociology Department, she worked at the Department of Social Medicine and Public Health of the Faculty of Medicine, University of Singapore. Her work on Medical Sociology and Public Health has continued throughout her career. She introduced and taught medical sociology at both the Department of Sociology and the Faculty of Medicine. She designed different medical sociology modules for social science students, nursing students, and graduate medical students at the Department of Community, Occupational, and Family Medicine, NUS. When the Graduate School of Medical Studies was set up at the Faculty of Medicine, she taught the medical sociology modules as part of the ‘Foundations of Public Health’ and ‘Lifestyle and Behaviour in Health and Disease’ for the MMed (Public Health). During her long career at NUS, she spent research sabbaticals as Research Associate and Visiting Scholar, by invitation, at the Institute of Governmental Studies, University of California Berkeley (1986–87); the Center for International Studies, MIT, and the Department of Sociology, Harvard University (1993–94), the Harvard-Yenching Institute (1997); the Stanford Program in International Legal Studies, Stanford University (1997); the National Centre for Developmental Studies, Australian National University (2002); and the Walter H. Shorenstein Asia–Pacific Research Center, Stanford University (2006). Her professional activities include her work as Chair of the Medical Sociology Research Committee (RC15) of the International Sociological Association (ISA) 1990–94; ISA Vice President for Research (1994–98); Chairperson of the ISA Research Council (1994–98); and consultant to WHO and UN-ESCAP, among other international and national organizations. She is member of the American Sociological Association and member of several institutional review Boards. On publications, she was Associate Editor of International Sociology (1998–2004) and is member of editorial advisory boards of several international peer-reviewed journals including the British Journal of Sociology; Associate Editor in Chief of the first edition of this Encyclopedia (2008); Coeditor of the Wiley Blackwell Encyclopedia of Health, Illness, Behavior and Society (2014); and Section Editor of Public Health of Elsevier’s Reference Module in Biomedical Sciences. Her areas of research and consultancy include health services utilization; self-medication; health risks behaviors (including smoking, alcohol consumption, and psychoactive substance use); sociocultural factors in infectious diseases, heart disease, and cancer; the governance of epidemics; and the role of family caregivers in mental health. She has published many journal articles and book chapters and has authored nine books; six as sole author. She is also editor and coeditor of 13 books. Her most recent publications include ‘Caring for persons with schizophrenia at home: Examining the link between family caregivers’ role distress and quality of life,’ Sociology of Health and Illness (2013); the Blackwell Encyclopedia of Health, Illness, Behaviour and Society (coeditor and contributor, 2014); ‘Sociology and Psychology in Public Health’ in the Oxford Textbook of Global Public Health (2015); ‘Partnership: The missing link in the process of de-institutionalization of mental health care,’ International Journal of Health Services (2015); Routledge Handbook of Families in Asia (editor and contributor, 2015); and ‘Public Health and Epidemiology: Prevention and surveillance of health risks,’ Elsevier’s Reference Module in Biomedical Sciences (2015).

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ASSOCIATE EDITOR IN CHIEF William Cockerham is Distinguished Professor and Chair of the Department of Sociology at the University of Alabama at Birmingham. He holds a PhD from the University of California at Berkeley. Among his books are Medical Sociology, 13th ed. (Routledge, 2016), with an earlier edition included on the International Sociological Association’s List of 100 Sociology Books of the Century (2000) and Social Causes of Health and Disease, 2nd ed. (Polity, 2013), listed as one of the key books in medical sociology in the twenty-first century in Contemporary Sociology (2014). Other recent books include Sociology of Mental Disorder, 10th ed. (Routledge, 2016) and Medical Sociology on the Move: New Directions in Theory (Springer, 2013). In addition, he is Editor in Chief of the five-volume Encyclopedia of Health, Illness, Behavior, and Society (Wiley-Blackwell, 2014) and Guest Coeditor of a forthcoming special issue of the American Journal of Preventive Medicine. He is also past President of the Research Committee on Health Sociology of the International Sociological Association and has served on the Medical Sociology Council of the American Sociological Association and the Editorial Board of the American Sociological Review.

EDITORIAL BOARD Annette Braunack-Mayer is a bioethicist and Professor of Health Ethics in the School of Public Health at the University of Adelaide. Her research, teaching, and community service focus on combining rigorous and robust analyses of health systems, policies, and practices with the views and experiences of community members. She is passionate about ensuring that the experiences and views of members of communities, including citizens, patients, consumers, and stakeholders, contribute to health services, policies, and systems. She has particular expertise in the use of deliberative methods of engagement with communities, but her research skill set extends across the full range of qualitative research methods. Professor Braunack-Mayer’s current research spans vaccination policy and programs, the appropriate use of big data, obesity prevention, and chronic disease prevention in Aboriginal and Torres Strait Islander communities. She has also completed studies of ethical reasoning among general practitioners, ethics in health technology assessment, and decision-making around the beginning and ending of life. She has published the first and second edition of a text on general practice ethics and over 110 refereed papers and book chapters. Professor Braunack-Mayer chairs a range of health councils and committees, including a government ethics advisory committee and human research and animal ethics committees. She teaches graduate and undergraduate courses in health ethics and qualitative research methods.

Karen Glanz, PhD, MPH, is George A. Weiss University Professor, Professor in the Perelman School of Medicine and the School of Nursing, and Director of the UPenn Prevention Research Center, at the University of Pennsylvania. A globally influential public health scholar whose work spans psychology, epidemiology, nutrition, and other disciplines, her research in community and healthcare settings focuses on obesity, nutrition, and the built environment; reducing health disparities; and health communication technologies. Her research and publications about understanding, measuring, and improving healthy food environments, beginning in the 1980s, has been widely recognized and replicated. Dr Glanz was elected to membership in the Institute of Medicine (IOM) of the National Academy of Sciences in 2013. She was named a Highly Cited Author and one of The World’s Most Influential Scientific Minds 2015 by Thomson Reuters.

Editorial Board

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Davidson H. Hamer, MD, is a graduate of Amherst College and the University of Vermont College of Medicine. After internship and residency in internal medicine at the Washington Hospital Center, he completed a fellowship in infectious disease at Tufts-New England Medical Center. Dr Hamer has a special interest in tropical infectious diseases and has more than two decades of field experience in diarrheal diseases, pneumonia, malaria, and maternal and newborn health. His research interests include emerging infections, neonatal sepsis, antimicrobial resistance, Water, Sanitation and Hygiene (WASH), integrated community case management, interventions for the treatment and prevention of malaria, micronutrient deficiencies, diarrheal disease, and childhood pneumonia. Dr Hamer is a Professor of Global Health and Medicine at the Boston University Schools of Public Health and Medicine, and he holds a position as an Adjunct Professor of Nutrition at the Tufts University Friedman School of Nutrition Science and Policy and adjunct scientist at the Jean Mayer USDA Human Nutrition Research Center on the Aging. Dr Hamer also is the current Principal Investigator for GeoSentinel, a multicountry emerging infections surveillance network.

Japhet Killewo is a professor of Epidemiology at the Muhimbili University of Health and Allied Sciences (MUHAS) in Tanzania. He teaches epidemiology and biostatistics to undergraduate and postgraduate students in the university and offers short courses in data management, research methodology, and monitoring and evaluation to other scholars. He does research in communicable and noncommunicable diseases, and he was the first in Tanzania to design the largest field study for monitoring HIV infection trends and evaluating the impact of HIV interventions in one of the 20 or so regions of Tanzania. He has also worked with the International Center for Diarrheal Disease Research (ICDDRB) in Bangladesh monitoring and evaluating reproductive health interventions in a health and demographic surveillance system. Since 2010 Professor Killewo has been involved in initiating an urban-based health and demographic surveillance system in Tanzania where more than 100,000 residents of all ages are being followed up for in- and out-migration, vital events, socioeconomic status, and food insecurity issues. The population is also being followed up for noncommunicable diseases of various kinds. Professor Killewo has critically reviewed a considerable number of research proposals and manuscripts for various peer-reviewed international journals. Professor Killewo has published widely in local as well as international journals and has written chapters in books and edited a section in the International Encyclopedia of Public Health. He is also the Editor in Chief of the derivative volume on Epidemiology and Demography in Public Health and has more than 80 published articles in journals to his credit.

Jonathan D. Mayer, The overriding emphasis in Professor Mayer’s career has been synthesizing the epidemiologic, geographic, and clinical understanding of health and disease. Health and disease cannot be easily separated into individual disciplines, and so doing may introduce bias into the overall understanding. Professor Mayer’s current position, spanning three different schools at the University of Washington (Public Health, Arts and Sciences, and Medicine) is ideal for this. Similarly, his joint position in Epidemiology and Geography facilitates this. In addition, Professor Mayer has adjunct appointments in two clinical departments: Internal Medicine (Division of Allergy and Infectious Diseases) and Family Medicine, as well as two additional departments in the School of Public Health: Health Services and Global Health. Several leadership positions in the School of Public Health have further facilitated insights into an integrative understanding. Specific interests include (1) diarrheal diseases, especially in sub-Saharan Africa; (2) tuberculosis (TB), especially in densely settled slum areas; (3) vector-borne diseases, including malaria, dengue, and Zika; and (4) emerging infectious diseases – previously unrecognized or genuine de novo diseases, such as Ebola, HIV, Zika, and the emergence of new forms of antimicrobial (‘antibiotic’)-resistant infections. Professor Mayer is particularly interested in understanding the underlying epidemiologic, social, demographic, and political factors underlying disease emergence. Recent attention has been devoted to the epidemiology and geography of pain – especially chronic pain – and the conditions that underlie pain, such as low back pain, postherpetic neuralgia, and injury. Professor Mayer is also interested in health services and the provision of health care. Recent work includes organ transplantation, especially inequities in access to organs; access to pain treatment and pain medications; evolution of hospital systems and consolidation; and, throughout his career; rural health and the urban–suburban–rural inequities in access to care.

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Editorial Board Wayne D. Rosamond, PhD, MS, is a Professor in the Department of Epidemiology, Gillings School of Global Public Health at the University of North Carolina (UNC) at Chapel Hill (USA) and an Adjunct Professor in the Department of Emergency Medicine at UNC. Professor Rosamond is an investigator and teacher in cardiovascular disease (CVD) epidemiology with research expertise in design, conduct, and analysis of community-based surveillance studies and registries of coronary heart disease, heart failure, and stroke. He has also published on the etiology of myocardial infarction, heart failure, sudden cardiac death, venous thromboembolism, and stroke. Dr Rosamond is principal investigator for the North Carolina Stroke Care Collaborative and a coprincipal investigator with the Atherosclerosis Risk in Communities (ARIC) study and Comprehensive Post Acute Stroke Service (COMPASS) trial. Dr Rosamond has collaborated on international CVD epidemiology studies including the WHO-MONICA Project, the Stroke Registry of the Canadian Stroke Network, and the Emerging Risk Factor Collaboration at the University of Cambridge, the United Kingdom. Dr Rosamond is Director of the Cardiovascular Epidemiology NRSA-NIH T32 training grant at UNC. He is past Chair of both the American Heart Association’s (AHA) Statistics and Executive Database Steering Committees and is immediate past President of the Board of Directors of the AHA Mid-Atlantic Affiliate.

Dr Vijay K. Sharma is currently working as Associate Professor at YLL School of Medicine, National University of Singapore, Singapore, and as Senior Consultant, Division of Neurology, National University Hospital, Singapore. He is the current recipient of the prestigious Clinician Scientist Award from National Medical Research Council, Singapore. He has published 187 peerreviewed scientific papers and 19 book chapters. Dr Sharma is Associate Editor for BMC Neurology and serves on the editorial boards of many scientific journals including Stroke, Neural Regeneration Research, Recent Patents on Medical Imaging, Journal of Behavioral and Brain Science, World Journal of Hypertension, ISRN Neurology, American Journal of Cardiovascular Diseases, World Journal of Neurology, Journal of Neurology & Translational Neuroscience (JNTN), International Journal of Medical Sciences and Biotechnology, Advances in Neuroscience Research and Neurological Research and Therapy.

CONTRIBUTORS TO VOLUME 3 Sandeep Aggarwal Cardiac Wellness Institute of Calgary, Calgary, AB, Canada; University of Calgary, Calgary, AB, Canada; and Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada Ahmed B Al-Khafaji University of Pittsburgh, Pittsburgh, PA, USA Pascale Allotey Monash University, Selangor, Malaysia Niall Anderson University of Edinburgh Medical School, Edinburgh, UK Ann Ashworth London School of Hygiene and Tropical Medicine, London, UK Roy W Batterham Population Health Strategic Research Centre, School of Health and Social Development, Deakin University, Geelong, VIC, Australia Alison Beauchamp Population Health Strategic Research Centre, School of Health and Social Development, Deakin University, Geelong, VIC, Australia Jonathan N Bella Bronx Lebanon Hospital Center, Bronx, NY, USA

Annette Braunack-Mayer School of Public Health, University of Adelaide, Adelaide, SA, Australia Robert Burkard University at Buffalo, Buffalo, NY, USA Harry Campbell University of Edinburgh Medical School, Edinburgh, UK Stacy M Carter Centre for Values, Ethics and the Law in Medicine, The University of Sydney, Sydney, NSW, Australia Kenneth Chambaere End-of-Life Care Research Group, Vrije Universiteit Brussel (VUB), Brussels, Belgium; and Ghent University, Brussels, Belgium Rehema Chande-Mallya Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania Catherine Chittleborough School of Public Health, University of Adelaide, Adelaide, SA, Australia William C Cockerham University of Alabama at Birmingham, Birmingham, AL, USA

Benjamin E Berkman Georgetown University, Washington, DC, USA

Joachim Cohen End-of-Life Care Research Group, Vrije Universiteit Brussel (VUB), Brussels, Belgium; and Ghent University, Brussels, Belgium

Boakye Boatin World Health Organization, Geneva, Switzerland

Jane C Cottingham Independent Consultant, Geneva, Switzerland

Gerard Bodeker University of Oxford, Oxford, UK; and Columbia University, New York, NY, USA

Horacio B Croxatto Chilean Institute for Reproductive Medicine, Santiago, Chile

Michel Boussinesq Institut de Recherche pour le Développement (IRD), Montpellier, France

Dina Czeresnia Oswaldo Cruz Foundation (ENSP-FIOCRUZ), Rio de Janeiro, Brazil

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Contributors to Volume 3

Pradeep K Das Vector Control Research Centre, Pondicherry, India Christopher T De Rosa Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA Alex de Waal World Peace Foundation, Fletcher School of Law and Diplomacy, Tufts University, Medford, MA, USA Philip Willem Downs RTI International, Washington, DC, USA Erin A Dreelin Michigan State University, East Lansing, MI, USA Samer S El-Kamary University of Maryland School of Medicine, Baltimore, MD, USA Michael Emch University of North Carolina, Chapel Hill, NC, USA Lars Engstrand Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden Helena Enroth Laboratory Medicine, Unilabs, Skaraborgs Hospital Skövde, Skövde, Sweden Ruth R Faden Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA M Fay Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA Alan Fenwick Imperial College London, London, UK Bernard Fried Lafayette College, Easton, PA, USA Albis Francesco Gabrielli World Health Organization, Geneva, Switzerland Maria Garefalakis University of Western Australia, Perth, WA, Australia Ailsa Gebbie NHS Lothian Family Planning and Well Woman Services, Edinburgh, UK

John D Glover Public Health Information Development Unit (PHIDU), Torrens University Australia, Adelaide, SA, Australia Miguel A Gonzalez Block Centro de Investigacion en Sistemas de Salud, Cuernavaca, Morelos, Mexico Sebastian González McQuire Wyeth Pharmaceuticals Mexico and Central America, Mexico City, Mexico Lawrence O Gostin Georgetown University, Washington, DC, USA Stefan Greß University of Applied Sciences, Fulda, Germany Sofia Gruskin University of Southern California, Los Angeles, CA, USA; and Harvard T.H. Chan School of Public Health, Boston, MA, USA Davidson H Hamer Center for Global Health and Development, Boston University School of Public Health and Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA, USA Roger Härtl New York-Presbyterian Hospital, New York, NY, USA M T Hatcher Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA Trina Hauer Cardiac Wellness Institute of Calgary, Calgary, AB, Canada Mark Haykowsky University of Alberta, Edmonton, AB, Canada Wolfgang Herrmann University of Saarland, Homburg, Germany Diana M S Hetzel Public Health Information Development Unit (PHIDU), Torrens University Australia, Adelaide, SA, Australia Martha Hickey University of Western Australia, Perth, WA, Australia

Karen Glanz Perelman School of Medicine and School of Nursing, University of Pennsylvania, Philadelphia, PA, USA

H E Hicks Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA

Anna Glasier NHS Lothian Family Planning and Well Woman Services, Edinburgh, UK

James S Holler Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA

Contributors to Volume 3

Jane E Huffman East Stroudsburg University, East Stroudsburg, PA, USA Scott H James University of Alabama at Birmingham, Birmingham, AL, USA Bruce Jennings Center for Humans and Nature, New York, NY, USA Barry L Johnson Rollins School of Public Health, Emory University, Atlanta, GA, USA Neil Johnson University of Auckland, Auckland, New Zealand Niklas Juth Centre for Health Care Ethics, Karolinska Institutet, Stockholm, Sweden Phua Kai Hong Lee Kuan Yew School of Public Policy, National University of Singapore, Singapore Nancy E Kass Johns Hopkins Berman Institute of Bioethics, Baltimore, MD, USA; and Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Lisa Keay The George Institute for Global Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia Corinna Keeler University of North Carolina, Chapel Hill, NC, USA L S Keith Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA Usman Khan Bronx Lebanon Hospital Center, Bronx, NY, USA

Madelon W Kroneman NIVEL (Netherlands Institute of Health Services Research), Utrecht, The Netherlands Paul A L Lancaster Menzies Centre for Health Policy, University of Sydney, Sydney, NSW, Australia Edda Tandi Lwoga Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania Amanda J MacFarlane Cornell University, Ithaca, NY, USA Jennifer H Madans National Center for Health Statistics, Hyattsville, MD, USA Jean Maguire van Seventer Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA M G Venkatesh Mannar University of Toronto, Toronto, ON, Canada Colin Mathers World Health Organization, Geneva, Switzerland Sarah K McDonald Public Health Information Development Unit (PHIDU), Torrens University Australia, Adelaide, SA, Australia Summer Johnson McGee College of Business, University of New Haven, West Haven, CT, USA Donald P McManus QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia Maurice B Mittelmark University of Bergen, Bergen, Norway

Ilona Kickbusch Graduate Institute of International Studies, Geneva, Switzerland

Mohammed H Moghadasian Canadian Centre for Agri-Food Research in Health and Medicine, University of Manitoba, Winnipeg, MB, Canada

Hanna Kienzler McGill University, Montreal, QC, Canada

Stephanie L Molloy University of Hawai’i at Hilo, Hilo, HI, USA

Jared Knopman New York-Presbyterian Hospital, New York, NY, USA

Antonio Montresor World Health Organization, Geneva, Switzerland

Suminori Kono Kyushu University Faculty of Medical Sciences, Fukuoka, Japan

Sydney Enock Msonde Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania

John Kraemer Georgetown University, Washington, DC, USA

Wulystan Pius Mtega Sokoine University of Agriculture, Morogoro, Tanzania

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Contributors to Volume 3

Moiz M Mumtaz Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA

P Ruiz Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA

Christian Munthe University of Gothenburg, Gothenburg, Sweden

Dieudonné P Sankara World Health Organization, Geneva, Switzerland

Kenneth D Murrell Uniformed Services University of the Health Sciences, Bethesda, MD, USA

Lorenzo Savioli World Health Organization, Geneva, Switzerland

Niels Nijsingh Independent Scholar, Utrecht, The Netherlands

Susan M Sayers Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia

Rima Obeid University of Saarland, Homburg, Germany

Jorgen Schlundt Nanyang Technological University, Singapore

Sara Oliver University of Alabama at Birmingham, Birmingham, AL, USA

Angela Scriven Brunel University, Uxbridge, UK

Richard H Osborne Population Health Strategic Research Centre, School of Health and Social Development, Deakin University, Geelong, VIC, Australia Lisa S Parker University of Pittsburgh, Pittsburgh, PA, USA

Michael J Selgelid Centre for Human Bioethics, Monash University, Clayton, VIC, Australia Fereidoon Shahidi Memorial University of Newfoundland, St. John’s, NL, Canada

Calum Paton Keele University, Newcastle-under-Lyme, UK

Ranganatha K Shenoy TD Medical College Hospital, Kerala, India

Duncan Pedersen McGill University, Montreal, QC, Canada

Karol Sikora Medical School, University of Buckingham, Buckingham, UK

H R Pohl Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA Stephen G Post Case Western Reserve University, Cleveland, OH, USA Marc-André Prost London School of Hygiene and Tropical Medicine, London, UK Stella R Quah Duke-NUS Medical School, Singapore Arslan Rafiq Bronx Lebanon Hospital Center, Bronx, NY, USA Jan H F Remme World Health Organization, Geneva, Switzerland

Jana Sisnowski School of Public Health, University of Adelaide, Adelaide, SA, Australia Teresa C Soares Federal University in Juiz de Fora, Juiz de Fora, Brazil Carolyn Stephens UCL Institute of Health Equity, London, UK; Universidad Nacional de Tucumán, Tucumán, Argentina; and London School of Hygiene & Tropical Medicine, London, UK Fred C J Stevens Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands

Irving Rootman University of Victoria, Victoria, BC, Canada

James A Stone Cardiac Wellness Institute of Calgary, Calgary, AB, Canada; University of Calgary, Calgary, AB, Canada; and Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada

Joan B Rose Michigan State University, East Lansing, MI, USA

Patrick J Stover Cornell University, Ithaca, NY, USA

Véronique L Roger Mayo Clinic College of Medicine, Rochester, MN, USA

Contributors to Volume 3

Jackie M Street School of Public Health, University of Adelaide, Adelaide, SA, Australia G Thomas Strickland University of Maryland School of Medicine, Baltimore, MD, USA Daina L Sturnieks Neuroscience Research Australia, University of New South Wales, Randwick, NSW, Australia Lia P Suazo Hernandez University of Texas Medical Branch, Galveston, TX, USA Daniel Tarantola Consultant in International and Global Health, Ferney-Voltaire, France Allyn L Taylor University of Washington School of Law, Seattle, WA, USA Holly A Taylor Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; and Johns Hopkins Berman Institute of Bioethics, Baltimore, MD, USA

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Juerg Utzinger Swiss Tropical Institute, Basel, Switzerland Jouke van der Zee Maastricht University, Maastricht, Netherlands; and NIVEL (Netherlands Institute of Health Services Research), Utrecht, The Netherlands Sharuna Verghis Health Equity Initiatives, Kuala Lumpur, Malaysia Marcel Verweij Wageningen University, Wageningen, The Netherlands Carol Vlassoff University of Ottawa, Ottawa, ON, Canada Juergen Wasem University of Duisburg Essen, Essen, Germany Annie S Wesley International Development Research Centre, Ottawa, ON, Canada A Clinton White Jr. University of Texas Medical Branch, Galveston, TX, USA Clare L Whitehead University of Melbourne, Melbourne, VIC, Australia

George Thomson University of Otago, Wellington, New Zealand

Nick Wilson University of Otago, Wellington, New Zealand

Anne Tiedemann The George Institute for Global Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia

Yang R Yang QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia

Keith Tones Leeds Metropolitan University, Leeds, UK

Kojo Yeboah-Antwi Center for Global Health & Development, Boston University School of Public Health, Boston, MA, USA

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GUIDE TO USING THE ENCYCLOPEDIA Structure of the Encyclopedia

3.

All articles in the encyclopedia are arranged alphabetically as a series of entries.

A subject classification list has been developed by the editors to group articles under broad topics. This index is useful for making broad connections between articles and locating the relevant article for a topic that is covered in more than one article. This can be found in the front matter of Volume 1.

1.

Alphabetical Contents List

Your first point of reference will likely be the contents. The contents list appears at the front of each volume providing volume and page numbers of the entry. We also display the article title in the running headers on each page so you are able to identify your location and browse the work in this manner. 2.

Cross-references

All articles within the encyclopedia have an extensive list of cross-references which appear at the end of each article, for example: See also: HIV Prevention and Treatment in Children and Adolescents; Mental Health and Substance Abuse; Mental Illness, Historical Views of; Specific Mental Health Disorders: Child and Adolescent Mental Disorders.

4.

Subject Classification List

Index

The index provides the volume and page number for where the material is located, and the index entries differentiate between material that is a whole article; is part of an article, part of a table, or in a figure. This can be found at the rear of Volume 7. 5.

Contributors

A list of volume contributors appears in the front matter of each volume.

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CONTENTS OF VOLUME 3 Editorial Board

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Contributors to Volume 3

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Guide to Using the Encyclopedia

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VOLUME 3 Ethics and Health Promotion Stacy M Carter

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Ethics of Immunization Marcel Verweij

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Ethics of Infectious Disease Control Michael J Selgelid

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Ethics of Organ Transplants Ahmed B Al-Khafaji and Lisa S Parker

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Ethics of Public Health Research: Moral Obligations to Communities Holly A Taylor, Summer Johnson McGee, Ruth R Faden, and Nancy E Kass

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Ethics of Screening Niels Nijsingh, Niklas Juth, and Christian Munthe

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Ethnic Conflict and Public Health Duncan Pedersen and Hanna Kienzler

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Euthanasia and Public Health Kenneth Chambaere and Joachim Cohen

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Evidence-Informed Public Health Policy Jana Sisnowski and Jackie M Street

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Exercise Therapy for Heart Failure Patients in Canada James A Stone, Trina Hauer, Mark Haykowsky, and Sandeep Aggarwal

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Extreme Weather Events and Human Health Stephanie L Molloy, Erin A Dreelin, and Joan B Rose

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Facility-Based Treatment of Severe Malnutrition Ann Ashworth

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Falls Anne Tiedemann, Daina L Sturnieks, and Lisa Keay

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Family Planning/Contraception Anna Glasier and Ailsa Gebbie

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Famine Marc-André Prost and Alex de Waal

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Fatty Acids Mohammed H Moghadasian and Fereidoon Shahidi

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Female Reproductive Physiology/Function Horacio B Croxatto

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Fetal Growth Restriction: Causes and Outcomes Susan M Sayers, Paul A L Lancaster, and Clare L Whitehead

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Food Fortification M G Venkatesh Mannar and Annie S Wesley

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Food Safety Jorgen Schlundt

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Foodborne Diseases Jean Maguire van Seventer and Davidson H Hamer

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Forced Migration and Health Pascale Allotey and Sharuna Verghis

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Foundations in Public Health Ethics Bruce Jennings

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Foundations in Public Health Law Lawrence O Gostin, Benjamin E Berkman, and John Kraemer

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Functions and Deficiencies of B-Vitamins (and Their Prevention) Wolfgang Herrmann and Rima Obeid

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Future Organization of Cancer Care Karol Sikora

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Gastric Cancer Suminori Kono

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Gastrointestinal Disorders: Overview Amanda J MacFarlane and Patrick J Stover

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Gender Aspects of Sexual and Reproductive Health Jane C Cottingham

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Gender in Health and Illness Carol Vlassoff

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Genetic Epidemiology Harry Campbell and Niall Anderson

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Geographic Information Systems (GIS) in Public Health Corinna Keeler and Michael Emch

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Contents of Volume 3

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Global Burden of Disease Colin Mathers

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Global Health Law: International Law and Public Health Policy Allyn L Taylor

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Global Issues: Urban Health in Developing Countries Carolyn Stephens

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Global Tobacco Industry George Thomson and Nick Wilson

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Global Trends in Cardiovascular Disease Usman Khan, Arslan Rafiq, and Jonathan N Bella

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Governance Issues in Health Financing Phua Kai Hong

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Gynecological Morbidity Maria Garefalakis, Martha Hickey, and Neil Johnson

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Happiness, Health and Altruism Stephen G Post

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Hazardous Wastes Christopher T De Rosa, M Fay, L S Keith, Moiz M Mumtaz, H R Pohl, M T Hatcher, H E Hicks, James S Holler, P Ruiz, and Barry L Johnson

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Head Trauma Jared Knopman and Roger Härtl

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Health and Disease, Concepts of Dina Czeresnia and Teresa C Soares

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Health and Human Rights: Overview Sofia Gruskin and Daniel Tarantola

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Health Behavior and Risk Factors Karen Glanz

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Health Care of Indigenous Peoples/Nations Gerard Bodeker

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Health Inequalities Catherine Chittleborough

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Health Information on the Internet Rehema Chande-Mallya, Sydney Enock Msonde, Wulystan Pius Mtega, and Edda Tandi Lwoga

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Health Insurance Plans and Programs: An Overview Stefan Greß and Juergen Wasem

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Health Literacy Roy W Batterham, Alison Beauchamp, and Richard H Osborne

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Health Policy: Overview Calum Paton

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Health Promotion Maurice B Mittelmark, Ilona Kickbusch, Irving Rootman, Angela Scriven, and Keith Tones

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Health Surveys Jennifer H Madans

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Health Systems of Australia and New Zealand Diana M S Hetzel, John D Glover, and Sarah K McDonald

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Health Systems of Mexico, Central America and the Caribbean Miguel A Gonzalez Block and Sebastian González McQuire

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Health Systems: United States, Health System of the William C Cockerham

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Health Technology Assessment: Ethical, Legal and Social Issues Annette Braunack-Mayer

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Health-Care Delivery Systems Fred C J Stevens, Madelon W Kroneman, and Jouke van der Zee

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Health-Related Stigma Stella R Quah

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Hearing Disorders Robert Burkard

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Heart Failure Véronique L Roger

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Helicobacter pylori Helena Enroth and Lars Engstrand

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Helminthic Diseases: Dracunculiasis Philip Willem Downs, Dieudonné P Sankara, and Kojo Yeboah-Antwi

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Helminthic Diseases: Echinococcosis Donald P McManus and Yang R Yang

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Helminthic Diseases: Filariasis Pradeep K Das and Ranganatha K Shenoy

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Helminthic Diseases: Foodborne Trematode Infections Bernard Fried and Jane E Huffman

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Helminthic Diseases: Intestinal Nematode Infections Lorenzo Savioli, Albis Francesco Gabrielli, and Antonio Montresor

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Helminthic Diseases: Onchocerciasis and Loiasis Jan H F Remme, Boakye Boatin, and Michel Boussinesq

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Helminthic Diseases: Schistosomiasis Alan Fenwick and Juerg Utzinger

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Helminthic Diseases: Taeniasis and Cysticercosis due to Taenia solium Lia P Suazo Hernandez and A Clinton White Jr.

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Helminthic Diseases: Trichinellosis and Other Helminthic Tissue Helminthic Infections Kenneth D Murrell

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Hepatitis, Viral Samer S El-Kamary and G Thomas Strickland

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Herpesviruses Sara Oliver and Scott H James

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Ethics and Health Promotion Stacy M Carter, Centre for Values, Ethics and the Law in Medicine, The University of Sydney, Sydney, NSW, Australia Ó 2017 Elsevier Inc. All rights reserved.

Introduction This article considers ethical issues facing those who plan, implement, and evaluate health promotion programs and activities. It begins with foundational questions: how health promotion and health should be defined, whether the promotion of health is justified, and if so who can legitimately do it, the moral significance of health promotion as a collective enterprise, problems of evidence, and working with diversity. The second section considers three strategies: segmenting populations, changing environments, and delivering persuasive messages. The final section notes three ways health promotion can harm: by increasing disparities, by labeling or stigmatizing, and by denying valued practices. This article is focused on the ethics of health promotion practice: it is beyond scope to consider the issue of the ethics of health promotion research. Health promotion, like most of public health, is informed by and generates varieties of evidence; consequently, there is a lot of researchlike activity in health promotion in the form of needs assessment, quality assurance, or evaluation. There are important debates at present about the ethical dimensions of these activities. We cannot consider those here, but will instead focus on ethical aspects of health promotion interventions.

Foundational Issues for Health Promotion Ethics Health Promotion, Public Health, and Well-being Health promotion ethics begins with two central questions about categorization and definition. The first is: what is health promotion? The second is: what is health? In the last 15 years, there has been a rapid expansion and recognition of public health ethics, a form of applied ethics that focuses on the purpose and practice of public health. You will have noticed, however, that the title of this article is not Ethics and Public Health, but Ethics and Health Promotion. This implies that health promotion ethics should be considered distinct from public health ethics, presumably because health promotion itself is somehow distinct from public health. The iconic definitions and documents of the World Health Organization, exemplified by the Ottawa Charter (First International Conference on Health Promotion, 1986), seem to distinguish health promotion from public health. Many health promotion workers see themselves as having a unique set of values (Carter et al., 2012), and health promotion associations have expressed interest in developing their own distinct code of ethics (Bull et al., 2012), suggesting that health promotion and public health may be organizationally and culturally distinct. But it does not follow that the moral issues involved are so very different. It is likely that health promotion activities are a subset of public health activities and that ethically they have a lot in common. For the purposes of this article though, let us assume that health promotion is

International Encyclopedia of Public Health, 2nd edition, Volume 3

a distinct enough practice as to require its own ethical tools and approaches. The second question of definition is: what is this thing called ‘health’ that is being promoted? Many readers will be familiar with the World Health Organization definition of health as complete physical, mental, and social well-being. Despite its popularity in health promotion practice, this definition has been widely criticized. It is seen by many ethicists as unsupportable, both too demanding (nothing but complete well-being counts as health) and too inclusive. A good human life has many good qualities. These can be thought of as things we value, or as dimensions of well-being, or as capabilities. Health is certainly among these. But there are many other good things on this list, including selfdetermination, personal safety, civic and political participation, education and the resulting ability to reason, being socially connected through relationships with others, enjoying the respect of other people, and having opportunities for rest and recreation. If we follow the World Health Organization and equate health with complete well-being, there are several problematic consequences. First, it distracts from the intrinsic value of all the other good things listed above. A person’s social relationships, for example, are good in themselves and make their own contribution to well-being, whether or not they improve health. Second, health is often a determinant of other dimensions of well-being and vice versa: keeping them distinct makes these bidirectional causal relationships clearer. Finally, and perhaps most importantly for the ethics of health promotion, keeping health distinct from and in balance with other dimensions of well-being makes it easier to keep health in its place and see the proper limits of health promotion. A quest for health alone can become a crusade with moral overtones, leading some to pursue it relentlessly at the expense of other dimensions of well-being, and others to feel inadequate for not doing so. Overemphasizing the dominant value of health can feed overuse of health services and escalate expectations of medicine and the health-care system. This has implications for fairness, as it may distract from work on the social determinants of health and encourage the already-advantaged to demand additional health services at the expense of those who need them most (Heath, 2005).

Is the Promotion of Health Justified? Who Can Legitimately Promote Health? If health is an important dimension of human well-being, most people will want to be healthy. If most people want to be healthy, then intervening to assist people to be healthier may seem easily justified. But not all ethicists accept this. Particularly in early health promotion ethics, there was a strong focus on the so-called Harm Principle of John Stuart Mill, the influential nineteenth-century British moral and political philosopher. The Harm Principle is, loosely, the idea that people should be at liberty to live as they please unless they are

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harming others. It has been used to argue that individuals should be free to decide whether and how they want to be healthy: it is not the business of the state or others to meddle in those decisions. In recent scholarship, ethicists have challenged these Harm Principle–based arguments, noting that they often misuse or caricature Mill’s work (Powers et al., 2012). Mill argued only that freedoms of conscience and speech were absolute. Many potentially health promoting interventions, such as banning dangerous substances or introducing laws that protect workers, were arguably excluded from Mill’s formulation of the Harm Principle. And he thought it was quite reasonable to expect citizens to contribute to the production of common goods and a working society. So often the version of the Harm Principle that is employed in debates about health-promoting actions is a misrepresentation of Mill’s original argument. Further, states may be obliged to provide at least some conditions needed for their citizens to be healthy. This could be argued in several ways. For example, some would argue that people are only free when they enjoy conditions that allow them to live in accordance with their values and that these conditions include being healthy to at least some minimum threshold. Liberal democratic societies are built around the value of freedom for citizens. So then, it follows that liberal democratic states should ensure that basic conditions for freedom, including the conditions for reasonable health, are met for all citizens. An alternative and more inclusive argument relies on Article 25 of the International Bill of Human Rights. This states that all people, regardless of what kind of society they live in, have a right to the conditions required to be healthy simply by virtue of being human. Either of these arguments could be used to support the idea that states have at least some responsibility to ensure that their citizens have access to the conditions needed for reasonable health. Health promotion is not only the work of states: nonprofits, commercial organizations, employers, and others also engage in health promotion. Their legitimacy as promoters of the health of others is generally less clear. Nonprofits – especially those focused on a single disease – may have expertise, but their narrow focus may make them susceptible to overstating the costs of, and harms done by, their particular disease, or being prepared to pursue risk reduction at any cost. For-profits such as private health insurers may have divided interests, especially if they are beholden to shareholders. And because of the power employers have over employees, there are special ethical concerns when they also become health promoters, including the potential for coercion, and the importance of privacy and confidentiality of personal health information that can have significant consequences for insurability and employability.

Individualism, Collectivism, Publics, and Responsibility Health promotion has a collective or public character: it emphasizes working with communities more than individuals (Carter et al., 2012). Health promotion interventions may be collective or public in that they: 1. achieve health improvement at a scale large enough to be observed in populations or communities;

2. improve the fairness of distribution of health in whole communities or populations; 3. alter underlying causes of health and ill-health; and/or 4. involve collective efforts (Verweij and Dawson, 2007). This publicness or collectiveness can contribute to the ethical justification of health promotion, because it provides an emergent, larger-than-the-sum-of-its-parts character. Health promotion strategies with this collective quality can enable the achievement of goals that most individual citizens want, but are not capable of achieving alone (Verweij and Dawson, 2007; Coggon, 2012). However, health promotion scholars have expressed concerns about threats to this notion of collectiveness, arising from individualization, behaviorism, a focus on reducing risk factors for particular diseases rather than promoting health more broadly, and attribution of responsibility for health and disease to individuals. Scholars from Australia (Lin, 2007), the USA (Goldberg, 2012), and elsewhere have expressed concern that health promotion is abandoning Ottawa Charter values of community action, supportive environments, enablement, and advocacy and pursuing individual behavior change rather than intervening in shared root causes of ill-health. This, critics propose, reduces effectiveness, increases inequalities, and risks further stigmatization of the alreadydisadvantaged (Goldberg, 2012). Behavioral, individualistic interventions tend to be based on an assumption that individuals have agency in, and responsibility for, their health. This may be at least partly correct and ethically justified. Treating people as though they are in charge of their own lives, and are the best people to make decisions about their own well-being, recognizes the autonomy they have and shows them respect. But often, people’s choice to engage in or to refrain from certain practices depends to a large extent on factors outside their control or on limited resources and opportunities: people are often not autonomous, or at least not fully autonomous, in respect of their health. Overemphasizing individual responsibility and agency can deemphasize structural and institutional influences on health such as the work environment, housing conditions, or pollution (Wikler, 2004), which usually require collective responses to change. Attributions of personal responsibility may also arise from conventions about social acceptability, taste, or social roles rather than sound moral reasoning. This means individuals may be held responsible because of conventions, social disapproval, or enforcement of roles, rather than for good ethical reasons. A rowdy working class man drinking bourbon may attract more censure than an upper-middle-class woman drinking the same amount of alcohol in the form of white wine, for example, or a mother may be held more responsible for the health of her children than their father. In summary, while citizens are rarely utterly passive victims (most of us have some agency in respect of our health most of the time), attributions of blame and moral desert often follow attributions of responsibility and can be made for unsound reasons, so these must be apportioned with extreme care. Finally, the publicness of health promotion underscores the need for legitimacy, which rests on procedural justice or fair processes. In clinical ethics, clinicians are expected to seek

Ethics and Health Promotion consent from patients before providing treatment. This entails making sure that patients are competent to make decisions about their own care, providing patients with the information and support they need to consider their options, and ensuring patients can endorse the final treatment plan. But this kind of individual informed consent makes little sense at a community level. A health promotion worker cannot identify all of the individuals who might be affected by their interventions and seek their consent. Even if they could, in a pluralistic society there will almost always be disagreement about policies or community-level interventions, so achieving consent from 100% of affected people would rarely be possible. The complexity of working with publics or communities demands that health promoters pursue legitimacy and procedural justice, rather than individual consent. A more legitimate policy or program might be one that engages with a wide range of stakeholders, makes decisions public, ensures decisions are not arbitrary or discriminatory, ensures that citizens receive adequate support to do what is being expected of them, is clear about the basis for decisions, and is willing to revise decisions if new evidence or arguments come to light (Daniels and Sabin, 2008). These are challenging demands, but are more relevant to community-level interventions than the individualistic conception of consent.

Evidence, Effectiveness, and Uncertainty Making good ethical judgments relies on having good evidence: about the relative health of different groups of people, the causes of ill-health, and the effectiveness of different health promotion strategies. However, the knowledge base for health promotion is often limited, and that knowledge is often uncertain, either in its conclusions or its transferability to other contexts. One important ethical tension in health promotion work is the degree to which health messages should acknowledge this uncertainty. Health communicators may sometimes sound more certain than the evidence would support, because they want to increase the impact of their message, or because they want to appear authoritative. There are reasons to reject this practice: pragmatically, risk communication experts generally suggest that trust is likely to be bolstered rather than diminished by transparency about uncertainty, and most ethicists would emphasize the value of honesty in communication. More broadly, however, if there is little knowledge to suggest that a health promotion intervention will be effective, its moral justifiability may be lessened, even more so if there are other important ethical considerations at stake, such as high cost, likely harms, or serious burdens for citizens.

Tailoring, Scaling up, and Working with Cultural and Moral Pluralism A final foundational issue for health promotion ethics concerns the degree to which interventions can be universal or should be particularized for different communities. Within health promotion practice this tension is often expressed as the difference between tailored interventions – those adapted for particular communities, often defined by cultural background or level of literacy – and scaled-up

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interventions, which can be run in a standardized way across entire populations. Traditional health promotion values have emphasized the importance of tailoring, which has been seen as respectful of difference, and potentially more effective as a result of being more comprehensible or acceptable to communities. More recently, as health promotion has moved away from a community development model and toward a behavioral model (Lin, 2007), scaling-up has become more highly valued, usually justified on utilitarian grounds of increased efficiency. While practitioners on the ground may subtly tailor these scaled-up interventions, the program goal of scaled-up interventions is uniformity rather than responsiveness. This is a direct tension between conflicting sets of values. A related issue is the degree to which health promotion should incorporate or challenge cultural heritage, beliefs and customs, or indeed the deeply held values of any community member. In a liberal democracy, particularly a multicultural one, we would expect to find a range of views on what constitutes a good life and how such a life should be lived. These will only sometimes be concordant with the values commonly held by health promotion professionals. The challenge is to determine when, and on what grounds, it is reasonable to attempt to change the views and values of others, or even to override them. To take a position of moral and cultural pluralism is to recognize and seek to understand the diversity of relevant values. In contrast, moral and cultural relativism holds that there is no basis for adjudicating between different values, or no basis for drawing conclusions about what is ethically justified. Relativism is untenable (at least, it is if we think that ethical guidance for action has any value). But pluralism is an important principle, encouraging practitioners and their managers to be respectful of difference in a way that is likely to enhance the procedural justice, and thus legitimacy, of health promotion work.

Ethical Dimensions of Health Promotion Strategies The foundational issues considered above relate to every aspect of health promotion work. But some ethical issues in health promotion arise from the particular strategies that are implemented. Strategies with challenging ethical implications include targeting and segmenting populations, intervening in environments and nudging, persuading, and empowerment.

Targeting and Segmenting Populations Identifying segments of populations, and focusing interventions on only some of those segments, is accepted as a basic strategic approach in health promotion. Segmentation is sometimes done on the basis of demographic characteristics and sometimes on the basis of consumer research designed to provide behavioral insights. Deciding to segment populations and target services raises ethical questions: questions about who makes the segmentation decision, how procedurally just this decision is, and the reasons for prioritzsing some citizens over others. This issue will be considered further in the section below on increasing disparities.

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Intervening in Environments and Nudging In 2009, Richard Thaler and Cass Sunstein published their book Nudge, based on research in cognitive psychology, behavioral economics, and other fields. It was hugely influential and is beginning to be taken up in health promotion, although there is some contention regarding its evidence base. Central to nudge was the idea of ‘choice architecture’: the way choices are presented to us. The arrangement of food on a salad bar, the size of a portion of popcorn at the movies, the layout of a school canteen menu, or the default options on an electronic form are all examples of choice architecture, and – according to the theory – they will produce reasonably predictable choices because human cognition is biased in predictable ways. Thaler and Sunstein argued that choice architecture should be altered to capitalize on human cognitive biases. This will encourage people to choose in their own best interests – for example, to choose the healthy rather than the unhealthy food from the buffet – perhaps even without them realizing that they have been influenced. The effect of physical and social environments on behavior is well recognized in health promotion: this is strongly reflected in the Ottawa Charter. Health promotion practitioners tend to prefer ‘making healthy choices easy choices’ over educational or informational interventions. Environmental changes are seen to provide people with needed support, to be more likely to benefit those people who are least well-off via decreasing the effort required for health improvement, and to be more effective than informational interventions alone. However, among ethicists there has been some debate about whether it is acceptable to nudge people’s behavior for their own good without their knowledge. Opponents of nudging have generally come from a libertarian position, arguing that regulators should not presume to know individual citizens’ interests or impose their own moral judgments (at least, not without an open debate) and that nudging violates the Harm Principle (see above) (White, 2013). Those in support of nudging have argued that choice architecture will always exist, influence our choices, and bypass our rationality (Quigley, 2013). It has been estimated, for example, that we make about 200 small, relatively inattentive decisions about food every day (Wansink and Sobal, 2007). If we accept the status quo, the architecture guiding these choices will either be indifferent to health, or be designed by corporations for the purpose of selling more unhealthy products. If this is so, there is no clear ethical reason why we should accept the status quo as correct: we should instead ask who is designing choice architecture, to what ends, and whether those goals are justifiable (Quigley, 2013). This again raises the question of legitimacy: the regulators who shape environments to promote health need to ensure that their choice of goals and strategies is procedurally just.

Persuading People to Change Nudging and environmental design encourage people to change their behavior without requiring much cognitive effort from them. But this is not always possible: sometimes for change to occur, people need to consciously and voluntarily decide to make changes to improve their health. Some health

promotion interventions are intended to persuade citizens to make such decisions. Persuasion seeks to influence people by giving them good reasons. It can be distinguished from coercion (that is, exerting control through force, or through the threat of harm) or manipulation (that is, attempting to control people’s behavior by bypassing their capacity for reason using strategies such as deception, exaggeration, or the use of strong emotions) (Rossi and Yudell, 2012). Persuasive communication can be morally justifiable, but only under certain conditions. If health promoters are attempting to persuade citizens to change, for example, they may owe them a certain amount of information about why they should change. This may include information about potential benefits or avoidable harms and should be expressed in absolute rather than relative risks because relative risks tend to be misleading. As with all health promotion strategies, health communicators should explicitly consider legitimacy: for example, whether their choices could be justified to a reasonable citizen (Rossi and Yudell, 2012). This is likely to bring a much wider range of considerations, beyond simple effectiveness, into decisionmakers’ reasoning. Persuasive campaigns can also cause harm (e.g., distress, anxiety, or stigmatization), which will be considered further in the next section.

Empowerment Empowerment is a central concept in health promotion, denoting working with communities to enable them to identify and achieve their own goals. In this context, empowering strategies are often presented as freedom enhancing and therefore good. Taking community values and knowledge seriously is an important part of ensuring the legitimacy of health promotion. But in practice, empowerment may not be achievable, may enable some to dominate others, or may support communities to demand ineffective or harmful interventions. An alternative to simply empowering communities is to seek a reflective balance between the expertise of health promotion professionals and the lay expertise of affected communities (Braunack-Mayer and Louise, 2008).

Harms, Burdens, and Wrongs in Health Promotion The goal of health promotion is to deliver a benefit: improved health. However, in the pursuit of this goal, health promotion activities can cause harms or burdens or do things that are morally wrong. Causing harms or burdens can sometimes be justified: they may be outweighed by much greater benefits, or may be in proportion to an extreme and imminent risk that needs to be countered, or may simply be unable to be anticipated or unavoidable. But this presumes careful attention to and weighing up of potential bad outcomes, explicit decision-making about whether they can be justified and on what grounds, and appropriate effort to minimize them. All but the most trenchant utilitarian would reject the idea that any kind of harm is acceptable if the consequent benefits are greater. There may also be some obligation on health promotion services to reciprocate citizens who have experienced harms, burdens, or wrongs as a result of health promotion activities. This reciprocation could take a variety of forms,

Ethics and Health Promotion ranging from simple assistance to minimize the burden of participation in health promotion activities (e.g., providing free transport to attend skills training), through to more extensive reparation for serious harms (e.g., making public apologies or providing supportive services to people who experience stigmatization as a result of a social marketing campaign).

Increasing Disparities Health promotion practitioners are typically committed to increasing health equity, that is, to distributing health, or the opportunity to be healthy, more fairly across social groups. Yet health promotion activities that achieve significant improvements in the adoption of healthier practices among large populations may inadvertently reinforce, rather than reduce, existing social disparities. Large-scale programs focused on changing health behavior (such as tobacco smoking or physical activity) are more likely to have an impact on individuals with greater economic resources. Further, it is not uncommon for interventions to target those segments of a population thought to be most likely to change, on the grounds that this will use resources most effectively (that is, maximize utility). But this will often mean working with already relatively advantaged people, as they are more likely to have the resources and skills needed to change, and seeing the most disadvantaged people as ‘hard to reach’ and an inefficient target for intervention (that is, of lower utility). An alternative is to focus efforts on those with the greatest need, on the grounds that this will do the most to reduce inequalities and so be more equitable, fairer, or more just. There are a range of competing theories of justice relevant here, but they generally share a concern for the least well-off in society and require that institutions (such as public health promotion services) are structured for the benefit of the least well-off, rather than simply to maximize utility (see e.g., Powers and Faden, 2006). This is an example of a contest between two conflicting goals for health promotion: increasing fairness or maximizing aggregated health improvement.

Labeling, Stigmatization, and Emotional Suffering Health promotion can harm by labeling individuals or groups in a way that negatively affects their identity, causes them to feel shame, stigmatizes them, or reinforces existing stigmatization. This is a particular danger in health communication campaigns that attempt to motivate people to change their behavior by presenting potential health consequences in frightening, disgusting, or embarrassing ways. Whether or not this motivates individuals to change their own behavior to mitigate future risk, there will always be many people in the same communities who are already experiencing the conditions depicted, and who will be affected by the message either directly or indirectly through its effect on others. The ethical concerns about this are numerous. Stigmatization can undermine selfrespect and the respect experienced from others, thus diminish well-being. People who experience stigma are likely to be disadvantaged in other ways, so further stigmatization may contribute to a particular, deep kind of disadvantage that is difficult to escape. Stigmatizing messages construct a healthy us and an unhealthy them, which undermines solidarity and trust. And finally, some have argued, the liberal state is based on

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fundamental ideas about the equality and dignity of all people, and so it is always completely unacceptable for the state to engage in the humiliation of its own citizens, including for the purpose of improving their health (Burris, 2008).

Denying Valued Practices Health promotion activities often call upon people to relinquish practices that help them cope with stress, are part of their identity or daily routine, have cultural significance, or are simply an important source of pleasure or enjoyment. While to a health promoter these practices may simply look like health risks, to the communities and individuals engaged in them they may seem essential to a good life. Those who live in communities where those practices are culturally significant may be marginalized as a result of relinquishing them, and those less economically or socially privileged may have fewer options for healthier substitutions. An ethical issue is whether health promoters are morally obligated to reciprocate in some way if they expect people to eliminate practices that serve important social, cultural, or emotional functions, particularly among people who are already disadvantaged. This reciprocation may include modifying the recommendations made to increase their cultural appropriateness, facilitating substitutions, or working with community leaders to reset cultural norms rather than expecting individuals to bear the burden of change alone.

Conclusion Thinking about the ethics of health promotion has several advantages for health promotion itself. First, it can identify potentially problematic strategies that unjustifiably harm or burden people, and act as a corrective. Second, it can encourage attention to the range of possible goals and methods for health promotion, requiring more careful consideration of why some are chosen over others, for what reasons, and whether these reasons would be considered legitimate in the communities affected. Finally, it can provide arguments that support the need for health promotion to continue, particularly as a responsibility of states. A more ethically justified and legitimate health promotion is potentially a more robust and resilient health promotion, with stronger foundations, more appropriate strategies, and fewer consequent harms.

See also: Ethics of Immunization; Ethics of Infectious Disease Control; Ethics of Screening; Ethnic Conflict and Public Health.

References Braunack-Mayer, A., Louise, J., 2008. The ethics of community empowerment: tensions in health promotion theory and practice. Promot. Educ. 15, 5–8. Bull, T., Riggs, E., Nchogu, S.N., 2012. Does health promotion need a code of ethics? Results from an IUHPE mixed method survey. Glob. Health Promot. 19, 8–20. Burris, S., 2008. Stigma, ethics and policy: a commentary on Bayer’s “Stigma and the ethics of public health: not can we but should we”. Soc. Sci. Med. 67, 473–475. Carter, S.M., Klinner, C., Kerridge, I., Rychetnik, L., Li, V., Fry, D., 2012. The ethical commitments of health promotion practitioners: an empirical study from New South Wales, Australia. Public Health Ethics 5, 128–139.

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Coggon, J., 2012. What Makes Health Public? A Critical Evaluation of Moral, Legal and Political Claims in Public Health. Cambridge University Press, Cambridge. Daniels, N., Sabin, J.E., 2008. Setting Limits Fairly: Learning to Share Resources for Health. Oxford University Press, Oxford. First International Conference on Health Promotion, 1986. Ottawa Charter for Health Promotion, who/hpr/hep/95.1. World Health Organization, Ottawa. Goldberg, D.S., 2012. Social justice, health inequalities and methodological individualism in U.S. health promotion. Public Health Ethics 5, 104–115. Heath, I., 2005. Who needs health caredthe well or the sick? Br. Med. J. 330, 954–956. Lin, V., 2007. Health promotion in Australia: twenty years on from the Ottawa Charter. Promot. Educ. 14, 203–208. Powers, M., Faden, R., 2006. Social Justice: The Moral Foundations of Public Health and Health Policy. Oxford University Press, Oxford. Powers, M., Faden, R., Saghai, Y., 2012. Liberty, Mill and the framework of public health ethics. Public Health Ethics 5, 6–15. Quigley, M., 2013. Nudging for health: on public policy and designing choice architecture. Med. Law Rev. 21, 588–621. Rossi, J., Yudell, M., 2012. The use of persuasion in public health communication: an ethical critique. Public Health Ethics 5, 192–205. Thaler, R.H., Sunstein, C.R., 2009. Nudge. Penguin Books, New York. Verweij, M., Dawson, A., 2007. The meaning of “public” in “public health”. In: Dawson, A., Verweij, M. (Eds.), Ethics, Prevention and Public Health. Oxford University Press, Oxford. Wansink, B., Sobal, J., 2007. Mindless eating: the 200 daily food decisions we overlook. Environ. Behav. 39, 106–123. White, M.D., 2013. The Manipulation of Choice: Ethics and Libertarian Paternalism. Palgrave Macmillan, New York. Wikler, D., 2004. Personal and social responsibility for health. In: Anand, S., Peter, F., Sen, A. (Eds.), Public Health, Ethics, and Equity. Oxford University Press, Oxford.

Further Reading Anand, S., Peter, F., Sen, A. (Eds.), 2004. Public Health, Ethics, and Equity. Oxford University Press, Oxford. Buchanan, D.R., 2000. An Ethic for Health Promotion: Rethinking the Sources of Human Well-being. Oxford University Press, New York.

Buchanan, D.R., 2006. Further reflections on a new ethic for health promotion. Health Educ. Behav. 33, 308. Carter, S.M., Cribb, A., Allegrante, J.P., 2012. How to think about health promotion ethics. Public Health Rev. 34, 122–145. Carter, S.M., Rychetnik, L., Lloyd, B., Kerridge, I.H., Baur, L., Bauman, A., Hooker, C., Zask, A., 2011. Evidence, ethics, and values: a framework for health promotion. Am. J. Public Health 101, 465–472. Cribb, A., 2005. Health and the Good Society. Oxford University Press, Oxford. Cribb, A., Duncan, P., 2002. Health Promotion and Professional Ethics. Blackwell Publishing, Hoboken. Dawson, A. (Ed.), 2011. Public Health Ethics: Key Concepts and Issues in Policy and Practice. Cambridge University Press, Cambridge. Dawson, A., Verweij, M. (Eds.), 2007. Ethics, Prevention, and Public Health. Oxford University Press, New York. Guttman, N., 2000. Public Health Communications Interventions. Sage Publications, Thousand Oaks. Mittelmark, M.B., 2008. Setting an ethical agenda for health promotion. Health Promot. Int. 23, 78–85. Public Health Ethics, 2012. Oxf. Univ. Press J. 5 (2). Special issue on the ethics of health promotion. Seedhouse, D., 2004. Health Promotion: Philosophy, Prejudice and Practice. John Wiley & Sons, West Sussex, England. Sindall, C., 2002. Does health promotion need a code of ethics? Health Promot. Int. 17, 201–203. Tannahill, A., 2008. Beyond evidence-to ethics: a decision-making framework for health promotion, public health and health improvement. Health Promot. Int. 23, 380–390. Wardrope, A., 2015. Relational autonomy and the ethics of health promotion. Public Health Ethics 8, 50–62.

Ethics of Immunization Marcel Verweij, Wageningen University, Wageningen, The Netherlands Ó 2017 Elsevier Inc. All rights reserved.

special topics in vaccination, notably vaccine research and vaccination of health-care workers.

Immunization Programs and Tensions between Collective and Individual Perspectives Immunization programs are a fascinating subject for ethical reflection. Moreover, such reflection is mandatory for wellconsidered and responsible vaccination policies. One of the salient aspects of immunization programs is that they not only protect vaccinated individuals, but also the population at large. The most effective way to avoid diseases such as poliomyelitis, measles, meningitis, or hepatitis is to have oneself immunized. And if many people choose similarly, this may lead to herd immunity, protecting the population at large including those who are not vaccinated and those in whom vaccination induces insufficient immunity. It might even give the prospect of worldwide eradication of the infectious agent. Collective vaccination programs have a large impact on the spread and transmission of certain viruses and microbes. Remarkably, the fact that a potentially dangerous virus or microbe becomes less prevalent may also have negative implications. In the early times of large-scale immunization programs, people developed long-lasting immunity against specific infectious diseases because, after vaccination they were regularly exposed to the virus or microbe which boosted their immunity. Thanks to successful vaccination programs, such exposure is less and less common, and, over time, vaccine-induced immunity may gradually decrease, which could be a reason for offering repeated vaccinations at a later age. For some infections such as varicella, disease may be worse if acquired at later age (shingles rather than chicken pox), and potentially, a childhood vaccination program against chicken pox could lead to an increase of shingles. In general, side effects of a reduced spread of an infection, thanks to vaccination, will often be outweighed by the overall reduction of morbidity and mortality that can be achieved in a successful program. Some individuals, however, might disagree with that assessment. Still other individuals may consider it unnecessary to participate in a vaccination program or to have their children immunized, given that most vaccines protect against diseases that seem to have been almost forgotten – at least in developed countries. In this way, the very success of a vaccination program may undermine people’s willingness to participate. Indeed, some groups of people have much more eye for alleged or potential risks of vaccination – especially in the case of childhood programs – than for the enormous effects vaccination has had and still has on reducing the spread of dangerous infectious diseases. Clearly then, immunization policies may raise conflicts between the common good of public health and the interests or preferences of specific individuals. This holds particularly for collective immunization policies, that are offered to the whole population or to large risk groups and that aim not just to protect each participating individual, but also to protect the health of the public at large. This article focuses on such collective programs and not on the ethical dimensions of

International Encyclopedia of Public Health, 2nd edition, Volume 3

New Vaccines, New Ethical Questions The possible tensions between public and private interests underline the necessity that immunization programs be based upon well-considered decisions, including not just systematic review of epidemiological and immunological evidence, but also ethical evaluation and justification. Such evaluation should concern the implementation of vaccination programs (voluntary or compulsory, requirements of informed consent, and so on), as well as the contents of the program (which vaccines should be offered). In the last decades of the 20th century, the introduction of new vaccines in a collective program did not raise much ethical debate. Childhood immunization programs grew slowly as new vaccines became available. Also, vaccines against poliomyelitis, pertussis and diphtheria, and measles, mumps, and rubella were timely and relatively inexpensive responses to clear public health threats. Nowadays, new vaccines are much more expensive, and they offer protection against diseases that are not as common and dangerous as, for example, measles used to be. Moreover, there are quite a large number of new vaccines in development, and it is far from self-evident that all can and will be incorporated in national vaccination programs. For the future, it is hoped that effective vaccines against malaria and HIV will become available. Examples of vaccines that have become available more recently are meningococcal B and C, varicella zoster, human papilloma virus, rotavirus, and respiratory syncytial virus. Which vaccines should be given priority?

Serious Public Health Problems As the number of available vaccines increases, priority setting seems inevitable. A first consideration then is the magnitude of the public health problems that could be avoided through introduction of a new vaccine. This factor involves not only mortality and morbidity figures, but also evaluation of the seriousness of the disease for individuals and of the risks for the public at large. In general, it seems reasonable to assume that universal vaccination programs should target diseases that might be fatal or that could lead to permanent disability, such as poliomyelitis, hepatitis B, or pneumococcal disease. Yet a vaccine that is to be given priority in a public program should also aim at preventing diseases that are major problems from the perspective of public health. Especially diseases that can spread rapidly in the public sphere and against which individuals cannot easily protect themselves should be given priority. This might hold for potentially dangerous infections that are very common, such as influenza or pneumococcal infection,

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but also for viruses that, although uncommon or even absent, would represent a major threat to public life, for example, through a bioterrorist attack. Giving priority to public health risks against which individuals cannot easily protect themselves is consistent with the core responsibilities of government. If individuals have good possibilities to protect themselves against infection and avoid infecting other persons, universal vaccination in a collective program might be given less priority than a vaccine against a disease that spreads rapidly in public life. This could be seen as a reason to consider collective vaccination against sexually transmitted infections, such as human papilloma virus, less urgent. However, sexually transmitted infections can still result in a very high disease burden, which offers strong grounds to prioritize effective vaccination against such infections. A new HIV vaccine would be absolutely relevant in many countries worldwide. Moreover, the assumption that individuals (and especially young women) are always capable to protect themselves against sexually transmitted diseases is far too simplistic in a world where sexual violence is common. Especially if priorities need to be set, it is important to specify disease-specific goals that must be attained with particular vaccines. If a disease cannot be completely eradicated, and if it is clear that the vaccine does not offer lifelong protection, one must weigh how much protection one should at least achieve (or, to put it more controversially, what levels of diseasespecific morbidity and mortality one is willing to accept). For example, vaccines against pertussis do not give lifelong protection, nor do they produce 100% protection in all individuals. As a result, pertussis is still spread through adolescents and adults, and although these groups normally experience only mild forms of whooping cough, they may infect newborn babies that have not yet completed their first immunizations. In the past, pertussis infections used to be prevalent and exposure to such infections would boost the immunity of pregnant women. This enabled the transfer of maternal antibodies to fetuses and newborn infants, which would protect them at least until the first pertussis vaccinations had been completed. Currently, such inborn protection is often absent, and regular childhood vaccination programs fail to offer protection to those who are most vulnerable and who are normally considered to be the most important target group: newborn babies. In several countries, this is now considered a reason to start a vaccinating pregnant women to protect their infants. Indeed, in a balanced immunization policy it might indeed sometimes be preferable to improve current vaccination strategies before introducing a completely new vaccine against a different disease. Formulating disease-specific vaccination goals (e.g., to have all infants and young children protected against infection) can contribute to the consistency and clarity of such programs.

Safety Collective vaccination programs aim to protect healthy persons against diseases that, at least in a number of cases, are relatively uncommon. These aspects support the claim that vaccination should be a highly safe procedure. Side effects of therapeutic drugs can often be well explained and justified to patients who need a drug to regain health. Yet such explanations are much more complex in the case of vaccination. Even very

rare risks of immunization might be considered unacceptable. A good example is the oral polio vaccine, which, when given to millions of children, might cause a form of poliomyelitis in some of them. Parents might consider forgoing vaccination of their children for that reason, which could undermine the global effort to eradicate the virus. The WHO Polio Eradication and Endgame Strategic Plan therefore aims to replace the oral polio vaccine with the Salk vaccine, which is much more expensive but does not have this potential side effect (WHO Polio Eradication and Endgame Strategic Plan). This example shows how the necessity to maintain high vaccination levels further increases safety standards.

Inconveniences and Burdens for Participants Most participants only experience inconvenience and small burdens from vaccination: on the one hand, successful vaccination results in a nonevent that one cannot really experience, and on the other hand, real risks are normally rare. Hence the most salient features of vaccination will often be the temporary fear and pain of an injection. Therefore it makes sense to take even such small inconveniences seriously by limiting the number of injections and developing needle-free immunization procedures. Minimizing small burdens is important not only because it benefits vaccinees, but also it may contribute to the willingness of people (especially parents) to participate and hence may promote high vaccination rates.

Cost-Effectiveness Analysis and Considerations of Justice The introduction of new vaccines should be assessed in terms of the full range of benefits, burdens, and costs resulting from the intervention, compared to alternative preventative options. A core element in such assessment can be provided by costeffectiveness analysis (CEA), which aggregates effects in terms of quality-adjusted life years or disability-adjusted life years gained and aims to specify the financial costs of a QALY that can be gained by introduction of the vaccine. Even though CEAs are a fruitful method for setting priorities, as they enable comparative evaluations of different interventions, such analyses can only be part of the overall evaluation of new vaccines. Many of the previously discussed factors that count in priority setting cannot be easily framed in CEA: inconvenience, feelings of safety, individual versus public responsibilities, protection against potential bioterrorist attacks, and so on. Moreover, quantitative analysis as such raises methodological and ethical controversies. There is an ongoing debate about whether health effects should be discounted over time in the way financial costs are; from an economical point of view it is better to have V1000 now than to get V1000 next year, yet does the same apply to benefits and health effects more specifically? Decisions about discounting and about discount rates are highly important for priority setting because they have a huge impact on the outcome of CEA. A last important ethical concern is that economic analyses such as CEA take an aggregate perspective on health benefits and costs; hence they ignore how benefits and burdens are distributed among a population. This might raise issues of distributive justice. For example, from a justice point of view,

Ethics of Immunization one might want to give priority to protecting the health of people who are worst-off in terms of health and financial resources. Yet CEA-guided decision making might give more priority to preventing diseases that are of less concern to those groups. Almost everyone will get chicken pox (varicella) at some point during childhood, and experience relatively mild symptoms. Only in some cases does chicken pox lead to serious complications requiring hospitalization. Yet all parents will face the problem that they must care for their child and be unable to work for some days. In aggregative economic terms, these latter negative effects of the disease are highly important and might even lead to the conclusion that vaccination against varicella reduces costs for society. The disturbing and possibly unjust implication would be that vaccinating for varicella may give priority to prevention of a disease of children of working parents over prevention of diseases that are most common among socioeconomically deprived groups.

Should Vaccination Be Compulsory? So far the focus has been on ethical evaluation of the contents of vaccination programs: Which vaccines should be introduced in a collective program? Obviously, there are also ethical concerns about how programs are implemented within society. During the last decades, patient autonomy and informed consent have become obvious principles in many areas of health care. Physicians must obtain informed consent before treatment. Does the same apply to preventative vaccinations? There are two reasons why voluntary informed consent might be less obvious and decisive in immunization than in regular health-care practices. First, choices about immunization do not just concern the candidate-vaccinee but also other persons. People have a common interest in attaining high immunization rates and herd immunity. If many people decide to forgo vaccination, this will undermine the common good of herd protection. Governments therefore have good reasons to promote immunization and persuade or even press people to participate by means of sanctions or other forms of compulsion. Second, in childhood vaccination programs, parents decide about protection for their children. If vaccination involves a very simple and burden-free procedure that effectively averts significant risk for the child, this raises the question of whether parental choice against vaccination can be morally justified. After all, parents should decide in the best interests of their child. Again, this would be a reason to set limits to voluntary informed consent. Notwithstanding these considerations, there are good reasons for thinking that immunization programs should be voluntary unless there are clear risks of outbreaks. The success of collective immunization in the Netherlands shows that voluntary programs can be as successful and attain immunization rates that are at least as high as in countries with compulsory programs. Hence, compulsion is not always a necessary condition for herd protection – at least not on a national level. Yet if rejection of vaccination becomes more common, this may result in ‘pockets’ where immunization rates are very low and outbreaks may occur after all. Moreover, compulsion and enforcement have all kinds of social costs and problems of their own. One problem is that if

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people are not given a say in immunization, this might undermine trust in the program, thus, in the long run, having detrimental effects on the success of immunization policies. Indeed, public trust should be considered one of the essential features of immunization policies. In order to secure confidence in immunization, it is important that people know that their concerns (e.g., the health of their children, the possibility of side effects) are taken seriously. Consent, on the basis of reliable information about risks and benefits, can play a role in this respect. From an ethical perspective, however, parents should not decide about, and consent to, childhood immunization merely by weighing of benefits and burdens for their own child; they should also take into account that collective immunization also at herd immunity and thus serves a wider public good.

Conclusion Choices about which vaccines to offer and how to implement a vaccination program have important ethical dimensions. These can be summarized in seven ethical principles: 1. Collective vaccination programs should target serious diseases that are a public health problem. 2. Each vaccine, and the program as a whole, must be effective and safe. 3. The burdens and inconveniences for participants should be as small as possible. 4. The program’s burden-to-benefits ratio should be favorable in comparison with alternative vaccination schemes or preventative options. 5. Collective vaccination programs should involve a just distribution of benefits and burdens. 6. Participation should generally be voluntary unless compulsory vaccination is essential to prevent a concrete and serious harm. 7. Public trust in the vaccination program should be honored and protected. These seven principles offer general guidelines to be taken into account in ethical and scientific assessment of new vaccines, vaccination schemes, and procedures. They stipulate the topics that should be taken into account when deciding about vaccination priorities. Immunization programs are an essential element in the protection of public health. The importance not only of immunization but also of people’s confidence in collective immunization underline the necessity that decisions about vaccines be well considered and ethically justified.

See also: Ethics of Infectious Disease Control; Foundations in Public Health Ethics; Immunization; Vaccines, Historical.

Further Reading Bradley, P., 1999. Should childhood immunisation be compulsory? J. Med. Ethics 25 (4), 330–334. Brock, D., 2007. Ethical issues in applying quantitative models for setting priorities in prevention. In: Dawson, A.J., Verweij, M.F. (Eds.), Ethics, Prevention and Public Health. Oxford University Press, Oxford.

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Caplan, A.L., Hoke, D., Diamond, N.J., Karshenboyem, V., 2012. Free to choose but liable for the consequences: should non-vaccinators be penalized for the harm they do? J. Law Med. Ethics 40 (3), 606–611. http://dx.doi.org/10.1111/j.1748720X.2012.00693.x. Dare, T., 1998. Mass immunisation programmes: some philosophical issues. Bioethics 12 (2), 125–149. Dawson, A.J., 2005. The determination of ‘best interests’ in relation to childhood vaccinations. Bioethics 19 (2), 188–205. Dawson, A.J., 2011. Vaccination ethics. In: Dawson, A.J. (Ed.), Public Health Ethics: Key Concepts and Issues in Policy and Practice. Cambridge University Press, Cambridge, pp. 143–154. Feudtner, C., Marcus, E.K., 2001. Ethics and immunization policy: promoting dialogue to sustain consensus. Pediatrics 107 (5), 1158–1164. Institute of Medicine, 2000. Ethical considerations and caveats. In: Institute of Medicine, Vaccines for the 21st Century. National Academic Press, Washington, DC. Navin, M., 2015. Values and Vaccine Refusal: Hard Questions in Ethics, Epistemology, and Health Care. Routledge, New York.

Obaro, S.K., Palmer, A., 2003. Vaccines for children: policies, politics and poverty. Vaccine 21, 1423–1431. Pierik, R., 2016. Mandatory vaccination: an unqualified defence. J. Appl. Philos. http:// dx.doi.org/10.2139/ssrn.2574634. Ross, L.F., Aspinwall, T.J., 1997. Religious exemptions to the immunization statutes: balancing public health and religious freedom. J. Law Med. Ethics 25, 202–209. Severens, J.L., Milne, R.J., 2004. Discounting health outcomes in economic evaluation: the ongoing debate. Value Health 7 (4), 397–401. Sorell, T., 2007. Public health, parental choice and expert knowledge: the strange case of the MMR vaccine. In: Dawson, A.J., Verweij, M.F. (Eds.), Ethics, Prevention and Public Health. Oxford University Press, Oxford. Verweij, M.F., Dawson, A.J., 2004. Ethical principles for collective immunisation programmes. Vaccine 22, 3122–3126. Verweij, M.F., 2005. Obligatory precautions against infection. Bioethics 19 (4), 323–335. Verweij, M.F., Houweling, H., 2014. What is the responsibility of national government with respect to vaccination? Vaccine 32 (52), 7163–7166. http://dx.doi.org/ 10.1016/j.vaccine.2014.10.008.

Ethics of Infectious Disease Control Michael J Selgelid, Centre for Human Bioethics, Monash University, Clayton, VIC, Australia Ó 2017 Elsevier Inc. All rights reserved.

Introduction Ethics is concerned with what is right, good, just, or fair. It is concerned with our duties and obligations, what ought to be the case, what one should do, or what social or institutional policy should be. In the context of public health, and infectious disease in particular, ethics seeks to define appropriate behaviors for members of the public, appropriate behavior for public health professions, and appropriate public health policy in regard to disease control. Rather than merely seeking the most effective means for controlling disease, ethics seeks right, fair, just means for controlling disease. From an ethical standpoint, the goal to control disease must be balanced against other legitimate social aims. One reason that infectious diseases are so important from an ethical standpoint is that their consequences are so severe. Throughout history they have caused more morbidity and mortality than any other cause, including war (Price-Smith, 2001). The Black Death killed one-third of the European population in the mid-fourteenth century; the 1918 flu killed between 20 and 100 million people; and smallpox killed between 300 and 500 million people in the twentieth century alone – i.e., three times more than were killed by all the wars of that period. More than 35 million people have been killed by HIV, which currently causes 2.1 new infections and 1.1 million deaths annually. While 36 million people are currently living with HIV, it is estimated that only 54% of those infected know their status – and many lack access to antiretroviral medication (WHO, 2016b). TB and malaria together kill
2 million people each year (WHO, 2016a; WHO, 2016c). Major concerns additionally include the large number of new infectious diseases that have emerged in recent decades, the growing problem of drug resistance, the inevitable threat of the next major flu pandemic, and the threat of bioterrorism (which has grown with recent rapid advances in the biological sciences). Most recently, the continued global threat of infectious diseases has been highlighted by the 2014 Ebola outbreak in West Africa and the 2016 Zika crisis in South America.

individuals to move about as they choose matters more in the context in question. This same kind of question arises in relation to numerous other infectious disease control strategies. Contact tracing and notification of third parties, for example, may promote public health, but they can each involve interference with individual privacy. Public health surveillance and/or the reporting the health status of infected individuals to authorities may likewise have public health benefits that come at a cost in terms of privacy. Depending on the circumstances, mandatory diagnostic testing, mandatory treatment, and mandatory vaccination might each on occasion have important public health benefits – but they can each interfere with an individual’s right to consent to medical procedures. What should be done in cases where the policies that would best serve the good of society in terms of public health involve violation of the rights, liberties, or interests of individuals? Most would deny that absolute priority should always be given to either the promotion of the good of society or to the protection of individuals in all circumstances, regardless of the extent to which one or the other is threatened. In exceptional circumstances it is commonly considered acceptable to compromise individual rights and liberties in order to promote the good of society. It is sometimes considered appropriate to sacrifice even the most basic right of all – i.e., the right to life, in times of war – to protect society as a whole. Few, however, believe that rights and liberties should be limited (or sacrificed) whenever this would maximally promote the good of society. Most would agree that one’s right to freedom to decide whether or not to drive to work, for example, should be respected even if public health and the overall good of society would be promoted through a requirement that all ride bikes or use public transportation. We generally try to strike a balance between the respecting of individuals’ rights and liberties, on the one hand, and the promotion of public health, on the other. A task for ethics is to determine which of these two goals has overriding importance in cases of conflict. This partly requires examination of the extent to which each is respectively threatened in any given situation.

Respecting Rights versus Promoting Public Health Difficult ethical questions arise in the context of infectious disease control because the promotion of the greater good of society in the way of public health may sometimes conflict with other legitimate social aims. In the event of an epidemic, for example, the measures needed to protect public health may require infringement of what are usually considered to be basic human rights and liberties. Depending on the disease and other factors, for example, quarantine may sometimes provide effective means for protecting population health, but quarantine requires interference with the right to freedom of movement. The ethical question is then whether promoting the good of society or respecting the rights and liberties of

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Consent The importance of informed consent is central to health ethics. Both with regard to human subject participants in research and with regard to patients being offered clinical treatment, it is widely held (1) that the subject or patient should (usually) be informed about the purpose, benefits, and risks of the research being proposed, or the treatment being offered, and (2) that he/she should be free to make his/her own voluntary choice about whether or not to participate in the research or undergo the treatment being offered. This ethos has evolved in response to an unfortunate history. During the World War II, for example, Nazi doctors

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coercively performed brutal, and sometimes deadly, experiments on prisoners (Annas and Grodin, 1992). Experimental subjects were placed in low-pressure chambers to simulate conditions endured by pilots ejecting at high altitude. Others were submerged in icy cold water, for prolonged periods of time, in order to determine how long German pilots shot down over the English Channel might survive before being rescued. Other Nazi experiments involved limb transplants, wound simulation, and intentional infection with pathogens. During the Tuskegee Syphilis Study – another famous example of unethical research, conducted by the US Public Health Service from 1932 to 1972 in Alabama – hundreds of black men were left untreated for syphilis (even after penicillin became available) so that the natural course of the disease could be observed (Reverby, 2000). Subjects in this experiment were not even told that they were being studied. Rather, they were misled to believe that they were receiving effective treatment when they were merely being seen for experimental data-gathering diagnostics tests. Revelations of horrors such as these led to the formulation of international research ethics guidelines such as the Nuremberg Code and the Declaration of Helsinki, and domestic research ethics guidelines such as the US Belmont Report. Such guidelines invariably enshrine informed consent as a central ethical requirement for research involving human subjects. In addition to the requirement of informed consent, the World Medical Association’s (WMA) Declaration of Helsinki (amended in 2013) further holds that “the goal [of medical research to generate new knowledge] can never take precedence over the rights and interests of individual research subjects.” Even if tremendous health and social payoffs – in terms of infectious disease control – might be gained by conducting experiments involving the intentional infection of healthy subjects with HIV or other especially dangerous diseases, such experiments would be unethical according to this requirement, whether or not informed consent is obtained. In the context of medical treatment, the requirement of informed consent arose in response to medical paternalism. While it was previously commonly held that the physician knows what is best for the patient and that the physician should therefore dictate treatment decisions, this practice came to be seen as disrespectful of patient autonomy during the second half of the twentieth century. Rather than deciding for the patient what will be done, the role of the physician is now to a much greater extent seen as that of informer. The physician is expected to inform the patient about his/her condition, the treatment options, and the advantages and disadvantages of each treatment option. The informed patient then autonomously makes his/her own decision about which course of action is most appropriate in light of his/her own goals and values. Informed consent to research and treatment is not an absolute requirement, and there are cases where it is technically impossible to obtain informed consent in the case of incompetent, unconscious, and/or very young patients. In the case of research, especially good justification must be given before experiments are conducted on those who cannot provide informed consent. In both the case of research and the case of treatment, the consent of parents or a guardian is generally

sought in lieu of the subject/patient when the latter cannot provide informed consent on his/her own behalf. In the context of infectious disease control, the question arises whether or not, or when, mandatory treatment or vaccination should be enforced against a patient’s wishes. This is an especially difficult issue in contexts where one person’s refusal to receive treatment or vaccination would pose risks to others or to the community at large. In many jurisdictions, for example, at least some vaccinations are legally required. The fact that something is legal, however, does not imply that it is ethical. It was previously legal to keep slaves, but that does imply this was an ethically acceptable practice at that time. In retrospect it is recognized that laws allowing slavery were themselves unethical.

Mandatory Vaccination If the right to autonomy is not absolute, then might mandatory vaccination be ethically acceptable in special circumstances? The World Health Organization’s (WHO) smallpox eradication campaign in the second half of the twentieth century sometimes involved the use of military physical force to vaccinate people in India and elsewhere (Tucker, 2001). To reach a conclusion about whether or not this was ethically justified, one should first ask how severe were the harms to, or rights violations of, those forcefully vaccinated. Second, one should ask how important was the social goal which required infringement of individual liberty in order to be achieved. Third, one should ask whether rights promotion outweighs, in importance, the promotion of the other social goals at stake, or vice versa. The first question refers to the fact that not all liberty infringements are equally serious. Some rights and liberties are more fundamental or basic than others. Freedom to drive a car without wearing a seat belt is not as basic, fundamental, or important as the freedom to choose one’s profession or the freedom to reproduce. Violating an innocent person’s freedom by holding him/her in confinement for 5 min is not as bad as holding him in confinement for 5 years which is not as bad as holding him in confinement for 50 years. The point here is that the more serious the rights violation of – or the restriction of the liberty of, or the harm inflicted on – the individual, the more we should be reluctant to infringe upon that right in order to promote the good of society. The second question refers to the fact that some social goals are more important than others. Achieving a tiny gain in a nation’s gross domestic product, for example, is not as important as preventing a major catastrophe. The point here is that the more serious the social goal at stake, the less we should allow the protection of individuals to stand in the way of achieving it. In the most extreme situations, we sometimes accept violation of the most basic rights. We even violate innocent people’s right to life, for example, when the protection of liberty and democracy are at stake during times of war. Returning to the case of smallpox vaccination, the apparent rights violation here was that (some) people were held against their wishes and pricked with a tiny needle containing the vaccine. It is safe to assume that individuals generally do have a right not to be physically interfered with in this way

Ethics of Infectious Disease Control and that many would have had religious or other objections to having this done to them. There is furthermore some risk associated with the smallpox vaccine. It is generally considered to be the most dangerous vaccine (partly because it involves a live virus), and it did have the potential to cause serious complications and even death (though only very rarely). One might agree with all of this and still believe that coercion was called for in the circumstances given the enormous global public health interest in smallpox eradication. Having no human hosts, smallpox was one of the few infectious diseases with potential for eradication. Because it was such a devastating disease, furthermore, there was a tremendous benefit to be gained from eradicating it. The benefits of eradication, furthermore, included the end of the need for worldwide vaccination which was expensive and itself a source of morbidity and mortality. Some will claim that, from an ethical perspective, the public health imperative to eradicate smallpox outweighed the rights that had to be violated in order to eradicate the disease. Such analysis depends on two things: (1) an ethical judgment that the social goal in question was more important than the rights that had to be violated in order to achieve it and (2) an empirical judgment that it would not have been feasible to fully eradicate the disease if only volunteers were vaccinated. Because smallpox killed more people than any other infectious disease in history, many believe that its eradication was one of medicine’s – and public health’s – greatest success stories. Smallpox eradication amounted to the elimination of one of humankind’s worst enemies. Because of the physical coercion involved, however, some may nonetheless deny that this achievement was worth the ethical costs involved. Moving to the present, there is debate about the extent to which coercion of various forms should be used to achieve a high uptake of routine vaccinations such as that for measles, mumps, and rubella (MMR). Perhaps because of the way that potential vaccine dangers are presented by the media and/or because of a lack of scientific understanding on the part of the public, low vaccination uptake results and threatens herd immunity. Policy decisions then must be made regarding ways to increase coverage. When vaccination rates are low – and when herd immunity drops as a result – then wellinformed parents would be motivated to have their children vaccinated (assuming there is good evidence that the risk of vaccination is smaller than the risk of remaining unvaccinated in such circumstances). To a certain extent then, as Thomas May (2005) argues, the goal of high vaccine uptake might be promoted via a well-developed public education campaign without resort to coercion. When sufficiently many children have been vaccinated, however, a point may be reached where the risk of vaccination (even if the risks of vaccination are in fact very low) exceeds the risk of infection for those who remain unvaccinated – i.e., because the chances of infection fall toward zero as the proportion of children in the population who have been vaccinated approaches 100%. In such circumstances informed parents may, if given the choice, decide not to have their children vaccinated. Their refusal to have their children vaccinated for the reasons here described, however, would be an instance of ‘free-riding.’ Such parents would aim to reduce the risks to their own children by taking advantage of the fact that so many other

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children have already endured the risks involved with vaccination. Because this sounds unfair, however, the ethical question is whether or not refusal to have one’s child vaccinated for this kind of reason, as opposed to religious reasons, for example, should be permitted. Given the problems of social coordination that exist in public goods contexts such as this, furthermore, it is questionable whether herd immunity would remain stable in scenarios where parents are well informed and the risks of vaccination are (small but) real. The ethical question is then whether the social good of stable herd immunity outweighs the importance of parental consent to children’s vaccination. Moran et al. (2006) illustrate the wide variety of ways in which this kind of issue has been handled in Europe. Policies there range from legal requirements to have one’s child vaccinated (with or without enforcement of criminal law), to disincentives regarding refusal to have one’s child vaccinated (i.e., in some countries the child is prohibited from attending school if he/she has not been vaccinated), to provision of financial incentives/rewards for having one’s child vaccinated, to noninterference in vaccination decisions.

Mandatory Treatment While the patient’s right to consent to medical treatment is generally respected, there are cases where this kind of freedom potentially poses risks to public health at large. Because tuberculosis (TB) is contractible via casual contact, those with untreated active disease run the risk of infecting others. Strangers on buses, for example, might be infected. The significance of this kind of threat has grown with the increase of multidrug-resistant TB (MDRTB) in recent decades. Ordinary TB is inexpensive and relatively easy to treat. A 6-month course of drugs costing only US $10 to $20 is usually all that is required to cure TB. For MDRTB, on the other hand, treatment may take 2 years and cost 100 times as much; and even then treatment might not lead to cure. Although it was previously thought that TB was under control, the disease was declared a global health emergency by the WHO in 1993. One in three people worldwide are currently infected with the latent form of the disease. The continued threat of TB to even wealthy developed nations was made clear in the late 1980s and early 1990s when New York City spent $1 billion fighting an epidemic of MDRTB – and more recently by the emergence and spread of virtually untreatable extensively drug-resistant TB (XDR-TB), which is resistant to both first- and second-line drugs. Does the fact that TB is – as opposed to AIDS, for example – contractible via casual contact provide grounds for requiring treatment of patients – at least when the overall public health threat related to drug-resistant TB (which is increased when a full course of treatment is not properly completed) is taken into account? Directly observed treatment (DOT) has become part of the standard of care for TB worldwide. Those diagnosed with TB are expected to take their medications under the supervision/observation of a health worker. Among other things, it is hoped that the oversight involved with DOT will help reduce the emergence and spread of drug-resistant TB.

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In many countries, the refusal of treatment is considered legitimate grounds for confinement. If a patient refuses to comply with TB treatment in the United States, for example, then the state may not physically force treatment upon him/ her, but it can hold him/her in detention against his/her wishes in order to prevent him/her from infecting others (Bayer and Dupuis, 1995). From an ethical standpoint, such an approach may be considered preferable to the use of force in treatment insofar as it at least gives the patient a choice to either be treated or be held in detention (and because actually forcing treatment poses practical difficulties). Some may question, however, whether TB’s threat to public health is sufficiently great to warrant restriction of freedom of movement in cases where patients refuse treatment. Although contractible via casual contact, infection with TB usually requires prolonged and/or repeated exposure, and, in wealthy countries at least, a cheap and effective cure is usually available to anyone who becomes infected. Only a minority of cases involve drug resistance, and even these are usually treatable.

Quarantine One of the most controversial issues regarding ethics and infectious disease control is the issue of quarantine. Although it is sometimes considered to be an archaic and draconian measure, quarantine has recently been employed in the contexts of SARS, XDR-TB, H1N1 influenza, and Ebola. Ethical concerns about quarantine are twofold. First, quarantine involves violation of the basic right to freedom of movement. Second, quarantine can endanger the lives of those whose movement is restricted. The quarantine of an airplane carrying passengers with a dangerous strain of flu or other contagious deadly disease, for example, may lead to the infection of previously uninfected passengers who are confined in close proximity with those who are infected. Quarantine may then violate the most fundamental right of all – the right to life. Does this mean that quarantine is therefore unethical or wrong? Not necessarily. Although it should be considered an extreme or exceptional measure, there is no reason to, in principle, rule out quarantine altogether, even if it sometimes ends up killing innocent people, just as there is no ethical reason to rule out participation in (just) war. As in other contexts, there are trade-offs to be made. If quarantine, despite its costs to individuals held in confinement, would enable prevention or minimization of what would otherwise be an enormous public health disaster, then it may be considered an acceptable and necessary, though unfortunate, means of controlling infectious disease. The ethical questions, then, are: Who should have authority to impose quarantine and how can quarantine decisions be made in a responsible, rational, well-informed, balanced manner? Claims about the ethical acceptability of quarantine should arguably include the following. First, an extreme measure such as this should not be employed unless there are compelling reasons to believe that it would be an effective means of controlling disease in the circumstances under consideration. While authors such as George Annas (2005) have denied that quarantine actually works, this is of course an empirical question. There are historical cases – such as that of American Samoa during the 1918–19 flu pandemic – where it

appears to have been highly effective (Crosby, 2003). The effectiveness of quarantine more generally warrants further study. Given the difficulty of conducting controlled studies in the context of quarantine, however, it will not be easy to conclusively demonstrate whether quarantine would be effective in any given circumstance. There is an ethical imperative, in any case, that researchers with relevant expertise examine this issue as best they can. Second, mandatory quarantine should not be employed unless it is actually required. If alternative, less restrictive, means are available to achieve the same ends regarding public health protection, then these should be employed instead. If voluntary quarantine, for example, would likely be just as effective as mandatory quarantine, then the latter should not be imposed. Third, an extreme measure such as quarantine should not be imposed unless consequences of failing to do so would be great. It would be wrong to think that rights violation and the imposition of harms on individuals are justified whenever this would lead to a net payoff for society as a whole. The maximal promotion of public health should not be the sole goal of ethical public health policy. Ethical public health policy should aim to balance the goal to promote public health with other legitimate aims such as respecting the rights and protecting the well-being of individuals. Fourth, for quarantine to be ethically acceptable it must be implemented in an equitable manner. It would be unjust, if quarantine is used (as it has often been used in the past) in a discriminatory fashion against those who are already socially marginalized or disempowered. One could argue that the grounds for using quarantine must be strongest when those who are being considered for confinement are members of the worst-off groups in society. Just as research ethics guidelines give special protection to those who are vulnerable, quarantine guidelines should perhaps do the same. Fifth, quarantine, if implemented, should be made as minimally burdensome as possible. Insofar as is feasible, those confined should be provided with basic necessities such as food, water, comfort, and health care. A sixth, and related, point is that those who endure quarantine for the benefit of society should be compensated in return. It would be wrong if confined individuals are expected to themselves suffer a disproportionate amount of the burdens required for the protection of society as a whole. The burdens associated with epidemic disease are shared more fairly if those who make sacrifices by succumbing to quarantine are provided with compensation for doing so. If there are limited amounts of medication and vaccine available, for example, those who have been quarantined may deserve special priority when making allocation of medical resource decisions, and they might also deserve financial compensation for inconvenience, missed work, and so on. A benefit of putting a compensation scheme into place is that this would likely enhance trust in – and thus cooperation with – the public health-care system (Ly et al., 2007).

Infectious Disease and Social Justice While the above discussion has focused on ethical conflicts between the greater good of society (in the way of public

Ethics of Infectious Disease Control health) and respect for individual rights and liberties, there is another crucial social value that comes into play in the context of ethics and infectious disease: social justice. The poor (in both developing and developed countries) are most affected by infectious disease because of things such as poor sanitation and hygiene, bad nutrition, lack of education, crowded living conditions, and so on. Reducing poverty and improving the health of the poor can thus address numerous social values at once – by both promoting equality and improving public health in general. Improving the health of the poor would also help prevent the kinds of conflicts considered above (because these would arise less often if there were less infectious disease, which would be the case if there were less poverty in the world). Among other things, the ethical concern with justice calls for improving poor people’s access to medication and increasing research on ‘neglected diseases’ (i.e., diseases of the poor – which are not usually attractive areas of investment for the profit-driven pharmaceutical industry). Above we focused on the rights to liberty that may be infringed by public health policy. There are other kinds of human rights that should also be considered in the context of ethics and infectious disease. According to the Universal Declaration of Human Rights, for example, “Everyone has the right to a standard of living adequate for the health and well-being of himself and his family, including food, clothing, and medical care . [and] every individual and every organ of society .shall strive . by progressive measures, national and international, to secure [its] universal and effective recognition.” If this latter right were better respected, then this would itself help control infectious disease – and it would then less often be necessary to violate the former kind of right in the name of public health protection.

Public Health Emergencies Recent public health crises and/or threats have revealed that distinctive ethical issues may sometimes be especially salient in particular contexts. Because influenza is extremely contagious, for example, much of the recent debate about ethics and pandemic influenza has focused on questions concerning health workers’ duty to treat patients when provision of care poses dangers (of infection by contagious patients) to health workers themselves. While it is commonly believed that health professionals do have obligations to face such risks – as facing such risks is arguably part of a health professional’s job – it is also often acknowledged that there must be limits to the extent of risk a health professional should be expected to face and that hospitals and/or society have reciprocal obligations to make health-care work as safe as possible (e.g., via adequate provision of protective equipment). Because a major influenza pandemic could rapidly outstrip available resources, furthermore, much of the debate about ethics and pandemic influenza has also focused on questions about just allocation of limited resources. Who, for example, should be prioritized in the event that there is inadequate supply of hospital beds, ventilators, and/or antiviral medications to meet demand? It has commonly been argued that, in such scenarios, both health workers and children should be

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prioritized for both utilitarian and fairness reasons (Selgelid, 2009). The utilitarian rationale for prioritizing health workers is that keeping them alive and healthy may be especially important to the fight against the pandemic in question. The fairness rationale appeals to reciprocity: because health workers are expected to face risks by treating patients, they arguably deserve priority access to health care in return. The utilitarian rationale for prioritizing children is that saving a younger person may avert more years of lost life than saving an older person (who would not continue to live for as many additional years if saved). The fairness rationale for prioritizing children is based on the ‘fair innings’ argument – i.e., the idea that one has a right to live through all the stages of life, which older persons have already done). Ethical debate about the 2014 Ebola crisis in West Africa, in contrast, largely focused on questions about the use and study of unregistered medical interventions that had not previously been used or tested in humans. This particular issue became prominent for context-specific reasons. The West African Ebola outbreak was unprecedented in scale, killing far more people than all previous Ebola outbreaks combined. While there were no existing proven vaccines, cures, or specific treatments for Ebola, a number of vaccines and treatments had been shown to be extremely effective in animal models. The urgency of the West African Ebola outbreak thus motivated use and rapid testing of such interventions in humans. Ethical debate then questioned whether the emergency situation of Ebola justified using unregistered interventions (that had not even gone through phase 1 testing) in human patients despite the fact that this would not usually be considered ethically acceptable in other contexts. A WHO ethics panel unanimously agreed that such use should be considered ethically acceptable assuming basic ethical requirements, such as informed consent and favorable risk–benefit analysis, are met, and it further concluded that such use should, insofar as possible, be scientifically studied (WHO, 2014). This led to additional ethical questions about the conditions under which relevant emergency research should be conducted. Should placebocontrolled trials, for example, be considered ethical acceptable? The current Zika crisis in South America has likewise raised fairly distinctive ethical issues. Because the major danger of Zika is that an infected pregnant mother may give birth to a baby with microcephaly (or other neurological impairments), one of the major ethical issues associated with Zika has been the importance of women’s reproductive freedom. Though termination of pregnancy may enable prevention of birth of affected offspring, there are especially strict restrictions against abortion in many South American countries. A major conclusion of a Pan American Health Organization (PAHO) ethics consultation regarding Zika was thus that pregnant women infected with Zika should be free to make their own decisions about whether or not to continue pregnancy – and that they should be supported whatever their decision (PAHO, 2016). Although one of the most salient ethical issues in the context of Zika, abortion had not previously been a major focus of discussion regarding infectious disease ethics. While the primary ethical issues associated with both Ebola and Zika, in particular, were largely unanticipated in advance it might be expected that future infectious disease crises will likewise lead to distinctive, context-specific ethical issues.

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See also: Codes of Ethics in Public Health; Ethics and Health Promotion; Ethics of Immunization; Ethics of Public Health Research: Moral Obligations to Communities; Ethics of Screening; Foundations in Public Health Ethics; Foundations in Public Health Law; Infectious Disease Surveillance; Legal Issues in Public Health; Public Health Law and Public Health Policy; Quarantine through History; Re-emerging Diseases: Overview; Social Dimensions of Epidemics; Social Dimensions of Infectious Diseases.

References Annas, G.J., Grodin, M.A. (Eds.), 1992. The Nazi Doctors and the Nuremburg Code: Human Rights in Human Experimentation. Oxford University Press, New York. Annas, G.J., 2005. American Bioethics: Crossing Human Rights and Health Law Boundaries. Oxford University Press, New York. Bayer, R., Dupuis, L., 1995. Tuberculosis, public health, and civil liberties. Annu. Rev. Public Health 16, 307–326. Crosby, A., 2003. America’s Forgotten Pandemic: The Influenza of 1918, second ed. Cambridge University Press, Cambridge, UK (Originally published 1989.). Ly, T., Selgelid, M.J., Kerridge, I., 2007. Pandemic and public health controls: toward an equitable compensation system. J. Law Med. 15 (2). May, T., 2005. Public communication, risk perception, and the viability of preventive vaccination against communicable diseases. Bioethics 19, 407–421. Moran, N.E., Shickle, D., Munthe, C., Dierickx, K., Petrini, C., Piribauer, F., Czabanowska, K., Cowley, H., Blancafort, S., Petsetakis, E., 2006. Are compulsory immunisation and incentives to immunise effective ways to achieve herd immunity in Europe? In: Selgelid, M.J., Battin, M.P., Smith, C.B. (Eds.), Ethics and Infectious Disease. Blackwell, Oxford, UK, pp. 215–231. Pan American Health Organization (PAHO), 2016. Zika Ethics Consultation: Ethics Guidance on Key Issues Raised by the Outbreak. Available at: http://www.iris. paho.org/xmlui/bitstream/handle/123456789/28425/PAHOKBR16002_eng.pdf (accessed 01.08.16.). Price-Smith, A.T., 2001. The Health of Nations: Infectious Disease, Environmental Change, and Their Effects on National Security and Development. MIT Press, Cambridge, MA. Reverby, S.M. (Ed.), 2000. Tuskegee’s Truths: Rethinking the Tuskegee Syphilis Study. University of North Carolina Press, Chapel Hill. Selgelid, M.J., 2009. Pandethics. Public Health 123 (3), 255–259. Tucker, J.B., 2001. Scourge: The once and Future Threat of Smallpox. Grove Press, New York. Universal Declaration of Human Rights, Approved and Proclaimed by the General Assembly of the United Nations on 10 December 1948, as Resolution 217 A (III). World Health Organization (WHO), 2014. Ethical Considerations for Use of Unregistered Interventions for Ebola Virus Disease. Available at: http://www.who.int/csr/ resources/publications/ebola/ethical-considerations/en/l (accessed 01.08.16.). World Health Organization (WHO), 2016a. Fact Sheet No 104. Tuberculosis. Available at: http://www.who.int/mediacentre/factsheets/fs104/en/ (accessed 01.08.16.). World Health Organization (WHO), 2016b. HIV/AIDS Fact Sheet. Available at: http:// www.who.int/mediacentre/factsheets/fs360/en/ (accessed 01.08.16.). World Health Organization (WHO), 2016c. Malaria Fact Sheet. Available at: http://www. who.int/mediacentre/factsheets/fs094/en/ (accessed 01.08.16.). World Medical Association, 2013. Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. Available at: http://www.wma.net/en/ 30publications/10policies/b3/ (accessed 01.08.16.).

Further Reading Bayer, R., 2003. Ethics and infectious disease control: STDs, HIV, TB. In: Jennings, B., Kahn, J., Mastroianni, A., Parker, L.S. (Eds.), Ethics and Public Health: Model Curriculum. Association of Schools of Public Health (ASPH) and the Health Resources and Service Administration (HRSA), Washington, DC, pp. 133–146. Bayer, R., Fairchild, A.L., 2004. The genesis of public health ethics. Bioethics 18, 473–492. Beauchamp, D.E., Steinbock, B.S. (Eds.), 1999. New Ethics for the Public’s Health. Oxford University Press, New York. Childress, J.F., Faden, R.R., Gaare, R.D., Gostin, L.O., Kahn, J., Bonnie, R.J., Kass, N.E., Mastroianni, A.C., Moreno, J.D., Nieburg, P., 2002. J. Law Med. Ethics 30, 170–178. Coughlin, S.S., Beauchamp, T.L. (Eds.), 1996. Ethics and Epidemiology. Oxford University Press, New York. Farmer, P., 1999. Infections and Inequalities. University of California Press, Berkeley, CA. Gostin, L.O., 2006. Public health strategies for pandemic influenza. JAMA 295, 1700–1704. Gostin, L.O. (Ed.), 2002. Public Health Law and Ethics: A Reader. University of California Press, Berkeley, CA. Kass, N.E., 2001. An ethics framework for public health. Am. J. Public Health 91, 1776–1782. Mann, J.M., Gruskin, S., Grodin, M.A., Annas, G.J. (Eds.), 1999. Health and Human Rights: A Reader. Routledge, London. Schuklenk, U., 1998. AIDS: individual and ‘public’ interests. In: Kuhse, H., Singer, P. (Eds.), A Companion to Bioethics. Blackwell, Oxford, UK, pp. 343–354. Selgelid, M.J., Battin, M.P., Smith, C. (Eds.), 2006. Ethics and Infectious Disease. Blackwell, Oxford, UK. Upshur, R., 2002. Principles for the justification of pubic health intervention. Can. J. Public Health 93, 101–103. University of Toronto Joint Centre for Bioethics Pandemic Influenza Working Group, 2005. Stand on Guard for Thee: Ethical Considerations in Preparedness Planning for Pandemic Influenza. Available at: http://www.utoronto.ca/jcb/home/documents/ pandemic.pdf. Verweij, M., Dawson, A., 2004. Ethical principles for collective immunisation programmes. Vaccine 22, 3122–3126.

Relevant Websites www.bioethics.net – Bioethics (last accessed on 09.08.16.). http://www.cidrap.umn.edu – Center for Infectious Disease Research and Policy, University of Minnesota (last accessed on 09.08.16.). http://www.publichealthlaw.net/ – Center for Law and the Public’s Health (last accessed on 09.08.16.). http://www.fxb.org/ – François-Xavier Bagnoud Center for Health & Human Rights (last accessed on 09.08.16.). http://www.wits.ac.za/bioethics/AIDS-ELSI/ – HIV/AIDS Ethical, Legal and Social Issues (last accessed on 09.08.16.). http://www.bioethics-international.org/iab-2.0/index.php?show¼index – International Association of Bioethics (last accessed on 09.08.16.). http://www.georgetown.edu/research/nrcbl/nrc/index.htm – National Reference Centre for Bioethics Literature, Kennedy Institute of Ethics, Georgetown University (last accessed on 09.08.16.). www.unaids.org – UNAIDS (last accessed on 09.08.16.). http://www.cdc.gov/ – US Centers for Disease Control and Prevention (last accessed on 09.08.16.). www.who.int – World Health Organization (last accessed on 09.08.16.).

Ethics of Organ Transplants Ahmed B Al-Khafaji and Lisa S Parker, University of Pittsburgh, Pittsburgh, PA, USA Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Lisa S. Parker, Kathleen D. Williams, volume 2, pp. 493–498, Ó 2008, Elsevier Inc.

Introduction Diverse clinical, ethical, and public policy concerns arise at each stage of the organ transplantation process. Despite the benefits of organ transplantation, it remains controversial globally, including in the United States. First, some believe that society ought to direct its limited healthcare resources toward preventative and primary care efforts, rather than toward expensive, technologically-aided extensions of human life. Transplantation reflects and feeds society’s reluctance to accept human mortality. Second, some fear that acquiring another person’s organ(s) confuses one’s identity, while some oppose organ transplantation on religious grounds. Finally, some worry that proposed markets for available organs fosters commodification of the body. On the other hand, it is difficult to ignore the benefits of organ transplantation, which has saved the lives and improved the quality of life of thousands of organ recipients. Additionally, in some cases organ transplantation is more cost effective than other interventions, for example, dialysis for end-stage renal disease (Smith, 2003). Some argue that both cadaveric and living organ donation afford a valuable opportunity for altruism, and thus transplantation has nonconsequentialist moral value. Many of the ethical concerns surrounding organ procurement and transplantation arise because the demand for organs far outstrips the supply. According to the Organ Procurement and Transplantation Network (OPTN), in the United States, for example, over 123 000 individuals were registered transplant candidates at the start of 2015, yet in the preceding year only 7867 cadaveric and 5258 living organs were received (OPTN, 2015a). These figures reflect a 43% increase in demand over a 10-year period, which was not matched by a commensurate increase in supply: cadaveric donations only increased by 10% while living donations decreased by 25% (OPTN, 2015a).

Cadaveric Organ Procurement After Neurologic Determination of Death Cadaveric organ procurement is governed by an ethical consensus informally called the dead donor rule, which holds that an individual must be dead before organs are procured and may not be killed either by or for organ retrieval. Although the idea that one must be dead before an organ is harvested seems quite straightforward, technological advances that enable maintenance of cardiopulmonary function have presented conceptual and ethical challenges for determining when death has occurred. Prior to these technological advances, individuals were declared dead according to cardiopulmonary criteria, i.e., based on the cessation of their circulatory and respiratory function. Now, with the ability to maintain cardiopulmonary function in individuals who have suffered irreversible loss of brain function, neurologic criteria for

International Encyclopedia of Public Health, 2nd edition, Volume 3

declaring death have emerged. Being declared dead by either set of criteria – circulatory or neurologic – is a necessary condition for having one’s organs procured. Despite the relatively longstanding legal acceptance of neurologic determination of death, first introduced in 1968, debate continues as to whether irreversible loss of brain stem function is a requisite criterion, or whether the loss of only higher brain function is sufficient to constitute death. Those who challenge a whole brain standard for death (functional loss of both higher brain and brain stem) argue that part of being a living person involves sentient and socially interactive existence. Advocates of this view believe that loss of higher brain function renders someone dead, irrespective of intact or lingering brain stem function, because what makes a person a person is no longer present. This view, however, prompts ethical debate concerning what criteria define personhood. Community, cultural, and religious beliefs foster different attitudes toward death among the public, and acceptance of the concept of brain death is rendered emotionally challenging, in part, because mechanical ventilation maintains respiration, perfusion, and body temperature, thereby preserving the appearance of life. For some, beliefs about death center on the apparent cessation of these life-promoting functions, rather than on brain inactivity. Differences in beliefs about death have significant consequences for organ procurement. If protocols for determining death do not accord with public perception, people may become averse to organ donation or procurement. Indeed, people may become mistrustful of the healthcare system and fearful of entering hospitals if they believe they might be declared dead according to a definition gerrymandered for the purpose of transplantation.

After Circulatory Determination of Death Not all cadaveric donors are declared dead according to neurologic criteria. Procurement of organs from those declared dead according to cardiopulmonary criteria is called non-heartbeating organ procurement, also known as donation after circulatory determination of death (DCDD). Between 2000 and 2008, more than 5000 DCDD transplants were performed in Europe. There are two types: uncontrolled DCDD and controlled DCDD. Uncontrolled DCDD occurs when organs are recovered from a cardiac arrest patient for whom attempts at resuscitation fail, a practice rare in the United States. Even in Spain, the nation with the most extensive uncontrolled DCDD program, transplanted livers from these sources represented only 1–2% of the total grafts performed, while the remainder originated from brain dead cadavers (Ciria et al., 2012; Monbaliu et al., 2012). Controlled DCDD involves obtaining organs several minutes after life-sustaining treatment is withdrawn, resuscitation efforts are withheld, and death is declared – pursuant to the patient’s or surrogate’s decision. Such DCDD is usually governed by strict institutional protocols designed to ensure that

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Ethics of Organ Transplants

patients (or their surrogates) are not pressured into forgoing life-sustaining interventions and make an informed voluntary decision to donate organs following death. These protocols are also designed to ensure that organs are not rendered unusable by the process of withdrawing life-sustaining treatment. One ethical concern surrounding controlled DCDD is deciding how quickly death can be declared once circulation is absent. The concern is that some protocols flirt with the dead donor rule and risk gerrymandering the criteria for determining death by failing to do everything possible to reverse cessation of cardiopulmonary function. On the other hand, controlled DCDD protocols, by focusing on the donor’s intent and consent, permit patients (or their surrogates) to act altruistically, to make their values and preferences efficacious at the end of life, and to have something good come from the patient’s death. Lack of awareness about organ donation, perhaps stemming from a lack of concerted public education, may be the greatest obstacle to attracting donors. Religious beliefs also play a role in individuals’ reluctance to donate if a particular faith is perceived – accurately or not – to discourage organ harvesting upon death. Active decisions against donation stem from mistrust of healthcare providers and concern about undertreatment or premature declaration of death. A legacy of racism exacerbates these concerns, for example, among AfricanAmericans in the United States and fuels the belief that their organs will only go to Whites (Siminoff and Sturm, 2000). In fact, minority candidates do receive transplantation at a lower rate than Whites (see section Allocation). Healthcare provider -related factors also hinder procurement. These include misunderstanding of neurologic criteria for death (Youngner et al., 1989), difficulty in identifying donors, reluctance to approach grieving families, and concern about exposure to professional and institutional liability.

Living Related and Nonrelated Organ Donation Living donors are an important source of donated organs, providing roughly half of all donated organs in the United States. However, universal acceptance of organ donation is elusive; in some regions, parting with an organ is stigmatized and living donors may face ostracism akin to prostitutes, as in Moldova (Scheper-Hughes, 2003). Living donors face significant physical and psychosocial risks, including the physical risks of the surgery itself and of living without the donated organ tissue, as well as psychological and socioeconomic risks. Having embarked on the donor evaluation process, prospective donors may get cold feet, but be reluctant to back out. Donors may feel guilt or resentment if the recipient experiences organ rejection, or feel responsible for the recipient’s future life (and death). Also, the donor’s employment (especially physically taxing work) and lifestyle may be put at risk by donation. The donor’s insurability may be jeopardized by the surgery or by subsequent compromised health status. These risks arise for any of the following categories of living donors.

Related Donors In the United States, 61% of organ transplants from living donors in 2014 originated from someone legally or genetically

related to the recipient (OPTN, 2015b). Family members are encouraged to be evaluated for donation because increased histocompatibility between genetically related people affords medicoscientific advantage. Although relatives typically have an interest in the health and well-being of an ill loved one, these interests and family dynamics raise the question of whether familial donation can be adequately voluntary. In some cases, other family members or the potential recipient may place undue pressure on a potential related donor, or the donation may be prompted by personal guilt or concern about social approval and family ostracism. Ethical concerns are particularly significant when the potential donor is a minor. Because minors cannot give consent, they are not donors in the usual sense; usually parents give consent (or permission) on their behalf. There is substantial debate about the appropriateness of parents using their children’s organs to benefit other family members, including other offspring. A child may have an interest in a relative’s welfare or the intactness of the family unit, so that donation may be deemed to be in the donor-child’s interest. Yet, conflict of interest exists between donor and recipient with regard to the risks of donation and transplantation. A minor cannot weigh those risks as an adult can and, moreover, will typically live longer without the donated tissue than adult donors and thus face greater long-term health risks. Physical risks of donation must be balanced against the psychological risks and potential benefits of donating to preserve a family member’s life.

Nonrelated Donors Other types of living donation include nondirected donation, directed donation, and directed paired donation. Typically motivated by altruism, nondirected donation involves donation of an organ to the next matching candidate on the relevant waiting list. This practice was made legal in the United Kingdom under the Human Tissue Act only in 2004 and is utilized relatively rarely in the United States (Weale and Lear, 2007). Directed donation is the donation of an organ to a specific recipient, usually someone who is emotionally, but not genetically or legally, related to the donor. Integrating these practices yields living donor exchange chains that are initiated by a nondirected donation to the first recipient and directed donation from a relation of the recipient to the subsequent link in the chain (Anderson et al., 2015). Properly optimized, these protocols maximize organ supply and the number of transplants performed, yet they magnify the pressure on potential donors to donate. Directed paired donation involves two donor/recipient pairs who are not histocompatible within each pair. Recipients swap donors so that each recipient can receive a compatible organ (Delmonico, 2004). This type of donation is becoming increasingly accepted internationally. Potential recipients and their families may make mass media appeals for a donor, and various websites have emerged to link needy patients with willing donors. MatchingDonors. com, for example, lists profiles of potential recipients; potential living donors may contact the patients listed and begin the process of medical evaluation to determine whether the two are compatible. On its potential donor page, the site stresses that donors are not legally permitted to benefit financially

Ethics of Organ Transplants from organ donation. Beyond concern about financial incentives involved, there is concern that emotional appeals designed to inspire altruistic directed donation subvert established allocation systems. If such appeals prompt donation of an organ that would not otherwise have been donated, then it seems everyone benefits because the donor pool is increased and no one waiting on a transplantation list is made worse off in virtue of someone else receiving the directed donation. If instead such an appeal diverts from the general pool an organ that would have otherwise been allocated to the next medically eligible recipient on the list, then it directly subverts the allocation system. In addition, if such direct appeals and directed donations undermine confidence in the fairness and efficacy of the general system, overall procurement efforts may be undermined. Even when an eligible living donor is identified, barriers may prevent actual donation. These include donor concern about surgery, its disfigurement, and impact on future health, lifestyle, and relationships, as well as negative attitudes toward transplantation fostered by the media (Morgan et al., 2005). On the other hand, some potential donors may be willing, but not eligible to donate, either because of concern about the long-term functionality of the donor organ, or because of concern about the health status of the potential donor.

Alternative Proposals for Procurement Some argue that the scarcity of available organs reflects an inadequacy inherent in reliance on the current system of express donation, which offers little incentive (beyond social regard) for people to donate and little motivation for healthcare professionals to solicit organs. As a result, other incentive systems have been proposed including conscription, presumed consent, routine request, compensation, and a market system (Barnett and Kaserman, 1993).

Conscription, Presumed Consent, and Routine Request Conscription describes a program of mandatory organ retrieval in which all cadaver organs are retrieved regardless of the wishes of the deceased individual or the surviving family. In essence, cadavers are considered social resources rather than property of the decedent’s family, a notion that many find disturbing. No society has instituted a policy of universal conscription; however, some would contend that China’s policy of obtaining organs from executed prisoners borders on conscripting their organs, because of skepticism that prisoners can give voluntary informed consent to organ donation within the Chinese (or perhaps any) prison system, coupled with concern about China’s use of the death penalty (Chugh and Jha, 1996). In 2005, China acknowledged that 95% of transplanted organs originated from executed prisoners. Despite official statements promising an end to the practice, evidence suggests legitimization: executed prisoner organs are being incorporated into the existing public voluntary organ donation and allocation system (Sharif et al., 2014). A system of presumed consent is a milder form of conscription in which people are presumed to have consented to procurement of their organs upon death. This policy allows

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individuals to opt out of organ donation by entering their names on a national registry. Various presumed consent models have been adopted in Austria, Belgium, Columbia, France, Italy, Norway, Singapore, and Spain. In most countries with a presumed consent policy, in practice, relatives’ objections to donation are usually dispositive. The British Medical Association has lobbied for adoption of a soft presumed consent model whereby relatives would be informed that the deceased had not opted out of donation and that organs will be procured unless they object. However, the UK Human Tissue Act of 2004 does not permit procurement without explicit consent, although it does permit initial interventions to preserve organs while consent is being sought (Bell, 2006). Concerns exist that in a system of presumed consent, an individual’s opposition to donation may fail to be recorded, lost, or not discovered until after donation has mistakenly been performed (Caplan, 2008). Lastly, a routine request would require everyone, either upon receiving a driver’s license or at another specified point in time, to make their wishes known concerning disposition of their organs upon death. This policy appears to conform to respect for individualism, autonomy, and human dignity more than some alternatives, but in the absence of education to shape people’s preferences toward donation, it may not result in adequately informed choices or sufficiently increased supply. Experience suggests that there are a number of factors that influence donation and transplantation rates, including the rates at which potential donors become actual donors. For example, the Spanish Model consists of an integrated system designed to address procurement problems at three stages. This includes a system to identify eligible donors, measures to optimize medical management during donor evaluation, and programs to train hospital and regional personnel to approach families about donation. A 24-h transplantation hotline with a universal number for all of Spain was introduced, and the mass media were enlisted to inform the public about donation and transplantation. Following this model, Spain has enjoyed the world’s highest rates of both cadaveric organ donation and kidney and liver cadaveric transplantation (Matesanz and Miranda, 2002). Today, the rate of deceased donors per million population is highest in Spain (34.1), followed by Portugal (26.7), the United States (26.3), and Belgium (25.6) (Boyarsky et al., 2012).

Compensation and Open Markets A compensation system offers financial incentives to those who are willing to donate organs, a practice currently prohibited in many jurisdictions. Many argue that this prohibition preserves human dignity and prevents cadavers (or living donors) from being treated as mere commodities (Barnett and Kaserman, 1993). Creation of an open market system permits the trade of human organs dependent on capitalistic notions of supply and demand. Adopting a market system risks commodification of the human body thereby raising ethical concern for some, although Taylor (2005) contends that for people who respect personal autonomy and human wellbeing, adopting a market system is not only morally permissible, but morally imperative.

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Where a market in organs has existed – usually a black market or one tolerated by the state, but not officially sanctioned – concerns arise regarding exploitation of the illiterate and poor, deception on the part of middle-men who identify organ sellers for those who need them, and profits made by these agents and by transplant surgeons and centers (Chugh and Jha, 1996). On the other hand, some would contend that attempts to protect the poor from exploitation by making organ sale illegal impose ethical values shaped by affluent or more egalitarian societies and prevent the poor in developing nations from profiting from the resources available to them (Patel, 1996). In India, for example, the Transplantation of Human Organs Act of 1994 was enacted to regulate organ procurement and transplantation and to prohibit the sale of (and trafficking in) organs. Two features of the Act, however, make this prohibition difficult to enforce: (1) it permits not only living-related donation, but also donation by emotionally attached parties, thereby enabling a donor to pose as a concerned friend for a fee; (2) police officials may not investigate charges of corruption or violation of the Act without being granted special authority to do so. There is concern that hospital and regional committees charged with assuring that unrelated donors are not acting for pay are ineffective or in collusion with transplant surgeons, who themselves may rationalize the practice of paying for organs in the interest of saving lives (Mudur, 2004). Similarly, a black market in organs is said to flourish in China, with wealthy Japanese and other transplant tourists paying thousands or tens-of-thousands to receive organs removed from executed prisoners (Chugh and Jha, 1996; Rhodes and Schiano, 2010). Proposals more modest than an open market include paying something toward burial costs of those who donate, or payments for the inconvenience of living donors. In Iran, unrelated living kidney donors “receive a gift from the government as a reward. The majority . receive supplemental compensation, equivalent to US $1550 from the recipient” (Broumand, 2005). This compensation system has resulted in a reduction in the rate of related living donation and limits expansion of cadaveric kidney transplantation but is viewed as preventing uncontrolled commercial trade in organs (Larijani et al., 2004).

Allocation To avoid personal bias and to ensure integrity of the organ allocation system, many countries use centralized computerized networks to allocate procured organs. These networks use match programs based on ostensibly objective criteria to generate lists of possible recipients based on the donor organ characteristics. The criteria considered in the match program vary by organ type, but include time spent on the particular waiting list for that organ, medical urgency, blood type, size of the organ, tissue type, and geographical distance between the donor and recipient. Different transplant centers have different criteria for evaluating and listing candidates for transplantation. A person not listed at one center may be eligible at another.

Despite efforts to keep candidate evaluation and organ allocation decisions as fair and unbiased as possible, some inequity persists. Studies of the United States system have shown that members of minority groups are less likely to be considered for, express interest in, and undergo transplantation procedures (Alexander and Sehgal, 1998; McNamara et al., 1999). The development of the National MOTTEP (Minority Organ Tissue Transplant Education Program) and COMET (Council on Minority Education in Transplantation) are attempts to eliminate these discrepancies (Callender et al., 2003). Criteria for allocating organs reflect attempts to balance the potentially conflicting values of equity and utility. Maximizing utility would require allocating organs to maximize the number of high-quality life years from procured organs (typically to younger, healthier patients). What equity or fairness would demand in this context is less clear and depends on one’s preferred material principle of justice. Different principles of justice support use of criteria such as waiting list time, age, previous utilization of healthcare resources (including previous transplantation), and urgency of need, as well as controversial factors such as social worth or degree of responsibility for ill health. Social worth criteria fell into ethical disrepute in the early 1970s when their use for allocating spaces on kidney dialysis machines in the United States was exposed. Nevertheless, suggestions for employing such criteria have persisted in the context of transplantation. Social worth criteria are implicit in proposals that candidates should be given varying degrees of priority depending on whether their organ failure was the result of behaviors they could be expected to have avoided or controlled (e.g., tobacco or alcohol use) or the result of factors beyond their control (e.g., genetics, injury, or disease not associated with individual responsibility). Considerations of social worth are explicit in suggestions that criminals receive lower priority for organs than community members in good standing or people on whom others obviously depend (e.g., parents). At issue is both whether healthcare ‘should’ be made contingent on considerations of social worth or moral evaluation, as well as the degree to which disease conditions are the result of factors within individuals’ control and thus whether it is ‘possible’ to assign individuals’ responsibility for their health status. Ubel et al. (1993) argue that retransplantation candidates should receive lower priority on waiting lists not because of considerations of fairness, but because of the lower efficacy of retransplantation. Approximately 10% of available livers, 12% of kidneys, and 20% of pancreases (OPTN, 2015c), for example, go to retransplant patients who have a poorer prognosis than first-time candidates and who have already had access to the scarce number of available organs.

Alternatives to Organ Procurement and Transplantation One possible alternative to human cadaveric or living donor organ transplantation is xenotransplantation, the transplantation of organs or tissues across species, for example, from pigs to humans. Although this solution may help alleviate the shortage of available organs, there are numerous ethical concerns including how and on whom to test these experimental

Ethics of Organ Transplants procedures, uncertainties about safety, and unease about sharing body parts with non-human animals, as well as concern about their welfare and exploitation. Finally, the risk of transmitting infectious disease across the species barrier joins concerns about management of immunosuppression and graft rejection – acute or delayed – not only as fundamental patient-related challenges of xenotransplantation, but also as a special ethical concern because of the risk presented to communities and the human species (Dooldeniya and Warrens, 2003; National Health Medical Research Council (NHMRC), 2005). Organogenesis, the in vitro growth of implantable organs, is another possible alternative or addition to current transplantation methods. Ethical concerns include questions about consent to use and ownership of founder cell lines, concern about alteration of the genome in order to modify the properties of the transplantable cells, and concern about the safety of transplanting organogenic materials into humans. Also, for both clinical trials of xenotransplantation and organogenesis, questions arise about the identification of appropriate research subjects and whether those subjects can give truly voluntary informed consent, given the risk of death while waiting for a traditional transplant. Finally, mechanical devices may serve either as bridges to transplantation, or eventually as permanent mechanical substitutes providing the functional equivalent of organ systems. Dialysis may be considered such a mechanical substitute, but it provides an inferior quality of life compared to kidney transplantation. External left ventricular assist devices (LVADs) have enjoyed success as bridges to transplant and are sometimes used as destination therapies for patients not eligible for transplantation. The success of temporary devices serves to increase demand for organs and imposes difficult decisions on very sick patients. Although trials of a permanent mechanical substitute for a complete donor heart have not proved sufficiently free of adverse events, it is hoped that bridge devices may ultimately lead to development of permanent organ substitutes.

See also: Health Technology Assessment: Ethical, Legal and Social Issues; New Technologies: Ethics of Stem Cell Research.

References Alexander, G.C., Sehgal, A.R., 1998. Barriers to cadaveric renal transplantation among blacks, women, and the poor. J. Am. Med. Assoc. 280, 1148–1152. Anderson, R., Ashlagi, I., Gamarnik, D., Roth, A.E., 2015. Finding long chains in kidney exchange using the traveling salesman problem. Proc. Natl. Acad. Sci. U.S.A. 112 (3), 663–668. Barnett, A.H., Kaserman, D.L., 1993. The shortage of organs for transplantation: exploring the alternatives. Issues Law Med. 9, 117–137. Bell, M.D.D., 2006. Emergency medicine organ donation and the Human Tissue Act. Emerg. Med. J. 23, 824–827. Boyarsky, B.J., Hall, E.C., Deshpande, N.A., et al., 2012. Potential limitations of presumed consent legislation. Transplantation 93 (2), 136–140. Broumand, B., 2005. Transplantation activities in Iran. Exp. Clin. Transplant. 3, 333–337. Callender, C.O., Miles, P.V., Hall, M.B., 2003. Experience with national minority organ tissue transplant education program in the United States. Transplant. Proc. 35, 1151–1152. Caplan, A., 2008. Organ transplantation. In: Crowley, M. (Ed.), From Birth to Death and Bench to Clinic: The Hastings Center Bioethics Briefing Book for Journalists, Policymakers, and Campaigns. The Hastings Center, Garrison, NY, pp. 129–132.

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Ciria, R., Briceno, J., Rufian, S., et al., 2012. Donation after cardiac death: where, when, and how? Transplant. Proc. 44 (6), 1470–1474. Chugh, K.S., Jha, V., 1996. Commerce in transplantation in Third World countries. Kidney Int. 49, 1181–1186. Delmonico, F.L., 2004. Exchanging kidneys – advances in living-donor transplantation. N. Engl. J. Med. 350, 1812–1814. Dooldeniya, M.D., Warrens, A.N., 2003. Xenotransplantation: where are we today? J. R. Soc. Med. 96, 111–117. Larijani, B., Zahedi, F., Taheri, E., 2004. Ethical and legal aspects of organ transplantation in Iran. Transplant. Proc. 36, 1241–1244. Matesanz, R., Miranda, B., 2002. A decade of continuous improvement in cadaveric organ donation: the Spanish model,. J. Nephrol. 15, 22–28. McNamara, P., Guadagnoli, E., Evanisko, M.J., et al., 1999. Correlates of support for organ donation among three ethnic groups. Clin. Transplant. 13, 45–50. Monbaliu, D., Pirenne, J., Talbot, D., 2012. Liver transplantation using donation after cardiac death donors. J. Hepatol. 56 (2), 474–485. Morgan, S.E., Harrison, T.R., Long, S.D., et al., 2005. Family discussion about organ donation: how the media influences opinions about donation decisions. Clin. Transplant. 19, 674–682. Mudur, G., 2004. Kidney trade arrest exposes loopholes in India’s transplant laws. Br. Med. J. 328, 246. National Health Medical Research Council (NHMRC), 2005. Australian Government. Statement on Animal-to-Human Transplantation (Xenotransplantation) Research. http://www.nhmrc.gov.au/about/committees/expert/gtrap/_files/xenotrans.pdf (accessed October 2007). Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR), 2014. OPTN/SRTR 2012 Annual Data Report. Department of Health and Human Services, Health Resources and Services Administration, Rockville, MD. OPTN, 2015a. Donors Recovered in the U.S. by Donor Type. http://www.optn. transplant.hrsa.gov/converge/latestData/viewDataReports.asp (accessed 14.02.14.). OPTN, 2015b. Living Donor Transplants by Donor Relation. http://www.optn.transplant. hrsa.gov/converge/latestData/viewDataReports.asp (accessed 14.02.14.). OPTN, 2015c. Transplant: Organ by Previous Transplant. http://www.optn.transplant. hrsa.gov/converge/latestData/viewDataReports.asp (accessed 14.02.14.). Patel, T., 1996. India kidney trade. TED Case Stud. 5 (1). Case #240. http://www. american.edu/ted/kidney.htm (accessed October 2007). Rhodes, R., Schiano, T., 2010. Transplant tourism in China: a tale of two transplants. Am. J. Bioeth. 10 (2), 3–11. Scheper-Hughes, N., 2003. Rotten trade: millennial capitalism, human values and global justice in organs trafficking. J. Hum. Rights 2, 197–226. Sharif, A., Singh, M.F., Trey, T., Lavee, J., 2014. Organ procurement from executed prisoners in china. Am. J. Transplant. 14 (10), 2246–2252. Siminoff, L.A., Sturm, C.M.S., 2000. African-American reluctance to donate: beliefs and attitudes about organ donation and implications for policy. Kennedy Inst. Ethics J. 10, 59–74. Smith, S.L., 2003. Quality Aspects of Transplantation. Organ Transplantation: Concepts Issues Practice, and Outcomes. http://www.medscape.com/ viewpublication/704_about. Retrieved November 14, 2005, from Medscape database. Taylor, J.S., 2005. Stakes and Kidneys: Why Markets in Human Body Parts Are Morally Imperative. Ashgate Publishers, Burlington, VT. Ubel, P.A., Arnold, R.M., Caplan, A.L., 1993. Rationing failure: the ethical lessons of the retransplantation of scarce vital organs. J. Am. Med. Assoc. 270, 2469–2474. Weale, A.R., Lear, P.A., 2007. Organ transplantation and the human tissue act. Postgrad. Med. J. 83, 141–142. Youngner, S.J., Landefeld, C.S., Coulton, C.J., et al., 1989. Brain death’ and organ retrieval. A cross-sectional survey of knowledge and concepts among health professionals. J. Am. Med. Assoc. 261, 2205–2210.

Further Reading Ankeny, R.A., 1999. Recasting the debate on multiple listing for transplantation through consideration of both principles and practice. Camb. Q. Healthc. Ethics 8, 330–339. Ankeny, R.A., 2001. The moral status of preferences for directed donation: who should decide who gets transplantable organs? Camb. Q. Healthc. Ethics 10, 387–398. Arnold, R.M., Youngner, S.J., 1993. The dead donor rule: should we stretch it bend it, or abandon it? Kennedy Inst. Ethics J. 3, 263–278. Arnold, R.M., Siminoff, L.A., Frader, J.E., 1996. Ethical issues in organ procurement. Crit. Care Clin. 12, 29–48.

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Ben-David, O.B., 2005. Organ Donation and Transplantation: Body Organs as an Exchangeable Socio-cultural Resource. Praeger Publishers, Westport, CT. Institute of Medicine, 1996. Xenotransplantation: Science, Ethics, and Public Policy. National Academy Press, Washington, DC. Institute of Medicine, 1997. Non-heart-beating Organ Transplantation: Medical and Ethical Issues in Procurement. National Academy Press, Washington, DC. Kerridge, I.H., Saul, P., Lowe, M., et al., 2002. Death dying and donation: organ transplantation and the diagnosis of death. J. Med. Ethics 28, 89–94. Sells, R.A., 2003. What is transplantation law and whom does it serve? Transplant. Proc. 35, 1191–1194.

Shelton, W., Balint, J., 2001. The Ethics of Organ Transplantation. JAI, an Imprint of Elsevier Science, New York. Simmons, R.G., Marine, S.K., Simmons, R.L., 1987. Gift of Life: The Effect of Organ Transplantation on Individual, Family, and Societal Dynamics. Transaction Books, New Brunswick, NJ. Trzepacz, P.T., DiMartini, A.F., 2000. The Transplant Patient: Biological, Psychiatric, and Ethical Issues in Organ Transplantation. Cambridge University Press, New York. Veatch, R.M., 2000. Transplantation Ethics. Georgetown University Press, Washington, DC.

Ethics of Public Health Research: Moral Obligations to Communities Holly A Taylor, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; and Johns Hopkins Berman Institute of Bioethics, Baltimore, MD, USA Summer Johnson McGee, College of Business, University of New Haven, West Haven, CT, USA Ruth R Faden, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Nancy E Kass, Johns Hopkins Berman Institute of Bioethics, Baltimore, MD, USA; and Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Ó 2017 Elsevier Inc. All rights reserved.

Introduction Public health research often involves human subjects. Although some authors have argued that there are significant moral differences between public health research and public health practice (Human Research Protection Office, 1999; National Bioethics Advisory Commission, 2001), few have claimed that public health research presents unique ethical issues from other types of human subjects research. However, a number of examples in the recent history of research ethics, including the Kennedy Krieger Lead Abatement Study (Institute of Medicine, 2005; Buchanan and Miller, 2006) and the EPA’s Children’s Environmental Exposure Research Study (CHEERS) (Resnik and Wing, 2007) suggest that, at very least, public health research may bring into sharper focus unresolved issues in the ethics of human research. Public health research typically has been contrasted with public health practice according to criteria such as performance authority, intent to publish, the funding source, data collection methods, study design or investigator–participant relationship (Bellin and Dubler, 2001; Hodge and Gostin, 2004). Definitions of public health research have been slow to develop and, it has been suggested, are largely unsatisfying attempts to resolve ethical problems through categorization and redefinition (Fairchild and Bayer, 2004). In this article, we focus on one type of public health research involving human subjects. Specifically, we consider here the ethics of primary prevention research in which the overall goal is to contribute to our understanding of how to prevent the onset of disease or injury within an otherwise healthy population. In this respect, we focus on population-based research that often involves a specified group or community. The more particular objective of such research may be to characterize the relative health status or health risks of a population (or subgroups within a population), with an eye toward developing a population-based intervention to prevent the onset of disease or injury or to test the effectiveness of a particular population-based intervention. In some public health research, study populations are referred to as communities. The term community can be defined or circumscribed in many different ways. It is important for public health researchers who conduct communitylevel research to clearly and carefully define the community within which or about which they will conduct their research. For example, it is meaningful to speak of geographically bounded communities, such as the residents of Soweto, of sociocultural communities, such as Latin American immigrants, and of communities defined by a particular constellation of risk factors, such as injection drug users. Although it is often important for public health researchers to define

International Encyclopedia of Public Health, 2nd edition, Volume 3

a population as a community, identifying individuals who can legitimately speak on behalf of the community is a challenge. It may not be possible to find a group of individuals who can speak for a community, much less an entire population under study. To refine our focus further, the kind of population-based, primary prevention public health research of interest to us needs to be distinguished from standard clinical research. We conceptualize standard clinical research as human subjects research conducted to improve the capacity to treat or cure an active disease or medical condition, or the symptoms of a disease or medical condition (secondary or tertiary prevention of disease). Although the current system of ethical oversight over the conduct of research involving human subjects is in certain respects flawed, its ethical framework is better suited to clinical research than to primary prevention research in public health (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979; US Department of Health and Human Services, 2001). The purpose of this article is not to reach definitional clarity about these categories of human research but to highlight the ethical issues related to public health research that traditional human participant regulations and guidelines have not adequately addressed, presumably because the regulations were not written with this type of research in mind. In particular, we argue that the current regulatory framework does not provide adequate moral guidance for investigators conducting primary prevention research in community settings.

Key Ethical Issues In clinical research, the primary focus of moral attention is the relationship between individual patient-subjects and investigators who are conducting the research. Often these investigators are physicians and nurses who must navigate the complex moral territory of conflicting duties to the medical interests of their patient-subjects and to the scientific objectives of the research (Beauchamp, 1976; Beauchamp and Childress, 2012). The object of study in clinical research is generally a particular disease state or process. Potential patient-subjects are selected because they have characteristics that are relevant to the disease process under study, not because they are members of a particular community. Thus, the structure of clinical research does not generally create a relational connection between the investigator and any specific community. By contrast, in population-based public health research investigators often have a relationship with a particular community as well as with the individual participants in their research. The object of study is often an entire community at risk of a poor

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Ethics of Public Health Research: Moral Obligations to Communities

health outcome. When this is the case, arguably, the community itself is a subject of the research. Assuming communities as well as individuals have interests, and perhaps even rights, investigators studying communities should consider these interests and the correlative responsibilities they generate in thinking through the ethics of their research. Specifically, at least three possible kinds of duties to communities need to be considered: The duty to respect the community, the duty not to harm the community, and whether a duty to benefit the community exists.

Duty to Respect the Community Respect for persons, as one of the three moral principles enshrined in the Belmont Report, is widely accepted as central to the ethics of research involving human subjects (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979). However, respect is owed not only to identifiable persons, but also to a wide range of other entities including, where relevant, groups and communities. We can, for example, speak meaningfully of respecting a religious group or a village. The duty to respect the community under study in a public health research project can create a spectrum of obligations for investigators at all phases of research (Buchanan et al., 2007). For example, some argue that researchers ought to engage the community to inform and consult them about the proposed research and listen to community concerns (Grady, 1995; Wiejer and Emanuel, 2000; Israel et al., 2001; Dickert and Sugarman, 2005). Others argue that respectful engagement means that communities ought to be given every opportunity to participate in the development of research, but also requires being respectful of both communities’ and individuals’ rights not to participate during the course of the study (Wallerstein et al., 2005). In practice, community engagement can take many forms. Public health researchers can, for example, work with a community to tailor the research agenda to the communities’ own health interests and priorities. This approach requires an investment of time and energy and a level of methodological and scientific flexibility that is often beyond most public health investigators. Alternatively, public health researchers can approach a community with an interest in conducting research in a particular area and work with the community to help shape the specifics of the initiative. For example, a public health researcher interested in developing and testing interventions to prevent childhood injuries could work with the community to specify which childhood injuries are of greatest concern and should be research priorities. Any approach that involves some level of community engagement obviously relies on community cooperation. A community disinterested in being the subjects of public health research or in a particular research proposal can refuse the offer to collaborate which in itself is an opportunity to evidence respect for the community. In order to engage and inform at the community level, the investigator will have to consider both how best to access the community and how best to deliver information about the planned research. A first step may be to identify and meet with individuals considered leaders, elders, or representatives; stakeholders who can legitimately speak on behalf of some members of the potential study population to seek their

support and advice. Admittedly, what is harder is figuring out whether a second step is in order. Do investigators have a responsibility to seek input from members of the community that are not identified as designated stakeholders? In addition to any community-based approach to orient potential subjects to the study, depending on the design of the research, individual consent ought to be obtained as well. When the entire community rather than individuals within a community is the target of research, there may be little or no role for individual informed consent. For example, a public health investigator may want to assess the effectiveness of a media campaign to increase seat belt use. The study may include randomizing at the community level – two neighborhoods exposed to radio and billboard ads, two other neighborhoods included as control sites. The investigator could measure the impact of the intervention by surveying individuals in the community about their seat belt behavior, in which case the investigator would need to solicit the individual informed consent of each person surveyed regardless of how fully the community endorses the research. Alternatively, the investigator could measure impact by observing seat belt use at random intersections or by accessing injury surveillance records; in these cases she would not have an obligation to obtain individual informed consent. If the investigator chooses the design in which individual informed consent is not required, this does not mean she is always relieved of a moral obligation to inform the public of her plans and notify them of her presence in the community (e.g., she could utilize media outlets or other methods to reach the study population). As a general rule, investigators conducting research in a defined community ought to, at a minimum, inform the public of their plans and presence. The investigator’s obligation to engage the community beyond mere disclosure increases as the potential social harm to the community increases. The absence of community engagement and information sharing in advance of such a study that does result in social harm may compromise the trust the community has in the research enterprise more generally. In some cases not disclosing the intent of the research in advance may be a necessary component of the chosen research design. While in general deception in research ought to be avoided, it may be morally acceptable to withhold information from the population under certain circumstances, especially when the intent of the research is to improve the public’s health and the potential risks to individuals or to the community are small. The seat belt study example above presents no reputational, social, or economic risk to the neighborhoods targeted; therefore the investigator will likely not be required by an IRB to obtain informed consent from each individual in the population to be studied but ought to engage and inform the community of the research to be conducted. In addition, the investigator may not be morally obligated to inform the population of her plan and presence in the community in advance if she can justify the need to withhold information from her subject (the community) in order to obtain a scientifically valid result from her research. In this example, if the community within which seat belt use is to be monitored is told in advance of the intent of the research, the investigators may fail to get an accurate assessment of routine seat belt use. Drivers on alert to observation may be more likely to buckle their belts. In those

Ethics of Public Health Research: Moral Obligations to Communities instances in which it is ethically acceptable to conduct community-based research without providing the community with information about the research, investigators have a special moral obligation to consider whether the research would otherwise be acceptable to the community in which it will be conducted. If, on the other hand, the proposed research may expose the community to reputational, social, or economic risk, the investigator ought to engage and inform the community in advance. At the conclusion of research, the results from a study ought to be shared with the community, particularly when the knowledge is actionable or interventions are available. This is yet another reason why it is better to err on the side of disclosure to the population. A community unaware of the research underway may be hesitant to embrace the findings of a project conducted without their knowledge.

Duty to Leave Community No Worse off Public health research often is justified in terms of potential benefits to a community-at-risk or society at large through findings that contribute to public health practice or policy. When public health investigators intend to conduct research that raises the prospect of harm to the community, they ought to consider such risks in advance and make every reasonable effort to minimize both the likelihood that the risks will materialize and the magnitude of the harm that might result. Public health investigators have a general duty not to set back the interests of others without acceptable offsetting benefits (Beauchamp, 1976; Kass, 2001; Childress et al., 2002). Moreover, even if the overall balance of potential harms and benefits is favorable, wherever feasible researchers should seek to obtain the agreement of the community stakeholders whose interests are at risk of being harmed. In the ethics of clinical research, the focus of this general duty not to impose harm has been the identifiable research subject. There are certain kinds of public health research where it is not only the interests of research subjects but also the interests of entire communities that may be affected by either the conduct of the research or the research findings. One example of such community-level harm is social stigma. A study meant to identify predictors of alcoholism among a Native American tribe or a study to measure the prevalence of injection drug use in an inner-city neighborhood may lead to social stigma, which may in turn lead to other community-level harms. A commercial developer, for example, may incorporate the results of either study in deliberations about the advisability of future economic investment. Moreover, when the research community consumes community resources, the very conduct of the research may set the community back as, for example, when a study set in a community hires day care workers to conduct interviews, thus leaving day care centers in the community understaffed. Public health investigators should consider the possibility of community-based harms in advance of their research, disclose and discuss potential harms with the community wherever possible, and, most importantly, identify and implement strategies to minimize such harms. For example, if an individual enrolled in a randomized placebo-controlled trial of a novel Human Immunodeficiency Virus (HIV) prevention strategy fails to understand that they may be randomized to

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a placebo or an intervention with less than 100% effectiveness, he or she may engage in behaviors that increase the likelihood of his or her own exposure to infection, believing that they are protected by their enrollment in the trial (‘I am taking antiretrovirals and am therefore protected from infection.’), and increase the exposure risk within their community (Philpott, 2013). Because the behavior of the individual research subject has implications for the health of the community at large, the investigator has an obligation to consider these potential risks in advance of implementation and clearly inform the subject, and the community from which they have been recruited, about the risk of disinhibition as well as about how to minimize risks of infection to themselves and others.

Duty to Leave Community Better off That public health researchers have a general obligation to leave communities no worse off as a consequence of their research is likely to be uncontroversial. What is less clear is whether, or to what extent, public health researchers have any positive obligations to leave the communities in which they conduct their work better off after the research is completed. Some have argued that there is a duty to leave such individuals or communities better off, but that this duty is limited and dependent upon a number of factors in the investigator–participant relationship such as participant vulnerability, risk, the intensity and duration of the relationship, and dependence upon the investigator (Richardson and Belsky, 2004; Richardson, 2012) others have argued that the duty is based on the investigator’s relationship with the participant whole person beyond their relationship as investigator and participant (Dickert and Wendler, 2009). The generally accepted rule in the conduct of clinical trials is that investigators have, at minimum, an obligation at the end of a trial that finds an intervention to be helpful to provide access to the intervention to those to whom it was not provided during the study (i.e., the group that received a placebo is provided with access to the successful intervention). In the context of conducting population-based research, the question becomes how expansive the investigators’ obligation becomes. If, for example, the public health researcher finds that a community-based intervention is successful, does the obligation to provide access to the successful intervention extend beyond the control communities within which the study was conducted? The issue seems to arise most often when research is conducted in low resource settings (settings that indeed are the target of considerable public health investigation). A related question is whether leaving a population better off extends to interventions beyond the implementation of the successful intervention. In low resource contexts, there are likely many unmet public health needs such as access to clean water or condoms or other methods of birth control. The extent to which the public health investigator has an ethical obligation to secure supplies or funds to provide access to such public health interventions is unclear. Some argue that communities ought to be given the right to negotiate with investigators in what way they would like to be left better off as a result of hosting a clinical trial. Participants in the 2001 Conference on Ethical Aspects of Conducting Research in Developing Countries (2004) argue that populations that

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Ethics of Public Health Research: Moral Obligations to Communities

host a trial ought to be able to negotiate what benefits are left behind. They argue that host communities ought to be given the power to choose to accept improved access to clean water in addition to or in lieu of broader access to the successful intervention or in exchange for hosting a trial that provides no direct benefit to the individuals enrolled or the community more generally. Alternative perspectives in the literature include the human development approach and research for health justice framework - direct investigators to consider investments in health related institutions or systems (London, 2005; Pratt and Loff, 2014). We argue that, at minimum, public health investigators should make every effort to ensure that a successful public health intervention continues to be available to those communities who participated in the research that established the intervention’s effectiveness. In community research in which no intervention is being tested, there also may be circumstances when investigators are obligated to provide goods or services related to the public health problem under study. It remains an open question whether or under what conditions the fair benefits analysis is applicable to community-based public health research. For example, after a study of the impact of an intensive community health education campaign on HIV transmission rates is completed, if the intervention is determined to be effective, should the investigators’ obligations be limited to providing the community with the capacity to sustain the campaign or should the community be able to determine whether it would prefer the distribution of free condoms or the resources to dig a well? A related debate has to do with the investigators’ obligation to provide ancillary care to study participants. The currently accepted definition of ancillary care is “medical care for research participants beyond what is necessary to ensure scientific validity, to prevent study-related harms, or to redress studyrelated injuries” (Richardson and Belsky, 2004; Dickert and Wendler, 2009; Merritt, 2011). The prevailing view in the field of research ethics holds that researchers working in low resource settings have some limited duty to offer ancillary care (Richardson and Belsky, 2004). The current debate in the research ethics literature is about the extent of this limited duty and how best to put it into practice (Merritt, 2011; Bright and Nelson, 2012). Limits on this duty could be dictated by the influence the provision of ancillary care may have on the results of the study. That is, the provision of too much ancillary care may mask the efficacy of a particular intervention, resulting in the abandonment of an otherwise beneficial intervention. The provision of ancillary care is a question often faced by investigators conducting clinical research in resource-poor settings. When investigating the efficacy of a new combination of drugs for HIV for example, investigators are likely to encounter subjects with medical care needs beyond what might be required either scientifically or for patient safety given their subjects’ compromised immune status. Public health investigators, because they often enroll thousands of subjects, may be less likely to encounter acute medical needs but are likely to encounter an overwhelming amount of minor health needs. In some settings, public health researchers may be able to exhaust their limited duty to provide ancillary care by arranging for referrals to local health centers where subjects will receive the local standard of care for their condition. In other settings, the public health investigator may not be able to exhaust this

limited duty so easily. At least two issues require further thought and deliberation: One, whether it is ethical for public health researchers to conduct research in settings where access to medical care is absent and two, whether sponsors of research in such settings have a limited duty to provide funds to allow for investigators to provide necessary medical care beyond the local standard of care.

Conclusion The goal of this article was to highlight aspects of public health research that require public health investigators to consider their moral relation to the community, and not only to the individual research participant. While the consideration of community as research subject may not be unique to public health research, the community as potential research subject is at the core of population-based prevention research and therefore at the core of the ethics of public health research.

See also: Codes of Ethics in Public Health; New Technologies: Ethics of Stem Cell Research; Public and Consumer Participation in Policy and Research.

References Beauchamp, D., 1976. Public health as social justice. Inquiry 13 (1), 3–14. Beauchamp, T.B., Childress, J.F., 2012. Principles of Biomedical Ethics, 7th edition. Oxford University Press, New York. Bellin, E., Dubler, N.N., 2001. The quality improvement-research divide and the need for external oversight. Am. J. Public Health 91, 1512–1517. Bright, P.L., Nelson, R.M., 2012. A capacity-based approach for addressing ancillary care needs: implications for research in resource limited settings. J. Med. Ethics 38 (11), 672–676. Buchanan, D.R., Miller, F.G., 2006. Justice and fairness in the Kennedy Krieger Institute lead paint study: the ethics of public health research on less expensive, less effective interventions. Am. J. Public Health 96 (5), 781–787. Buchanan, D.R., Miller, F.G., Wallerstein, N., 2007. Ethical issues in community-based participatory research: balancing rigorous research with community participation in community intervention studies. Prog. Community Health Partnersh. 1 (2), 153–160. Childress, J.F., Faden, R.R., Gaare, R.D., et al., 2002. Public health ethics: mapping the terrain. J. Law, Med. Ethics 30, 170–178. Dickert, N., Sugarman, J., 2005. Ethical goals of community consultation in research. Am. J. Public Health 95, 1123–1127. Dickert, N., Wendler, D., 2009. Ancillary care obligations of medical researchers. JAMA 302 (4), 424–428. Fairchild, A.L., Bayer, R., 2004. Ethics and the conduct of public health surveillance. Science 303, 631–632. Grady, C., 1995. The Search for an AIDS Vaccine: Ethical Issues in the Development and Testing of a Preventive HIV Vaccine. Indiana University Press, Bloomington, IN. Hodge, J.G., Gostin, L.O., 2004. Public Health Practice vs Research: A Report for Public Health Practitioners. Council of State and Territorial Epidemiologists. Biotech.law.lsu/research/fed/cdc/CSTEPHResRptHodgeFinal.5.24.04.pdf (with the CTSE Advisory Committee). Human Research Protection Office, 1999. Defining Public Health Research and Public Health Non-research. Centers for Disease Control and Prevention, Atlanta, GA. Institute of Medicine, 2005. Ethical Considerations for Research on Housing-related Health Hazards Involving Children. National Academies Press, Washington, DC. Israel, B., Schulz, A., Parker, E., Becker, A.B., 2001. Community-based participatory research: policy recommendations for promoting partnership approach in health research. Educ. Health 14, 182–197. Kass, N.E., 2001. An ethics framework for public health. Am. J. Public Health 91, 1776–1782.

Ethics of Public Health Research: Moral Obligations to Communities London, A.J., 2005. Justice and the human development approach to international research. Hastings Cent. Rep. 35 (1), 24–37. Merritt, M.W., 2011. Health researchers’ ancillary care obligations in low-resource settings: how can we tell what is morally required? Kennedy Institute Ethics J. 21 (4), 311–347. National Bioethics Advisory Commission, 2001. Ethical and Policy Issues in Research Involving Human Participants. National Bioethics Advisory Commission, Washington, DC. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Department of Health, Education, and Welfare, Washington, DC. Participants in the 2001 Conference on Ethical Aspects of Conducting Research in Developing Countries, 2004. Moral standards for research in developing countries: from “reasonable availability” to “fair benefits”. Hastings Cent. Rep. 34, 17–27. Philpott, S., 2013. Social justice, public health ethics, and the use of HIV pre-exposure prophylaxis. Am. J. Prev. Med. 44 (1 Suppl. 2), S137–S140. Pratt, B., Loff, B., 2014. A framework to link international clinical research to the promotion of justice in global health. Bioethics 28 (8), 387–396. Resnik, D.B., Wing, S., 2007. Lessons learned from the children’s environmental exposure research study. Am. J. Public Health 97 (3), 414–418. Richardson, H., Belsky, L., 2004. Medical researchers’ ancillary clinical care responsibilities. Br. Med. J. 328, 1494–1496. Richardson, H., 2012. Moral Entanglements: The Ancillary-care Obligations of Medical Researchers. Oxford University Press, New York.

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US Department of Health and Human Services, 2001. Code of Federal Regulations. 45 (Public Welfare), 46 (Protection of Human Subjects). US Department of Health and Human Services, Washington DC. Wallerstein, N., Duran, B., Minkler, M., Foley, K., 2005. Developing and maintaining partnerships with communities. In: Israel, B., Eng, E., Schulz, A., Parker, E. (Eds.), Methods in Community-based Participatory Research for Health. Josey Bass, San Francisco, CA. Wiejer, C., Emanuel, E.J., 2000. Ethics. Protecting communities in biomedical research. Science 289, 1142–1144.

Further Reading Bayer, R., Gostin, L.O., Jennings, B., Steinbock, B. (Eds.), 2006. Public Health Ethics: Theory, Policy and Practice. Oxford University Press, New York. Beauchamp, D.E., Steinbock, B. (Eds.), 1999. New Ethics for the Public’s Health. Oxford University Press, New York. Dawson, A. (Ed.), 2011. Public Health Ethics: Key Concepts and Issues in Policy and Practice. Cambridge University Press, Cambridge, UK. Soskolne, C.L., Goodman, K., Coughlin, S.S. (Eds.), 1998. Case Studies in Public Health. American Public Health Association, Washington, DC.

Ethics of Screening Niels Nijsingh, Independent Scholar, Utrecht, The Netherlands Niklas Juth, Centre for Health Care Ethics, Karolinska Institutet, Stockholm, Sweden Christian Munthe, University of Gothenburg, Gothenburg, Sweden Ó 2017 Elsevier Inc. All rights reserved.

Introduction Since the emergence of screening largely coincides with that of public health in general, it serves as a prime example of the intricacies of promoting population health (Holland, 2006). Furthermore, screening programs are conducted in complex interaction across several societal sectors and are usually ambitious and costly societal undertakings, where several types of vested interests figure, as well as idealistic concerns of various parties (Juth and Munthe, 2012: Ch. 1). It is therefore not surprising that the debate on the ethics of screening programs in recent years has developed into one of the largest fields within public health ethics and that the topic received extensive attention by bioethicists, public health practitioners, policy makers, and advisory boards (Council of Europe, 1992, 1994; Dondorp and van Lith, 2015; Juth and Munthe, 2007, 2012; The President’s Council on Bioethics, 2008).

Definition Notwithstanding widespread ethical debates on particular screening programs (e.g., neonatal, prenatal, and various cancers), clear definitions of the notion of screening itself are relatively scarce. The word ‘screening’ invokes the imagery of sifting through a large number of seemingly similar items, in order to identify (and set apart) individual cases, which differ in a relevant aspect from the larger mass thus ‘screened.’ Accordingly, most definitions of screening involve the testing of individuals for conditions or risks, which are not yet manifest, and thus distinguish the individuals detected from others in the screened population. For example, screening has been defined as “applying a test to a defined group of persons in order to identify an early stage, a preliminary stage, a risk factor or a combination of risk factors of a disease” (Council of Europe, 1994) or, alternatively, as “the presumptive identification of unrecognised disease or defects by means of tests, examinations, or other procedures that can be applied rapidly” (Wilson and Jungner, 1968). These characterizations are, however, insufficient to capture what is at stake in an ethics of screening, as they do not explicitly exclude those health-care situations where a person approaches a health-care professional or institution to straighten out an initial suspicion or worry, or performs a self-test. Although much can be said from an ethical perspective about such activities, there are crucial ethical differences between them and the practice of screening. Much of the ethical complexities particular to screening emerge from the fact that the initiative to test was not taken by the person tested, but by institutions or health professionals (Juth and Munthe, 2012: pp. 6–11). Although there is a gray area where the initiative partly derives from the individual tested (e.g., in case of testing for sexually transmitted diseases (STDs) and some types of prenatal testing), this feature

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sets screening apart from typical medical interventions in a fundamental way, as these usually start with an individual seeking health care due to a worry of some sort. Therefore, in this article, we will assume that screening is (1) the medical testing of individuals (2) on the initiative of institutions or health-care professionals, which (3) aims to clarify the presence or nonpresence of (a risk of) disease. On this definition, screening does not necessarily involve a multitude of persons. Usually, however, screening takes place in the context of a screening program, targeting populations, and ethical debates usually focus on these, rather than individual instances. In addition to screening as defined, the notion of a ‘screening program’ implies an institutional structure that identifies and approaches a particular population (Shickle, 1999; Kinzler et al., 2002). A further distinction can be made between ‘pure’ and ‘impure’ screening. Pure screening refers to those instances where there is no prior indication of an individual tested being at risk, whereas impure screening targets a specific part of the population (Juth and Munthe, 2012: pp. 6–11). Examples of pure screening are neonatal screening, which targets every newborn and routine health and developmental monitoring of infants. Examples of impure screening are programs for cascade screening, which target the family members of people with genetic disorders, HIV screening for drug addicts or prenatal screening for women over a certain age. Screening of the entire population (or a large subset, such as all people of a certain gender and/or age or all newborns) is also referred to as universal or mass screening (Wilson and Jungner, 1968; Childress et al., 2002; Mant and Fowler, 1990).

Three General Challenges: Costs, False Results, and the Individual – Population Tension It follows from the previous section that any screening program involves approaching people in a population in order to detect who have an elevated risk of some condition and to offer them some sort of intervention. If such an undertaking is successful, extensive individual and public health benefits may result, which is also the main argument in favor of any screening suggestion. However, because such undertakings are quite extensive, the justification of their cost is always a potential ethical challenge. As the resources for a screening program could instead have been spent on more immediate health-care needs, it is critical for its ethical justification that it creates enough goods in terms of prevention or treatment and sufficiently avoids risks and side effects to justify this spending. When assessing the utility of a screening program, it is necessary to consider the scientifically necessary errors and uncertainties. Screening programs will always have varying success rates in delivering risk assessments in so far as they correspond to the results of subsequent diagnostic tests and actual symptoms of disease. For instance, a new noninvasive

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Ethics of Screening prenatal test celebrated for its dazzling accuracy still has at least a 20% margin of error, and much higher for less common conditions (Munthe, 2015; Norton et al., 2015). Moreover, for any binary medical test, there is a trade-off between two types of errors, false negatives and false positives, that is, missing the presence of a risk or condition and indicating a risk or condition when there is in fact none. All these sources of uncertainty and error bring peculiar ethical considerations which need to be taken into account whenever a program is contemplated. These include the seriousness of nontreatment due to false negatives, or the overtreatment, unnecessary anxiety, and stigma effects in cases of false positives. In other words, even if a program on average looks good in terms of benefits and burdens, these may be unevenly distributed among participants which may create uncertainty regarding how much real good the program actually does and by what standard that issue should be assessed. Unsurprisingly, the most general ethical concerns surrounding screening connect to general ethical tensions within public health. In particular, the issue of how to balance concerns for individuals against statistical aims in terms of population health occupies a central place and influences, for example, the issue of how much weight to assign to autonomy considerations, which are often seen as fundamentally important in ordinary health-care ethics (Dawson, 2011; Juth and Munthe, 2012).

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array CGH, have vastly enlarged the range of options for prenatal screening, renewing the urgency of questions concerning the selection of conditions and the way of offering prenatal tests (De Jong et al., 2011; Dondorp and van Lith, 2015; Newson, 2008; Gregg et al., 2013). Whereas traditional invasive tests, such as amniocentesis and chorionic villus sampling, involve risks such as miscarriage, NIPT uses mere blood sampling and/ or ultrasound. And while detected high risks have to be confirmed by an invasive test, screening with NIPT radically reduces the number of patients exposed to the associated risks. This is an improvement, given that testing is to be performed, but in itself that does not provide an argument for a screening program. For instance, organizing NIPT in such a way may make it even more difficult for prospective parents to refuse a specific offer, or more likely for people to be ‘lured’ into testing. Additionally, the potentially enormous amount of information produced by new analytic methods raises the question which information should be sought and communicated. Much of the information will be clinically unclear, and large portions will have uncertain relevance for the reproductive choices of the woman or couple. Moreover, as some of this knowledge will not be linked to any intention to abort, the line between prenatal and newborn screening will become increasingly blurred, raising issues with respect to the autonomy rights of future children.

Newborn Screening

Target Groups Apart from the general themes of the ethics of screening, there are also specific ethical complexities associated with particular types of screening programs. Below we list some of the more frequently discussed issues linked to common types of screening programs.

Prenatal Screening The purpose of prenatal screening is often understood as facilitating autonomous reproductive choice for prospective parents (De Jong, 2011). Knowledge of the presence or nonpresence of conditions (or risks) provides ground for choosing whether or not to terminate pregnancy. This link to abortion is one of the aspects that have traditionally made prenatal screening controversial. For example, it has been argued that, rather than empowering couples, the programs may be a source of guilt and burdensome choice and/or trap people into oppressive and discriminatory structures, which are thereby reinforced (Alderson, 2001; Asch and Barlevy, 2012; Munthe, 2015). The distinction between diagnostic testing and screening is prominent in discussions of prenatal tests. While prenatal diagnosis may more easily promote a couple’s autonomy, the implicit normative judgment conveyed by the active offering of a test by a health-care system may be considered to direct, rather than support reproductive choice (Juth and Munthe, 2012). As the overall tendency is toward further expansion of the offer of prenatal tests, ethical questions emerge concerning (reproductive) autonomy, equity of access, and the proportionality of testing (Parens and Asch, 2000). New technological developments, such as noninvasive prenatal testing (NIPT), and new analytic techniques, such as

Newborn screening generally takes place in the first week after the birth of a child and typically involves a blood sample, which is tested for a variety of conditions. The first disease screened for in this way was PKU (phenylketonuria) and over the years many conditions have been added (Mak et al., 2013), although with vast differences between different health-care systems and with controversial rationales (Juth and Munthe, 2012: pp. 49–52). Whereas screening for PKU is virtually uncontested, many later additions to the screening programs vary greatly in terms of treatability, reliability of the test, and seriousness (Ross et al., 2009). A further complication emerges in cases where newborn screening may lead to ‘unsolicited information’ on diseases, susceptibilities, or carrier status that was not the object of the initial screening. In recent years, it has been suggested that newborn screening could be augmented by genomic tests, such as whole genome or whole exome analysis (Solomon et al., 2012). The ethical implications of such an expansion would be huge, since not only would it expand the problem of unsolicited information, but also the sheer amount of information and logistic requirements would greatly exceed those of the current newborn screening programs, thus threatening their core objectives (Goldenberg and Sharp, 2012).

Children and Adolescents To a larger extent than screening of neonates, screening of older children and adolescents raises issues concerning the extent of parental authority, and these are particularly pronounced in the adolescent case. Adolescents may be argued to have decision competence of their own, requiring respect in much the same way as that of normal adults, but also certain weaknesses related to impulse control, susceptibility to peer pressure, and attention

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Ethics of Screening

to long-term consequences, as well as vulnerability to various health risks specific for their phase of psychosomatic development toward adulthood (Larsman et al., 2012). Adolescents are targeted by screening programs for a variety of conditions, such as depression, drug use, autism, STD’s, and hearing loss (Simon et al., 2014), and partly for this reason the potential area for complex multiparty conflicts of interests and wants is fairly large. Following standard health-care ethical ideas, professionals involved in adolescent screening need to take into account the opinion of adolescent people (Juth and Munthe, 2012: pp. 53–58), but parents may also harbor valid reasons in their role of guardian with regard to offered tests, and it is far from clear how such conflicts should be resolved. Bearing on this issue is also the more general risk of children and adolescent screening to upset parental–child relationships. Besides the risk of triggering internal family conflicts, this also includes socalled stigma effects of positive test results, where the parents respond with exaggerated views of their child as ill, incapable, and vulnerable (Juth and Munthe, 2012: pp. 53–58).

Cancer Screening Cancer screening programs target, most famously, breast cancer, prostate cancer, and colon cancer. Assessment of such screening activities tends to focus on benefits, primarily in terms of reduced mortality, compared to various sorts of burdens, primarily in terms of the invasiveness and costs of the screening test and follow-up tests, overdiagnosis and overtreatment, and increased anxiety when waiting for follow-up measures (Juth and Munthe, 2012). Although cancer figures as one of the leading causes of mortality worldwide, the balance of the benefits and risks of universal cancer screening is contested. At least in breast and prostate cancer, almost all central issues are disputed, both regarding the extent of the benefits of the programs, how well they avoid relevant risks, as well as the seriousness of the latter. Besides the risk of false negatives and positives, breast cancer and prostate cancer screening result in both overdiagnosis, leading to unnecessary treatment, and overtreatment, that is, correct diagnosis of conditions, which are then unwarrantedly or excessively treated (for example, because they would not have burdened the patient had they remained undetected). However, there is fierce disagreement on the magnitude of both these phenomena (Juth and Munthe, 2012). Disagreements on the burdens and benefits of cancer screening sometimes develop into bona fide ideological standstills, which not only may impede the establishment of a common scientific vocabulary to resolve issues (Juth and Munthe, 2012: Ch. 5) but also contaminate the discussion. For example, disagreement on the way communication and information strategies should be designed reveals underlying ethical tensions regarding how people targeted by the programs are viewed and treated (Parker et al., 2015).

Genetic Screening Genetic screening for adults is usually only performed on individuals who are at risk due to family history, such as susceptibility tests for Huntington and BRCA1 and BRCA2 (Burke et al., 2001). Parallel to the developments in prenatal and newborn

screening, the possibilities for the genetic screening of adults have expanded dramatically as the possibilities for affordable genome analysis come more and more within reach. Worries may still arise concerning the implicit negative stigma and known psychosocial side effects, such as negative ‘survivor’s guilt’ reactions of those who receive the result of lacking a risk mutation, as well as adverse effects, such as difficulties for affected individuals in attaining insurance or employment (Burris and Gostin, 2002). Recently, so-called preconception screening has been a topic of attention as a possible way of matching partners for reproduction or helps couples to decide whether or not to use techniques, such as IVF with donor gametes or preimplantation genetic diagnosis, to avoid having children with recessive genetic conditions. Besides actualizing the worries already mentioned, this development blurs the line between adult genetic screening and the ethical issues of prenatal screening and assisted reproductive technologies (De Wert et al., 2012).

Communicable Disease Screening Most contemporary screening programs aim to promote the health or autonomy either of the individuals tested or of the population targeted by the program. However, the roots of screening are to be found elsewhere. The first screening programs were performed in the USA with the aim to keep unwanted foreigners out of the country by screening immigrants for communicable diseases, such as tuberculosis and venereal diseases (Bateman-House and Fairchild, 2008). Similarly, compulsory communicable disease screening is part of practices, such as gamete and blood donation. Compulsory screening of immigrants for communicable disease management purposes is still a topic of some debate (Coker, 2004), as well as the related topic of border screening, for example, during the SARS epidemic (John, 2005). Contrary to the initial screening of immigrants, most communicable disease screening today is motivated by concerns of being able to intervene by means of treatment and prevention within high-risk groups (for example, drug addicts), or linked to particular procedures, such as tissue donation. In times of threatening epidemics or pandemics (like H1N1 or other serious seasonal influenza), there may be more universal initiatives, albeit on a voluntary basis. However, all screening programs for communicable disease carry with them an inherent tension between the interests or the autonomy of targeted or tested persons and that of the community as a whole, as an identified infection as well as an elevated pan- or epidemic may trigger more draconian coercive elements in existing legislation that exist to protect society against individual threats. This creates good ethical reasons to worry extra about confidentiality and stigmatization effects of programs (Smith et al., 2004). At the same time, developments such as antimicrobial resistance may well put screening programs of this sort on the top of the agenda once again in the not-too-far future, actualizing very difficult ethical balancing (Littman and Viens, 2015).

Forensic Screening A recently suggested but highly controversial area for screening regards the idea of testing children and young people for

Ethics of Screening indicators of elevated risk of future violent and criminal behavior (Horstkötter, 2015). Such notions, developed in novel areas such as neurocriminology, forensic genetics, and psychiatry, highlight even more than the example of communicable disease the potential of screening programs to aim for outcomes of slight connection to the health of targeted individuals or groups. It is still highly unclear what methods might be used in such programs, but genetic, neurological, behavioral, and general psychiatric approaches have been suggested in the literature, leading up to a vast area of possible and often pronounced ethical tensions. In particular, this idea introduces a mix of health care and public health ethical aspects already mentioned, as well as values and concerns coming out of criminal law and policy (Munthe and Radovic, 2015).

Wilson and Jungner: Traditional Criteria Requiring Ethical Backup One early WHO report on screening by Wilson and Jungner (1968), ‘Principles and Practice of Screening for Disease’ has come to exert a tremendous influence on practices and policy in this area. This report proposes 10 ‘principles’ of screening (see Box 1), which since then have widely been adopted, sometimes in a modified form, as guidelines for screening (Shickle, 1999; Andermann, 2008). Here we address three of the most debated criteria, mainly to demonstrate how ethical issues are at the root of what needs to be dealt with to arrive at rational analysis and solutions of ongoing controversies.

‘The Condition Should Be an Important Health Problem’ This criterion links to the basic question mentioned in section Definition: does the problem justify the costs of a screening program, including offered intervention following a positive test? In other words, is the program worthwhile relative to the importance of the problem? This ‘importance’ has two dimensions: the seriousness and the prevalence of a condition, and

Box 1 Wilson and Jungner screening criteria 1. The condition sought should be an important health problem. 2. There should be an accepted treatment for patients with recognized disease. 3. Facilities for diagnosis and treatment should be available. 4. There should be a recognizable latent or early symptomatic stage. 5. There should be a suitable test or examination. 6. The test should be acceptable to the population. 7. The natural history of the condition, including development from latent to declared disease, should be adequately understood. 8. There should be an agreed policy on whom to treat as patients. 9. The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole. 10. Case-finding should be a continuing process and not a ‘once and for all’ project.

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these may often pull in opposite directions. For example, most conditions in newborn screening are rare (and some extremely rare) but quite serious for the person suffering them, so a newborn screening facilitating a reasonably effective treatment may still be justified. Conversely, relatively mild conditions could be claimed to justify screening if the prevalence is high, and this is the common argument to include, for example, Down syndrome or sex chromosome aberrations in prenatal screening (Juth and Munthe, 2012). Another example of a disease that is relatively mild and relatively common is celiac disease, which has for that reason been suggested as an object for newborn screening (Aggarwal et al., 2012). A distinction can be made between the situation where a screening program is already in place and that in which a new program requires justification. Additions to an existing program, such as newborn screening, have been argued to require less justification in terms of ‘importance’ (Moyer et al., 2008), since the infrastructure is already present and thus an expansion will require a lot less costs than instigating an entirely new program. Assessment of which conditions are sufficiently common and/or serious to warrant screening depends on basic ethical and political values: determining which diseases are perceived to be sufficiently important requires substantial – normative judgment (Shickle, 1999; Juth and Munthe, 2012: Ch. 6).

‘There Should Be an Accepted Treatment’ Without an effective intervention following positive tests, having a screening program justify its costs and side effects (risks of stigma, anxiety, discrimination or overtreatment) will be difficult, no matter how serious the targeted condition. At the same time, the presence of an effective intervention tends to strengthen the case for a program considerably. Early detection of disease may provide options of combating the disease, or at least to provide people facing the risk with more options. Perhaps not surprisingly, Wilson and Jungner themselves considered the criterion of treatability to be the ‘most important’ one. The term ‘treatment’ can be understood more or less inclusive, however. Traditionally, the term was understood to denote biomedical reparative interventions, but for many screening programs today this does not apply. For example, many treatments of newborn screening intervene before there are any symptoms to ‘repair’ and may not involve any sort of biomedical procedure (but instead, for example, life style changes, such as strict diet) and the ‘treatment’ in the context of prenatal screening consists in the offer of having an abortion. In the case of newborn screening for Duchenne Muscular Dystrophy, the knowledge provided by the test may be used to prevent the birth of a sibling with the same condition (Ross, 2009). Also, measures such as quarantine and (genetic) counseling have been described as ‘treatment’ in the sense of an intervention following a positive test result. This stretching of the meaning of the term ‘treatment’ raises questions concerning the goals, purpose, and justification of screening, specifically to whose benefit screening should be (Wilcken, 2003; Holland, 2006; Juth and Munthe, 2012; Dierickx, 2011). In the absence of a reparative or secondary preventive treatment, the purpose of a screening program is not to combat the individual burden of disease but, rather, either the prevention

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of psychosocial suffering or the promotion of autonomy, or overarching societal utility in terms of statistically aggregated population health over time. As these respective objectives are well known to conflict in the public health context (Munthe, 2008), it is difficult to argue consistently for any one of them having universal primacy (Coggon, 2012; Wilson, 2009), and this makes for a delicate balancing in many cases of screening. This requires taking into account questions of, for example, to what extent benefits to the family or society as a whole can be considered as ‘treatment’ benefits, and under what condition they can make for an ‘accepted treatment.’ Furthermore, as the initiative comes from societal institutions, there is an initial pressure on individuals to participate also in cases of less clearly acceptable treatments, creating special challenges for patient autonomy. The basic ethical issue regarding any suggested treatment, bearing in mind the complications of screening as such, as well as the plasticity of what may be thought to qualify as a treatment in screening, regards how efficient and safe a treatment needs to be in order for screening to be warranted. This question must be answered by weighing in all of the factors mentioned, that is, the seriousness of the disease and the suitability of the test.

‘There Should Be a Suitable Test or Examination’ This fifth criterion of Wilson and Jungner, though obviously plausible, poses serious challenges to many screening programs and connects to the basic ethical challenges of such programs mentioned in section Definition. The balance to be struck is between the seriousness and prevalence of the disease and the benefits of the offered treatment, on the one hand, and the quality and side effects of the test, on the other. Even a small discomfort can be considered overly burdensome if the expected benefit is small. Furthermore, since screening programs usually affect a large number of people, even small risks can significantly burden a program as a whole (Gøtzsche and Jørgensen, 2013). As mentioned in section Definition, a test may provide false test results in two ways, false positives and false negatives. For tests that are based on a statistical quantitative analysis, the relation between these two is determined by the cutoff point of the tested variable between what is considered to be a positive indication of pathology and what remains within the bandwidth of normal variation (Shickle and Chadwick, 1994; Shickle, 1999: pp. 13–7; Holland, 2006: pp. 168–9). A higher cutoff point limits the number of false positives but increases the number false negatives. But neither this nor the rules of mathematical statistics will answer the query of where the cutoff point should be set. To answer the question, one must investigate what is most important: should the objective be to minimize unnecessary worries and side effects, such as stigmatization and overtreatment, or should it be to reduce incidence or effects of the disease in question. This issue, in turn, links to almost all of the factors and issues already mentioned and thus requires basic ethical analysis of what should be aimed for in different screening programs, an area that still needs development (Juth and Munthe, 2012: Ch. 6). As mentioned in section Definition, a further source of error of tests used for screening is their positive predictive value, that is, how likely it is that whatever the test signals for, is in fact the

case. There is always a balance between, on the one hand, having tests pick up on signals that could indicate the presence or nonpresence of a condition and, on the other, the likelihood that such signals may occur in spite of the nonpresence of a condition. The latter tends to be more likely the less prevalent a condition is, and this has recently fueled skepticism regarding the inclusion of rarer disorders in planned noninvasive prenatal screening programs (Dondorp et al., 2015; Norton et al., 2015). Moreover, even if a test is very accurate in all the mentioned respects, it may cause overdiagnosis, that is, identify something that would have otherwise gone undetected and not caused any problem for the individual. Mammography and prostate cancer screening tests are known for this feature, as they are unable to distinguish aggressive disease from positive findings where there would not have been any symptoms for the person in question (Gøtzsche and Jørgensen, 2013). This relates to the Wilson and Jungner (1968) idea that the natural history of the condition should be adequately understood. On a strict reading of this criterion, it is likely seldom satisfied by most screening programs today, as these tend to look for statistical indicators of a condition, rather than factors or processes known to be part of its causal mechanism (Juth and Munthe, 2012).

Voluntariness and Informed Consent Public health considerations tend to conflict with the individual perspective implicit in the principle of respect for autonomy. In the case of screening, this conflict often takes the shape of a dilemma between promoting choice and promoting health – although matters are not always that simple.

Mandatory versus Voluntary Particularly when children are involved, there seems to be an argument for mandatory screening programs, emphasizing the benefits of early detection. This argument, based on the best interest of the child, may conflict with the authority that parents are recognized to have with respect to their child. Different countries balance these considerations differently, leading to mandatory newborn and adolescent screening programs in some countries, and voluntary ones in others. When diseases are involved where the benefits of early detection are uncertain or the test is unreliable, there is proportionally less ground to impose screening. For example, screening for Krabbe disease in New York has been heavily criticized for being insufficiently efficient to warrant a mandatory program (Dees and Kwon, 2012). It should be noted, however, that ‘mandatory’ does not always signify the same extent of compulsion: in newborn screening ‘mandatory’ sometimes merely means that the possibility of an opt-out is not explicitly mentioned, whereas in other cases, legal sanctions have been imposed (Tarini and Goldenberg, 2012). For adults a mandatory program seems justifiable only when there is a sufficiently significant risk of harm to others or to the wider society, for example, in the case of communicable diseases. In these cases, there is a potential conflict between the interests of the individual and public health (Dawson, 2011). Screening for genetic conditions or risks for reproductive purposes here occupies a tricky middle ground, as the choice here lies with someone else than the one who is

Ethics of Screening

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affected by the test result, for example, the fetus and possible future child in prenatal screening, or perhaps the partner in the case of preconception screening.

rather than individual health outcomes, they have strong societal ethical dimensions. We will here highlight three wide areas of such concern.

Informed Consent

Justice

Assuming that a screening program should be offered on a voluntary basis still does not settle in what way this voluntariness should be realized. Within medical and research ethics, the idea of a right of patients and participants to make informed decisions is widely embraced, as is the inferred obligation not to subject people to procedures without a prior socalled informed consent (Beauchamp and Childress, 2001). Traditionally, it is thought that this requirement is stronger in research, as benefits are less certain while risks are more pronounced. Similar thoughts have been voiced regarding screening, as the individual benefits are less clear in this case as well. This raises the question of how to balance the requirement of consent against the burdens and costs of screening: more thorough informed consent procedures are costly and more likely to be considered burdensome (Nijsingh, 2007). Particularly for genetic screening, the amount and complexity of information to be disclosed may, moreover, well exceed the capacities of most individuals (including health professionals) to relate the information to one’s personal situation. The information required for a valid consent depends on what is relevant in a particular setting. If the test itself is risky (as in invasive prenatal testing), this has to be included, while in the case of less risky procedures (such as smears or urine samples), this is less acute. What will always be highly relevant is the nature of the condition and the likely outcomes of positive and negative tests, as well as of entering or not entering the program. This includes also risks associated with the offered intervention, including not only somatic harm but also psychosocial aspects, such as risk of anxiety, troubled family relations, or societal discrimination, and positive possibilities. What is at stake is the right of the subject to either know or not know that she has a medical condition or a health risk (Nijsingh, 2015). Particularly where there is no effective cure, the knowledge of an impending condition or carrier state may be considered by testing subjects as a mere burden. A final aspect regards how the collection of informed consent is concretely organized within a screening program. This is a particular challenge since the implementation of a screening program often involves approaching many people, while most of them are quite unprepared for the offer, or at least have little prior understanding of its meaning. A further challenge in organizing consent is the strong tendency to embed screening programs within routine care procedures, such as neonatal, child, or pregnancy care. While this may serve to reduce costs and promote a strong uptake, it brings salient risks of people being unaware of their right to abstain from the screening. One widely run program known to suffer heavily from this latter downside is second trimester obstetric ultrasound screening (Munthe, 2015).

Justice, as one of the key concepts in bioethics in general and public health in particular, plays a significant, if sometimes overlooked, role in the ethics of screening. Considerations of justice are pertinent to issues concerning employment, insurance, the availability of proper follow-up care, and funding. The issue of the funding of screening programs is one of political resource allocations: the question to what extent public funds should be used to cover the program’s costs (Juth and Munthe, 2012). Egalitarian arguments in terms of equal access have sometimes been invoked in favor of screening programs: if some testing procedure is offered for the benefit of someone, all those who could benefit should be made the same offer (Shickle, 1999). This argument may exert an especially strong pull in the light of the fact that socioeconomically disadvantaged people tend to use health-care services to a lesser extent (Marmot and Wilkinson, 2005). However, the argument presupposes that offering tests in the form of a screening program would be an overall benefit for all those involved, and as we have seen, this is not evident. Thus, the egalitarian argument for screening is only valid when the other already mentioned justifying factors are present. As noted in section Three General Challenges: Costs, False Results and the Individual – Population Tension, since screening is typically run by public health-care institutions, it can be justified only to the extent that such public spending is justified, and this is a matter of justice too. The justification of spending depends partly on the reasons in favor of, as well as against, the program, including the mentioned egalitarian reasons. However, even if all such reasons are present, the justifiability of public spending will also depend on what financial basis is available and what other societal priorities compete with it. A screening program may well be a very good idea, but may nevertheless be unjustified, since better ideas should claim the available money, and debating which social ventures are better or worse will require substantial political justice arguments.

Public Dimensions of the Ethics of Screening Since a screening program is a substantial societal undertaking and usually addresses large populations, aiming for public

Privacy and Confidentiality Screening programs by definition involve the collection of large amounts of individual biological samples and health data, which can subsequently be discarded or stored and, in the latter case, reused somehow. For instance, any sample or data archive can be included in the basis of regular quality assurance work within health care, or for general epidemiological registry studies, but possible applications go far beyond such familiar examples. Newborn screening registers are known to be used to identify criminal suspects on the basis of crime scene tissue residue (Nørgaard-Pedersen and Hougaard, 2007), and in the presently ongoing push for ‘big data’ and large-scale biobank research and associated commercial innovation, archives of screening programs become an increasingly coveted item, just as the regular registries and sample repositories of health care. As an example, the British government has recently attempted to open National

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Health Service registries for not only university researchers but also commercial enterprises, such as pharmaceutical and insurance companies, resulting in considerable controversy and apparent collapse (Presser et al., 2015). As a consequence, any program needs to address the issue of how to deal with privacy and confidentiality in these respects. And whatever solution is put into policy, the resulting effects on individual privacy need to be clearly explained in the context of collecting informed consent (or dissent). Also, the societal context with regard to how an individual may be affected by there being certain health information about him or her needs to be taken into account, and possibly how this affects the pros and cons of a program. For example, if a society allows insurance companies or employers to use and ask for such information, its mere existence in a registry may pose a risk of discrimination for individuals (Radetzki et al., 2008).

The Communicative Output of a Program As a screening program is a major societal undertaking, it will also have a public communicative dimension by expressing a message about officially accepted societal priorities and values. In many cases, this dimension is unproblematic, as this message will be about society caring for good health. However, in certain areas, this particular dimension may add to other ethical complications. This is, for instance, obvious in the case of immigration screening, in forensic screening, in some communicable disease and genetic screening, and so on. The risk of social stigma plays an important role in this respect. Particularly prenatal screening programs have been much debated and criticized for expressing a message that it would be better for society if disabled people did not exist and that society therefore prioritizes this outcome over putting resources into creating less discrimination and disadvantage for disabled people (Parens and Asch, 2000).

Conclusion The ethics of screening is a highly complex area, where basic tenets and values from several different areas can meet, such as health care and public health, criminal law, migration policy, and general political and economic considerations. Similarly, many different stakeholders at different levels may be involved behind the advocacy of or resistance to screening, besides people targeted by a program, organized society and subcommunities, commercial enterprises, professional collectives, public agencies from different areas, NGO’s, and so on. While there is a wide surface agreement on general principles of screening, practical policy making in the area is mostly determined by contingent circumstances, leading to a great variation of screening practices in different legislatures (Grosse et al., 2010; Juth and Munthe, 2012: Chs. 1 & 6). For public health professionals, it is important to acknowledge this complexity, especially when assessing whether or not proposed or ongoing programs should be started or modified. To the extent that screening is used for nonmedical purposes, for example, in border control or crime prevention schemes, it is a critical matter for professional ethics how to respond to societal requests of service.

Acknowledgments The authors acknowledge funding from the projects Addressing Obstacles in Person Centred Care, Swedish Research Council for Health, Working Life and Welfare, FORTE and Swedish Research Council, VR [project no. 2014-4024], Practices of Responsibility in Change, Dutch research Council, NWO [project no. 236-20-009], and Gothenburg Responsibility Project, Swedish Research Council, VR, and the University of Gothenburg [Decision no. 2014-40].

See also: Cancer Epidemiology; Cancer Screening: Theory and Applications; Epidemiology of the Acquired Immunodeficiency Syndrome; Ethics of Infectious Disease Control; New Technologies: Ethics of Genomics; Resource Allocation: Justice and Resource Allocation in Public Health.

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Ethnic Conflict and Public Health Duncan Pedersen and Hanna Kienzler, McGill University, Montreal, QC, Canada Ó 2017 Elsevier Inc. All rights reserved.

Introduction According to the United Nations (UN), in today’s changing political world map, there are 193 member states, the majority of which have been created since the World War II. Yet the number of major cultural groupings has been estimated to be somewhere between 900 and 1500, composed of a myriad of diverse ‘nationalities,’ also called nations, while the number of spoken languages in the world – attesting for its ethnic diversity – is even greater: around 6000. All such nations when combined are estimated at around 600 million people (or 10–15% of the world’s population) who claim rights over 25–30% of the earth’s land surface and natural resources. These apparent discrepancies in the population/resources equation have become a lasting source of conflict among ethnic groups, often involving indigenous nations and nation-states, since generally it is the latter that control access to and exploit these resources for their own benefit, and are ready to use force to advance or protect their interests. Serious and often violent conflicts may arise when access to critical resources is under dispute, especially at times of general economic decay. In the second half of the twentieth century, the number of ethnic conflicts has increased significantly, showing extreme forms of violence and intractable conflict. Since 1945, the death toll resulting from ethnic conflict and organized violence has been estimated at over 20 million. Additionally, the most recent UNHCR Global Trends report highlights that the year 2014 saw the highest number of displaced people on record with 59.5 million forcibly displaced worldwide consisting of 19.5 million refugees, 38.2 million internally displaced persons, and 1.8 million asylum seekers. The number of people seeking refuge due to conflict and persecution increased fourfold in only 4 years, and 53% of refugees come from only three countries: Syria, Afghanistan, and Somalia, all affected by ethnic and sectarian conflicts (UNHCR, 2014). The escalation of deadly conflicts among ethnic collectivities is usually related to one or more of the following: the emergence of nationalism and the political legacies of colonialism and the Cold War; unresolved cultural, religious, ethnic, or class disparities; political opportunity; the enduring presence of illegitimate, corrupt, authoritarian, or repressive regimes; international or externally driven interventions, such as military occupation or forcible intrusions; and, most importantly, persistent inequalities over access to critical resources. It is fairly well established that ethnic conflict, organized violence, and wars have been major causes of suffering, general ill-health, and increased mortality rates throughout human history (Murray et al., 2002). In recent decades, the number of victims and survivors of traumatic events has significantly increased as war, armed conflict, and political upheaval engulf civilian populations worldwide, contributing to a lingering additional burden of disease, death, and disability. There seems to be consensus that the short- and long-term health

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consequences of political violence and wars extend far beyond death, disease, and destruction of local infrastructure to increased human suffering and devastation of the social and economic fabric. As such, the short- and long-term consequences of violent conflict can be observed not only in individuals – in local biographies and individual trajectories – but also in the collective space, between the interstices of daily life experiences and memories of survivors, and in the range of responses and strategies for coping with violence and adversity of the society at large. There is a growing consensus that armed conflict and intentional violence in its various manifestations is an emerging public health problem of major significance in the world today (Pedersen, 2002). The high levels of lethal violence are not randomly distributed, but tend to concentrate in the low-income countries and regions, which today account for more than 90% of the total global death toll for violencerelated deaths (WHO, 2000). Moreover, ethnic conflict and violence are closely related to certain social characteristics, such as poverty and social inequalities (Pedersen, 2015). Across time, the societies with higher levels of intentional violence are also those mostly poor, with high inequalities in the distribution of wealth, less educated, more intolerant to racial differences, living under autocratic regimes, and less likely to engage in commerce and trade. Conversely, the more peaceful societies also tend to be richer and more equalitarian, living under more democratic governments, healthier and better educated, more respectful of their women, and more likely to engage in trade and nonviolent exchanges (Pinker, 2011). Under the growing influence of globalization and an imposition of a ‘global culture,’ we are more and more confronted with rising tensions between nationalism on the one hand, and cosmopolitanism on the other. The intersection of global processes with local or regional differences brings into focus how collective identity is shaped, constructed, imagined, and reconstructed for various political ends. Moreover, the relentless process of globalization (transnational economic trade, global communication patterns, and transnational social movements, including migration) has generated mixed responses around the idea of identity, challenging the very notion of nationalism and the existence of the nation-state, projecting an image of a world without borders. At the same time, the fragmentation of blocks of countries, such as the former Soviet Union or Yugoslavia, and the rising number of states claiming secession or sovereignty seem to reaffirm nationalism as a political force and a contemporary reality. While nationalism is perhaps the most common expression of an ethnic group’s assertion of its claims for political recognition and legitimacy, it often leads to violent conflict aimed at resolving disagreement and dissent. Genocide and the atrocities of ethnic cleansing – most often fueled by extreme nationalism, tinted with religious or political aims – is another way to put an end to ethnic conflict by imposing one group’s total supremacy over another.

International Encyclopedia of Public Health, 2nd edition, Volume 3

http://dx.doi.org/10.1016/B978-0-12-803678-5.00148-X

Ethnic Conflict and Public Health The rise of nationalism and ethnic conflict and the emergence of various forms of extreme violence and human rights abuses are often precursors or ensuing aspects closely related to environmental degradation and socioeconomic development initiatives. Various authors point at the growing body of evidence linking environmental degradation to human rights abuses through the process of selective victimization or ‘environmental racism’ (Bullard, 1994), in which development efforts result in a deteriorated environment with loss of valuable resources often critical for the survival of local populations. Environmental forces at play, including those derived from weather warming and climate change, do have an important role in shaping the nature of conflict in many regions of the world today. Some of the natural and also man-made disasters, which are attributed to climate change, are often at the root of deadly conflicts that emerge and/or follow earthquakes, hurricanes, and floods. Likewise, the social and economic impact created by protracted ethnic conflict is often aggravated by episodic natural disasters, as happened in the Sri Lankan case, where Tamil settlements in the northern and eastern parts of the island were exposed to extreme violence, ethnic conflict, and war for over three decades, while settlements in the eastern and southern regions were further devastated by the tsunami of late 2004, having a compounding adverse effect in the population as a whole.

Defining Terms and Concepts While recognizing most definitions are arbitrary, we need, however, to try to define some of the terms and concepts used previously, to reduce misunderstandings or ambiguities associated with the central ideas under discussion: ethnicity and conflict. An ethnic group may be defined as a descent group bounded socially by inbreeding and spatially by territory. It is from this core that more extended ethnicities evolve by preferential endogamy, extended nepotism, fictional kinship, descent myths, and extension or occupation of larger territories. At one extreme, there is the small, cohesive local group or clan, and at the other the vast, extended symbolic boundaries of modern ethnic identities. Many scholars agree that for ethnicity to emerge, groups must hold relations and have a minimum of contact with one another and must consider each other’s ideas as being culturally different. According to some authors, ethnic groups exhibit, although to varying degrees, six main features. These include a common name and common myth of descent, a shared history and distinctive culture, a more or less stable association with a specific territory, and a sense of reciprocity or solidarity among themselves. These categories, however, are not as clear-cut in practice and, therefore, members of ethnic groups as well as social scientists are faced with paradoxes and contradictions when they aim to refer consistently to a stylized ethnic taxonomy. Accordingly, dimensions of ethnicity cannot be referred to as givens or static notions but have to be considered dynamic and evolving concepts. The term nation used previously can be understood as a politically conscious aggregate of peoples claiming statehood rights on the basis of common ethnicity and language, while the term nationalism is more of a peoples’ movement driven by will and ideology in support of a given nation. Nationality

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is conceived as identification with and loyalty to the state structure, regardless of ethnic composition. Collectivities defined by birth and cultural or physical distinctiveness are also called ethnicities, which may or may not be internally stratified. Conflict, in turn, has been given multiple definitions, from psychological, social, economic, political, and cultural perspectives. Rivalry and individual competition should be distinguished from collective opposition and overt conflict aimed at displacing, injuring, or destroying opponents. Different types of conflict imply a certain degree of centralized organization and control, different extent of mass involvement and mobilization, and the magnitude, characteristics, and type of violence. Following these, categorization of at least three levels of collective ethnic conflict may be distinguished, ranging from simple turmoil – for example, strikes, demonstrations, civil unrest, mutinies, protests, sabotage, rioting, and so forth; to internal war – coups d’état, secessionist rebellions, terrorism, civil wars, and revolutions; to massacre – genocide, politicide, ethnic cleansing, mass killings and executions, and so on. A broader classification of ethnic conflicts dives them into irredentist conflicts, secession conflicts, and conflicts derived from decolonization between colonial powers and national groups. Irredentism is a term used in the international arena that involves advocating annexation of territories administered by another state on the grounds of common ethnicity and/or prior historical possession, actual or alleged. Separatist and secessionist ethnic conflicts refer to those that arise when groups attempt to separate themselves culturally and economically or racially, though not always seeking political authority. Although most ethnic conflicts have their origins within state settings, they may involve third parties and become interstate conflicts. Finally, anticolonial ethnic conflicts are framed by the UN declaration of the right to self-determination and policies of decolonization.

Some Examples Ethnic conflict has become more common in recent decades. Conflict between smaller nonstate groups or against such by governments has increased in frequency and brutality. A prime example reported by the news media is the ongoing ethnic conflict in Syria, pitching the country Sunni majority against the Shia Alawite minority in power, drawing in neighboring countries and world powers, which has resulted in more than 220 000 casualties in the 4 years of war and over 11 million people forcibly displaced from their homes. Another example is Darfur, Sudan, where at least 2 million non-Arab civilians have been systematically driven from their homelands by the Janjaweed, a militia group recruited from local Arab tribes and assisted by the Sudanese government. The Arab League countries also have a distinct experience of revolt and rebellion against authoritarian regimes and a recent history of violent military repression, with a high death toll among civilians engaged in massive demonstrations and exposed to different forms of organized violence. The revolutionary wave of demonstrations and violent protests, riots, and civil wars is known by the name of Arab Spring. It began with the Tunisian Revolution in late 2010 and spread throughout the countries of the Arab League and its surroundings. By 2012, rulers had been

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forced from power in Tunisia, Egypt, Libya, and Yemen. Major protests, ethnic conflicts, and violence had also broken out in Algeria, Iraq, Jordan, Kuwait, Morocco, Sudan, and the occupied Palestinian Territories. The siege and bombardment of cities, the use of heavy artillery and aerial bombing, and other abusive, destructive, and repressive measures, including harassment, jail, torture, suicide bombings, and summary executions, are common occurrence in these countries, resulting in large numbers of civilians killed and wounded, and massive displacement of civilian populations and refugees. Other prominent ethnic conflicts that erupted in recent history include, for instance, the violence that erupted in Sri Lanka when Tamil Tiger rebels decided to sink two government gunships and the government responded by sinking five of the Tiger’s vessels and later bombarding their strongholds. In Iraq, Zarqawi’s appeal to Sunnis led them to commit violence against and control over the ‘incredulous’ Shiites. Within the last two decades, fierce and violent ethnic conflicts have also erupted in Yemen, the Democratic Republic of Congo, Nigeria, and Bangladesh, among many others. Other relatively recent examples are the genocide of Tutsi by Hutus in Rwanda; the Chechen revolt against the Russian state; the Bosnian war involving Serbs, Croats, and Muslims followed by the ethnic cleansing of the Kosovar Albanian majority by their Serbian overlords; lethal encounters between Muslims and Christians in the Indonesian Maluku province; and killings between Muslims and Hindus in the Indian state of Gujarat. In other regions, such as Central and South America, we find many instances of ethnic conflicts and internal wars resulting in high death tolls, particularly among indigenous peoples: extrajudicial executions of Miskito Indians in Nicaragua; massive killing of Mayas in Guatemala and Tzotzils in Chiapas, Mexico; and the annihilation and disappearance of Quechua peasants in the Peruvian highlands undertaken by Shining Path guerrillas and the military repression. In the case of Guatemala, large segments of the population have been displaced because of internal conflict and violence, the vast majority (more than 80%) of them Maya Indians from the central and northwestern regions of the Guatemalan altiplano. It is estimated that in the last three decades, approximately 250 000 Guatemalans have disappeared or been killed, more than 1.5 million have been internally displaced, and 150 000 are still refugees abroad, mostly in Mexico.

Political Science and Sociological Theories of Ethnic Conflict: 1960s to 1980s In the 1950s and 1960s, the initial theorizing about ethnic fragmentation and conflict in multiethnic societies did not focus on political mobilization per se, but argued that certain factors associated with the modernization process lead to societal fragmentation and the rise of ethnic nationalism. This period may be characterized by the emergence of indirect theories of ethnic conflict, to be followed in the 1970s and 1980s by the so-called direct theories described later.

Indirect Theories of Ethnic Political Mobilization and Conflict Indirect theories of ethnic political mobilization can be grouped together as negative theories of integration, negative theories

of cohesion, and indirect theories of disintegration and revolution. Negative theories of integration were mainly coined by scholars such as Karl Deutsch (1953) and Samuel Huntington (1968), who argue that rising ethnic frustrations are predominantly caused by modernization processes. One of the best-known and most influential theories is that of Karl Deutsch. In his 1953 work Nationalism and Social Communication, he introduced a paradigm of national integration in developing states by employing two key concepts, namely mobilization and assimilation. According to him, mobilization and assimilation lead to national integration, the basis for civic nationalism. However, should mobilization outpace assimilation, national fragmentation will occur and result in the rise of ethnic nationalism (Deutsch, 1953). Hence, to cope successfully with modernization, a political system must be able to innovate and to assimilate successfully the social forces produced by modernization into the existing system. Negative theories of cohesion include the plural society approach and the theory of ‘consociationalism’ (Taras and Ganguly, 1998). Plural societies exist where different sections of the community live side by side, but separately, within the same political unit. To keep society from fragmenting, external forces such as colonialism may be implemented. Other scholars, such as Arend Lijphart (1977) and Eric Nordlinger (1977), addressed matters concerning stability, harmony, and democracy in multiethnic states. In his work Democracy and Plural Societies, Lijphart explores the conditions under which stable and democratic multiethnic states, such as Switzerland, Belgium, Austria, and the Netherlands, are possible and concludes that consociational democracies involve multiparty cabinets, a multiparty system, proportional representation, political decentralization, and a written constitution that recognizes certain rights of minority groups, among other supporting conditions. Indirect theories of disintegration are summarized as “the various interpretations of inter-group conflict, including revolts and rebellion, all of which contain clues that can lead to a general theory of disintegration” (Heraclides, 1991: p. 6). Most disintegration theories emphasize socioeconomic factors, including relative deprivation, resource scarcity, and the sudden rise in unfulfilled aspirations that give rise to frustration, rebellion, revolutions, and conflict. In his book Why Men Rebel (1970), Ted Gurr states that the tendency to revolt increases when people perceive an inequality in the wretchedness of their condition; that is, when they receive less than they feel they deserve. In line with social disintegration, we must acknowledge social inequalities as a primary force in determining negative outcomes resulting from rapid social and economic change, including ethnic conflict. The role of international financing institutions such as the World Bank, the International Monetary Fund, and the World Trade Organization introducing structural adjustment programs and fostering a neoliberal economic developmental model, with drastic deficit reduction and privatization of social services, has been often linked to an increasing gap between the rich and the poor and rising social inequalities, with negative consequences in the health status and well-being of the low-income segments of the population.

Ethnic Conflict and Public Health Direct Theories of Ethnic Political Mobilization and Conflict A new wave of theoretical constructs evolved in the 1970s and 1980s focusing directly on political mobilization as opposed to social and economic developmental issues. Three main approaches dealing with the causes of ethnic political mobilization were developed during this period: primordialism, internal colonialism, and the communalist approach (Taras and Ganguly, 1998). Primordialists mainly focused on ethnic identity and consciousness as the single independent variable that explains the emergence of political assertiveness and militant separatism leading to conflict, regardless of the existence of social inequalities or dominance of one group over the other. Primordialism considered ethnicity in itself to be a biologically driven phenomenon organized around objective markers like common cultural attributes. Prominent scholarly representatives of this approach are Connor (1972, 1973), Glazer and Moynihan (1975), Enloe (1993), Horowitz (1985), and Armstrong (1982). Connor, an early exponent of the primordialist perspective, explained ethnic political mobilization as driven by modernization in four different ways. First, rapid social communication and mobilization increase cultural awareness and exacerbate interethnic division and conflict. Second, improvements in communication and transportation increase the cultural awareness of ethnic minorities by making their members more aware of the distinctions between themselves and others. Third, the rise of a militant ethnic consciousness in many parts of both the developed and the developing worlds can be explained not in terms of the “nature of density of the communication media but of the message” (Connor, 1972: p. 328). Fourth, changes in the global political environment contribute to the upsurge in ethnic consciousness by making it much more unlikely that a militarily weak polity will be annexed by a larger power. Accordingly, ethnic conflict is seen as an outcome of incongruence between economic modernization and political development – both processes associated with the emergence of the modern state. Lack of agreement on the effects modernization had on ethnic political mobilization led to the development of the internal colonialism approach. The main representative of this approach is Michael Hechter (1975). His argument focuses on the concept of exploitation, which prevails in the relationships between members of a dominant cultural group and those of the periphery. According to this argument, exploitations of this sort cause an asymmetric allocation of valued roles and resources to the dominant ethnic group, which in turn leads to political mobilization, protests, and eventual separatist movements claimed by peripheral ethnic groups. Hechter added an important dimension to the analysis of politicized ethnicity by combining economic explanations with cultural ones. However, the cultural division of labor is considered to be only a necessary but not a sufficient condition in the formation of ethnic political movements. The communalist approach focuses on ethnic political mobilization by looking at modernization, scarcity of resources, and elite competition. Modernization and its inherent processes and consequences are believed to influence core and peripheral ethnic groups in two ways. It reduces ethnic diversity within both dominant and subordinate ethnic groups by eroding local

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identities and, as a result, large-scale ethnic identity formation is promoted. Based on data from India, the former Soviet Union, and Eastern Europe, Brass (1991) shows how the emergence of new elites, added to resource scarcity and centralizing tendencies of the state, has been combined to generate intense elite competition and ethnic polarization in many of these societies. Although communalist approaches tend to overemphasize the element of ‘greedy elites,’ overall they enhance the understanding of large-scale ethnic identity formation in modernizing societies at the same time (Taras and Ganguly, 1998).

Analyzing Ethnic Conflict from an Anthropological Perspective In the first half of the last century, empirical studies of ethnic conflict, including armed conflict and ethnic wars, were left to the military or to historians, political scientists, and anthropologists with ‘antiquarian’ interests. Peace was taken for granted even though Max Gluckman (1963) pointed out that ‘custom’ and ‘conflict’ have been intrinsically tied to one another throughout history. Gluckman argued that while conflicts are an inevitable part of social life, it is important to examine the causes and mechanisms leading to their initiation and resolution. This appeal was taken up by anthropologists who approached the subject from different perspectives such as materialism, practice theory, and experiential approaches, including those more concerned with the consequences of ethnic conflict, such as medical anthropologists. Materialists like Brian Ferguson (1984) describe the broader phenomena underlying violent conflict as “organized, purposeful group action, directed against another group . involving the actual or potential application of lethal force” (Ferguson, 1984: p. 5). His approach is generally consistent with theories of cultural materialism proposed by Harris (1979) and Prince (1982) in that war breaks out when those who make the decision to fight estimate that it is in their material interest to do so. However, the war path is not always deliberately chosen, since it may also be an unintentional outcome or unwanted last resort. The materialist perspective has been criticized for forsaking human decision-making processes by focusing solely on the material realm (i.e., land, food, mates, or other limited resources), thus essentially reducing human motivation as being driven by material rewards. Clayton Robarcheck argues that people define a conflicting situation in terms of cultural values and ideals, and violent conflict does not necessarily erupt over limited or scarce material resources. Emanating from this, this author provides a description of how Semai community headmen and disputants accompanied by their kin meet to resolve conflicts by emphasizing key values such as nurturance, dependency, and nonviolence (Robarcheck, 1997). Notions of human motivation and social action as conflict-driving forces are further explored by scholars adhering to practice theory. Paul Richards (2004) argues that war, like peace, is organized and negotiated by individual as well as collective social agents who mobilize resources (including weapons) and train fighters, devise tactics, and execute campaigns. Violent behavior as an outcome entails strategizing and manipulating as well as the interplay of cultural values, social pressures, and emotions. Even though practice theory

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scholars focus on social relations and actions, scholars privileging an experiential approach criticize that not enough attention has been paid to everyday experiences of individuals living in war-torn areas. Carolyn Nordstrom (2004) and Feldman (2003) portray the ways people cope with conflict, war, and its memories by capturing notions of “what [war] lives, experiences, tastes, feels, looks and moves like” (Nordstrom, 2004: p. 10). Those using experiential approaches to analyze conflict and war argue that anthropologists should be able not only to record how weapons are traded, or delve into why an armed individual pulls the trigger against another human being, but to illuminate how people experience the destructive forces of conflict, violence, and grieving, while crafting resistance and exhibiting resilience and coping. To capture ethnic conflict not only from an institutional perspective but to illustrate how transformations in collective experiences during violent conflict reshape interpersonal responses, medical anthropologists provide a different perspective on subjectivity, social suffering, and resilience within a group (see, e.g., Das et al., 2001). Suffering is considered a social experience which could be seen as first, an interpersonal engagement with pain and hardship in social relationships; second, a societal construction that serves as a cultural model; and third, a professional discourse that organizes forms of suffering as bureaucratic categories and objects of technical intervention (Farmer, 1996). Instead of giving those affected by violent conflict the social status of victim or patient, anthropologists argue for the need to better understand exactly how individuals, families, and whole societies construct their experiences and respond to extreme forms of conflict and violence (Kleinman and Kleinman, 1997). The need to focus on the social and cultural dimensions of conflict is of utmost importance as these have to be altered to work toward its prevention and eventual resolution. The anthropology of ethnic conflict helps us to better understand how the actors on each side have come into conflict with one another, what they are fighting about, as well as their subjective experiences. Furthermore, it provides information on the levels of resilience and solidarity within a group, the interethnic relations, and the stake of international interests in the particular situation. However, research performed on the macrolevel of social interaction (i.e., on the upper end of the social power structure), the intermediate level (i.e., neighborhood or village), and its interactions with the microlevel (i.e., peer group, household, and individuals) is relatively rare. We may conclude that social scientists, as they engage with a wider public, should pay attention to these questions by employing a multilevel and comparative perspectives approach thus contributing to public debates over possible, desirable (or undesirable) futures.

Gendered Aspects of Ethnic Conflict In response to political science and anthropological theories on ethnic conflict, feminist scholars draw attention to the conflict’s distinct impacts on women and men. Their goal is to find out about the many faces of individuals confronting war and provide answers to questions of how women and men are impacted by and respond to ethnic conflict.

The Impact of War on Women and Men Feminist scholars have described that women and men suffer from war in different ways in their confrontations with death, the experience of sexual abuse and torture, fleeing and searching for refuge, and losing loved ones, including homes, social networks, and entire communities. The impact of war on men and women has changed due to increasingly efficient war-making technologies that make armed conflict more and more deadly. The adoption of high-altitude bombing, cluster bombs, and strategies of low-intensity war and of ‘total war’ have collapsed the distinction between combatants and civilian targets of war. During World War II, 50% of the direct casualties were civilians, while in the 1980s this figure rose to 80%; by 1990 the proportion of civilian casualties as a direct consequence of war was well over 90%. The largest numbers of civilians killed in war are women and children and the elderly. Patterns of victimization during wartime may range from sexual violence to more subtle methods of abuse. Gender-based and sexual violence has been defined as “physical, sexual and psychological violence against both women and men that occurs in the family and the community and is perpetrated or condoned by the state” (Bouta et al., 2005: p. xxi). In conflict zones, gender-based violence is directed against civilians as well as soldiers. However, women tend to be more vulnerable to sexual abuse than men due to prevailing hegemonic gender relations. The trafficking and sexual exploitation of women tends to increase in times of conflict, and the spread of sexually transmitted diseases such as HIV/AIDS rises significantly. Such violence is not an accidental side effect of war but should be considered a crime against the individual and the community or nation. In October 1997, for the first time in history, a woman took the stand to testify before the International Criminal Tribunal for Rwanda to describe her experiences of sexual abuse and torture during the massacre. Her charge was that what had happened to her was a violation of international humanitarian law. The Tribunal passed the judgment that it was indeed a war crime, a crime against humanity, and an important element of the ethnic conflict and genocide. Sadly, however, this example is the exception rather than the rule. Rape and sexual violence have been rather invisible in the discussion of international humanitarian law; they are often dismissed as private acts, the “ignoble conduct of perverts, and the excess of the occasional soldier” (Coomaraswamy, 2003: p. 92). Official failure to condemn or punish rape thus gives it an overt political sanction, which allows rape and other forms of torture and ill-treatment to become tools of military struggle. Rape and other forms of sexual violence, then, have been applied as strategic weapons of war. The wars and atrocities committed during ethnic conflicts in Bosnia–Herzegovina, Rwanda, and Kosovo show that sexual violence can be an important and efficient instrument of terror especially in campaigns that involve ethnic fratricide or nationalist wars (Coomaraswamy, 2003). Cases of mass rape during conflict and war have been reported for Mozambique, Somalia, Cambodia, and other countries. The head of the UN mission in Cambodia, Yasushi Akashi, replied when he was asked to report on sexual violations of women and girls by UN troops that he was “not a puritan: 18-year-old, hot blooded

Ethnic Conflict and Public Health soldiers had a right to drink a few beers and chase after young beautiful things of the opposite sex” (Fetherston, 1995: p. 23). By accepting rape as a part of military life, militaries around the world also support and often enforce prostitution attached to their military installations. Depending on their home society, their economic status, and their racial/ethnic identity, women and children may be more or less vulnerable to the effects of war and militarization. It is women living in low-income countries who tend to experience war and are often driven out from their homelands. According to the Office of the UNHCR, women and young girls constitute the vast majority of the world’s refugee population and are vulnerable to rape and sexual abuse when they flee war-torn areas. In 1994, after the Rwanda massacre, virtually every adolescent and young girl was raped. Another example is among the so-called Vietnamese boat people, again mostly women and children, who have regularly suffered rape and abduction by pirates: “Any possessions left were taken and they were either direct victims of rape or were forced to watch their children being raped” (Vickers, 1993: p. 28). Once the refugees arrive in the camps, women and young girls are also at the receiving end of sexual harassment and violence from camp officials and other refugees. Refugee women are often their children’s sole caretakers, since a great number of them are widows or separated from their partners and other extended family. Loss of family members is experienced and suffered by men and women alike, although they suffer the loss in gender-specific ways. Women may lose their husbands and sons on the battlefield and their daughters and young children as civilian casualties. Nationalist propaganda, shortly before or during violent conflicts, calls on women to give up their sons and husbands and to be proud of their achievements in combat. Losing husbands and sons in battle is not only an emotional but also an economic loss for many women, since they tend to rely on male relatives for economic survival.

Women’s and Men’s Responses to War Women and men respond to and engage in war differently. Neither men nor women have proven to be inherently violent or peaceful; “instead humans have the capacity to be both” (Turpin, 1998: p. 13). Since state propaganda and social pressures often dictate how men and women behave during times of peace and conflict, it may be suggested masculinity and femininity are learned roles, rather than inherited. At some point in history, to date, over 50 countries have elected a female head of state or government. Data for 2015 reveal that 10 women served as Head of State and 14 served as Head of Government. Although the percentage of women in parliament has doubled over the past two decades (1995– 2000), this translates into a mere 22% of women in parliament today (UN Women). According to some observers, only 10 major conflicts and crises have risen where female leaders held positions of leadership as decision makers of last resort. Furthermore, it is important to note that none of the female leaders initiated any of the crises or were held ultimately responsible for the conflict. Though none of the crises were initiated by women, an examination of the actions taken by female leaders shows that “the violent character of most of

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these crises is maintained, and the use of violence as a crisis management technique escalated in many instances” (Caprioli and Boyer, 2001: p. 507). From a social and interpersonal level, female leaders who gained power through a male-dominated political environment may be required to show more aggressiveness in crises than their male counterparts to prove themselves in international politics. Thus, “female leaders must emulate male gender stereotypes partly to overcome stereotypes about female leadership weaknesses because female leaders are often perceived as weaker at realpolitik issues of security, defence, and economics” (Caprioli and Boyer, 2001: p. 508). Female leaders must often battle with negative perceptions and discriminatory behavior from male opponents. Gender played, for instance, an important role during the Indo-Pakistan armed conflict in 1971. President Yahya Khan of Pakistan announced that he would have reacted less violently and been less rigid if a male had headed the Indian government. He was quoted saying: “If that woman thinks she is going to cow me down, I refuse to take it.” (Malhotra, 1989: p. 137). Throughout history, women have participated in violent conflicts by joining the military. Although fulfilled important roles in the defense industry, they were mostly excluded from public military domains, where they tended to occupy subordinate roles and menial positions such as cook, driver, secretary, or nurse (Vickers, 1993). Another gender-specific role in armed conflict and warfare relates to motives of joining the army. Modern warfare has facilitated women’s inclusion into the armed forces because face-to-face combat has become less important and personal arms are lighter and easier to handle. Physical and psychological differences between men and women have lost their importance as an obstacle for women’s active participation in the military. Although men and women might have similar reasons for joining the army (including forced recruitment, agreement with the war goals, patriotism, religious or ideological motives, lack of educational opportunities, economic necessity), many women also join to obtain more rights and gender equality. However, although gender roles may be more equal with regard to opportunities in the armed forces, this is often dampened by negative effects such as discrimination and sexual harassment.

Ethnic Conflict as an International Problem: 1980s to the Present Only in the late 1980s and 1990s did social scientists begin to shift their attention from intra- to interregional conflicts by analyzing how ethnic conflicts impact on the interstate system and international norms and regulations, as well as on models for resolving ethnic conflicts through international third-party actions. Most ethnic conflicts tend to emerge within states; however, few remain confined within state borders, since most sooner or later transform themselves into international problems. The transformation of ethnic conflicts from national to international affair may follow one of two paths. The first is referred to as the internationalization of ethnic conflicts and may, at the national level, generate actors and consequences whose operations and effects are felt at the international level. The second has been

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termed the ethnicization of international politics and refers to developments taking place in the international system that affect domestic ethnic conflict, thereby lending it an international character (Taras and Ganguly, 1998). In turn, there are different courses leading to the internationalization of ethnic conflicts. One well-known course of action is through the international diplomatic activity of ethnosecessionists and states confronted with ethnic conflict. The main goal of such international activity is to derivate supportive responses from other influential international actors. More specifically, in international conflicts, the incumbents always (and by definition) hold international connections, simply because either one of the parties is in charge of the legitimate machinery of the state, which includes diplomatic relations and other international networking mechanisms. Or, alternatively, the insurgents, by virtue of having to approximate the incumbents as closely as possible to supplant them, must develop the same machinery. Another way for ethnic conflicts to acquire an international dimension is through direct or indirect partisan intervention by outside states in a domestic ethnic conflict. One form of such interventions is described as ‘humanitarian.’ Humanitarian interventions can be defined as “the threat or use of force by a state, group of states, or international organization, primarily for the purpose of protecting the nationals of the target state from widespread deprivations of internationally recognized human rights” (Murphy, 1996: pp. 11–12). Similarly, the Danish Institute of International Affairs (1999) defines humanitarian intervention as “coercive action by states involving the use of armed force in another state without the consent of its government, with or without authorization from the United Nations (UN) Security Council, for the purpose of preventing or putting to halt gross and massive violations of human rights or international humanitarian law.” Rieff and Dworkin (2007) argue that the concept of intervention is “at once an immensely powerful and a terribly imprecise idea” as there is no such thing as “humanitarian military intervention distinct from war and counterinsurgency” (de Waal, 2007: p. 5). Similarly, Chomsky (1999) challenges what he calls the ‘new humanism,’ which justifies unauthorized military intervention and finds doubtful that humanitarian interventions are, in fact, multinational efforts fought exclusively for humanitarian reasons. He argues that the establishment of a new world order is marketed and headed by ‘enlightened states,’ which ‘happen to be the rich and powerful,’ possessing enough military might to turn a blind eye to international law and world opinion (p. 11). In short, humanitarian intervention is never apolitical but is largely driven by the military logic of powerful states and entails collective violence, and often torture and bloodshed, including the killing of civilians (Kienzler and Pedersen, 2012). Particularly, through partisan intervention international peace and stability may be threatened and, as a consequence, internal players may no longer find themselves as disputants in an internal conflict but as victims of a much wider international war. Also, international terrorism may transform ethnic conflict into an international problem. Lacking the resources needed for conventional military warfare, “ethnic separatists often resort to terrorism because it is cheaper and easier to get away with” (Taras and Ganguly, 1998: p. 81). By way of using

terrorist tactics, ethno-nationalists and secessionists not only intensify existing problems for the international community, but elevate themselves to direct participants at the international level. Thus, tactics such as pirating of international passenger flights, assassinating diplomats in foreign lands, and kidnapping businessmen and diplomats have become a familiar feature in international politics. Finally, massive population displacements, such as flows of refugees from conflict zones, cause not only enormous human suffering but put tremendous pressure on those states that receive the refugees by imposing a large economic and political burden on them. The growing refugee problem is a direct outcome of ethnic conflict and one of the most serious challenges facing the international community in the years to come. The ethnicization of international politics is also a process occurring at the international level but may in turn influence ethnic conflicts at the national level. Due to globalization processes, ethnic groups are able to multiply their networks of transnational interrelations and ensure greater opportunities for exchange of ideas, information, wealth, and political strategies. Globalization of the mass media and advances in communication technology have most likely advanced the cause of international terrorism. There is little doubt that television and the Internet give terrorist movements instant access to the world’s audience, enabling them to draw immediate global attention to their causes. The so-called terrorist groups often represent repressed ethnic minorities who see themselves in the vanguard for the struggle for national self-determination. Examples of this situation are many, such as the Sikh terrorists who planted a bomb on an Indian Boeing 747 that exploded off the coast of Ireland in 1985, killing 329 people. It is also a justification given by the provisional IRA for their attacks outside and inside the United Kingdom, and by the Armenian terrorist group (ASALA), which has carried out numerous attacks on Turkish diplomats. Another example of how globalization processes affect ethnic conflict is through the enormous proliferation of weapons across the globe. At the height of the Afghan war, for example, the United States and the Soviet Union provided a massive amount of highly sophisticated weaponry. However, when the Soviet–American confrontation ended, sophisticated weapons, such as Stinger antiaircraft arms supplied to the Afghan rebels in the 1980s by the United States, were transshipped to rogue states such as Iran and to various terrorist and insurgent groups in the region. This and other examples show that military capabilities of rebellious ethnic minorities have been boosted and the ability to challenge the power of existing states has been significantly increased in recent times. To understand how ethnic conflicts exert their impact on interstate politics, it is important to examine the interrelationships between universally recognized norms of behavior within the international system and the ethno-nationalist and secessionist movements. Although the international system is anchored by the principles of national self-determination and the nation-state, the international normative regime is biased against ethno-nationalist and secessionists, who invoke these same principles. Whereas existing states appeal to the doctrine of state sovereignty so as to justify their existence, ethnonationalists invoke the concept of self-determination to justify their case for statehood. National self-determination includes

Ethnic Conflict and Public Health two main elements, namely, the right to secession and the right to create independent states. As a basic democratic principle of international life, national self-determination received much attention under the UN system after its implementation in 1945. However, although the concept of self-determination was, in theory, extended to all people, it could be exercised only by those under colonial rule. Thus, the Friendly Relations Declaration of 1970 categorically rejected and denounced any secessionist movement threatening the national unity and territorial integrity of an independent state. Unstable multinational states often cause problems for interstate politics in that they may tempt outside powers to intervene in conflicts so as to pursue their own self-interest, triggering a spiral of conflict escalation that may lead to generalization of the conflict. A successful response to violent ethnic conflict, however, is not limited to the creation of a stable and well-ordered state but also involves the creation of a state that will respect the rights and needs of all of its citizens, irrespective of their origin or ethnicity.

Resolving Ethnic Conflicts and the International Community There are at least three main courses of action possible in the resolution of ethnic conflicts. First, conflicts may be resolved through violence by the disputants. The inevitable consequence of doing so is armed conflict or war, which may ultimately settle the dispute when one side secures a military victory. Second, diametrically opposite to the first, conflicts may be settled through peaceful bargaining and negotiation on the disputants’ own initiative. However, although this course of action is the one most often followed by the international community, the disputing parties usually fail to resolve their differences peacefully on their own initiative. The third strategy refers to the involvement of third parties, especially in those situations of protracted and complex ethnic conflict where the disputants have exhausted their own attempts to compromise. Dispute resolution through third-party action is defined as an intervention in a dispute by a person or an agency whose purpose is to act as an instrument for bringing about a peaceful settlement of that dispute, while creating structures whereby the foundation of a lasting settlement can be laid. Third-party intervention may include states or so-called international, multilateral, bilateral, or nongovernmental organizations. The intervention of states often presents a dilemma for the international community because the doctrine of state sovereignty precludes intervention by outsiders in the affairs of sovereign states. Exceptions are only acceptable when a government agrees to allow such intervention. According to Esman (2004), the most common form of intervention is to provide ‘good offices’ to mediate between contending parties, suspend hostilities, and facilitate negotiations. Other forms of intervention are the provision of humanitarian assistance, foreign aid (technical and economic assistance), nonviolent sanctions (military and economic embargoes), preventive intervention, and coercive sanctions, such as application of military power to terminate a conflict or embargoes to put an end to flagrant violations of human rights.

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Interventions undertaken by international agencies are often perceived as being more legitimate than those organized by a single state. The UN, for example, usually gets involved in conflicts when all other apparent options have failed. However, the UN system is often confronted with a paradox that is not easy to resolve. It has to maintain the integrity of the state system from which its political existence is derived and, at the same time, promote and protect the interests of minorities for whom it was created. As a consequence, its relationship with the various parties and ethnic minorities involved in the conflict is ambiguous. Nevertheless, the UN Security Council has been called on to mediate a number of ethnic conflicts, using its good office to induce the parties to forego or halt violent activity and begin negotiation. Should the interventions be successful in that they bring about peace, the UN may be called on to bring peacekeepers into the respective region. Thus, the UN is not only responsible for maintaining order, but also for organizing and operating a government and managing humanitarian services until the economy has been partially restored and indigenous personnel have received training to assume the responsibilities of the (new) government. The three main strategies third parties have to opt to restore or bring peace to a region shaken by conflict are referred to as peacekeeping, peacemaking, and peace-building. Peacekeeping interventions by third parties involve “the prevention, containment, moderation and termination of hostilities between or within states” (Childe, 1980; cited in Ryan, 1990: p. 54). Operations of this kind have to fulfill three requirements. First, all parties involved in the conflict have to give their prior consent to the intervening actors. Second, international peacekeepers must remain impartial when dealing with the adversary parties. Finally, the use of force in peacekeeping operations must be limited, and peacekeepers may only use a limited amount of force, mainly for the sake of self-defense. In contrast to peacekeeping, peacemaking usually involves political or diplomatic activities aimed at bringing the leaders of the disputing parties closer to a political settlement. Methods evoked during such negotiation processes are arbitration, mediation, and facilitation. The final aspect of conflict resolution is peace-building. Peace-building has been defined as local initiatives or structural efforts taken by third parties that foster social, political, and institutional structures and processes, which strengthen the prospects for peaceful coexistence and decrease the likelihood of the outbreak, reoccurrence, or continuation of the violence. It often requires an international third party to undertake long-term action directed mostly at the ordinary members of the disputing parties to change their negative image, perceptions, and attitudes toward the followers of the other side. Therefore, the main objective is to implement peaceful social change through socioeconomic reconstruction and development. The crucial elements for peace-building are the financial resources at the third party’s disposal and its patience and perseverance in what is bound to be a slow and arduous process. However, third-party intervention does not always lead to peace and might, on the contrary, increase the scale of conflict, either by introducing new political issues to the basic dispute or by expanding the number of parties involved. Often it may take attention away from core issues of how to create solid and

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stable interethnic relations. Thus, if an intervention is perceived as one-sided or unfair, it will increase the intransigence of the supported side and increase the fears of other parties involved, derailing intervention efforts and consolidating the conflict even further.

See also: Famine; Health Care of Indigenous Peoples/Nations; Health and Human Rights: Overview; Relief Operations; Torture and Public Health.

References Armstrong, J., 1982. Nations before Nationalism. University of North Carolina Press, Chapel Hill, NC. Bouta, T., Frerks, G., Bannon, I., 2005. Gender, Conflict, and Development. World Bank, Washington, DC. Brass, P., 1991. Ethnicity and Nationalism: Theory and Comparison. Sage Publications, Newbury Park, CA. Bullard, R.D., 1994. Overcoming racism in environmental decision making. Environment: Science and Policy for Sustainable Development 36 (4), 10–44. Caprioli, M., Boyer, M., 2001. Gender, violence and international crisis. J. Conflict Resolut. 44 (4), 503–518. Childe, J., 1980. Peacekeeping and the inter-American system. Mil. Rev. 60 (10), 61–82. Chomsky, N., 1999. The New Military Humanism: Lessons from Kosovo. Pluto, London. Connor, W., 1972. Nation-building or nation-destroying. World Polit. 24 (3), 319–355. Connor, W., 1973. The politics of ethnonationalism. J. Int. Aff. 27 (1), 1–21. Coomaraswamy, R., 2003. A question of honour: women, ethnicity and armed conflict. In: Giles, W., de Alwis, M., Klein, E., Silva, N. (Eds.), Feminists under Fire. Between the Lines, Toronto, ON. Danish Institute of International Affairs, 1999. Humanitarian Intervention, Legal and Political Aspects. Danish Institute of International Affairs, Copenhagen. Das, V., Kleinman, A., Lock, M., Ramphele, M., Reynolds, P., 2001. Remaking a World: Violence, Social Suffering and Recovery. University of California Press, Berkeley, CA. Deutsch, K., 1953. Nationalism and Social Communication. An Inquiry into the Foundations of Nationality. Technology Press (MIT)/Wiley, New York. Enloe, C., 1993. The Morning after: Sexual Politics at the End of the Cold War. University of California Press, Berkeley, CA. Esman, M., 2004. An Introduction to Ethnic Conflict. Polity Press, Cambridge, MA. Farmer, P., 1996. On suffering and structural violence: a view from below. Daedalus 125 (1), 261–283. Feldman, A., 2003. Political terror and the technologies of memory: excuse, sacrifice, commodification, and actuarial moralities. Radical Hist. Rev. 85, 58–73. Ferguson, B., 1984. Introduction: studying war. In: Ferguson, B. (Ed.), Warfare, Culture, and Environment. Academic Press, Orlando, FL, pp. 1–81. Fetherston, A.B., 1995. U.N. Peacekeepers and cultures of violence. Cult. Surv. Q. 19 (1), 19–23. Glaser, N., Moynihan, D. (Eds.), 1975. Ethnicity: Theory and Experience. Harvard University Press, Cambridge. Gluckman, M., 1963. Custom and Conflict in Africa. Basil Blackwell, Oxford, UK. Gurr, T.R., 1970. Why Men Rebel. Princeton University Press, Princeton, NJ. Harris, M., 1979. Cultural Materialism: The Struggle for a Science of Culture. Random House, London. Hechter, M., 1975. Internal Colonialism: The Celtic Fringe in British National Development 1536–1966. Routledge and Kegan Paul, London. Heraclides, A., 1991. In: The Self – Determination of Minorities in International Politics. Frank Cass, London, p. 6. Horowitz, D., 1985. Ethnic Groups in Conflict. University of California Press, Berkeley, CA. Huntington, S., 1968. Political Order in Changing Societies. Yale University Press, New Haven, CT. Kienzler, H., Pedersen, D., 2012. Strange but common bedfellows: the relationship between humanitarians and the military in developing psychosocial interventions for civilian populations affected by armed conflict. Transcult. Psychiatry 49 (3–4), 492–518.

Kleinman, A., Kleinman, J., 1997. The appeal of experience; the dismay of images; cultural appropriations of suffering in our times. In: Kleinman, A., Das, V., Lock, M. (Eds.), Social Suffering. University of California Press, Berkeley, CA, pp. 1–24. Lijphart, A., 1977. Democracy in Plural Societies: A Comparative Exploration. Yale University Press, New Haven, CT. Malhotra, I., 1989. Indira Gandhi: A Personal and Political Biography. Northeastern University Press, Boston, MA. Murray, C.J.L., King, G., Lopez, A.D., Tomijima, N., Krug, E.G., 2002. Armed conflict as a public health problem. BMJ 324 (9), 346–349. Murphy, S., 1996. Humanitarian Intervention: The United Nations in an Evolving World Order. University of Pennsylvania Press, Philadelphia. Nordlinger, E., 1977. Conflict Regulation in Divided Societies. Harvard Center for International Affairs, Cambridge, MA. Nordstrom, C., 2004. Shadows of War: Violence, Power, and International Profiteering in the Twenty-First Century. University of California Press, Berkeley, CA. Pedersen, D., 2015. Rethinking trauma as a global challenge. In: Schouler-Ocak, Meryam (Ed.), Trauma and Migration – Cultural Factors in the Diagnosis and Treatment of Traumatized Immigrants. Springer International Publishing, Switzerland, pp. 9–31. http://dx.doi.org/10.1007/978-3-319-17335-1. Pedersen, D., 2002. Political violence, ethnic conflict and contemporary wars: broad implications for health and social well-being. Soc. Sci. Med. 55 (2), 175–190. Pinker, S., 2011. The Better Angels of Our Nature: Why Violence Has Declined? Penguin Books Inc., New York, pp. 129–188. Prince, B., 1982. Cultural materialism: a theoretical review. Am. Antiq. 47, 709–741. Richards, P., 2004. New war: an ethnographic approach. In: Richards, P. (Ed.), No Peace, No War. An Anthropology of Contemporary Armed Conflict. Ohio University Press, Athens, pp. 1–21. Rieff, D., Dworkin, A., 2007. Humanitarian intervention. In: Gutman, R., Rieff, D., Dworkin, A. (Eds.), Crimes of War. W.W. Norton and Company, New York, pp. 227–230. Robarcheck, C., 1997. A community of interests: Semai conflict resolution. In: Fry, D., Bjoerkqvist, K. (Eds.), Cultural Variation in Conflict Resolution: Alternatives to Violence. Erlbaum, Mahwah, NJ, pp. 51–58. Ryan, S., 1990. In: Ethnic Conflict and International Relations. Dartmouth, Aldershot, Brookfield and Hong Kong, p. 54. Taras, R., Ganguly, R., 1998. Understanding Ethnic Conflict. The International Dimension. Longman, New York. Turpin, J., 1998. Many faces: women confronting war. In: Lorentzen, L.A., Turpin, J. (Eds.), The Women and War Reader. New York University Press, New York, pp. 3–18. UNHCR, 2014. World at War. Global Trends: Forced Displacement in 2014. UNHCR, Geneva. Vickers, J., 1993. Women and War. Zed Books, London. UN Women. Facts and Figures: Leadership and Political Participation. Accessed (04.08.15.) at: http://www.unwomen.org/en/what-we-do/leadership-and-politicalparticipation/facts-and-figures. de Waal, A., 2007. March 21. No such thing as humanitarian intervention. Retrieved from http://www.hir.harvard.edu/no-such-thing-as-humanitarian-intervention/. Harvard International Review. WHO, 2000. Global Burden of Disease. World Health Organization, Geneva.

Further Reading Bullard, R.D., 1993. Confronting Environmental Racism: Voices from the Grassroots. South End Press, Boston, MA. Carment, D., 1993. The international dimensions of ethnic conflict: concepts, indicators, and theory. J. Peace Res. 30 (2), 137–150. Clay, J.W., 1994. Resource wars: nation and state conflicts of the twentieth century. In: Johnston, B.R. (Ed.), Who Pays the Price? The Sociocultural Context of Environmental Crisis. Island Press, Washington, DC, pp. 19–30. Farmer, P., Gastineau, N., 2002. Rethinking health and human rights: time for a paradigm shift. J. Law Med. Ethics 30, 655–666. Feldman, A., 1995. Ethnographic states of emergency. In: Nordstrom, C., Robben, A.C.G.M. (Eds.), Fieldwork under Fire. Contemporary Studies of Violence and Survival. University of California Press, Los Angeles, CA, pp. 224–252. Ferguson, B., 1990. Explaining war. In: Haas, J. (Ed.), The Anthropology of War. Cambridge University Press, Sydney, Australia, pp. 26–55. Ferguson, B., 2000. The causes and origins of ‘primitive warfare’: on evolved motivations for war. Anthropol. Q. 73 (3), 159–164.

Ethnic Conflict and Public Health Harbottle, M., 1980. The strategy of third party interventions in conflict resolution. Int. J. 35 (1), 118–131. Heraclides, A., 1997. The ending of unending conflicts: separatist wars. Millennium J. Int. Stud. 26 (3), 697. Pedersen, D., Gamarra, J., Planas, M.E., Errazuriz, C., 2003. Violencia política y salud mental en las comunidades Altoandinas de Ayacucho, Perú. In: Cáceres, C., Cueto, M., Ramos, M., Vallenas, S. (Eds.), La salud como derecho ciudadano. Perspectivas y propuestas desde Amárica Latina. Universidad Peruana Cayetano Heredia, Lima, pp. 289–307. Pedersen, D., 1996. Disease ecology at the crossroads: man-made environments, human rights and perpetual development utopias. Soc. Sci. Med. 43 (5), 745–758. Ragin, C., 1977. Class, status and reactive ethnic cleavages: the social bases of political regionalism. Am. Sociol. Rev. 42, 438–450.

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Ragin, C., 1979. Ethnic political mobilization: the Welsh case. Am. Sociol. Rev. 44, 619–635. Robarchek, C., 1990. Motivations and material causes: on the explanation of conflict and war. In: Haas, J. (Ed.), The Anthropology of War. Cambridge University Press, Sydney, Australia, pp. 56–76. Smith, A., 1999. The Ethnic Origins of Nations. Basil Blackwell, Oxford, UK. Scheper-Hughes, N., 1992. Death without Weeping: The Violence of Everyday Life in Brazil. University of California Press, Berkeley, CA. Stewart, P., Strathern, A., 2002. Violence: Theory and Ethnography. Continuum, London. Tessler, M., Warriner, I., 1997. Gender, feminism, and attitudes toward internal conflict. World Polit. 49, 250–281. Van der Berghe, P.L., 1983. Class, race and ethnicity in Africa. Ethn. Racial Stud. 6, 221–236.

Euthanasia and Public Health Kenneth Chambaere and Joachim Cohen, End-of-Life Care Research Group, Vrije Universiteit Brussel (VUB), Brussels, Belgium; and Ghent University, Brussels, Belgium Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Bregje Onwuteaka-Philipsen, Luc Deliens, volume 2, pp. 519–526, Ó 2008, Elsevier Inc.

Introduction The end of life is, in developed countries, increasingly typified by chronic illnesses with protracted dying trajectories and increasing possibilities to prolong life and manage the diverse illness-associated problems. The second epidemiological transition, as first described by Omran (1971), has meant that death as a relatively acute event due to infectious disease has to a great extent been transformed into a death typified by protracted ailments (Illich, 1975), for instance as a result of cancer, cardiovascular disease, or in people living to a very old age by multiorgan failure toward the end of life. Moreover, the number of people dying from cancer, organ failure, and dementia has increased in recent years (Wilson et al., 2011). It is estimated that two-thirds or more of all deaths occur nonsuddenly and expectedly and involve a period with a need for end-of-life care before death (van der Heide et al., 2003). This material transformation of death has also coincided with social transformations of death. Ivan Illich (1975), for instance, describes how death became gradually medicalized over the centuries, due to the changing role of physicians and the changing role of medical technologies. The continuing advances in medicine seem, indeed, to have greatly improved the possibilities to treat seriously ill patients and to prolong life. However, this has also entailed that medical decisions potentially influencing patients’ life span become a pertinent part of end-of-life medical practice (van der Heide et al., 2003; Bilsen et al., 2009; Chambaere et al., 2011; Onwuteaka-Philipsen et al., 2012; Chambaere et al., 2015a). These end-of-life decisions become even more pertinent in a society where the dominant discourses around death are also changing. The medicalized death is increasingly being criticized by a discourse that is referred to as a revivalist death discourse with as its nodal points autonomy, control, dignity, heroism (i.e., persons ideally have to accept their death and face it), and awareness about impending death (Van Brussel and Carpentier, 2014). These are seen as incompatible with a medicalized death. Prolonging life is, as such, no longer seen as always an appropriate goal of medicine. The rise of the discourse coincided with both the palliative care movement (often also referred to as the modern hospice movement) and the right to die movement. It became accepted that physicians may – for reasons of autonomy, comfort, or dignity – decide to withhold or withdraw life-prolonging treatment or to carry out intensified symptom treatment or continuous sedation, or not to intervene when patients decide to stop eating and drinking. In some cases, however, physicians are also confronted with a request of patients for assisted dying which can take the form of assistance in suicide of a patient or euthanasia. Euthanasia and physician-assisted suicide are intensely debated medical end-of-life practices. This article particularly focuses on these practices. It seems clear that the acceptance of euthanasia and physician-assisted suicide is increasing in

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many developed countries, judging from the increasing legislative debate worldwide (Cohen-Almagor, 2013; Materstvedt, 2003), trends in its actual performance (Chambaere et al., 2015a; Onwuteaka-Philipsen et al., 2012; Oregon Public Health Division, 2015; Washington State Department of Health, 2014), as well as public opinion polls (Cohen et al., 2006a,b, 2013, 2014a). A public health approach to euthanasia and physician-assisted suicide implies three important functions: (1) assessment and monitoring of the practice, (2) assurance that the practice adheres to due care criteria and that there is no abuse, and (3) mapping and evaluating policy developments. These functions are discussed consecutively in this article. The article first provides data from empirical studies about the frequency of euthanasia and physician-assisted suicide in relation to all deaths and in relation to other potentially life-shortening end-of-life decisions. The focus is thus limited to countries where comprehensive and population-based statistics of actual end-of-life practices are available (i.e., Australia, Belgium, Denmark, France, Italy, Sweden, Switzerland, the United Kingdom, and the Netherlands). Next, the article evaluates the available empirical data in countries that have decriminalized euthanasia and/or assisted suicide to discuss whether and how the decision making around the practices adheres to criteria of prudent medical practice. Lastly, the regulation of euthanasia or physician-assisted suicide worldwide and its effects on end-of-life care in those jurisdictions that have regulated the practices are discussed. Euthanasia and physician-assisted suicide have to be understood in the context of other medical end-of-life decisions in order to better understand the practice. Before focusing on euthanasia and its regulation, we describe a conceptual framework of end-of-life decision making and the incidence of different end-of-life decisions in several countries.

Conceptual Framework for End-of-Life Practices First, it is important to give conceptually clear and distinct definitions of euthanasia and physician-assisted suicide. A wide range of end-of-life decisions and practices have been described and distinguished via a conceptual framework first developed by the Dutch Remmelink Commission in 1990 (van der Maas et al., 1991). This framework seeks to classify end-of-life decisions with a potential or certain life-shortening effect, based on a number of distinguishing criteria. The broad classification of end-of-life decisions and practices is as follows: l

Forgoing treatment: This encompasses the withholding or withdrawing of potentially life-saving or life-prolonging treatment. Decisions in this category include not starting up antibiotics treatment or CPR, withholding artificial nutrition and hydration, and disconnecting mechanical ventilation.

International Encyclopedia of Public Health, 2nd edition, Volume 3

http://dx.doi.org/10.1016/B978-0-12-803678-5.00149-1

Euthanasia and Public Health Intensified treatment of pain and other symptoms: This is to be understood as the administration of drugs intended to alleviate severe pain and other symptoms, but in such high dosages that hastening death as a cause of the treatment cannot be precluded. This practice is often characterized as ‘double effect treatment’ – unintended life-shortening effect next to the primary, intended effect of symptom alleviation (Gillon, 1986; Emanuel, 2001). A special, and indeed the most far-reaching form of this practice is continuous deep sedation until death: the patient is deeply sedated (i.e., the patient’s consciousness is lowered or taken away completely) as a last resort for treatment of refractory symptoms. Other terms used for this practice include palliative sedation and terminal sedation (Emanuel, 2001; Morita et al., 2002). l Physician-assisted death: Use of drugs with the explicit intention of hastening death: l

l

l

l

Administration of lethal drugs without the patient’s explicit request. Euthanasia: Lethal drugs administered by someone other than the patient (i.e., the physician), at his/her explicit request. Physician-assisted suicide: Lethal drugs prescribed or supplied by the physician to the patient at his/her explicit request, administered by the patient him-/herself.

As can be seen from this classification, euthanasia has quite a strict definition. It presupposes the following core characteristics: an action from the physician (i.e., administering drugs), an explicit intention to hasten death, and an explicit request from the patient. This follows the legal definitions in countries that have decriminalized one or both of the practices (see section Mapping and Evaluating Regulation of Euthanasia and Physician-Assisted Suicide). It is thus clear that this definition excludes ‘passive’ decisions such as withholding or withdrawing life-sustaining or life-prolonging treatment, often termed ‘passive euthanasia’ – which is a contradiction in terms. Similarly, ‘nonvoluntary euthanasia’ or ‘involuntary euthanasia,’ oft-used terms for the act of administering lethal drugs without the patient’s explicit request, constitute contradictions in terms. Euthanasia is by definition active and voluntary. Physician-assisted suicide is conceptually akin to euthanasia with the only difference that it is the patient who administers the drugs herself while the physician only fulfills a facilitating role in prescribing or supplying the drugs.

Assessment and Monitoring of End-of-Life Practices Incidence of End-of-Life Practices Several studies conducted in eight European countries (Belgium (Flanders), Denmark, France, Italy, the Netherlands, Sweden, Switzerland, and the United Kingdom) and Australia have shown that end-of-life practices with a possible or certain life-shortening effect are a substantial part of contemporary medical practice (Kuhse et al., 1997; van der Heide et al., 2003; Seale, 2009; Pennec et al., 2012; Onwuteaka-Philipsen et al., 2012; Chambaere et al., 2015a). To provide data on the incidence and background characteristics of end-of-life

47

practices, these studies surveyed either a sample of deaths where the respondents were the certifying physicians (death certificate survey) or a sample of physicians asking these physicians about the most recent death they attended (physician survey). The percentage of all deaths in which dying was preceded by at least one medical end-of-life decision varied between 23% (Italy) and 64.8% (Australia) (Table 1). Physician-assisted suicide and/or euthanasia were reported in all countries but Sweden. The percentages varied from approximately 1% or less in France, the United Kingdom, Denmark, Italy, and Switzerland to 4.6% in Belgium. Euthanasia occurs predominantly in Belgium (4.6%) and the Netherlands (2.8%). Administration of lethal drugs without explicit request from the patient occurred more frequently than euthanasia in all countries except Belgium and the Netherlands. The incidence of forgoing treatment and intensified treatment of pain and other symptoms was much higher than the incidence of physician-assisted dying in all countries. The percentage of deaths preceded by intensified treatment of pain and other symptoms was highest in the Netherlands (36.4%) and lowest in the United Kingdom (17.1%). The incidence of nontreatment decisions ranged from 4% in Italy to 28.6% in Australia. Data on the use of continuous sedation until death are only available for the United Kingdom (16.5%), the Netherlands (12.3%), and Belgium (12%). For most countries no data are available on the incidence of end-of-life practices through large-scale and reliable studies.

Trends in End-of-Life Practices in the Netherlands and Belgium Of the countries mentioned above, only Belgium and the Netherlands have data from repeat studies allowing evaluation of trends. While the percentage of cases in which at least one end-of-life decision was made increased in the Netherlands from 42.5% in 2005 to 57.8% in 2010, this remained stable at 47.8% in Belgium between 2007 and 2013 (Figure 1). The euthanasia rate increased in the Netherlands (from 1.7% to 2.8%) and in Belgium (from 1.9% to 4.6%) due to a rise in the number of patients requesting euthanasia and an increase in the proportion of requests granted. Intensified treatment of pain and other symptoms increased strongly in the Netherlands (from 24.7% to 36.4%) while it occurred less frequently in Belgium in 2013 compared to 2007 (from 26.7% to 24.2%). During the same period, the incidence of forgoing treatment rose in the Netherlands (from 15.6% to 18.2%) and remained stable in Belgium (from 17.4% to 17.2%). An increased proportion of decedents were continuously deeply sedated in the Netherlands (from 8.2% to 12.3%) while this occurred less frequently in Belgium in 2013 compared to 2007 (from 14.5% to 12.0%).

Evaluating the Practice of Euthanasia and PhysicianAssisted Suicide To evaluate carefulness of practice more insight is required into who is requesting euthanasia or physician-assisted suicide, for what reasons, and how physicians are handling these requests. Additional important evaluations have to do with whether certain potentially vulnerable groups have an increased risk

48

Incidence of end-of-life decisions in eight European countries and Australia

Country

Belgium

Netherlands

France

United Kingdom

Denmark

Italy

Sweden

Switzerland

Australia

Year last survey Method

2013 Death certificate study 3751 47.8 24.2

2010 Death certificate study 6861 57.8 36.4

2009 Death certificate study 4891 47.7 28.1

2007–08 Physician survey 2869 39.2 17.1

2001 Death certificate study 2939 41 26

2001 Death certificate study 2604 23 19

2001 Death certificate study 3248 36 21

2001 Death certificate study 3355 51 22

1995 Physician survey 1112 64.8 30.9

17.2 – – 6.3 4.6 0.05 1.7

18.2 – – 3.1 2.8 0.1 0.2

18.8 14.6 4.2 0.8 0.2 0.0 0.6

21.8 – – 0.51 0.21 0.00 0.30

14 – – 0.79 0.06 0.06 0.67

4 – – 0.10 0.04 0.00 0.06

14 – – 0.23 0.00 0.00 0.23

28 – – 1.04 0.27 0.36 0.42

28.6 – –

12.0

12.3

–

16.5

–

–

–

–

–

Number of studied cases Total end-of-life decisions Intensified treatment of pain and other symptoms Forgoing treatment Treatment withheld Treatment withdrawn Physician-assisted death Euthanasia Physician-assisted suicide Administration of lethal drugs without the patient’s explicit request Continuous deep sedation until death

1.7 0.1 3.5

Data for the table are based on the following publications: Belgium: Chambaere, K., Vander Stichele, R., Mortier, F., Cohen, J., Deliens, L., 2015. Recent trends in euthanasia and other end-of-life practices in Belgium. N. Engl. J. Med. 372 (12), 1179–1181; Netherlands: Onwuteaka-Philipsen, B.D., Brinkman-Stoppelenburg, A., Penning, C., de Jong-Krul, G.J., van Delden, J.J., van der Heide, A., 2012. Trends in end-of-life practices before and after the enactment of the euthanasia law in the Netherlands from 1990 to 2010: a repeated cross-sectional survey. Lancet 380, 908–915; France: Pennec, S., Monnier, A., Pontone, S., Aubry, R., 2012. End-of-life medical decisions in France: a death certificate follow-up survey 5 years after the 2005 act of parliament on patients’ rights and end of life. BMC Palliat. Care 11 (25), 25; United Kingdom: Seale, C., 2009. End-of-life decisions in the UK involving medical practitioners. Palliat. Med. 23 (3), 198–204; Denmark, Italy, Sweden, and Switzerland: van der Heide, A., Deliens, L., Faisst, K., Nilstun, T., Norup, M., Paci, E., et al., 2003. End-of-life decision-making in six European countries: descriptive study. Lancet 362, 345–350; Australia: Kuhse, H., Singer, P., Baume, P., Clark, M., Rickard, M., 1997. End-of-life decisions in Australian medical practice. Med. J. Aust. 166 (4), 191–196.

Euthanasia and Public Health

Table 1

Euthanasia and Public Health

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Total end-of-life decisions

Intensified treatment of pain and other symptoms

Forgoing treatment

Continuous deep sedation

Euthanasia or physician-assisted suicide

Administration of lethal drugs without explicit patient request 0% NL 2010

NL 2005

10% BE 2013

20%

30%

40%

50%

60%

BE 2007

Figure 1 Incidence of end-of-life decisions in the Netherlands (2010 vs 2005) and Flanders, Belgium (2013 vs 2007). Figure made by the authors based on Chambaere, K., Vander Stichele, R., Mortier, F., Cohen, J., Deliens, L., 2015. Recent trends in euthanasia and other end-of-life practices in Belgium. N. Engl. J. Med. 372 (12), 1179–1181 and Onwuteaka-Philipsen, B.D., Brinkman-Stoppelenburg, A., Penning, C., de Jong-Krul, G.J., van Delden, J.J., van der Heide, A., 2012. Trends in end-of-life practices before and after the enactment of the euthanasia law in the Netherlands from 1990 to 2010: a repeated cross-sectional survey. Lancet 380, 908–915. The bars represent percentages of all deaths.

for euthanasia or physician-assisted suicide, to which extent the (legal) due care requirements are met, and which affects decriminalization or legalization of assisted dying may have on end-of-life care in general.

Handling of Requests by Physicians It is known that some patients request euthanasia or physician-assisted suicide from their physicians in many countries. Studies have shown this in countries including the United States of America, Australia, the United Kingdom, Norway, Germany, Belgium, and the Netherlands (Chambaere et al., 2015a; Maitra et al., 2005; Førde and Aasland, 2014; Ganzini et al., 2008; Neil et al., 2007; Seale and Addington-Hall, 1994; van der Heide et al., 2003). Of course not all requests are granted by the physician. However, robust and reliable data about what proportion of dying patients makes an explicit request for euthanasia or physician-assisted suicide, the reasons for these requests and how these requests are handled, have only been collected for a number of countries where a legal framework for the practice is present. Countries or states with a legal framework for euthanasia or physician-assisted suicide include, at the time of this writing, six countries (Belgium, Canada, Colombia, Luxemburg, Switzerland, and the Netherlands) and five US states (Oregon, Washington, Montana, Vermont, and California) (see section Mapping and Evaluating Regulation of Euthanasia and Physician-Assisted Suicide).

Reasons for the Requests

In the United States, collected data concern Oregon (Ganzini et al., 2008). In Oregon, data from a cross-sectional survey with family members of 83 decedents who made explicit requests for legal physician-assisted suicide before their deaths

indicated that wanting to control the circumstances of death, fear of poor quality of life and about loss of independence and loss of dignity in the future, fear of self-care inability in the future, and wanting to die at home were the most important reasons to ask for PAS. The least important reasons included depression, financial concerns, and poor social support. Both in the Netherlands (Jansen-van der Weide et al., 2005) and Belgium (Van Wesemael et al., 2011) large-scale surveys have been conducted in representative samples of physicians, asking them about their most recent case of an explicit request for euthanasia by one of their patients. The most important reasons patients had for requesting euthanasia or physician-assisted suicide were both in Belgium and the Netherlands pointless suffering/suffering without prospect of improvement, and loss of dignity (see Table 2). In the Netherlands patient requests for euthanasia or PAS were more often refused when they included as a reason not wanting to be a burden on the family, tired of living, or depression (Jansen-van der Weide et al., 2005). In Belgium, if depression was one of the reasons for the request this more often led to not granting it (Van Wesemael et al., 2011). If suffering without prospect of improvement (in the Belgian study) or unbearable/ pointless suffering (in the Dutch study) or loss of dignity (Belgian study) were one of the reasons for the request this increased the chance of having that request granted.

Granting of the Requests by the Physician

Recent data that provide information about the proportion of dying patients with an explicit request for euthanasia or physician-assisted suicide and the proportion of these requests that is granted have been collected for the Netherlands and Flanders (Belgium). The most recent published large-scale population-based postmortem surveys about end-of-life

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Euthanasia and Public Health

Table 2 Reasonsa for explicitly requesting euthanasia or physician-assisted suicide in Belgium and the Netherlands (rounded percentages)

Suffering without prospect of improvement Pointless suffering Deterioration/loss of dignity General weakness/tiredness Pain Fear of suffocating Disability/immobility Not wanting to be a burden on family Dependence Tired of living Dyspnea Vomiting Depression

Netherlandsb n ¼ 1681

Belgiumb n ¼ 355

n/a

72

67 65 56 30 20 19 18 n/a 17 n/a 14 7

n/a 44 32 34 13 14 32 22 26 7 3 12

a

Multiple answers possible. In the Netherlands questionnaires were sent to all GPs in 18 of 23 GP districts. In Belgium a questionnaire with comparable core questions was sent to a representative sample of physicians. Both questionnaires included a number of questions regarding the most recent case of a euthanasia request the physicians received from one of their patients. Percentages for the Netherlands: Reproduced with permission from Jansen-van der Weide, M.C., Onwuteaka-Philipsen, B.D., van der Wal, G., 2005. Granted, undecided, withdrawn, and refused requests for euthanasia and physician-assisted suicide. Arch. Intern. Med. 165 (15), 1698–1704, copyright Ó 2005, American Medical Association.

b

decision making in both countries show that in the Netherlands 6.7% of all deaths (in 2010) and in Flanders (Belgium) (in 2013) 6% of all deaths had a request expressed for euthanasia or physician-assisted suicide prior to death (Chambaere et al., 2015a; Dierickx et al., 2015; Onwuteaka-Philipsen et al., 2012). This request was granted in 45% in the Netherlands and 77% in Flanders (Belgium). The latter was a substantial increase compared with the study in 2007 in Flanders (Belgium), both in terms of the proportion of dying people with a request (3.5–6%) and in the proportion of granted requests (56–77%) (Chambaere et al., 2015a; Dierickx et al., 2015). In the Netherlands the granting rate rose more moderately from 37% to 45% (Onwuteaka-Philipsen et al., 2012). The authors of the studies suggest that several years of experience with a euthanasia law has led to a large acceptance among patients and physicians of euthanasia as a valid option at the end of life (Chambaere et al., 2015a; Dierickx et al., 2015). The 2013 data in Belgium also indicate that the most frequent reasons for not granting the request were that the patient died before the request could be or was granted, the patient revoked the request, or the legal criteria for euthanasia were not met. There were no cases of objections from physicians on personal grounds and institutional policies of hospitals or nursing restricting the performance of euthanasia was only in one case reported by the physician as a reason for not granting the request, which was a significant change from the situation in the 2007 study (Dierickx et al., 2015). The large-scale physician surveys in Belgium (2010) and the Netherlands (2005) that asked about physicians’ most recent case of explicit request for euthanasia by one of their patients provide additional information on what influences the

granting of a euthanasia request. Contrary to the discourse that specialist palliative care and euthanasia are (or should be) mutually exclusive, a euthanasia request was no less likely to be granted in Belgium if the physician had palliative care training or belonged to a palliative care team. Nonreligious Belgian physicians were more likely to grant a request than their religious counterparts (Van Wesemael et al., 2011). In the Netherlands younger physicians were more likely to refuse a request (Jansen-van der Weide et al., 2005).

Procedure of Handling the Request

Robust data on how physicians handle euthanasia requests are, again, only available for the countries or states that have a legal framework. A qualitative study in Oregon indicated that physicians receiving a request for physician-assisted suicide often felt unprepared and experienced apprehension and discomfort after receiving requests, particularly due to their concerns about adequate management of suffering, not wanting to abandon patients, and incomplete understanding of patients’ preferences (Dobscha et al., 2004). The study indicated that actually engaging in an assisted suicide required a large investment of time and was emotionally intense. Neither the physicians who decided not to grant the request nor those who decided to do so expressed major regrets about their decisions. Requests often facilitated discussion of important issues, and many physicians felt that the process increased their confidence and assertiveness in discussing end-of-life issues with other patients. In Belgium (2010) and the Netherlands (2000–02) the large-scale surveys in representative samples of physicians asked about how the most recent euthanasia requests from a patient were handled (Jansen-van der Weide et al., 2005; Van Wesemael et al., 2011). In 21% (in Belgium) and 9% (in the Netherlands) cases the attending physician’s initial position toward the request was negative, meaning he or she had already decided to probably or certainly refuse the request. This usually also led to no further consideration of the request, for example, by not consulting a colleague physician. Sixty-five percent (in Belgium) and 87% (in the Netherlands) of all requests led to a consultation with an independent second physician about the request, and 77% (Belgium) and 80% (Netherlands) of these consultations resulted in positive advice from the independent physician. Of all the requests, 48% (Belgium) and 44% (Netherlands) eventually ended in euthanasia or assisted suicide. In cases where the second physician gave negative advice, he judged that there was no unbearable suffering (26%), that the medical situation was not hopeless (31%), that it was not a well-considered request (10%), or that there were palliative options available (26%). All laws regulating euthanasia and/or physician-assisted suicide worldwide stipulate a number of substantive requirements and procedural safeguards to be met by the patient and physician for a case to be legal. The consultation of an independent second physician is one such legal requirement in all countries with a euthanasia law. Similarly, the reporting of a performed case of euthanasia to a controlling and evaluation committee is mandatory. The studies in the Netherlands and Belgium indicate that a majority, but not all, cases of performed euthanasia comply with these legal requirements (Jansen-van der Weide et al., 2005; Van Wesemael et al.,

Euthanasia and Public Health 2011). Studies from both countries have also indicated that if Life’s End Information Forum (LEIF) (in Flanders, Belgium) or Support and Consultation on Euthanasia in the Netherlands (SCEN) (in the Netherlands) physicians – i.e., physicians specifically trained to handle euthanasia requests and to act as an independent consulting physician for physicians receiving a request – are consulted, the legal criteria for the handling of a euthanasia request are significantly more often met (Cohen et al., 2014b; Jansen-van der Weide et al., 2007). It remains unclear, of course, how euthanasia requests are handled in countries or jurisdictions that do not have a legal framework. It is clear, however, from the studies in Belgium that cultural differences also play an important role in how requests are handled: comparison of physicians in the Walloon region (French speaking) and the Flanders region (Dutch speaking) indicated that Walloon physicians held more negative attitudes toward performing euthanasia and toward the reporting obligation, consulted less often with an independent physician, less often granted a request, and less often officially reported a performed case as legally required (Cohen et al., 2012).

Reporting and Adherence to Due Care Requirements In Belgium and the Netherlands, the Federal Control and Evaluation Committee for Euthanasia and the regional review committees, respectively, review every case that is reported to them (which is mandatory) and assess whether the legal due care requirements have been met. In Belgium, the first case was referred to the public prosecutor only in the Fall of 2015 – though throughout the years the anonymity had been lifted for a number of reported cases to acquire more information from the physician relating to the circumstances of the euthanasia case (Federal Control and Evaluation Committee on Euthanasia, 2014). In the Netherlands, since the enactment of the euthanasia law, no cases have been legally prosecuted though a limited number have been forwarded to the public prosecutor for investigation due to noncompliance with legal safeguards (Rietjens et al., 2009). In Oregon, only one case of assisted suicide is known to have been legally prosecuted (Rich, 2002). Overall, prosecution of reported cases is thus extremely limited. However, these findings only relate to cases reported to the review committees. Reporting is itself a requirement in the laws of Belgium and the Netherlands, and population-based surveys in these countries have found that not all euthanasia cases are reported to the Committees (Smets et al., 2010; Rurup et al., 2008). The percentage of reported cases of euthanasia in the Netherlands increased from 18% in 1990 to 41% in 1995, 54% in 2001, and up to 80% in 2005 (Rurup et al., 2008). In the latest Dutch survey dating from 2010, the reporting rate remained at 80% (Ownuteaka-Philipsen et al., 2012). In Flanders, Belgium, a reporting rate of 53% was found in 2007, 5 years after the euthanasia law (Smets et al., 2010). The unreported cases in both countries often did not meet all procedural requirements: a written declaration was often absent, a second physician was not always consulted, and the drugs used were mainly opioids and benzodiazepines, not recommended for euthanasia. In the latest Flemish survey in 2013, an analysis of due care characteristics of euthanasia cases showed an increased adherence to legal requirements in all euthanasia cases (Chambaere et al., 2015a).

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Physicians’ reasons in both countries for not reporting a euthanasia case seldom had to do with their unwillingness. The main reason for not reporting was that the physician did not consider their action to be active ending of life, despite having administered drugs intended to hasten the patient’s death at his/her request (this was especially the case when physicians used morphine rather than sedatives followed by a muscle relaxant) (Smets et al., 2010; Rurup et al., 2008; van der Heide et al., 2007). Compared to reported cases, the amount of life shortening estimated by the physicians themselves was low, limited to hours or a few days (Smets et al., 2010).

Vulnerable Patient Groups A fundamental concern worldwide regarding legalization of euthanasia and physician-assisted suicide has to do with the risks for vulnerable patients, such as the oldest old, the disabled, the poor, and the uninsured (Lewis and Black, 2013). From a public health perspective, it is important for governments to protect particularly the most vulnerable groups of society. A study of socio-demographic and clinical groups in the Netherlands and Oregon showed that such vulnerable groups do not have a higher risk for euthanasia or assisted suicide than other patient groups (Battin et al., 2007). Studies in Oregon, Belgium, and the Netherlands have consistently shown that euthanasia or assisted suicide are predominantly practiced in people with advanced cancer, people with high education levels, and people under 80 years of age (Chambaere et al., 2011; Onwuteaka-Philipsen et al., 2012; Steck et al., 2013; Dierickx et al., 2015; Smith et al., 2015). As regards the question of the uninsured being at risk, in Belgium and the Netherlands, there is quasi-universal health-care coverage, and in Oregon no heightened risk for the uninsured was found (Battin et al., 2007). These population-level data thus do not corroborate the concern of heightened risks for vulnerable patient groups. There is much debate in Belgium and the Netherlands concerning euthanasia for patients who can be regarded as particularly vulnerable: (1) patients with advanced dementia, (2) minors, (3) patients with chronic mental illness (mostly severe depression), and (4) people who are ‘tired of life’ (Legemaate and Bolt, 2013). For patients with advanced dementia, discussion on legislative level is ongoing to expand the scope of the euthanasia law to this group, whereby the patient’s request is made through an advance directive designating a specific point in the patient’s illness trajectory when euthanasia can be performed. Euthanasia is now only possible for persons in the early stages of dementia, where competence is intact and for whom all other due care criteria are met. Euthanasia for minors is possible in the Netherlands from 12 years onward and without age limit in Belgium, but both jurisdictions stipulate additional due care requirements in the decision-making process, next to the ones in the original law (Chambaere et al., 2014). Patients suffering from chronic mental illness, such as longstanding depression or personality disorder, can be eligible for euthanasia according to the Belgian and Dutch laws, yet here also extra safeguards are put in place by the lawmakers. Particularly in the Netherlands there is much debate on allowing euthanasia or assisted suicide for the oldest old who are tired of life, but as of yet no legal amendments have been formulated (Legemaate and Bolt, 2013).

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Euthanasia and Public Health

Data about euthanasia practice in these populations is scarce (and often needs updating with more recent data). The 2007 large-scale population-based postmortem survey about end-of-life decision making in Flanders identified no cases of euthanasia in persons who died from dementia although a request for euthanasia was present in 1.3% of them (Chambaere et al., 2015b). In the Netherlands, the regional committees for euthanasia received 97 and 81 reports, in 2013 and 2014 respectively, of euthanasia for persons with dementia (Regional Evaluation Commissions Euthanasia, 2014). In nearly all cases it concerned dementia in early stages, and all cases were approved by the committees. The most recent public report from the Belgian euthanasia review committee mentions 4% of reported euthanasia cases in 2012 and 2013 to concern neuropsychiatric conditions including (early onset of) Alzheimer and vascular dementia (Belgian Federal Control and Evaluation Committee on Euthanasia, 2014). One of the prominent media cases in Belgium also concerned a famous writer in early stage Alzheimer who received euthanasia (Van Brussel and Carpentier, 2014). A study in Flanders including all deaths of children (aged 1– 17 years) during one and a half year in 2007 and 2008 (i.e., prior to the extension of the law to include minors) identified no cases of euthanasia in minors (Pousset et al., 2010). The first case of euthanasia in a minor patient is still to be reported in Belgium. A similar study in the Netherlands in 2001 identified euthanasia in 0.7% of deaths in children aged 1–17 years (Vrakking et al., 2005). In the Netherlands, only five euthanasia cases of minors have been reported since the legalization in 2002 (Rietjens et al., 2014). Good data on euthanasia/end-of-life decision making is absent for patients with chronic mental illness (mostly severe depression), and people who are ‘tired of life,’ presumably also because this is a rather marginal practice. However, it is clear from the public reports from the euthanasia review committees in Belgium and the Netherlands that a small number of persons with chronic and incurable mental illnesses receive euthanasia. There are no indications of euthanasia cases where tiredness of life and not one or multiple major physical or psychiatric conditions was the main reason for a euthanasia request (Belgian Federal Control and Evaluation Committee on Euthanasia, 2014; Regional Evaluation Commissions Euthanasia, 2014) Assistance in dying for these potentially vulnerable groups is highly controversial, and decision making particularly complex. Both in Belgium and the Netherlands, initiatives have been launched mainly for such controversial cases, offering consultation and guidance to people whose requests for assistance in dying are complex, and collectively reviewing their case in light of the legal requirements. In Belgium, this organization is known as ULTeam (Uitklaring Levenseindevragen Team), in the Netherlands it is the end-of-life clinic (Levenseindekliniek) (Snijdewind et al., 2015).

Mapping and Evaluating Regulation of Euthanasia and Physician-Assisted Suicide Regulations Although some countries have legally accepted both euthanasia and physician-assisted suicide, some countries or jurisdictions

have chosen to only regulate physician-assisted suicide. The current situation is that, as of December 2015, euthanasia and physician-assisted suicide have been legalized in five countries: the Netherlands (2002), Belgium (2002), Luxembourg (2009), Colombia (2015), and Canada (2015). Physician-assisted suicide is legalized or legally practiced in one country (Switzerland) and five US states (Oregon, Washington, Montana, Vermont, and California).

Regulations Regarding Euthanasia

The Netherlands was the first country to adopt a law on euthanasia in April 2002 after about 30 years of experience with the practice and regulated tolerance between 1990 and 2002 (Deliens and van der Wal, 2003). The law also includes physician-assisted suicide. The Belgian law, adopted by parliament in May 2002, was strongly based on the Dutch law (Deliens and van der Wal, 2003). Although it does not mention physician-assisted suicide the practice is considered to be a form of euthanasia by the euthanasia review committee (Belgian Federal Control and Evaluation Committee on Euthanasia, 2014). Luxembourg followed with a law in March 2009, largely based on the Belgian and Dutch laws and also included physician-assisted suicide (Watson, 2009). In Canada, the Quebec province legalized physician-assisted suicide and euthanasia in June 2014 (Dyer, 2014). As of February 2015, assisted suicide and euthanasia are also legal in the whole of Canada as a result of the ruling of the Supreme Court of Canada in the Carter versus Canada case, pending a 12-month period of suspension (Attaran, 2015). The court ruling implies that a law regulating the practice needs to be in place by February 2016. In Colombia, the government issued regulation for euthanasia in April 2015. In several other countries in the world, such as the United Kingdom (Delamothe et al., 2014), legalization of assisted dying is being discussed and it is likely that the number of countries with a law will increase in the coming decades. The existing laws stipulate several strict substantive criteria for the practice to be considered legal (Smets et al., 2009). The euthanasia laws in the Benelux (Belgium, Netherlands, and Luxembourg) all specify rigorous conditions for euthanasia. The patient’s request has to be explicit, voluntary, well considered, repeated, and not the result of external pressure. The patient must suffer from an incurable condition caused by disease or accident, with constant and unbearable suffering that cannot be alleviated, and with no reasonable prospect for improvement of his/her medical condition. Note that (1) the patient’s medical condition is not necessarily terminal, merely incurable, and (2) the type of suffering is not specified and that not only physical but also psychological or existential suffering can be invoked as admissible precondition. The physician must also inform the patient about his or her medical situation and prospects. Next to the substantive criteria, procedural criteria were invoked to enhance the quality of decision making, to introduce safeguards and to enable control, both a priori (the attending physician must consult a second, independent physician before deciding to grant a request) and a posteriori (the physician must notify the case of euthanasia to a local or federal committee of peers).

Euthanasia and Public Health Supplementary measures apply for specific patient groups. First, if the physician believes the patient is not expected to die in the foreseeable future he/she must consult a third physician about the request who should be a psychiatrist or a specialist in the illness from which the patient suffers. The physician must also allow at least 1 month waiting time between the request and the act of euthanasia. Second, the right to request euthanasia was extended in Belgium in 2014 to terminally ill minors. Supplementary measures are the obligation to consult a child psychiatrist or psychologist to ascertain the patient’s capacity to understand the consequences of their decision and a parent or legal guardian must support the decision. Minors are only eligible for euthanasia in case of unbearable physical suffering.

Regulations Regarding Physician-Assisted Suicide

Switzerland has had a non-prosecution of assistance in suicide based on a law from 1942 promulgating that only assistance in suicide out of selfish motives can be prosecuted (Bosshard, 2012). From the 1980s onward, several right-to-die movements across the country interpreted the law as a legal permission to set up organizations to facilitate assisted suicide. Switzerland is the only country that allows assisting in suicide not only for residents, but also for foreigners. In October 1997 Oregon became the first state in the United States to enact a law regulating physician-assisted suicide, the Death with Dignity Act (Coombs Lee, 2014). The Act applies to terminally ill patients only, with a life expectancy of at most 6 months. Washington (in 2009) and Vermont (in 2013) followed Oregon in enacting laws on physician-assisted suicide with a protocol for practice (Dyer et al., 2015). In Montana, a court ruling in 2009 and the ensuing jurisprudence decriminalized the practice. A similar court ruling occurred in New Mexico in 2014, but it was reversed on appeal in August 2015. California became the latest US state to legally regulate the practice in September 2015. In several other states legalization is under consideration (Orentlicher et al., 2014).

Influence of Regulation on End-of-Life Care Evaluating the effects of decriminalized euthanasia or physician-assisted suicide on end-of-life care is inherently problematic given that cause-and-effect relationships are difficult to substantiate and many other societal and cultural evolutions in health care may affect observed changes or trends. Nevertheless, it is possible to assess whether any anticipated or plausibly attributable trends materialize in jurisdictions that allow euthanasia or assisted suicide.

Palliative Care

One supposed effect of regulation is on the development of the palliative care movement in health care. Assisted dying is often regarded as antagonistic to palliative care (Bernheim et al., 2008), which is “an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual” and which intends neither to postpone nor to hasten death (Sepúlveda et al., 2002). Therefore,

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a prevalent concern is that the development of palliative care and its services could be impeded by legalization of euthanasia or assisted suicide, and that severely ill and dying patients will be deprived of adequate end-of-life and palliative care (Gordijn and Janssens, 2004; Bernheim et al., 2008; Hudson et al., 2015). Research and legislative developments in jurisdictions with decriminalized euthanasia or assisted suicide do not corroborate these concerns. A majority of Oregon nurses and social workers believed that in the 5 years after enactment of the law, Oregon physicians improved their palliative care skills and were more willing to refer and care for hospice patients (Goy et al., 2003). In the last decade, palliative care services have also developed considerably in the Netherlands, Belgium, and Luxembourg (Chambaere and Bernheim, 2015). In Belgium and Luxembourg, the euthanasia laws were enacted together with laws on palliative care declaring palliative care as a basic patient right and ordaining the structural and financial organization of palliative care services so as to facilitate universal access to palliative care. Belgian government spending on health care costs pertaining to palliative care has been increasing considerably annually since the enactment of the euthanasia and palliative care laws (Chambaere and Bernheim, 2015). Although it is not certain that these developments in palliative care are related to the law, they are at least likely to be related to the euthanasia debate and the larger societal focus on end of life and quality of death and dying (Gordijn and Janssens, 2004; Onwuteaka-Philipsen et al., 2005). There is further evidence suggesting that, in some jurisdictions, euthanasia/assisted suicide and palliative care are not mutually exclusive and that palliative care is given to patients requesting assisted suicide or euthanasia. The official stance of the Federation for Palliative Care Flanders (Belgium) is that euthanasia should be embedded in palliative care (Vanden Berghe et al., 2013), and a historical analysis of the euthanasia and palliative care movements revealed a synergistic relationship rather than an antagonistic one (Bernheim et al., 2008). Empirical facts reveal their interrelationship in end-of-life practice. An independent study in Flanders found that three in four patients receiving euthanasia had been referred to a palliative care service at the end of life (Chambaere et al., 2015a). Also in Oregon (over 90%) and Washington (68%) the latest reports show that a large majority of those dying by physician-assisted suicide were enrolled in hospice care (Oregon Public Health Division, 2015; Washington State Department of Health, 2014).

Physicians’ Attitudes and Practices

While public support for euthanasia and assisted suicide is generally high, particularly in Western European countries including Belgium, the Netherlands, and Switzerland (Cohen et al., 2013, 2014), it is ultimately the attitudes of physicians (and other care professionals) that determine whether and to what extent these practices will be performed. A study in 2009 found that 90% of Belgian physicians supported the euthanasia law, and that around one out of five doctors would never perform euthanasia themselves (Smets et al., 2011). In Oregon, shortly after the Death with Dignity Act was enacted, 69% of physicians did not oppose the legalization of assisted suicide and 46% were not willing to prescribe a lethal medication consistent with the Death with Dignity Act (Ganzini et al., 2001). In the Netherlands, one out of 10 physicians would

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4% 3.2% 3%

Belgium

The Netherlands

1.8%

2% 1.5% 1%

0.8%

0.7%

1.7%

Conclusion

0.7% 0.4%

0.2%

0% 1990

1995

2001

of all deaths in 1998 was down to 1.7% in 2013 (Figure 2). With these data the concern of higher rates of life ending without explicit request is not supported. More research is necessary internationally to evaluate the effects that regulating euthanasia or assisted suicide have on the dying population.

2005

2010

1998

2001

2007

2013

Figure 2 Shifts 1990–2013 in the actual use of life-ending drugs without explicit patient request in Flanders, Belgium, and the Netherlands. Figure made by the authors based on Chambaere, K., Vander Stichele, R., Mortier, F., Cohen, J., Deliens, L., 2015. Recent trends in euthanasia and other end-of-life practices in Belgium. N. Engl. J. Med. 372 (12), 1179–1181 and Onwuteaka-Philipsen, B.D., Brinkman-Stoppelenburg, A., Penning, C., de Jong-Krul, G.J., van Delden, J.J., van der Heide, A., 2012. Trends in end-of-life practices before and after the enactment of the euthanasia law in the Netherlands from 1990 to 2010: a repeated cross-sectional survey. Lancet 380, 908–915. The bars represent percentages of all deaths.

never perform euthanasia or physician-assisted suicide (Gordijn and Janssens, 2004; Onwuteaka-Philipsen et al., 2005). It is unclear to what extent attitudes toward and willingness to perform these practices have changed under the influence of the legal regulations, as no reliably comparable repeat surveys have been conducted within any country. Monitoring changes in this context would be important as this could provide relevant indications for issues raised by critical voices regarding the impact of assisted dying laws on physicians themselves, in terms of emotional problems, stress, burnout, professional and deontological confusion, as well as strained physician–patient relationships (Cohen-Almagor, 2013; Deschepper et al., 2014). One often voiced concern regarding physicians’ attitudes and practices relates to a possible shift in their willingness to hasten death without the patient’s request (van Marwijk et al., 2007; Lewis, 2007; Chambaere et al., 2010). Indeed, a study in 2001 among physicians in seven countries found that between 9% (Netherlands) and 46% (Italy) agreed with the statement that “permitting the use of drugs in lethal doses on the explicit request of the patient will gradually lead to an increase in the use of drugs in lethal doses without a request of the patient” (Miccinesi et al., 2005). While reliable data on shifts in physicians’ willingness is nonexistent, large-scale repeat surveys in Belgium (Flanders) and the Netherlands have monitored actual practices at the end of life, including the use of drugs intended to hasten death without explicit patient request over time (Chambaere et al., 2015a; Onwuteaka-Philipsen et al., 2012). The main results of those studies are shown in section Assessment and Monitoring of End-of-Life Practices (see above). Figure 2 shows the shifts in the actual use of life-ending drugs without explicit patient request, from which can be seen that the trend is toward lower rates rather than higher rates. Between 1990 and 2010 the incidence of this practice decreased from 0.8% to 0.2% of all deaths in the Netherlands, whereas in Belgium the initial rate of 3.2%

In all studied (Western) countries, death comes suddenly and unexpectedly in about one-third of cases. For the remaining two-thirds of deaths, end-of-life decision making appears to be an important issue in all countries. Intensified alleviation of pain or symptoms and nontreatment decisions occur relatively frequently, while euthanasia and physician-assisted suicide are relatively rare. All over the world, it is likely that physicians every now and then will be confronted with patients requesting euthanasia or physician-assisted suicide. This, together with the trend of increased public acceptance of euthanasia over the last three decades (at least in Europe) might increase pressure for a regulation debate in more countries. Although experiences of countries with relatively long-standing legislation cannot be straightforwardly translated to other countries, they give an indication that regulation, at least to some extent, can bring transparency, public oversight, and legal control. Seriously studying and discussing medical practices and experiences in different countries can add much to debates about morally laden issues within end-of-life care, to further improve the understanding of desirable and undesirable differences and similarities in end-of-life care in different countries. Data about the practice of assisted dying are scarce, particularly from countries that do not have a legal framework for euthanasia or physician-assisted suicide. Nevertheless, data from countries without such legislation (as well as data from time periods prior to the legalization in Belgium and the Netherlands) show that the practice of assisted dying is taking place. Collecting good data to evaluate and monitor end-of-life practice should therefore be a substantive public health aim to most developed countries, and not only to countries that have created a legal framework. The latter countries face the additional challenge of adequately monitoring the effects of regulation on end-of-life practice. This article addressed only industrialized countries, while end-of-life care is a global public health problem: 85% of all deaths annually occur in developing countries. However, most research and end-of-life care initiatives take place in industrialized countries. This is probably caused not only by the differing epidemiology of mortality (in the developing world, death is often a faster process, occurs earlier in life, and is less frequently cancer related), but also by differences in economic situation (adequacy) of health-care systems, and cultural factors. Nevertheless, the quality of end-of-life care should be seen as a global public health-care problem (Singer and Bowman, 2002).

See also: Cancer Mortality; Cancer Survival; Hospice and Palliative Care; Infant Mortality; Legal Issues in Public Health; Public Health Approaches to Dying, Death, and Loss; Public Health Law and Public Health Policy.

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Evidence-Informed Public Health Policy Jana Sisnowski and Jackie M Street, School of Public Health, University of Adelaide, Adelaide, SA, Australia Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Vivian Lin, volume 2, pp. 527–536, Ó 2008, Elsevier Inc.

Why the Interest in Evidence-Informed Public Health Policy?

Transitioning from the Idea of Evidence-Based to Evidence-Informed Public Health Policy

The desire for scientific evidence as the basis for public health policy is not new (Terris, 1980). There was, however, sharply increased interest in the idea of evidence-based policy making during the 1990s, in part derived from the advent of the evidence-based medicine (EBM) movement. At the core of the EBM paradigm is the ‘conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients’ (Sackett et al., 1996). The principle that health policy, and in fact policy generally, should be based on knowledge of what works also arose with the increasing use of social programs and their evaluation in the 1960s and the push for cost-effectiveness in the public sector management reforms of the 1990s. There are many reasons put forward by analysts about why the notion of evidence-based policy making became popular. Ham et al. (1995) suggested that if medicine should be evidence based, then so too should health policy. The UK government broadly adopted this thinking across public policy, with their Modernizing Government White Paper (United Kingdom Cabinet Office, 1999), which argued for a more professional approach to policy making. More recently, the UK launched a set of ‘what works’ centers bringing the discourse of evidence-based public health policy into an institutional structure (United Kingdom Cabinet Office, 2013). Mounting pressures for transparency, accountability, and efficiency, in all areas of public health, has increased the demand for use of evidence (Cookson, 2005), but it became apparent that there were other benefits to be gained as well. In particular, the use of evidence in policy making helps to shift the focus away from expert opinion, thereby minimizing the dominance of competing interest groups (Rodwin, 2001). Basing policy on what had been proven to work (rather than speculation, guesswork, or intuition) also reduces the risks associated with policy making (Rix and Matete, 2005). The pace of technological change and the rise of personalized medicine have meant that decisions are increasingly being made which involve very high costs with the associated impact on government budgets. Effective public health policy can promote health in a number of ways thereby reducing medical costs and the pressure on medical systems. Gelijns et al. (2005) have suggested that rigorous clinical and economic evidence can help depoliticize difficult policy decisions. Public health policy decisions can also be highly contentious, and it follows that good evidence to support such decisions will go some way to defusing public tensions. However, as we discuss later in this article, evidence is the only one factor in a complex highly political web of influence and pressure. Therefore, while there is much agreement about the ideals and rationale for evidence-based policy making, how to make it a reality has been much more challenging. These perspectives and debates are explored in this article.

Definitions of EBM were adapted to public health as ‘the development, implementation, and evaluation of effective programs and policies in public health through application of principles of scientific reasoning including systematic uses of data and information systems and appropriate use of program planning models’ (Brownson et al., 1999: p. 87). Kohatsu et al. (2004): p. f419) further broadened the definition of evidence-based public health as “the process of integrating science-based interventions with community preferences to improve the health of populations.” However, as Black (2001) stated, “evidence based policy is not simply an extension of EBM: it is qualitatively different.” In particular, evidence-based public health policy has a focus on health policy decisions across populations, rather than decisions about individual patients. By way of distinction, health policy could be considered to be focused on health-care structures while public health policy is concerned with systems, laws, and regulations which produce health. In an extension of this, the ‘health in all policies’ approach aims to improve population health through consideration of the determinants of health across all policies and all parts of government (Kickbusch, 2010). If evidence-based public health policy was to draw from the best knowledge available, then the first two points of contention were (1) what is the nature of that knowledge or evidence and (2) should policy be based solely on this evidence? In the mid-2000s, there were two views about the role of scientific evidence in informing public health policy (Lomas et al., 2005): (1) that science can reveal universal truths and offer context-free guidance and (2) that scientific evidence has little meaning or importance for decision-making until it is adapted to the circumstances of its application. The first view is now largely discredited and it is clear that the applicability of evidence will vary depending on the context or setting in which the policy will be applied (Dobrow et al., 2004). This has been recognized as a particular issue in developing country settings since most evidence is produced in developed health settings (Hutchison et al., 2011). In response, the World Health Organization developed the Evidence Informed Policy Network along with a set of tools to assist policy developers in the assessment of evidence in different contexts (for example, Lavis et al., 2009). Furthermore, the notion of what counts as evidence expanded. The importance of qualitative research (VicHealth, 2011) and deliberative democratic methods such as citizens’ juries (Street et al., 2014) in policy development is now well recognized. Similarly the notion of colloquial evidence emerged (Lomas et al., 2005; CHSRF, 2006) recognizing that expert and professional opinion; political judgment; values, habits, and traditions; and outputs by lobbyists and pressure groups could be incorporated into evidence to provide contextual information and fill information gaps.

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Much of the early discourse about EBM, and evidence-based public health policy, presumed that evidence is context free, value free, and interest neutral. However, this assumption discounted the political element of agenda setting in research. Not only is research overwhelmingly publicly funded and therefore dependent on government priorities, but private funders also exert influence about the direction and expected results of research. The Coca-Cola Company funding a not-for-profit organization, intended to emphasize physical inactivity rather than caloric overconsumption as the main contributor to obesity, is a recent example of commercial interests attempting to shape the evidence base in their favor. While the group has since been dissolved and the University of Colorado School of Medicine returned a US$1 million grant (O’Connor, 2015), this example is just one instance of research being anything but interest neutral. Moreover, as Gelijns et al. (2005) argue, the policy-making process itself necessarily has to wrestle with conflicts of value, and is therefore, inherently political. Gray (2005) not only recognized the existence of social and political influences in health care, but was also an early proponent of the idea that value-based decision-making is also important. In recent years, the discourse has shifted to evidence-informed health policy to recognize that decisionmaking is informed by research, but not driven by it.

What Evidence Is Required for Public Health Policy? The process of evidence-based clinical practice includes decision-making. The potential nature of this process is described by the Sicily Statement (Dawes et al., 2005): translation of uncertainty to an answerable question; systematic retrieval of the best evidence available; l critical appraisal of evidence for validity, clinical relevance, and applicability; l application of results in practice; l evaluation of performance. l l

In theory, this same rational, technical model would apply to public health policy making. That is, a policy question would be defined and evidence systematically retrieved and appraised with subsequent adoption of evidence-based policy. This approach is problematic in public health policy in that opinion varies regarding the quality and appropriateness of different types of evidence: EBM favors randomized controlled trials and systematic reviews with an evidence hierarchy guiding assessment of quality (Petticrew and Roberts, 2003). By contrast, in public health policy, cause and effect chains are often considerably more complex and indirect than in clinical interventions. Furthermore controlled environments, if feasible, are likely to be a poor predictor for real-life human behavior (for example, see Victora et al., 2004). In response, Petticrew and Roberts (2003) suggest a typology based on the nature of the policy question is more helpful than a single hierarchy of evidence. In addition, as Swinburn et al. (2005: p. 24) observe, population-level obesity prevention, approaches that indiscriminately target ‘personal behaviors in the society at large’ through policy present the additional difficulty that the desired impact might emerge only gradually and cumulatively. These considerations indicate that the spectrum of evidence

considered admissible for public health policy making needs to be broad and diverse, including end points other than direct health impact. This point forms the basis for the realist systematic review method: as Pawson and et al. (2005) explain, the goal of a selection and appraisal of evidentiary sources in form of a focus on program logic and intermediate outcomes reflects the complexity of real-life public health policy interventions. Further obstacles to the realization of a rational model in public health policy making might be that the relevant research or evaluation has not been undertaken or the available research lacks relevance or is of poor quality. Even when rigorous research or evaluation is undertaken the results may not be published or are difficult to find. Part of the problem is that the usual expectation is that real-life public health policy interventions should be evaluated by those who implement them. However, public health departments often lack the organizational capacity to carry out complex evaluations and have a lesser incentive to publish their findings in peer-reviewed journals than academic researchers. Where administrations such as the New York City Department of Health and Mental Hygiene have embraced an active contribution to the evidence base as part of their role (Farley and Van Wye, 2012), they are seen as exceptional (Laugesen and Isett, 2013). Furthermore, what is published is likely to be skewed toward developed countries because of the availability of research funding, orientation of research-funding bodies, the interests of scientific journals, and the nature of peer-reviewing processes. Reporting of real-life experiments in public health policy may be seen as insufficiently rigorous in design, leading to underrepresentation of some forms of evidence (Kavanagh et al., 2002). For example, a simple pre–post study intended to assess the effect of New York City menu labeling laws on the average caloric value of meals purchased (Dumanovsky et al., 2011) was criticized for the chosen methodology (Pande and Soumerai, 2011). In response, the authors from the New York City Department of Health and Mental Hygiene pointed to the essential requirement for any evaluation of real-life public health policy interventions to align with the reality of a policy in progress and the limited resources of a public agency (Silver and Bassett, 2011). Health and medical research is typically focused on either describing the nature and magnitude of specific health problems, or on the effectiveness of particular clinical interventions. From the perspective of public health policy, there may be a range of other questions for which policy makers want answers, but for which evidence is not available, such as the conditional effectiveness and the return on investment for policy measures, the feasibility and acceptability of policy proposals, and the possible distributional impact of different policy options. In other words, it is likely that evidence will be needed from economic, social, political, and cultural perspectives. A wide range of disciplines, from epidemiology to anthropology to management sciences, all contribute to policy making. Certainly, more evidence is needed that offers possible solutions rather than simply describing the problem. For example, despite progress since the early call by Millward et al. (2003) for more research addressing reducing health inequities the lack of research in this area persists (Paudel et al., 2012).

Evidence-Informed Public Health Policy Lavis (2002) investigated what information decision makers did want in the policy domains that might alter health inequalities (i.e., tax transfer, labor market, social services) and found their interests to be in finding what the effective policy interventions and their trade-offs are (including the health consequences of policy alternatives). His findings suggest that decision makers are interested in research leading to actionable recommendations. It is clear that different types of research are needed to influence policy making, as seen in Table 1. Lin and Fawkes (2005), in looking at health promotion effectiveness, point to a long pathway between the availability of good-quality evidence and the successful implementation of that evidence. They suggest that evidence only provides a theoretical understanding about effectiveness, and achievement of effectiveness in situ depends on adequate infrastructure and capacity (such as a skilled workforce, sufficient financing, and policy and management support), as well as an appropriate scale of intervention (including adequate population coverage and targeting). The problem of adequate infrastructure and capacity may be a particularly important barrier to implementing evidence-informed public health policy in developing countries. By the logic outlined by Lin and Fawkes (2005), the mere assessment of evidence on intervention (or policy) effectiveness requires an understanding of the implementation conditions for various policy regimes or program delivery. Process evaluation becomes as important as summative evaluation (that is, evaluation of outcomes, outputs, and efficacy upon Table 1 Examples of research paradigms for generating policyrelevant evidence Research paradigm Applied

Descriptive

Evaluative

Community

Systems

Description

Links to policy

Seeks to apply information learned from basic research to develop practical use Explore in-depth information and phenomenon to gain fuller understanding Assess processes and outcomes of interventions or of prevailing practices and current policies Collaborative research effort between researchers and stakeholders, particularly the affected communities Examines the organization, financing, staffing, governance, and delivery of services

Clarify immediate societal problem Clarify problem, context, and response to possible interventions Clarify effects of policy

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completion of active intervention) for policies and programs, as the evidence derived from process evaluation informs how new policies and programs could be successfully implemented.

How Does Evidence Get Taken up in the Policy Process? The rational technical model of policy making as described by Althaus et al. (2013) makes two claims: it is rational and cyclical (Figure 1). Within such a model, knowledge derived from research and evaluation can be fed into decisionmaking at different points in time, just as information obtained through consultation and other sources can be incorporated. In theory, formative evaluation (concerned with the process of program development and delivery) becomes particularly important during the implementation stage, while summative evaluation contributes to the reformulation of the policy, or to the translation of policy approaches to other settings based on the experiences in earlier iterations by early adopter jurisdictions. In reality, both policy making and research transfer into decision-making are more complex processes. Multiple meanings can be attributed to research utilization. Writers such as Weiss (1979) and Short (1997), early on, suggested that a range of models of research utilization exist in addition to the rational model (Table 2). These models might describe the relationship between research evidence and policy making, but there remains another question of the role evidence plays in policy formulation, and by implication, what are the other influences on the decision-making process, including whose evidence counts? A number of theories are pertinent (Table 3). Bowen and Zwi (2005) propose that many different forms of evidence are taken up and utilized in a nonlinear or diffusive manner, in evidence-informed policy and practice pathways, which may have three progressions: (1) sourcing the evidence, whereby knowledge, research, ideas, interests, politics, and economics influence the extent to which evidence is adopted or rejected; (2) using the evidence, where evidence is introduced, interpreted, applied, and then either used or rejected; and (3) implementing the evidence, where individual, organizational, and system-level actions are taken. The policy advocate’s skills, experience, and networks may be critical in determining the pathway by which evidence travels. Similarly, Consultation

Coordination

Decision

Focus on stakeholders’ concerns to target better possible solutions

Policy instruments Suggest ways to improve quality, performance, efficiency, and effectiveness of service delivery

Adapted from Potter, M., Quill, B., Aglipay, G., et al. 2006. Demonstrating excellence in practice-based research for public health. Public Health Report 121, 1–16.

Policy analysis

Implementation

Identify issues

Evaluation

Figure 1 Policy-making cycle. Adapted from Althaus, C., Bridgman, P., Davis, G., 2013. The Australian Policy Handbook, fifth ed. Sydney, Allen and Unwin, pp. 38.

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Table 2 Models of research utilization relevant for policy making. The relationship between research evidence and policy making Model

Description

Rational

Basic research leads to applied research, which in turn leads to product development, and then finally to application The results of a specific study are applied to a pending decision Research is used to support a predetermined

Problem solving Political policy position Tactical Interactive

Enlightenment

Materialist Elective affinity

Research is used as a delaying tactic to avoid responsibility for unpopular policies Researchers are one set of participants among many, with policies also being informed by politics, experience, insights, and judgment calls Research diffuses through multiple channels over time and provides new ways of thinking, so that policy reflects the indirect influence of research, rather than being the direct outcome of particular research findings Policies are informed more by economic imperatives than by scientific truths or moral stance Policy makers are more likely to respond to research findings if they have participated in the research process, and where the beliefs and values of the policy audience coincide with research finding

Adapted from Weiss, C., 1979. The many meanings of research utilization. Public Adm. Rev. 39, 426–431; Short, S. 1997. Elective affinities: Research and health policy development. In: Gardner, H., (Ed.) Health Policy in Australia. Melbourne: Oxford University Press.

Table 3

organizational culture in the policy-making agency is crucial to opening up additional pathways by way of collaboration and active engagement with research and researchers (Sisnowski et al., 2016). However, despite all the theoretical explanations of how evidence may be taken up into policy, the possibility of serendipity should not be ruled out (Lin, 2003a). Being at the right place, at the right time, in the company of the right people may be a predesigned course of action; it can also be pure circumstance and accidental. Given the complex factors that influence policy making and the uptake of research in that process, there are likely to be a number of conditions that have to be met if research evidence is to be taken up in public health policy (Buse et al., 2005: p. 160): l l l l l l l

The existence of comprehensive, authoritative statements based on systematic reviews of research evidence. The usefulness of such statements to provide direct guidance to decision-making in specific circumstances. Knowledge and acceptance of such statements by all relevant players. Adequate resources to act upon the statements of evidence. Appropriate and sufficient incentives to apply the evidence. Concurrent absence of disincentives to apply the evidence. Control over the implementation chain to ensure compliance with direction and with the evidence base.

These conditions are not easily met. As Pawson (2002) observes, the policy cycle is generally quicker than the research cycle such that policy makers need to turn to systematic reviews to gather evidence. The systematic review of natural policy experiments may be particularly useful in this context but such experiments are rarely evaluated. In concert with the

Theories of the role of evidence in policy formation

Theory

Originator

Description

Old institutionalism

For example, Woodrow Wilson, Herbert Simon

Garbage can model

Cohen et al. (1972)

Organizational epistemology

Dery (1984)

Advocacy coalition

Sabatier and Jenkins-Smith (1993)

Agenda setting

Kingdon (1984)

There are formal processes for policy making and institutions and actors designated to play. Therefore, research is necessarily filtered by the formal policy processes and the political and organizational context of decision-making within these bodies. Within policy-making organizations, there are a myriad of policy problems looking for solutions, as well as policy ideas looking for problems for which they can provide the solution. Policy-making bodies (i.e., government bureaucracies) may adopt and lock into preferred positions. In these instances, systematic bias occurs in policy making through search for and use of data that supports predetermined organizational imperatives. Policy making does not happen within a closed organizational system. There are advocates for different policy solutions who work within the bureaucracy as well as outside. These advocacy coalitions work across government and civil society, with shared values and common ways of framing problems and solutions. Research thus influences policy through beliefs of advocacy coalitions. Many policy problems persist without solutions. Many policy ideas persist without being taken up in decisions. Policy making relies on political will, but that policy will be focused on matters other than long-standing policy problems or policy solutions. Thus, policy making occurs only when these three streams (policy problems, policy solutions, and political will) come together.

Evidence-Informed Public Health Policy EBM movement, the use of systematic reviews has increased in health policy and practice, particularly following the establishment of the Cochrane Collaboration in the early 1990s. While systematic reviews are mostly focused on evidence of effectiveness, the call by policy makers for a wider range of evidence means that the methodologies used for the synthesis of diverse sources of evidence are being widened and are continually in a process of development (Popay, 2006; Pawson et al., 2005).

Why Does Evidence Not Always Get Taken up (or Why Are Public Health Policies Not Always EvidenceInformed)? The history of public health policy points to examples of evidence-informed policy as well as numerous instances where policies lack an evidence base. It could be argued, for instance, that the ill effects of tobacco on smoking were known in the 1950s, but policy action was relatively minimal until the 1980s and onward. Similarly, although the health issues associated with obesity and poor nutrition are well recognized, evidence-informed policy responses are relatively rare and systematic multisectoral approaches are absent (Sisnowski, 2015). Theories about the policy-making process, which incorporate recognition of the politics of decision-making, start to provide some answers as to why evidence is not always taken up. There are numerous influences that shape public health policy making. Given that the focus of public health policy is to drive decisions beneficial for society as a whole, there are many factors to be considered: the adequacy and completeness of evidence; the possible benefits and consequences (and their distribution); how to trade off short-term and long-term costs and gains; and how to reconcile potentially conflicting economic interests, social values, cultural beliefs, and traditions, institutional and political structures, and processes for policy making. Thus, decision-making at the population level is often taken in a milieu of uncertainty (Dobrow et al., 2004) and competing demands of stakeholders are ever present. Communities adopt different conceptions of health risk (Beck, 1992), and these notions of risk may be shaped by mass media representation of events. Media can also create political risk by bringing attention to debates or popular concerns (Davies and Marshall, 2000; Marshall et al., 2005). Also, the debate about policy choices may be masked as conflicting perspectives about evidence (Atkins et al., 2005). Decision makers may be confronted with both moral and informational uncertainty, as the definition of the problem, the possible solutions, and the nature of evidence that underpins both are contested. Additionally, policy makers may have goals other than effectiveness with regard to health outcomes when producing health policy. Health service policies, which should ultimately improve clinical outcomes, may be made with financial, social, or strategic development goals in mind (Black, 2001). By way of example, public health policies, particularly those targeting risk factors for chronic disease, frequently intervene on the market through taxation or regulation. Excise taxes imposed on sugar-sweetened drinks or a range of foods and beverages deemed unhealthy may serve the double purpose of reducing

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consumption and raising general or health-specific revenue. The short-lived Danish tax on saturated fat content illustrates the conundrum of such a double purpose where the goals are not necessarily 100% congruent: the design of the Danish tax was considered cumbersome and illogical, in part because certain rules did not seem to prioritize health outcomes, but rather emphasized maximizing revenue collection (Vallgårda et al., 2015). Analysts argue that the fact that the tax was part of a larger fiscal reform package that proceeded through financial rather than health decision-making structures contributed to its quick abolition because it allowed the political and public discourse to shift rapidly from addressing health concerns to a discussion of adverse economic impact and prevented public health advocates from forcefully supporting the tax (Bødker et al., 2015; Vallgårda et al., 2015). Politics, ideology, and political economy may thus be more important drivers of policy making, especially when there is scientific and policy uncertainty about the appropriate course of policy action. Beyond political complexities, there are also practical barriers to evidence-informed health policy making. Even with the best intentions, it has not always been possible for researchers and policy makers to connect the results of research with decision-making. Researchers and policy makers have been characterized as living in two worlds (Lomas, 2000). There are numerous differences between these two groups in terms of imperatives and styles in decision-making (Choi et al., 2005; Brownson et al., 2006) (Table 4). Even where systematic reviews of evidence do exist, public health decision makers may still encounter a number of challenges in incorporating them into decision-making. These include locating relevant evidence and critical appraisals of that evidence, the timeliness of evidence provided and the difficulty in knowing how best to use the information (Tirilis, 2011). Weiss (1991) suggests that research outputs may be classified as (1) data and findings, (2) ideas and criticism, and (3) arguments for action, each being perceived to be useful for different purposes. Research data and findings may be Table 4 Two worlds: Different characteristics of researchers and policy makers may prevent connection of research results with decisionmaking Characteristic

Researchers

Policy makers

Nature of work

Discrete, planned projects

Incentives Time frame for action Knowledge span

Publications, grants Longer

Continuous, unplanned flow of ever-changing tasks Reelection, recognition Shorter

Deep but on narrow issues Empirical data

Broadly across many issues All forms of information

Beyond reasonable doubt Scientific peers and research-funding agencies Research funding and research ethics

On the balance of probabilities Politicians and electorate

Type of evidence used Basis for decision Accountability Constraints

Political and bureaucratic imperatives

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Evidence-Informed Public Health Policy

useful for choosing policy options when the nature of the policy problems and possible solutions are clear. Ideas and criticisms may be more useful for policy agenda setting, to obtain attention on policy problems and provide possible solutions. Arguments for action, however, are likely to require active advocacy by those involved in the policy-making process. In addition to the availability and suitability of research evidence for policy making, it should be noted that even a good evidence base does not automatically translate into successful policy implementation. As Rutten (2012) points out “if these policies fail [.] to approach key determinants of effective policy development and implementation,” for reasons such as insufficient organizational capacity or failure to take into account political considerations and public opinion, their content may be evidence-based, but they will not reach expected goals.

Building Bridges Across Sectors for Effective Evidence-Informed Policy There are numerous suggestions about how to reduce the gap between researchers and policy makers. These fall into the categories of (1) content, what should be researched and how; (2) what mechanisms should be put in place; and (3) capacity building and culture change. In relation to content, it has been recognized that there is a need to move from RCTs to gathering evidence about a range of determinants of health through interdisciplinary research teams and evaluation of policy interventions (Macintyre, 2003; NIH, 2006; Nutbeam, 2004). In addition, the use of systems thinking and modeling to produce useful practice-based evidence for policy making has progressed (Swinburn, 2015; Smith, 2016; Green, 2006), while Pawson et al. (2005) and Brennan et al. (2011) have promoted a broader approach to evidence collection through recognition of the policy process – and therefore the forms of evidence – as a continuum. Brownson et al. (2006) suggest that policy research should include (1) understanding the determinants of policy making and (2) assessing impact of policy implementation, with case studies being a useful methodology. The mechanisms mooted as useful for improving links between researchers and policy makers are numerous. The development of a strategic, priority-driven research program has been suggested as one method for ensuring research will be more overtly directed toward informing policy (and practice) (Nutbeam, 2004). Lomas (2000) promoted knowledge transfer by the use of knowledge brokers who have a role in linking policy makers and researchers through translating questions and findings to one another. Oldenburg (2000) suggested, however, that effective dissemination involves more than linkage and exchange, and points to the need to invest in factors that support dissemination (such as organizational resources and infrastructure). Hanney et al. (2002) also argued that a range of strategies are required for research translation, including long-term liaison, knowledge brokers, evidence champions, change agendas, diffusion networks and communication training. The particular approaches need to suit the stage of policy development, as

well as the types of evidence required or in use. The importance of systematic collation and dissemination of international evidence of effectiveness has been recognized in Sweden, the Netherlands, and the UK (Macintyre, 2003). Independent institutions may be in the strongest position to offer trustworthy synthesis of research data as the basis for informing policy debates (Ham et al., 1995). To encourage collaboration across sectors, Black (2001) called for changes in researchers’ attitudes, funders’ understanding, and the way research is conducted. However, despite considerable efforts by researchers, funders, and policy makers to link research to policy, there is, in many jurisdictions, considerable room for improvement (Otten et al., 2015). Capacity building has been recognized as the basis for culture change. Brownson et al. (2006) suggested that researchers become more involved in the policy process, through development of short policy summaries, presenting data in more understandable forms, and providing testimony at public hearings. Further, public health training programs should ensure communication skills, including working with the media, are imparted to students. Kavanagh et al. (2003) suggested increasing policy makers’ skills for critical appraisal of research and its methodology as one strategy, and Ross et al. (2003) suggested that interactions between researchers and decision makers needs to occur within and outside the research process. In the latter approach, decision makers can become involved as formal supporters, responsive audience, and integral partners depending on the context. The disparities in the priorities and approaches between researchers and policy makers are not the only gap in the policy-making process for public health policy. The last decade has seen increased adoption of deliberative democratic methods as a means to bring people’s opinions and values into public health policy processes (Degeling et al., 2015; Street et al., 2014) and/or to bring together scientific and decisionmaker communities (CHSRF, 2006). Such participatory forums can be used to consider a range of evidence, to pay explicit attention to underpinning values and to promote consensus. Rather than being a policy consultation process, a deliberative process fosters an integration of rigorously collected evidence with stakeholder views (Street et al., 2014). The practical steps most commonly advocated for reducing the gap between research and policy are summarized in Table 5 (Lin, 2003b; Buse et al., 2005). These practical approaches are useful starting points, but are not a substitute for institutional cultural change or for effective information collection which permits ongoing monitoring of policy impact (Lin, 2003b). Since the establishment of the Cochrane Collaboration, other collaborative institutions have been created with the aim of producing high-quality systematic reviews of research in the health (and other) fields. Notably, the Campbell Collaboration has been set up as a parallel organization to Cochrane for reviewing interventions in social policy, education, and criminology. Additionally, entities such as the European Observatory on Health Systems and Policies offer a template for systematic tracking of health system development and change, and entities such as Public Health England and the UConn Rudd Center for Food Policy and Obesity offer dedicated centers for the collection and evaluation of public health evidence.

Evidence-Informed Public Health Policy Table 5 Practical steps for improving knowledge transfer between researchers and policy makers: reducing the gap Steps to be taken by researchers

Steps to be taken by policy makers

Communicate research findings simply through newsletters, summaries, etc. Hold briefings, seminars, and workshops for policy makers

Set up advisory mechanisms to help identify research priorities

Discuss policy implications or include policy recommendations in research Target opinion leaders for research disseminations

Involve policy makers in all stages of the research process Conduct more policy-relevant research, including more action research, evaluation research, and systems research Offer training to policy makers on critical appraisal and commissioning of systematic reviews

Built evaluation research into programs and budgets and publish findings Ensure research-funding bodies develop program of strategic, priority-driven research Develop a culture of learning organization within government departments, including regular seminar programs and sabbaticals for policy analysts Develop in-house research capacity, including commissioning of policy research Establish policy research institutions that have ongoing involvement in policy monitoring and analysis Provide training for researchers on, and involve them in, policydevelopment processes

Adapted from Lin, v., 2003b. Improving the research and policy partnership: An agenda for research transfer and governance. In: Evidence-Based Health Policy: Problems and Possibilities, pp. 285–297. Melbourne: Oxford University Press; Buse, K., Mays, N., Walt, G., 2005. Making Health Policy Maidenhead: Open University Press

The use of ‘business intelligence’ and ‘predictive analytics’ to monitor population health and for use in public health is also emerging (New, 2014; Choucair et al., 2014). For example, during a major Ebola epidemic, a partnership of government and telecom companies in Liberia was able ‘to analyze cell tower data to detect outbreaks faster’ (New, 2014): a spike in cell phone traffic was taken to suggest a possible outbreak (African Strategies for Health, 2014). This collaboration is an exemplary case of an alliance of diverse multisectoral partners building on local capacity and linking local knowledge with more global research evidence while respecting diverse value systems and challenging existing power differentials (Blagescu and Young, 2006; African Strategies for Health, 2014). Information and communication technology tools are also useful in developed countries: for example, in Australia, a weekly community survey tracks influenza-like illness and provides a measure of the current influenza vaccine effectiveness (Carlson et al., 2010). Such partnerships between researchers, government, nongovernment organizations, and private industry may help overcome some of the traditional barriers for research translation. However, there is still a need for further systematic partnerships across this network of players supported by funding bodies and with goodwill and buy-in from relevant organizations. Knowledge transfer requires explicit recognition that a range of individuals may play roles in the process

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(Thompson et al., 2006), for example, opinion and community leaders can exert informal social influence on an issue while judicious use of informed citizen voices in deliberative forums can, with political support, drive evidence-informed policy change (YourSAy, 2015). Bringing the public into the decision-making space may be essential for the adoption of evidence-informed public health policy particularly where the policy is contentious. As Kerner (2006) suggests, translating research into policy requires a common language and common understanding about the meaning of knowledge translation and the nature of evidence. This may be as true across the gulf between governments and the people they govern as it is for gaps between researchers and policy makers. Linking agents (or knowledge brokers), formal and informal, can help to bridge the gaps across sectors, organizations, and people. For developing countries, donor organizations and international institutions will have a particular role to play in supporting capacity development. The World Bank Institute, the capacity development branch of the World Bank, is one such example. The aim of the Institute is to not only reach policy makers, researchers, and practitioners across the globe, but also to share knowledge with parliamentarians, journalists, teachers, youth, and civil society leaders through their Open Learning Campus e-learning platform launched in January 2016. The World Health Organization also has a similar agenda of removing barriers to research use. Civil society organizations and educational institutions may be particularly important in reaching key segments of society, as well as converting local knowledge from anecdote to evidence.

Conclusion In public health policy, the key question is not just what works, but what works for whom, in what circumstances, and in what ways? Research and evaluation that help answer these questions can assist with the development of appropriately considered policies while also allowing a broad range of voices to be heard in the political process of policy making. The differences between the worlds of researchers, policy makers, nongovernment organizations, industry, and the public can provide obstacles preventing research from being taken up into policy making. New infrastructure to promote knowledge transfer and capacity building across gaps between communities is increasingly being recognized as important for evidence-informed health policy. Linear models of research utilization for the making of public health policy are generally recognized as too simplistic because they disregard the many contextual factors influencing decision-making. The language of evidence-informed policy and practice is increasingly seen as appropriate for health policy making. Research can improve the evidential basis for public health policies, but this requires that more stakeholders – in civil society, in government, and in the business sector – are both skilled in appraising research as well as being an integral part of the research agenda–setting process. More policy evaluation studies and health system observatories may also be useful for both informational and capacity-building purposes.

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Acknowledgments Rachel Canaway, La Trobe University – School of Public Health, for research and editorial comment on the original chapter by V. Lin.

See also: Planning, for Public Health Policy; World Bank; World Health Organization.

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Further Reading Lin, V., Gibson, B. (Eds.), 2003. Evidence-Based Health Policy: Problems and Possibilities. Oxford University Press, Melbourne, Australia.

Relevant Websites http://www.chsrf.ca – Canadian Health Services Research Foundation (CHSRF) (last accessed on 29.07.16.). http://www.campbellcollaboration.org – The Campbell Collaboration (last accessed on 29.07.16.). http://www.cochrane.org – The Cochrane Collaboration (last accessed on 29.07.16.). http://www.euro.who.int/observatory – European Observatory on Health Care Systems and Policies (last accessed on 29.07.16.). http://www.eppi.ioe.ac.uk/cms/ – Evidence for Policy and Practice Information and Coordinating Centre (EPPI-Centre) (last accessed on 29.07.16.). http://www.joannabriggs.org/ – The Joanna Briggs Institute. http://www.nice.org.uk – National Institute for Clinical Excellence (NICE) (last accessed on 29.07.16.). https://www.gov.uk/government/organisations/public-health-england – Public Health England (last accessed on 29.07.16.). http://www.worldbank.org/wbi/home.html – The World Bank Institute (last accessed on 29.07.16.). https://www.olc.worldbank.org/ – Open Learning Campus, World Bank Group (last accessed on 29.07.16.). http://www.who.int/kms/en – World Health Organization (WHO): Knowledge management and health (last accessed on 29.07.16.).

Exercise Therapy for Heart Failure Patients in Canada James A Stone, Cardiac Wellness Institute of Calgary, Calgary, AB, Canada; University of Calgary, Calgary, AB, Canada; and Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada Trina Hauer, Cardiac Wellness Institute of Calgary, Calgary, AB, Canada Mark Haykowsky, University of Alberta, Edmonton, AB, Canada Sandeep Aggarwal, Cardiac Wellness Institute of Calgary, Calgary, AB, Canada; University of Calgary, Calgary, AB, Canada; and Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Heather M. Arthur and James A. Stone, volume 1, pp. 507–511, Ó 2008, Elsevier Inc.

Keypoints l

l l l l

Contemporary HF pharmacologic therapies are intended to improve ventricular function and reduce ventricular afterload HF patients have significant central and peripheral deconditioning Incidence of HF in Canada is similar to other industrialized countries HF patients require carefully tailored, individualized exercise programs Exercise therapy for HF patients, both aerobic and resistance training, should start with ultrashort episodes of exercise activity, gradually increasing the frequency and duration of the exercise episodes

Introduction Time was when a diagnosis of congestive heart failure (HF) gave rise to the treatment of patients with digoxin and diuretics. Although these therapies almost invariably acutely improved patient’s symptoms, mostly through a reduction in volume overload, decades later they were shown to probably hasten mortality, possibly through increased sympathetic activation (Hasselblad et al., 2007). In contemporary cardiology practice, beta blockers for severe left ventricular (LV) systolic dysfunction, once contraindicated, ace inhibitors or angiotensin receptor blockers, aldosterone inhibitors, and judicious use of diuretics, often on a PRN basis based on weight and symptoms, have become the mainstays of pharmacologic therapy (McKelvie et al., 2012). Despite these significant and substantial advances in medical therapy, with subsequent significant and substantial reductions in mortality, many patients remain significantly debilitated from a functional capacity perspective. What has not been generally appreciated in the medical community, even the cardiology community or the wider associated health-care professions, is the massive deconditioning influence of systolic HF on skeletal muscle aerobic function, along with reductions in capillary density, and thus aerobic capacity (Arena et al., 2014). Many individuals, despite optimal pharmacologic therapy, continue to have significant functional impairment with concomitant shortness of breath during exertion. The general assumption is that these individuals are short of breath secondary to reduced cardiac output from their LV systolic dysfunction, even in the absence of volume overload or elevations in B-type natriuretic peptide (BNP) levels.

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Decades of medical dogma dictated that if patients can improve their LV function, they could reduce their symptoms of exertional breathlessness. Like most dogma, it is based on personal and professional beliefs rather than hard science. In reality, patients with significant LV systolic dysfunction are very commonly severely deconditioned from an aerobic capacity perspective, due to a significant reduction in oxidative enzymes within skeletal muscle. With reductions in forward blood flow, as a consequence of reduced cardiac output from LV systolic function, there is less tissue oxygenation of skeletal muscle (Arena et al., 2014; see Figure 1, Conraads et al., 2013). At a very simplistic level, the reduction in tissue oxygenation eventually translates into a reduction in oxidative enzymes within skeletal muscle. Interestingly, in the same manner that deprivation of myocardial blood flow can produce a reduction in myocyte function and subsequent hibernating myocardium, the same deprivation of oxygen at the skeletal muscle level may result in the reduced formation of oxidative enzymes in order to protect skeletal muscle from oxidative injury (Tabet et al., 2011). From a patient perspective, it makes little difference whether or not their exertional shortness of breath and physical incapacitation are secondary to diminished cardiac output or secondary to diminished oxidative enzymes and energy production within the working skeletal muscles. Patients understand that within hours, even days, after a major cardiac insult that reduces cardiac output, anything other than minimal exertion causes significant shortness of breath. In hyperacute and acute situations, this is almost certainly a manifestation of poor cardiac output. Very quickly, however, the reduced cardiac output translates into reduced oxidative enzymes, reduced capillary density, and reduced energy production at the level of the skeletal muscle. Contemporary pharmacotherapy of HF, particularly with beta blockers and renin–angiotensin–aldosterone system antagonists, can frequently result in increases in cardiac output (McKelvie et al., 2012). However, as already pointed out, this is only one half of the exercise intolerance equation. The other half of the equation is what happens at the level of the skeletal muscle. Furthermore, it is clearly very oversimplistic to look at cardiac output and the oxidative generation of skeletal muscle energy as the only two major components contributing to an individual’s functional capacity. Exercise training not only increases levels of oxidative enzymes within skeletal muscle, it also increases motor unit recruitment within skeletal muscle, thereby increasing muscle efficiency. In addition, exercise training also reduces sympathetic tone and tends to increase parasympathetic tone, both of these alterations having

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Figure 1 Determinants of exercise intolerance in patients with chronic heart failure. Reduced cardiac performance will trigger compensatory neuroharmonal mechanisms to preserve cardiac output, blood pressure, and organ perfusion; these include the renin–angiotensin–aldosterone pathway, the sympathetic nervous system, increased levels of endothelin and vasopressin. However, as these compensatory systems become chronically stimulated, they initiate a vicious circle and cause cardiotoxicity, myocyte hypertrophy/death, changes in peripheral and coronary artery compliance, and excessive fluid retention. Progressively, other detrimental pathways are turned on, leading to oxidative stress, a proinflammatory status and reduced nitric oxide bioavailability, which initiate peripheral endothelial dysfunction; skeletal muscle wasting and ventilator inefficiency occur. Both central cardiac and hemodynamic changes, as well as these peripheral abnormalities, will determine the heart failure phenotype and will culminate in symptoms of exercise intolerance.

favorable effects on outcomes and exercise capacity. Along with these favorable changes in a patient’s neurohormonal status and central nervous system tone is the favorable influence of exercise training on ventricular–vascular coupling. Exercise training in persons with HF may promote improved afterload reduction and improved ventricular–vascular coupling, through increased peripheral vasodilation in working skeletal muscles, as a consequence of exercise (Arena et al., 2014). Indeed, improvements in ventricular–vascular coupling, as a result of exercise training, are likely to have a much more significant contribution to improvements in functional capacity in patients with HF, than that has been appreciated previously (Borlang and Kass, 2011). This article will examine the current incidence of HF in Canada, recommendations for the treatment of HF in Canada, and recommendations for the use of exercise therapy in patients with HF in Canada.

Incidence of HF in Canada The prevalence of HF in the general adult population in Canada is estimated to be in the range of 1.5% with an annual incidence of approximately 0.5% (Statistics). Large, diagnostic code-based government databases do not differentiate between those with significant LV systolic dysfunction as the etiology of their HF versus those with preserved LV ejection fractions. Historically,

the majority of patients with HF were felt to have significant LV systolic dysfunction. However, with the general aging of the baby boomer population, approximately 50% of patients now seen in HF clinics in Canada have HF with preserved LV ejection fractions (McKelvie et al., 2012). Once a diagnosis of HF has been established, the majority of patients in Canada will eventually undergo an imaging study to differentiate HF secondary to ventricular systolic dysfunction versus HF with a preserved ejection fraction (McKelvie et al., 2012). As with most westernized medical models, the diagnosis of HF is based on a combination of symptoms, exertional breathlessness, orthopnea, paroxysmal nocturnal dyspnea, nocturnal cough, peripheral edema, physical examination evidence of volume overload, elevated jugular venous pressure, wet lung crackles, as well as ancillary imaging tests such as chest X-rays and echocardiograms. Following these investigations, those patients appropriate for revascularization therapy will generally undergo invasive revascularization. In the last decade, the use of BNP levels has increased significantly and may help to establish the diagnosis of HF, particularly in circumstances where clinical or imaging evaluation is ambiguous (McKelvie et al., 2012).

Treatment Recommendations for HF in Canada For almost a decade, practitioners in Canada have had the benefit of using evidence-informed clinical practice guidelines

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for the diagnosis and management of HF (McKelvie et al., 2012). These guidelines emphasize the importance of appropriate diagnosis, investigation, treatment, ongoing monitoring, and optimal patient disposition (HF clinics, family practice, internal medicine, cardiology practice). Recommended pharmacologic therapies and interventions include PRN diuretics (both acutely and chronically to relieve volume overload), the use of aldosterone antagonists, the use of beta blockers, and, where clinically indicated, supplemental inclusion of digoxin, hydralazine, and long-acting nitrates. In addition, depending on the patient’s clinical circumstances, the implantation of an implantable cardioverter defibrillator may be appropriate, as is the institution of pacemaker-mediated cardiac resynchronization therapy (McKelvie et al., 2012). In 2004, the Canadian Association of Cardiac Rehabilitation (CACR) issued the first Canadian evidence-informed guidelines on the use of exercise therapy in patients with a history of congestive HF (Haennel et al., 2004). At that point in time, the benefits of exercise therapy in patients with HF were mostly limited to clinical trials demonstrating improvements in functional capacity, improvements in skeletal muscle mitochondrial size and density, improvements in skeletal muscle oxidative enzymes, reductions in arterial endothelial dysfunction, decreases in circulating catecholamines, and improvements in exertional breathlessness, general fatigue, sleep disturbances, and muscle weakness (Haennel et al., 2004). The Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial was published in 2009 (O’Conner et al., 2009). In Canada, as elsewhere around the world, the lack of a clearly demonstrable improvement in hard outcomes, without adjusting for baseline patient characteristics, observed within the largest randomized controlled trial of exercise therapy in patients with documented systolic dysfunction, was to say the least disappointing. Not surprisingly, many practitioners in the field of cardiac rehabilitation and exercise therapy simply refused to believe the results and questioned the adherence of patients to the prescribed intervention. Indeed, subsequent analysis of the HF-ACTION exercise training intervention indicated that, at any point during the study, only 30% of the patients in the intervention group were reaching their targeted weekly exercise times, compared to almost a similar number of patients in the socalled nonintervention group (Moe et al., 2014). The 2009 CACR Guideline provided very specific recommendations concerning the use of aerobic training and resistance training, and highlighted the need for greatly enhanced patient surveillance, principally with significantly increased numbers of exercise therapists supervising limited numbers of patients, as well as the importance of closer hemodynamic, rhythm, and rate of perceived exertion monitoring.

Treatment Recommendations for Use of Exercise Therapy in HF Patients In addition to the evidence-informed treatment investigations from the CACR, in 2013, the Canadian Cardiovascular Society Heart Failure Guidelines Working Group issued similar recommendations (Moe et al., 2014). These guidelines were, however, specifically targeted at a physician population,

principally internal medicine specialists and cardiologists. These guidelines, like the CACR guidelines, encourage the use of exercise training in patients with documented HF. Taking into account the significant shortcomings of the HF-ACTION trial as the definitive statement on the benefits, or lack thereof, of exercise therapy in patients with HF, these guidelines do emphasize the important contribution that exercise therapy may have in improving patients’ functional capacity and quality of life. With respect to aerobic training, these guidelines acknowledge the clinical fact documented in previous exercise and HF guidelines, and observed by practitioners in the field, that patients with acute, chronic, and acute-on-chronic HF may only be capable of sustaining aerobic or resistance training exercises for a very short period of time (i.e., seconds to minutes). However, with patience and diligence, 10 s bouts of aerobic training such as walking can turn into 20 s, which can turn into 30 s, etc. The key in this patient population is not to push them too hard and not to become frustrated with an apparent lack of progression. As indicated in the opening paragraphs, the vast majority of these patients are tremendously deconditioned from a skeletal muscle aerobic activity perspective, even when their cardiac function has been maximized, and thus it will take 10–12 weeks or longer to obtain clinically obvious improvements in functional capacity. The exercise mantra for this patient population is absolutely, ‘Start with low exercise interval durations and increase the duration slowly.’ In noncardiac populations, interval training, using bouts of higher intensities interspersed with bouts of lower intensities, is regarded by many as an optimal training method for obtaining higher increases in aerobic capacity. What limits most patient populations, cardiac patients, and healthy individuals alike is the effort required during high-intensity exercise. Not surprisingly, however, it is precisely this high-intensity effort which provides greater improvements in functional capacity. For patients with coronary artery disease, high-intensity interval training looks very attractive and may potentially lead to long-term reductions in major adverse cardiac events (Mezzani et al., 2012). The use of high-intensity interval training in patients with HF is not commonplace in Canadian rehabilitation practices; if practitioners are generally fearful of performing high-intensity interval training in cardiac populations with documented coronary artery disease, they are even more leery in patients with HF. Initial evidence indicates that the same may be true for patients with HF (Arena et al., 2013). Specifically, a recent major meta-analyses by Haykowsky et al. demonstrated that high-intensity interval training was significantly more effective than typical moderate-intensity continuous exercise training in patients with HF (Haykowsky et al., 2013). Specifically, of 168 HF patients randomized to usual exercise therapy or high-intensity interval training, patients in the high-intensity interval training group obtained significantly higher increases in their maximal oxygen consumption (Haykowsky et al., 2013). For patients with HF who are severely debilitated at the onset of exercise training, ultrashort, 5–20 s bursts of lowto-moderate intensity exercise interspersed with rest periods may be a useful approach until a functional reserve is established. In addition, although data are limited, external support or the use of antigravity treadmills may allow for

Exercise Therapy for Heart Failure Patients in Canada debilitated HF patients to exercise longer and thus increase functional capacity faster at the onset of an exercise training program. The use of antigravity treadmills in a very small randomized clinical trial has suggested that they may be beneficial in helping morbidly obese patients attain weight loss (Scholar). Morbidly obese individuals are often also significantly deconditioned from a skeletal muscle aerobic capacity perspective. It is very interesting to speculate that antigravity treadmills or externally supported walking with harnesses etc. could significantly improve, potentially in a much shorter period of time, aerobic capacity in HF patients with severe disability. Patients with HF may also benefit from resistance training (Haennel et al., 2004, 2009; Moe et al., 2014). Resistance training in this patient population may improve the ability to perform activities of daily living, may improve quality of life, may increase skeletal muscle mass and strength, and, potentially as a consequence of the increase in muscle mass, may also improve insulin resistance (Haennel et al., 2004, 2009; Moe et al., 2014). As with aerobic training, HF patients should start with light weights that easily facilitate higher numbers of repetitions, i.e., 15–20 repetitions are higher. As an alternative to the use of dumbbells, many patients may benefit from utilizing thera-bands as an alternative. Therabands have the advantage of being relatively low cost, portable, and may allow HF patients, particularly elderly ones, to perform resistance training activities within their own daily living environment.

Summary The diagnosis and management of HF in Canada is not significantly different from most industrialized countries throughout the world. Significant advances in pharmacological therapy, in conjunction with targeted revascularization therapies, have helped to significantly improve outcomes for patients with HF. However, improvements in functional capacity and quality of life have lagged behind. From a patient perspective, quality of life is extremely important. Individuals with HF look forward to mobilizing on a daily basis without being extremely short of breath and extremely fatigued. Exercise therapy for patients with HF, both aerobic training and resistance training, may significantly improve patient symptoms. Those patients, who participate in an exercise program, may also see significant improvements in their longevity and reductions in rehospitalization for HF. The exercise modalities available for patients with HF are changing rapidly. In particular, high-intensity interval training may become the preferred mode of exercise therapy for certain HF patients. In addition, helping severely debilitated HF patients improve their aerobic capacity through partially supported weight exercise therapies, such as antigravity treadmills, harnesses, or aquasize, may also lead to significant exercise improvements. Fortunately, the

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prognosis for HF patients in Canada has never been more optimistic and has never looked brighter. In the management of patients with HF in Canada, exercise therapy is one of the cornerstones to the attainment of enhanced longevity and improved quality of life.

See also: Coronary Heart Disease; Diet and Heart Disease; Heart Failure.

References Arena, R., Cahalin, L.P., Borghi-Silva, A., Phillips, S.A., 2014. Improving functional capacity in heart failure: the need for a multifaceted approach. Curr. Opin. Cardiol. 29, 467–474. Arena, R., Myers, J., Forman, D.E., et al., 2013. Should high intensity aerobic interval training become the clinical standard heart failure. Heart Fail. Rev. 18, 95–105. Borlang, B.A., Kass, D.A., 2011. Ventricular-vascular interaction in heart failure. Cardiol. Clin. 29, 447–459. Conraads, V.M., Van Craenenbroek, E.M., De Maeyer, C., et al., 2013. Unraveling new mechanisms of exercise intolerance in chronic heart failure. Role of exercise training. Heart Fail. Rev. 18, 65–77. Hasselblad, V., Stough, W.G., Shah, M.R., et al., 2007. Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE Trial. Eur. J. Heart Fail. 9, 1064–1069. Haennel, R.G., Tomczak, C., Haykowsky, M., et al., 2004. Chapter 14: special populations. In: Stone, J.A., Arthur, H.M. (Eds.), Canadian Association of Cardiac Rehabilitation Guidelines for Cardiac Rehabilitation and Cardiovascular Disease Prevention, pp. 258–308. Winnipeg, Manitoba. Haennel, R.G., Brassard, C.P., Tomczak, C., et al., 2009. Chapter 14: special populations. In: Stone, J.A., Arthur, H.M., Suskin, N. (Eds.), Canadian Association of Cardiac Rehabilitation Guidelines for Cardiac Rehabilitation and Cardiovascular Disease Prevention, pp. 449–515. Winnipeg, Manitoba. Haykowsky, M.J., Timmons, M.P., Kruger, C., et al., 2013. Meta-analysis of aerobic interval training on exercise capacity and systolic function in patients with heart failure and reduced ejection fractions. Am. J. Cardiol. 111, 1466–1469. McKelvie, R.S., Moe, G.W., Ezekowitz, J.A., et al., 2012. The 2012 Canadian Cardiovascular Society heart failure management guidelines update: focus on acute and chronic heart failure. Can. J. Cardiol. 29, 168–181. Moe, G.W., Ezekowitz, J.A., O,Mera, E., et al., 2014. The 2013 Canadian Cardiovascular Society heart failure management guidelines update: focus on rehabilitation exercise and surgical coronary revascularization. Can. J. Cardiol. 30, 249–263. Mezzani, A., Hamm, L.F., Jones, A.M., et al., 2012. Aerobic exercise intensity assessment and prescription in cardiac rehabilitation: a joint position statement of the European Association for Cardiovascular Prevention and Rehabilitation, the American Association of Cardiovascular and Pulmonary Rehabilitation, and the Canadian Association of Cardiac Rehabilitation. J. Cariopulm Rehabil. Prev. 32, 327–350 and 2013, Eur. J. Prev. Cardiol. 20, 442–467. O’Conner, C.M., Whellan, D.J., Lee, K.L., et al., 2009. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA 301, 1439–1450. Tabet, J.-L., Meurin, P., Ben Driss, A., et al., 2011. Benefits of exercise training in chronic heart failure. Arch. Cardiovasc. Dis. 102, 721–730.

Relevant Websites www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics. htm#references. (accessed 30.06.14.). http://www.scholarworks.boisestate.edu/td/857. (accessed 11.08.14.). 2013 18, 65–77.

Extreme Weather Events and Human Health Stephanie L Molloy, University of Hawai’i at Hilo, Hilo, HI, USA Erin A Dreelin and Joan B Rose, Michigan State University, East Lansing, MI, USA Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 2, pp. 536–544, Ó 2008, Elsevier Inc.

Introduction Human health has been linked with weather. Changes in human society and the environment have exacerbated the impacts of extreme temperatures, precipitation, floods, and hurricanes on health. Several areas of interest that have influenced this linkage include (1) global climate change, (2) increased human population size in coastal areas, (3) higher population size of susceptible individuals (e.g., elderly, immunocompromised) in communities, and (4) increased urbanization, which concentrates people, buildings, and sewage. Along with these changes it has been established that weather patterns, and particularly extreme weather, affect human health and well-being. In order to address the topic of extreme weather and human health, this article includes the definition of extreme weather, a description of how extreme events have changed and why, and a discussion of some key direct and indirect effects of several types of extreme weather events on human health.

Weather and Climate The term ‘climate’ describes the long-term weather patterns over a large region e.g. mean temperature or average precipitation of a region. The term ‘weather’ refers to the state of the atmosphere at a given place and time in regard to variables such as temperature, precipitation, and wind velocity. An extreme weather event is weather of an unusual intensity for a specific location. Extreme weather is perceived as rare and is commonly defined in statistical terms based on the probability of occurrence of an event. Extreme events occur at the tail ends of a frequency distribution for a specific variable (Figure 1). Specific definitions of ‘rare’ vary, but are commonly those events in the 10th or 90th percentile. Extreme events vary

with location; for example, a 6-inch snowfall may be an extreme event at low altitudes in the tropics but not in northern temperate zones.

Global Climate Change and Extreme Weather Events One cannot discuss extreme weather events without considering global climate change. The Intergovernmental Panel on Climate Change (IPCC) assessment reports provide an overview of the causes, observed changes, and potential future consequences of global climate change. Atmospheric concentrations of key greenhouse gases (i.e., CO2, CH4, N2O, and O3) have increased since the industrialized era. Consequently, there is increasing evidence for global warming based on observations from around the world, as well as increasing evidence that much of this warming is due to human activities (IPCC, 2001). IPCC climate models predict an increase in atmospheric concentrations of greenhouse gases and an increase in globally averaged surface temperatures of 1.4–5.8
C between 1990 and 2100. As a result of the increase in atmospheric concentrations of greenhouse gases, the frequency, intensity, and duration of extreme weather events is predicted to change. For example, more hot days, heat waves, and heavy precipitation events are expected. In addition, the risk of floods and droughts in many regions would increase. Global annual precipitation is also projected to increase, although both increases and decreases in annual precipitation are projected at the regional scale. The IPCC predicts that global climate change will increase the threat to human health, ecosystems, and socioeconomic conditions. The relationship between global impacts and increase in global mean temperature for water, health, energy, and aggregate impacts is uncertain. One consistent pattern identified in a survey of climate change literature is that beyond an approximate 3–4
C increase in global mean temperature, most of the studies show increasing adverse impacts. These impacts vary by region and with scale; there is greater uncertainty in predicting changes at smaller geographic scales. In northern regions, climate change can include changes in precipitation magnitude and frequency, reductions in sea ice extent and thickness, and climate warming and cooling.

Direct and Indirect Effects of Extreme Weather Events on Human Health

Figure 1 Extreme events are those at the tail ends of a frequency distribution (shaded areas) for a specific variable at a specific location.

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Extreme weather events invariably have adverse impacts on human health (Table 1), which can be categorized into direct and indirect effects. Direct effects on human health caused by extreme weather include (1) death, (2) injury, (3) displacement, (4) loss of social structures and services (e.g., health care), (5) loss of access (e.g., safe water, housing, food), and (6) change in distribution and exposure to pathogens and disease-causing substances (spatial and temporal, as well as concentrations).

International Encyclopedia of Public Health, 2nd edition, Volume 3

http://dx.doi.org/10.1016/B978-0-12-803678-5.00151-X

Extreme Weather Events and Human Health Table 1

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Summary of health effects of extreme weather events

Extreme weather

Effects

Selected references

Extreme heat

Dehydration; heat stress; heat stroke; increased violent behavior; increased myocardial infarction; respiratory distress; death Hypothermia; increased mortality due to cardiovascular disease, respiratory disease, and stroke; ischaemic heart disease; broken bones from falls Contamination of water supplies; disease outbreaks

Smoyer-Tomic et al. (2003), Morabito et al. (2005), Schar et al. (2004), and De et al. (2004)

Extreme cold Extreme rainfall Floodinga Hurricanes

McGregor (2005), Diaz et al. (2005), Laschewski and Jendritzky (2002), and Davis et al. (2004)

Drowning; heart attack, physical injury; disease outbreaks; mental illness; death Death; drowning; loss of medical services and drinking water; disease outbreaks

Curriero et al. (2001), Thomas et al. (2006), and Harvard Medical School (1999) WHO Europe (2002), Katz et al. (2002), Reacher et al. (2004), and Durkin et al. (1993) PAHO (2004), Knabb et al. (2005), Pardue et al. (2005), and CDC (Centers for Disease Control) (2005a,b, 2006a,b)

a

See also Table 2.

For example, direct effects of extreme heat events are heat cramps, heatstroke, or heat exhaustion, whereas direct effects of extreme cold events include broken bones from falls on ice, exhaustion from snow clearing, breathing problems caused by cold air, and hypothermia (a drop in core body temperature). Indirect effects are those caused by (1) unsafe or unhealthy conditions related with a loss or disruption of usual services (including medical care services) and (2) temporary or permanent displacement, property damage, and other personal loss or stress. A death, injury, or illness is indirectly related to a weather event if it is caused by unsafe or unhealthy conditions that occurred because of the anticipation or occurrence of the weather event. These conditions include the loss or disruption of usual services, personal loss, and disruption of an individual’s lifestyle. Indirect effects include psychological responses related to disruption of normal life and displacement, such as short-term changes in mood, emotional well-being, and aberrations from normal behavior. Indirect effects also include changes in the geographical distribution and incidence of water-, food-, and vector-borne diseases, exposure to chemical pollutants released into floodwaters, decreased food productivity, mental illness, exacerbation of preexisting chronic conditions, and excessive societal and political upheaval (e.g., displacement, loss of livelihood). Indirect health effects can be mediated or exacerbated by changes in ecological systems (such as bacterial and fungal proliferation) and in public health infrastructures (such as the availability of safe drinking water, sanitation, and health care). Indirect effects may also have a longer lag time between the weather event and health impact; consequently they may be more difficult to measure.

Temperature Extremes and Impacts on Human Health As with other extreme weather events, there is no universal definition for extreme temperature events. An extreme heat event is one in which daytime and nighttime temperatures exceed normal temperatures for a specific location. Extreme heat events can also be defined as those which exceed the 95th percentile from a historical temperature distribution for a location or those that exceed the 99th percentile for summer minimum temperatures. Extreme cold events may be defined

as days with a daily maximum temperature at or less than the 1st percentile for a specific location, those which are less than the 5th percentile from a historical temperature distribution for location, or those which are less than the 15th percentile for daily average temperature. In essence, extreme temperature events, with temperatures well above or below the normal temperatures for a specific location, are rare.

Extreme Heat Although heat waves are a major cause of weather-related deaths, heat as an atmospheric hazard has been largely underrecognized. In 2003, the heat wave that affected Western Europe killed approximately 35 000 people and the 1998 heat wave in India resulted in an estimated 15 000 deaths. In addition, future climate scenarios suggest that heat vulnerability may increase significantly under global warming. Tol (2002) estimates that globally an additional 94 400 people could die from heat-related cardiovascular and respiratory problems for every 1
C increase in global mean temperature. The most common direct effects of extreme heat are dehydration and heatstroke. Other conditions associated with extreme heat include cardiovascular collapse and respiratory distress. Susceptible populations, such as the elderly, young children, and poor, are most at risk for extreme heat-related health effects. Also, deaths due to heat stress are more pronounced in regions that do not experience high temperatures normally or from heat waves early in the season, suggesting that populations may acclimate to extreme temperatures. The correlation between weather and mortality is weaker in areas with consistently hot summers, whereas the relationship is stronger in more temperate areas. Urban populations are also more at risk because urban areas typically experience hotter temperatures than suburban and rural areas because of the urban heat island effect. Heat stress has been linked to excess human mortality and illness, violent behavior, decreased agricultural and livestock productivity, construction and transportation difficulties, and reduced electrical power supply. Based on patterns of hospital admissions for myocardial infarction in winter and summer, daily event rates significantly increased with daily mean air temperature decrease; a 10
C decrease was associated with

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Extreme Weather Events and Human Health

a 19% increase in daily event rates for people older than 65 years. Drought and fire are also related to extreme heat events. Prolonged drought can result in water shortages and increased water scarcity. In industrialized areas, a larger component of stream flow is composed of effluent during droughts. Increases in metals concentrations have also been observed, possibly as a result of changes in soil dynamics during years with drought and fire.

Extreme Cold Extreme cold events occur when temperatures fall well below the average temperature for a specific location. Hypothermia is the major direct health effect of extreme cold temperature. In temperate regions, mortality from cardiovascular disease, respiratory disease, and stroke is higher during winter months. Cold weather is an ischemic heart disease (IHD) risk factor. Year-to-year variations of the level of IHD mortality may be partly determined by inter-annual variations in winter climate (McGregor, 2005). McGregor (2005) investigated whether there is any association between the level of IHD mortality for three UK counties and the winter North Atlantic Oscillation (NAO), which exerts control on the nature of the winter climate over Western Europe. He found a significant inverse association between a climate index and the level of IHD, thus indicating that climate change that causes strong negative phase of the NAO and anomalously low temperatures across England results in increased rates of IHD. Increasing cold stress results in increased death rates. However, the patterns in deaths due to extreme temperature differ between heat and cold. Cold spells lead to a relatively small increase in mortality over a period of weeks whereas the increase in mortality during heat waves is more peaked, with higher death rates occurring during the heat wave. Mortality data from Germany show a marked seasonal pattern with a minimum in death rates during summer and a maximum during winter. During the seasonal minimum in summer, death rates rise sharply with increasing heat load, reaching highest values during extreme heat events. In the United States, human mortality is highest on extremely hot, humid summer days, but in general, winter-mortality rates are significantly higher than summer rates. The effect of winter extreme temperatures compared with that of summer extremes occurs over a longer term and appears to be more indirect. Diaz et al. (2005) examined mortality rates of people over age 65 and found that daily maximum temperature was the best thermal indicator of the impact of climate on mortality. However, deaths peaked 7– 8 days after the extreme temperature event, implying that most mortality was perhaps through indirect rather than direct means.

Extreme Precipitation Events and Impacts on Human Health Extreme Rainfall Extreme rainfall can affect transport of disease organisms into the water supply. Weather also can affect survival and growth of pathogenic organisms through factors such as temperature change. Exposure to water-borne disease can result from drinking contaminated water, eating seafood from

contaminated water, eating fresh produce irrigated or processed with contaminated water, or from activities such as fishing or swimming in contaminated water. Water-borne pathogens of current concern include viruses, bacteria (such as Vibrio vulnificus, a naturally occurring estuarine bacterium responsible for a high percentage of the deaths associated with shellfish consumption), and protozoa (such as Cryptosporidium, associated with gastrointestinal illnesses). Changes in precipitation, temperature, humidity, salinity, and wind have a measurable effect on water quality. In 1993, the Milwaukee, Wisconsin drinking water supply in the United States became contaminated with Cryptosporidium, and as a result an estimated 400 000 people became ill. A contributing factor in the contamination, in addition to treatment system malfunctions, was heavy rainfall and runoff that resulted in a decline in the quality of raw surface water arriving at the Milwaukee drinking water plant. In a study of 548 community waterborne disease outbreaks in the United States over almost 50 years, 51% of waterborne disease outbreaks were preceded by precipitation events above the 90th percentile (p ¼ 0.002), and 68% by events above the 80th percentile (p ¼ 0.001). Outbreaks resulting from surface water contamination showed the strongest association with extreme precipitation during the month of the outbreak; a 2-month lag applied to groundwater contamination events (Curriero et al., 2001). A study examining extreme rainfall in association with 92 waterborne disease outbreaks in Canada between 1975 and 2001 found extreme rainfall to be a significant contributing factor to community-based drinking water outbreaks (Thomas et al., 2006). Impacts on water quality in coastal regions have also been observed. In Florida during the strong El Niño winter of 1997–98, heavy precipitation and runoff greatly elevated the counts of fecal bacteria and infectious viruses in local coastal waters. In Gulf Coast waters, Vibrio vulnificus bacteria are especially sensitive to water temperature, which dictates their seasonality and geographic distribution. In addition, toxic red tides proliferate as seawater temperatures increase. Reports of marine-related illnesses have risen over the past two and a half decades along the East Coast, in correlation with El Niño events. The 1997–98 El Niño event was associated with trends of extensive flooding and severe droughts, as well as a fivefold increase in risk of a malaria epidemic in the semiarid Punjab and fourfold increase in southwestern Sri Lanka.

Flooding Flooding is the most frequent natural disaster (30–46% of natural disasters in 2004–05), affecting over 70 million people worldwide each year (OFDA/CRED, 2006). Flooding is a worldwide phenomenon; approximately 2900 million people were affected between 1900 and 2006. However, the continent of Asia has been most affected; a total of approximately 2790 million people were affected by flooding in over 1200 events during this period (OFDA/CRED, 2006). Floods are highimpact events resulting from the interaction of rainfall, surface runoff, evaporation, wind, sea level, and local topography. Floods can overwhelm physical infrastructure, human resilience, and social organization. Floods may disrupt water purification and sewage systems, leading to contamination of water

Extreme Weather Events and Human Health Table 2

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Summary of the effects of floods on human health

Causes Direct effects Stream flow velocity; topographical features; absence of warning; rapid speed of flood onset; deep flood waters; landslides; risky behavior; fast-flowing waters carrying boulders and fallen trees Contact with water Contact with polluted water Increase in physical and emotional stress Indirect effects Damage to water supply systems; damage to sewerage and sewage disposal systems; insufficient supply of drinking water; insufficient supply of water for washing Disruption of transport systems Disruption of underground piping; dislodgment of storage tanks; overflow of toxic waste sites; release of chemicals; disruption of petrol storage tanks, possibly leading to fire Standing water; heavy rainfall; expanded range of vector habitats Rodent migration Disruption of social networks; loss of property, jobs, and family members and friends Clean-up activities following flooding Destruction of primary food products Damage to health services; disruption of ‘normal’ health service activities

Health implications Drowning; injuries Respiratory diseases; shock; hypothermia; cardiac arrest Wound infections; dermatitis; conjunctivitis; gastrointestinal illnesses; ear, nose, and throat infections; possible serious waterborne diseases Increased susceptibility to psychosocial disturbances and cardiovascular incidents Possible waterborne infections (enteropathogenic E. coli, Shigella, hepatitis A, leptospirosis, giardiasis, campylobacteriosis, cryptosporidiosis); dermatitis; conjunctivitis Food shortages; disruption of emergency response Potential acute or chronic effects of chemical pollution Vector-borne diseases Possible rodent-borne diseases Possible psychosocial disturbances Electrocution; injuries; lacerations; puncture wounds Food shortages Decrease in ‘normal’ health-care services; insufficient access to medical care

Source: Menne, B., et al., 2000. Floods and Public Health Consequences, Prevention and Control Measures. United Nations (document MP.WAT/SEM.2/1999/22), New York.

sources with pathogens such as vibrio cholerae, hepatitis A virus, and Leptospira. Health effects (Table 2) can appear during or immediately after flooding, in the first days or weeks afterward, or over a period of months or years. The health effects of flooding can be particularly devastating to already vulnerable populations, such as children, the elderly, disabled people, ethnic minorities, and those with low incomes. Direct health effects are caused by the rapidly rising and flowing water during a flood event and include death from drowning, heart attacks, and injuries. The number of deaths is closely related to the life-threatening characteristic of floods (rapidly rising and deep waters and objects carried by rapidly flowing water) and the behavior of victims. In addition, injuries (sprains and strains, lacerations, contusions, etc.) are likely to occur during and after a flood as people return to their homes to clean up damage and debris. Heavy monsoon rains may trigger flash floods and landslides. More than 400 people were killed in flash floods and landslides triggered by heavy annual monsoon rains across the mountainous Himalayan kingdom of Nepal in the 2002 monsoon season (June– August). Europe has also recently experienced torrential rains and flooding (August 2002). Torrential rains inundated Austrian villages, swept away tourists on Russia’s Black Sea coast, flooded London’s subway system, and battered important crops in northern Italy. In northern Italy, hail and heavy rain damaged wine grapes, tobacco crops, and olive groves. Several deaths were reported and about 2000 people were evacuated from flooded homes in southern Bohemia in the Czech Republic. In Bulgaria, flooding left dozens of villages without electricity, and two farmers were reportedly killed by lightning. Flood waters ravaged vast areas of central Europe, claiming at

least 91 lives in Germany, Russia, Austria, and the Czech Republic. Tens of thousands were evacuated and many residents lost their homes. Across the continent, over 110 people have been killed in what have been termed the ‘Floods of the Century.’ Indirect health effects result from damage to major infrastructure, water and wastewater facilities, and piping and property. Infectious diseases, poisoning, and posttraumatic stress disorders are all issues. Cases of infectious disease (gastrointestinal diseases, dermatitis, and conjunctivitis) might occur but are normally confined to illnesses endemic in the flooded region (WHO Europe, 2002). Water damage as a result of flooding can lead to health problems associated with exposure to mold. These health effects can range from irritated and bleeding lungs to hair loss to death. In areas that experience flooding, water quality is generally one of the biggest concerns beyond the risk of drowning. As floodwaters inundate farms and fields, they pick up animal waste, fertilizers, and pesticides. As they move through cities, floodwaters can accumulate toxins and other contaminants. The rupture of underground pipelines, dislocation of storage tanks, overflow of toxic waste, or release of chemicals stored at ground level can cause poisoning. In many cities, storm waters and sewage travel through the same pipes, overwhelming sewage treatment plants and washing untreated sewage into waterways. Enteric pathogens originating from sewage and wastewaters are swept into drinking water sources that, if overwhelmed and without adequate treatment, then cause waterborne disease. The rates of infectious disease may increase because of a reduction in sanitation services, which may coincide with overcrowding of displaced people with inadequate wastewater

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Extreme Weather Events and Human Health

facilities and without clean water. Both person-to-person transmission and environmentally mediated transmission may be enhanced in this situation. Increased fecal contamination of water from animals or humans can also exist. Leptospirosis is considered the most common zoonosis worldwide and is endemic in tropical environments such as Hawaii, where the mean annual incidence is 1.29 per 100 000 population (Katz et al., 2002). Natural disasters such as floods and hurricanes increase the risk for human exposure to leptospires through contact with animal-contaminated water or mud. In the Czech Republic, a small outbreak of leptospirosis occurred after the flooding in 1997. Finland reported 13 waterborne disease outbreaks with an estimated 7300 cases during 1998–99, associated with untreated groundwater from mostly flooded areas (WHO Europe, 2002). Aside from the trauma caused by the flooding itself, geographical displacement, damage to the home, loss of familiar possessions, and often lack of insurance might contribute to posttraumatic stress disorder, resulting in anxiety, depression, psychosocial disturbances, and sometimes suicide. There is evidence for an increase in the incidence of mental health problems following natural disasters such as floods. For example, there was a fourfold increase in risk of psychological distress (relative risk (RR) ¼ 4.1, p < 0.0005) in adults whose homes had been flooded compared to those whose homes were not (Reacher et al., 2004). One of the few studies investigating the effects of flooding on the mental health of children examined a cohort of 162 surviving children after floods in Bangladesh, reporting a 10% increase in aggressive behavior and a 34% increase in bedwetting behavior after the flood (Durkin et al., 1993).

Hurricanes Hurricanes are associated with high winds and rain and often result in widespread flooding. In August 1992, Hurricane Andrew hit southern Florida in the United States and then the Louisiana coast a few days later, causing US$27 billion worth of destruction and 61 deaths. Over 125 000 homes and businesses were damaged or completely destroyed, mainly because of high winds. The unprecedented economic devastation was along a path through the northwestern Bahamas, the southern Florida peninsula, and south-central Louisiana. The hurricane had a central pressure of 922 mbars (92.2 kpa), the third lowest recorded this century for a hurricane at landfall in the United States. In Dade County (Florida) alone, the forces of Andrew resulted in 15 deaths and up to one-quarter of a million people left temporarily homeless. An additional 25 lives were lost in Dade County from the indirect effects of Andrew. The direct loss of life was remarkably low, considering the destruction caused by this hurricane. In late 1998, Hurricane Mitch tracked its way across the Atlantic, devastating parts of Central America. Hurricane Mitch produced massive downpours affecting a number of Central American nations, including Nicaragua, Guatemala, Honduras, El Salvador, and Belize. An estimated 6 feet of rain drowned crops, not only creating food shortages but also displacing a high proportion of the workforce. An estimated 11 000 people were killed; gastrointestinal and respiratory diseases were rampant throughout the affected area. The number of cholera cases

across the region increased after the hurricane. Cholera is caused by toxigenic Vibrio cholerae, with symptoms that include severe watery diarrhea, sometimes accompanied by vomiting, that can lead to dehydration. Most cholera cases in epidemics are transmitted via water; however, Vibrio is a naturally occurring bacterium in marine and estuarine environments, and can also be transmitted via improperly prepared seafood. In Guatemala, the country most affected by cholera, the average weekly number of cases pre-Hurricane Mitch (January–October 1998) was 59, whereas after Hurricane Mitch (November 1998) the average number of cases per week was 485 (PAHO, 2004). Prior to Hurricane Mitch, there were no reported cases of leptospirosis in 1998; however there were 450 cases and 7 deaths reported in Nicaragua in the month of November. On 25 August 2005, Hurricane Katrina made landfall in Florida with sustained winds of 80 mph and high rainfall; certain areas reported over 14 inches of rainfall. After crossing southern Florida and entering the Gulf of Mexico, the hurricane strengthened and made landfall in southeastern Louisiana on August 29 as a Category three hurricane, with sustained winds of 125 mph. Katrina was one of the strongest hurricanes to strike the United States during the past 100 years and was probably the nation’s costliest natural disaster to date, with total losses estimated to exceed $100 billion. The total number of fatalities directly related to the forces of Katrina is estimated to be about 1500, with a further 333 fatalities estimated to be indirectly related to this hurricane. The state of Louisiana reported the greatest number of fatalities (1577, direct and indirect) associated with the hurricane. Storm surges along the Louisiana and Mississippi coastlines reached up to 28 feet; the majority of fatalities associated with Katrina resulted from these surges. However, the real numbers may never be known due to underreporting and the high numbers of displaced people; several 100 people are still reported missing in relation to Hurricane Katrina. The devastation caused by Katrina was largely due to the hurricane’s size – on August 29 Katrina had a 25–30 nautical mile radius, with hurricane winds extending approximately 75 nautical miles from its center. Furthermore, a total of 43 reported tornadoes were spawned by Katrina, thereby increasing the devastation of the hurricane. Hurricane Katrina destroyed entire communities in the areas affected and disrupted water and power supplies, food distribution systems, health-care facilities, and communication networks throughout the region. People who did not evacuate the area were concentrated in evacuation centers, creating severe crowding and straining impaired basic utilities, such as sewage systems. Chemical and bacterial contamination of water supplies, floodwaters, and sediments was a major concern. Levels of lead, arsenic, and chromium in flood waters were found to exceed drinking water standards, and although the levels found were often similar to typical storm water levels, the risk in this circumstance was due to the increased contact the public had with the floodwaters. Elevated levels of fecal pollution indicator bacteria were found in the floodwaters, and fecal coliforms were present in surface waters in concentrations ranging from 103 to 106 MPN/100 mL (Pardue et al., 2005); these levels may be compared to Louisiana’s freshwater primary contact standards of 200 MPN/100 mL. The presence of fecal coliforms in surface waters indicates the

Extreme Weather Events and Human Health possible presence of fecal pollution and microorganisms that cause disease in humans. Evidence of human disease related to Hurricane Katrina has emerged. Many excess cases of Vibrio illnesses, with five deaths, were reported after Hurricanes Katrina and Rita (Hurricane Rita hit the same area 1 month after Katrina). Illnesses reported were caused by V. vulnificus, Vibrio parahaemolyticus, and both nontoxigenic and toxigenic V. cholerae. Eighteen woundassociated Vibrio illnesses were reported, resulting in five deaths. Four non-wound Vibrio cases were reported, associated with gastrointestinal illness symptoms, such as diarrhea; nontoxigenic V. cholerae non-O1, non-O139 was isolated from two of these cases. Cholera is an extremely rare disease in the United States; however, two cases of toxigenic V. cholerae O1 infection were reported in Louisiana post-Katrina. These two cases of toxigenic V. cholerae infection were attributed to the consumption of improperly prepared or handled shellfish, perhaps because of the difficult living conditions after the hurricane. Crowded living conditions in evacuation centers also play a role in the acquisition and transmission of contagious diseases. This is highlighted by the number of visits for gastrointestinal illness and rashes to evacuation centers and healthcare facilities. During the first 3 weeks of September after Hurricane Katrina, gastrointestinal illnesses accounted for 27% of visits to evacuation center medical facilities; respiratory illnesses accounted for 20% of visits during 1–22 September and 52% of visits during 17–22 September. However, the percentages of visits to health-care facilities during this time for these reasons were much less in comparison (gastrointestinal illnesses and rashes accounted for less than 10% of visits). A gastrointestinal disease outbreak occurred in evacuation shelter facilities in early September at Reliant Park, a sports and convention center in Houston, Texas. During 2–12 September 2005, 1169 people visited the medical center at Reliant Park, with symptoms of acute gastroenteritis. Norovirus was identified in stool samples of many patients. In addition, emergency response people, including medical personnel and police officers, who had direct contact with patients, also reported symptoms of acute gastroenteritis. The compromising of the health of medical and emergency response personnel further complicates the rescue and recovery efforts in areas affected by such extreme weather events. Another indirect human health effect of flooding and hurricanes is the respiratory health concerns associated with mold growth in water-damaged homes. After Hurricane Katrina, mold was found in homes at levels that could cause respiratory impairment. People returning to their homes to clean often do not have the experience or knowledge regarding proper precautions to take to protect themselves. With communication systems often failing during extreme events, it is difficult to educate the public through typical mass-communication means. Even with the correct knowledge, protective gear may not be readily accessible because of lack of infrastructure after a flood.

Extreme Events and Emergency Preparedness The severity of the health impacts due to extreme weather events such as floods and storms hinge upon the vulnerabilities and recovery capacities of the natural environment and the

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local population. Populations most susceptible to extreme weather health events include the elderly, children, anyone with a chronic illness, and the urban poor. These people not only may have suppressed immune response but they also may have more difficulty escaping extreme weather events (i.e., evacuating areas that are at risk). This was illustrated in the United States during Hurricane Katrina, when many of the urban poor in New Orleans were unable to evacuate the city because they lacked transportation. Understanding the extent, impacts, and costs of both the direct and indirect effects of extreme weather events on human health is vital to developing effective risk assessments, as well as emergency preparedness policies and plans for action. The key to emergency responses to extreme weather events is to have an emergency preparedness strategy and an early warning system. Emergency response strategies rely on the public being notified about the anticipated occurrence of an extreme weather event and subsequently taking the appropriate steps to protect themselves. The following are effective warning strategies: Provide a reliable forecast of meteorological conditions. Require a deep understanding of the relationship between the extreme weather event and human health impacts. l Educate the public about appropriate responses to extreme weather. l Use response measures that can be implemented in the time given between the warning and onset of extreme weather. l Require a public infrastructure and a community plan to implement the needed response. l l

Warning systems for extreme weather events do exist. Many of these systems issue warnings for thunderstorms, tornadoes, floods, and hurricanes. The integration of climate-based health forecasts into decision-support tools for advanced general winter emergency service and capacity planning could form the basis of an effective adaptive strategy for coping with the health effects of harsh winters. Fewer warning systems exist for extreme temperature events, although a standardized warning system has been initiated in 12 cities around the world (Sheridan and Kalkstein, 2004). The test system is operative in several cities and has been tailored to local conditions. In addition, the EuroHEAT project led by the World Health Organization’s Regional Office for Europe is currently examining Europe’s responses to extreme heat events (see Relevant Websites). The project seeks to improve public health responses to heat by developing standards for warning systems, including a definition of heat wave so that all member states are on the same page; guidance on treating heat-related illness; and guidance on public health responses and outreach. Emergency preparedness can decrease both the direct and indirect effects of extreme weather events. Emergency preparedness ranges from individual behaviors to protect self to government response to protect public health, safety, and welfare. Health effects caused by extreme temperature can be prevented by relatively simple changes in behavior; for example, staying in air-conditioned facilities and remaining hydrated during extremely hot days or limiting outdoor activities during extreme cold events. Several cities in the United States and Canada are developing plans to provide air-conditioned or heated public spaces for citizens who do not have climate-controlled

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homes. For events affecting larger areas or populations, governments may call for evacuations and organize protection of infrastructure.

See also: Contaminants Associated with Drinking Water; Demography, Epidemiology, and Public Health; Drinking Water and Sanitation; Food Safety; Human Health Risk Assessment; Waterborne Diseases.

References CDC (Centers for Disease Control), 2005a. Vibrio illnesses after hurricane Katrina – multiple states, August–September 2005. Morb. Mortal. Wkly. Rep. 54 (37), 928–931. CDC, 2005b. Norovirus outbreak among evacuees from hurricane Katrina – Houston, Texas, September 2005. Morb. Mortal. Wkly. Rep. 54 (40), 1016–1018. CDC, 2006a. Morbidity surveillance after hurricane Katrina – Arkansas, Louisiana, Mississippi, and Texas, September 2005. Morb. Mortal. Wkly. Rep. 55 (26), 727–731. CDC, 2006b. Health concerns associated with mold in water-damaged homes after hurricanes Katrina and Rita – New Orleans area, Louisiana, October 2005. Morb. Mortal. Wkly. Rep. 55 (2), 41–44. Curriero, F.C., Patz, J.A., Rose, J.R., Lele, S., 2001. The association between extreme precipitation and waterborne disease outbreaks in the United States, 1948–1994. Am. J. Public Health 91 (8), 1194–1199. Davis, R.E., Knappenberger, P.C., Michaels, P.J., Novicoff, W.M., 2004. Seasonality of climate-human mortality relationships in US cities and impacts of climate change. Clim. Res. 26 (1), 61–76. De, U.S., Khole, M., Dandekar, M.M., 2004. Natural hazards Associated with meterological extreme events. Nat. Hazards 31 (2), 487–497. Diaz, J., Garcia, R., Lopez, C., Linares, C., Tobias, A., Prieto, L., 2005. Mortality impact of extreme winter temperatures. Int. J. Biometeorol. 49 (3), 179–183. Durkin, M.S., Khan, N., Davidson, L.L., Zaman, S.S., Stein, Z.A., 1993. The effects of a natural disaster on child behavior: evidence for posttraumatic stress. Am. J. Public Health 83 (11), 1549–1553. Harvard Medical School, 1999. Extreme Weather Events: The Health and Economic Consequences of the 1997/98 El Niño and La Niña. Center for Health and the Global Environment, Harvard Medical School, Boston, MA. Intergovernmental Panel on Climate Change (IPCC), 2001. In: Watson, R.T. (Ed.), Climate Change 2001: Synthesis Report. A Contribution of Working Groups I, II, and III to the Third Assessment Report of the Integovernmental Panel on Climate Change. Cambridge University Press, Cambridge, UK, and New York, p. 398 and the Core Writing Team. Katz, A.R., Ansdell, V.E., Effler, P.V., Middleton, C.R., Sasaki, D.M., 2002. Leptospirosis in Hawaii, 1974–1998: epidemiologic analysis of 353 laboratoryconfirmed cases. Am. J. Trop. Med. Hyg. 66, 61–70. Knabb, R.D., Rhome, J.R., Brown, D.P., 2005. NOAA Hurricane Katrina Tropical Cyclone Report. http://www.nhc.noaa.gov/data/tcr/AL122005_Katrina.pdf (Accessed on 12 July 2016). Laschewski, G., Jendritzky, G., 2002. Effects of the thermal environment on human health: an investigation of 30 years of daily mortality data from SW Germany. Clim. Res. 21 (1), 91–103. McGregor, G.R., 2005. Winter North Atlantic Oscillation, temperature and ischaemic heart disease mortality in three English counties. Int. J. Biometeorol. 49 (3), 197–204. Morabito, M., Modesti, P.A., Cecchi, L., et al., 2005. Relationships between weather and myocardial infarction: a biometerological approach. Int. J. Cardiol. 105 (3), 288–293. Office of U.S. Foreign Disaster Assistance (OFDA)/Centre for Research on the Epidemiology of Disasters (CRED), 2006. The International Disaster Database. http:// www.em-dat.net/ (accessed January, 2007). Pan American Health Organization (PAHO), 2004. Central America five years after Hurricane Mitch, Disasters Preparedness and Mitigation in the Americas, Issue 94, January. Pardue, J.H., Moe, W.M., McInnis, D., et al., 2005. Chemical and microbiological parameters in New Orleans floodwater following hurricane Katrina. Environ. Sci. Technol. 39 (22), 8591–8599. Reacher, M., McKenzie, K., Lane, C., et al., 2004. Health impacts of flooding in Lewes: a comparison of reported gastrointestinal and other illness and mental health in flooded and non-flooded households. Commun. Dis. Public Health 7 (1), 39–46.

Schar, C., Vidale, P.L., Luthi, D., et al., 2004. The role of increasing temperature variability in European summer heat waves. Nature 427 (6972), 332–336. Sheridan, S.C., Kalkstein, L.S., 2004. Progress in heat watch-warning system technology. Bull. Am. Meteorol. Soc. 85 (12), 1931. Smoyer-Tomic, K.E., Kuhn, R., Hudson, A., 2003. Heat wave hazards. An overview of heat wave impacts in Canada. Nat. Hazards 28 (2–3), 463–485. Thomas, K., Charron, D., Waltner-Toews, D., Schuster, C., Maarouf, A., Holt, J., 2006. A role of high impact weather events in waterborne disease outbreaks in Canada, 1975–2001. Int. J. Environ. Health Res. 16 (3), 167–180. Tol, R.S., 2002. Estimates of the damage cost of climate change Part I: benchmark estimates. Environ. Resour. Econ. 21, 42–73. World Health Organization (WHO) Europe, 2002. Flooding: Health Effects and Preventive Measures. Fact sheet 05/02. WHO, Copenhagen and Rome.

Further Reading Huppert, H.E., Sparks, R.S., 2006. Extreme natural hazards: population growth, globalization and environmental change. Philos. Trans. Ser. A Math. Phys. Eng. Sci. 364 (1845), 1875–1888. Kirch, W., Menne, B., Bertollini, R. (Eds.), 2005. Extreme Weather Events and Public Health Responses. Springer, Berlin, Germany. Menne, B., Pond, K., Noji, E.K., Bertollini, R., 1999. Floods and Public Health Consequences, Prevention and Control Measures. Presented at the UNECE Seminar on Flood Prevention, Berlin, 7–8 October 1999 (UNECE/MP.WAT/SEM.2/ 1999/22). WHO European Centre for Environment and Health, Rome, Italy. Patz, J.A., McGeehin, M.A., Bernard, S.M., et al., 2001. The potential health impacts of climate variability and change for the United States – executive summary of the report of the health sector of the US National Assessment. J. Environ. Health 64 (2), 20–28. Patz, J.A., Olson, S.H., 2006. Climate change and health: global to local influences on disease risk. Ann. Trop. Med. Parasitol. 100 (5–6), 535–549. Rose, J.B., Daeschner, S., Deasterling, D.R., Curriero, F.C., Lele, S., Patz, J., 2000. Climate and waterborne disease outbreaks. J. Am. Water Works Assoc. 92, 77–87. Rose, J.B., Epstein, P.R., Lipp, E.K., Sherman, B.H., Bernard, S.M., Patz, J.A., 2001. Climate variability and change in the United States: potential impacts on water- and foodborne diseases caused by microbiologic agents. Environ. Health Perspect. 109 (S2), 211–221.

Relevant Websites http://www.who.dk/globalchange/Topics/20050524_2 – EuroHEAT Project, World Health Organization’s Regional Office for Europe (last accessed on 19.06.16.). http://www.eca.knmi.nl/ – European Climate Assessment & Dataset (ECA&D) (last accessed on 19.06.16.). http://www.chge.med.harvard.edu/education/policy/domestic/briefings/ extremeweather/extemeweatherbrief.html – Harvard Medical School, Center for Health and the Global Environment (last accessed on 19.06.16.). http://www.lwf.ncdc.noaa.gov/oa/climate/extremes/2002/august/extremes0802.html %23top – National Oceanographic and Atmospheric Administration (NOAA) 2002. National Climatic Data Center Climate-Watch. Hurricane Andrew: 10th Anniversary (last accessed on 19.06.16.). http://www.ncdc.noaa.gov/oa/climate/research/2005/katrina.html – National Oceanographic and Atmospheric Administration (NOAA) 2005. National Climatic Data Center Climate. Climate of 2005: Summary of Hurricane Katrina (last accessed on 19.06.16.). http://www.lwf.ncdc.noaa.gov/oa/reports/mitch/mitch.html – National Oceanographic and Atmospheric Administration (NOAA) 2006. Mitch: The Deadliest Atlantic Hurricane Since 1780. National Climatic Data Center (last accessed on 19.06.16.). http://www.em-dat.net/ – Office of U.S. Foreign Disaster Assistance (OFDA)/Centre for Research on the Epidemiology of Disasters (CRED): The International Disaster Database (last accessed on 19.06.16.). http://www.paho.org – PanAmerican Health Organization (PAHO) (last accessed on 19.06.16.). http://www.crid.or.cr/crid/ing/index_ing.html – Regional Disaster Information Center (CRID) Latin America and the Caribbean (last accessed on 19.06.16.). http://www.bt.cdc.gov/disasters/ – United States Centers for Disease Control and Prevention Natural Disasters & Severe Weather website (last accessed on 19.06.16.). http://www.who.int/hac/en/ – World Health Organization (WHO) (last accessed on 19.06.16.).

F Facility-Based Treatment of Severe Malnutrition Ann Ashworth, London School of Hygiene and Tropical Medicine, London, UK Ó 2017 Elsevier Inc. All rights reserved.

Background Each year there are over 6 million deaths among children aged 0–4 years. Neonatal disorders, diarrhea, pneumonia, and malaria are the main reported causes, but poor nutrition contributes to 45% of these deaths. This is because common childhood infections are more severe and longer lasting in malnourished children and are more likely to be fatal compared with the same illnesses in well-nourished children. An important factor is that nutritional deficiencies impair immune function and other host defenses. Also, infections undermine nutritional status, and young children can quickly enter a cycle of repeated infections and ever-worsening malnutrition (Figure 1). It is therefore essential that policy makers, donor agencies and health professionals include prevention and treatment of malnutrition in child survival strategies. A major problem is that malnutrition as an underlying cause of death does not appear in routine statistics and so its importance is easily overlooked.

Other Consequences of Malnutrition In addition to its synergism with infection and its effects on morbidity and mortality, malnutrition affects cognitive development and behavior, leading to poor academic achievement and poor employment prospects. Childhood malnutrition also adversely affects work capacity in adulthood, adding to the poverty trap that ensnares families, communities, and ultimately national economies.

Poverty as a Cause of Malnutrition There are many causes of malnutrition, but poverty is a ubiquitous factor affecting, for example, the quantity and quality of

Infection

Impaired defenses

Malnutrition

Death Figure 1

Infection–malnutrition–infection cycle.

International Encyclopedia of Public Health, 2nd edition, Volume 3

food eaten and exposure to common childhood infections. Figure 2 shows that the determining factors operate at many levels and extend from the family to national and international levels. Inequitable distribution of resources because of political, economic, and agricultural policies often denies families their right to adequate food, health care, and a safe environment. Interventions to break the infection–malnutrition cycle should be part of all child survival strategies. These should include poverty-reduction programs and improved food security together with interventions to control common childhood infections (particularly diarrhea, pneumonia, malaria, measles, and HIV) and promotion of improved feeding practices. Actions to prevent fetal growth restriction and postnatal malnutrition are especially urgent in sub-Saharan Africa and southern Asia, because these regions account for 49% and 32% of global child deaths, respectively. There are many pathways that culminate in severe malnutrition: Food shortage may typify some pathways, whereas others may be predominantly infection-related, involving, for example, increased utilization and/or losses of specific nutrients. Consequently, severely malnourished children are heterogeneous as regards the magnitude of their deficiencies and imbalances, depending on the pathway traveled.

Severe Malnutrition Severe acute malnutrition is defined as the presence of severe wasting and/or edema of both feet. Severe wasting is extreme thinness (weight-for-height less than
3 standard deviations of the WHO Growth Standards). Thinness of the upper arm (mid-upper arm circumference 30) Adequately controlled hypertension

No (do not use the method)

Breast cancer

4

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a This column gives examples of how the medical eligibility criteria are used in practice for women wishing to use combined hormonal contraception. If the woman suffers from a depressive disorder there is no restriction on her using combined contraceptive pills. Women who are obese generally can also use combined pills but women with breast cancer should not use such pills and women with hypertension, even if adequately controlled, should also not use such pills unless no other method is available or acceptable. Reproduced from World Health Organization, 2004. Medical Eligibility Criteria for Contraceptive Use, third ed. World Health Organization, Geneva, Switzerland.

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Family Planning/Contraception

Table 3

Classification of progestogens within combined pills

Classification

Progestogen

2nd Generation

Norethisterone/norethisterone acetate Levonorgestrel Ethynodiol Gestodene Desogestrel Norgestimate Drospirenone Cyproterone acetate

3rd Generation 2nd/3rd Generation With antimineralocorticoid activity With anti-androgenic activity

that is, they are known as monophasic preparations, although some contain a mixture of two (biphasic) or three (triphasic) different pill combinations in the same pack. Most combined pill preparations contain 21 active hormone tablets and the user takes a tablet daily followed by a pill-free interval of 7 days. Some combined pills have seven placebo pills in the blister pack so that the user can continue with regular, daily pill-taking. Some women choose to run packets of combined pill preparations together, without the pill-free interval, often three at a time. This ‘tricycling’ of pills or continuous pill use avoids the regular, monthly withdrawal bleed and a marketed preparation is now available in the United States, which has 84 pills packaged for continuous use followed by a 7-day, pill-free interval.

Contraindications The WHOMEC Category 4 conditions (which represent absolute contraindications to prescribing of the combined pill) fall under the broad headings of past or present circulatory disease, diseases of the liver, and history of a serious condition known to be affected by sex steroids (e.g., breast cancer). Many underlying medical conditions are not adversely affected by use of the combined pill but lack of conclusive evidence makes most of them WHOMEC Category 2 (the advantages of the method generally outweigh the theoretical or proven risks).

Side Effects and Risks Most side effects of the combined pill are mild and often settle with time. Common complaints include irregular bleeding, including breakthrough bleeding, breast tenderness, bloatedness, mood changes, weight gain, and nausea. These troublesome symptoms can result in poor compliance and subsequent discontinuation of the combined pill in some users. Serious complications in combined pill users are very rare and the main risks relate to thrombotic events and cancer of the breast and cervix. Long-term data from the Royal College of General Practitioners’ Study in the United Kingdom showed no excess mortality in users of the combined pill compared with users of other methods (Beral et al., 1999).

Venous Thromboembolism

Estrogen within combined pills has a prothrombotic effect and the risk of venous thromboembolism (VTE) for users is increased compared to nonusers (Table 4). The risk is greater

Table 4 Risk of venous thromboembolism with combined pills Risk of venous thromboembolism

Per 100 000 women

Nonusers of combined pills 2nd-Generation combined pill users 3rd-Generation combined pill users Pregnancy

5 15 30 60

in women taking combined pills containing the newer progestogens – desogestrel and gestodene – rather than the older progestogens, but overall VTE risk in users (15–30 cases per 100 000 users) is still only about half of the risk associated with pregnancy (60 cases per 100 000 pregnant women). Risk of VTE in individual users of combined oral contraceptives is also influenced by factors such as obesity, immobility, and presence of any inherited thrombophilia.

Arterial Disease

The WHO Scientific Group on Cardiovascular Disease and Steroid Hormone Contraception (1998) reviewed risk of myocardial infarction and stroke in combined pill users and their conclusions are reassuring. Both conditions are very uncommon in young women of reproductive age so the absolute risks are extremely small. In brief summary, there is virtually no effect of combined pill use on risk of myocardial infarction in women with normal blood pressure who do not smoke. Risk of hemorrhagic stroke similarly is not increased in women under the age of 35 years who do not smoke and have normal blood pressure. The risk does, however, increase with age and this effect is magnified in users of the combined pill. The relative risk of thrombotic stroke is increased in combined pill users to around 1.5 and further increased in pill users who smoke or have high blood pressure.

Cancer

The relationship of the combined pill with both breast and cervical cancers is complex. Data from the Collaborative Group on Hormonal Factors in Breast Cancer (1996) found that current or recent users of the combined pill have an increased relative risk of breast cancer of around 1.24. This increased risk was not related to duration of pill use or hormone dose and disappeared 10 years after discontinuing the pill. In a recent reanalysis of worldwide data from 24 epidemiological studies, the relative risk of cervical cancer among women currently using oral contraceptives for 5 years or more was twice that of never-users and the risk increased with increasing duration of use (International Collaboration of Epidemiological Studies of Cervical Cancer, 2007).

Noncontraceptive Benefits In addition to highly effective protection against pregnancy, the combined pill offers significant noncontraceptive benefits for the user. Withdrawal bleeds are usually lighter and less painful than normal menstrual periods. Women are less likely to become anemic and iron stores rise. Premenstrual mood changes often improve and women using the combined pill are less likely to develop functional ovarian cysts and pelvic inflammatory disease.

Family Planning/Contraception The combined pill offers important long-term protection against both ovarian and endometrial cancers with a three-to fourfold reduction in the risk of both malignancies, which lasts for at least 15 years after the combined pill is stopped.

Combined Hormonal Patches, Injectables, and Rings All these delivery systems have been developed relatively recently and it may be of benefit for some individuals to avoid the oral route of hormonal administration in the presence of gastrointestinal disorders or if nausea and vomiting are a problem. Women may find these methods more convenient to use and thus compliance may also be improved.

Injectable

One monthly injection contains a natural estrogen ester, estradiol cypionate (5 mg), combined with medroxyprogesterone acetate (25 mg). Women experience a regular monthly bleed with this preparation and the return to fertility on discontinuation is rapid. Various other combinations have been used, particularly in China and Latin America, with varying dosage regimens and generally high efficacy.

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offer highly effective contraception in a range of dosages and delivery systems (Table 5). The individual characteristics of each progestogen-only method vary quite considerably and they offer a variety of options, including pills, implants, and injectables. A progesterone-releasing vaginal ring is marketed in South America for lactating women. In contrast to the estrogen-containing, combined methods, low-dose, progestogen-only methods have no significant prothrombotic effect and therefore can be used by women with risk factors for cardiovascular disease when combined hormonal contraception is contraindicated. High-dose, progestogen-only methods may exert some effect on coagulation so should be avoided in women with a personal history of thrombosis. All progestogen-only methods are associated with significant menstrual change ranging from total amenorrhea to daily bleeding, although the latter is rarely heavy.

Mode of Action Low-dose progestogen methods act mainly by interfering with cervical mucus and endometrial development, thereby affecting sperm transport and implantation. Higher-dose methods reliably suppress ovulation in addition.

Transdermal Patch

A combined hormonal patch is now available in many countries. It releases ethinylestradiol (20 mg) and norelgestromin (150 mg) daily. The monthly schedule consists of three patches, each worn for 7 days followed by a patch-free week during which a withdrawal bleed occurs. Efficacy is similar to the combined pill.

Vaginal Ring

The combined contraceptive ring is a soft silastic structure that is inserted high into the vagina. It measures 5.4 cm in diameter and releases ethinylestradiol (15 mg) and etonorgestrel (120 mg) daily. It is placed in the vagina for 21 days and then removed for a 7-day interval at which time a withdrawal bleed occurs.

Progestogen-only Contraception Progestogen-only methods avoid the estrogen-related side effects and risks of combined hormonal contraception. They

Table 5

Progestogen-only Pills The progestogen-only pill (POP) is a low-dose method that requires a meticulous pill-taking regimen to ensure effectiveness. Extra contraceptive measures are required if a POP is taken more than 3 h late. A small range of pills is available. One pill is taken every day without a break. Menstruation may be regular but is more likely to be erratic and unpredictable. Depending on the brand of POP up to 20% of women (in whom ovarian activity is suppressed) develop amenorrhea. Efficacy shows a clear relationship to age, with the POP being around 10 times more effective in women over 40 years compared to women aged 25–29 years. For this reason, the POP is rarely recommended for adolescents, who often find it difficult to achieve good compliance with the required, strict pill-taking. Many women take the POP while lactating and efficacy is very high in this situation. There is a recommendation in some countries that, if a woman weighs more than 70 kg,

Progestogen-only contraception

Mode of delivery

Method

Type of progestogen

Dose

Effective for

IM injection

DMPA Depo Provera NET-EN Noristerat Norplant Jadelle Implanon Progestasert Mirena

Medroxyprogesterone acetate

150 mg

3 months

Norethisterone enanthate

200 mg

2 months

Levonorgestrel Levonorgestrel Etonorgestrel Progesterone Levonorgestrel Norethisterone Levonorgestrel Ethynodiol Desogestrel

25–80 mg day 25–80 mg day 25–70 mg day 65 mg day 1 20 mg day 1 350 mg day 1 30 mg day 1 500 mg day 1 75 mg day 1

IM injection Subdermal implant Subdermal implant Subdermal implant Intrauterine Intrauterine Oral Oral Oral Oral

Various brands Cerazette

1 1 1

5 years 5 years 3 years 1 year 5 years Daily Daily Daily Daily

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she should then take a double dose of the POP to improve efficacy. If a woman taking the POP does become pregnant, there is a higher chance than normal that she might have an ectopic pregnancy. A new, more potent POP containing the progestogen desogestrel (75 mg) is available in some countries and reliably inhibits ovulation in virtually all cycles. As a result, it is theoretically more effective than the older preparations and can prove helpful in the management of conditions such as menstrual migraine and premenstrual syndrome.

Ortho-Gynae T 380

Nova-T 380

Injectables Two injectable progestogen-only methods are available. Depot medroxyprogesterone acetate (DMPA) (150 mg) is the more commonly used and is given by deep, intramuscular injection every 3 months. Norethisterone enanthate (NET-EN) (200 mg) is given every 8 weeks. Amenorrhea is common with both methods; many women welcome the lack of menstruation provided they are well counseled about this in advance. Long-term use of DMPA appears to cause a slight reduction in bone mineral density compared to nonusers. Most studies suggest that this is reversible on discontinuation of DMPA but it is of concern that adolescents using DMPA may fail to reach their peak bone mass and that women approaching menopause may not recover their bone mineral density and so may be at increased risk of osteoporosis in later life. DMPA is often associated with slight initial weight gain and in long-term users there is a delay in return of fertility of up to 6 months in comparison with other hormonal methods.

Implants Contraceptive implants consist of nonbiodegradable, flexible rods that are inserted subdermally into the upper arm. The active hormone is contained within the core of each rod and is released by steady diffusion into the circulation. Insertion and removal have to be undertaken by trained health professionals. Although the up-front cost of implants is higher than other methods, they are a highly cost-effective method of contraception if the user continues for the full duration of the implant’s lifespan. The most commonly used implants are listed here: Norplant has six rods that release levonorgestrel. It is effective for at least 5 years. l Jadelle is a two-rod system releasing levonorgestrel with a similar profile to Norplant. l Implanon consists of a single rod that releases etonorgestrel, a precursor of desogestrel. It is effective for 3 years. l

Implants are commonly associated with menstrual disruption and women should be carefully counseled prior to insertion about the menstrual change and risk of other minor hormonal side effects. Reinsertion of a new implant can be performed at the time of removal of the old implant. Fertility is immediately restored on removal of the implant.

Intrauterine Devices and Systems The modern copper-bearing IUD consists of a plastic frame with copper wire around the stem and, in some models,

Multiload Cu 375

Mirena intrauterine system

Figure 2 Commonly used intrauterine methods of contraception. Source: Glasier, A., Gebbie, A. (Eds.), 2008. Handbook of Family Planning and Reproductive Healthcare, fifth ed. Churchill Livingstone, Edinburgh, UK.

has copper sleeves on the arms (Figure 2). The copperbearing IUDs are smaller and more effective than the older, inert plastic devices. Both efficacy and duration of use are related to the amount of copper the device bears and many devices will provide up to 10 years of contraception. Insertion of an IUD should be performed by trained health-care staff.

Mode of Action The main mode of action of a copper-bearing IUD is to prevent fertilization by the toxic effects of copper ions on gametes. In addition, an IUD causes an inflammatory reaction of the endometrium that inhibits implantation.

Side Effects and Risks The risk of uterine perforation at the time of insertion is around 1 in 1000. The risk of spontaneous expulsion of an IUD is around 1 in 20 in the first 3–6 months after insertion. An IUD is associated with a menstrual change, with around a 25% increase in menstrual blood loss and increased dysmenorrhea.

Family Planning/Contraception Pelvic Infection

There is a slight increase in risk of pelvic infection in the first few weeks following insertion of an IUD. Thereafter, the overall risk of pelvic infection in IUD users is not increased significantly compared to women using no contraception. If a woman with an IUD contracts a sexually transmitted infection (STI) then the IUD may enhance the spread of ascending infection in the pelvic organs. The decision whether women are to be screened for STIs prior to insertion of an IUD should be based on prevalence of infection within the community and the individual’s own risk factors.

Ectopic Pregnancy

Women with an IUD are protected against all pregnancies, including ectopic pregnancies (pregnancies implanted abnormally, outside the uterine cavity). However, should the method fail, the risk of ectopic pregnancy is around three times higher than observed in pregnancies that occur without an IUD.

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Female Condom The female condom (Figure 3) is a lubricated polyurethane sheath that is designed to lie loosely within the vagina. There is a flexible polyurethane ring at the open, outer end and a second polyurethane ring inside the closed, inner end of the condom, which helps to insert the condom and anchor it within the vagina. It offers significant protection against sexually transmitted diseases. Designed for single use, it can be inserted either immediately or several hours prior to intercourse. Occasionally, the condom can be displaced or pushed right up into the vagina with penetration taking place outside the condom (i.e., between the vaginal wall and wall of the female condom). It is relatively expensive and many individuals dislike the concept and aesthetics of the female condom. If no fresh condom is available, a used female condom may be reused for a limited number of times provided it is carefully washed and disinfected.

Diaphragms Intrauterine System The intrauterine system (IUS), also known as the levonorgestrel-releasing IUD, releases 20 mg of levonorgestrel per day from a central hormone reservoir in the stem of the device (see Figure 2). It exerts its potent contraceptive effect by causing profound endometrial atrophy and making cervical mucus hostile to sperm transport. Ovulation is not inhibited. The IUS is associated with a profound reduction in menstrual blood loss and most long-term users will be oligo-amenorrheic (infrequent and scant menstrual bleeds). In addition to contraception, the IUS is also licensed in many countries for treatment of menorrhagia and as the progestogen component of hormone replacement regimens.

Barrier Methods Male Condom The male condom has been used in various forms for centuries. Most condoms are made of latex rubber but condoms made of both plastic and animal material are available. Allergy to latex condoms is a fairly common problem in either partner. Various sizes and shapes of condoms are manufactured. Some individuals dislike the altered sensation of wearing a condom during sexual intercourse and the necessity to interrupt the sexual act to put the condom on. It is important that condoms are manufactured to stringent standards and many countries use a recognizable mark indicating production to an accepted quality. Out-of-date condoms are more likely to tear or burst during use. Failure rates of condoms vary and are related to how consistently and diligently couples use them. The main benefit of using condoms as a method of contraception is the additional protection they offer against STI and, provided the condom is used prior to any genital contact, then the level of protection against infection is very high. Condoms have been heavily promoted in Safe Sex campaigns across the globe, particularly in respect to preventing HIV infection.

A contraceptive diaphragm consists of a thin latex rubber hemisphere with a reinforced rim of a flat or coiled metal spring (Figure 4). It is designed to cover the cervix by lying across the upper vagina. Diaphragms are made in various sizes ranging from 50 to 95 mm in diameter and a woman should be fitted with a diaphragm by a trained health-care professional. A diaphragm should always be used in conjunction with spermicide to improve efficacy as it does not have a tight seal around it in the vagina. Diaphragms offer protection against pelvic inflammatory disease and cervical cancer but do not protect against HIV or other lower genital tract infections.

Cervical Caps The traditional cervical cap is a thimble-shaped rubber device that is smaller than the diaphragm and is secured directly onto the cervix with a suction effect (see Figure 4). It comes in various sizes and should also be used with a spermicide to increase efficacy. It may be dislodged during intercourse without the woman noticing. Other cervical caps (e.g., Lea’s Shield and FemCap) are available in different countries and may be manufactured in plastic, which allows them to remain in position for longer periods.

Figure 3 Female condom. Source: Glasier, A., Gebbie, A. (Eds.), 2008. Handbook of Family Planning and Reproductive Healthcare, fifth ed. Churchill Livingstone, Edinburgh, UK.

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Family Planning/Contraception

CycleB

eads’

Diaphragm CycleBeads

’

Cervical cap

Figure 4 Diaphragm and cervical cap. Source: Glasier, A., Gebbie, A. (Eds.), 2008. Handbook of Family Planning and Reproductive Healthcare, fifth ed. Churchill Livingstone, Edinburgh, UK.

Spermicides A range of spermicidal products is available comprising creams, gels, pessaries, foams, sponges, and dissolving squares of film. The active constituent is the chemical nonoxynol-9, which has toxic effects on sperm cell membranes. Spermicides also offer some degree of protection against most STIs but not against HIV. In general, they should be used in conjunction with other barrier methods as they have an unacceptably high failure rate if used on their own. There is concern that spermicidal preparations can have an irritant effect on vaginal and penile tissues, which may enhance the risk of HIV transmission. As a result, it is recommended that individuals at high risk of HIV infection do not use spermicides. In addition, for this reason, condoms that are prelubricated with spermicide are no longer recommended.

Fertility Awareness Methods There are only a limited number of days in each menstrual cycle when fertilization can occur and, using this knowledge, it is possible to predict when intercourse should be avoided if a couple wishes to avoid pregnancy. The success of this approach is totally dependent on very careful adherence to the period of abstinence that many individuals find restrictive. Alternatively, individuals can choose to use a barrier method of contraception during the fertile period. These methods may be practiced by couples who have religious or moral objections to other contraceptive methods, have no consistent access to modern methods, or who prefer ‘natural’ methods. They require careful teaching of the method and good comprehension by the couple of the significance of the symptoms and signs of ovulation. There are various ways of detecting the fertile period:

Calendar or Rhythm Method

This method calculates fertile days by subtracting 18 from the length of the shortest cycle and 11 from the length of the longest cycle. These numbers then represent the start and the

Figure 5 Standard days method cycle beads. Source: Glasier, A., Gebbie, A. (Eds.), 2008. Handbook of Family Planning and Reproductive Healthcare, fifth ed. Churchill Livingstone, Edinburgh, UK.

end of the fertile period, respectively. In some countries a set of colored beads is used to help women keep track of the cycle and fertile times. Each color-coded bead represents a single day in the cycle, and the color of a particular bead on a particular day indicates whether the woman is fertile or not (Figure 5).

Temperature Method

This method monitors the small rise in basal body temperature that occurs after ovulation. Couples should abstain from intercourse for 3 days after this rise; this method does not identify the beginning of the fertile period.

Cervical Mucus Method or Billings Method

This method involves monitoring changes in cervical mucus that occur in the normal menstrual cycle. Fertile cervical mucus is clear and ‘stretchy.’ Abstinence should be maintained from the day the fertile mucus is first seen or felt in the vagina until 3 days after the final day it is detected.

Multiple Index Methods

These methods combine various indicators of fertility and, while this undoubtedly improves efficacy, the method does require particular diligence on the part of the user.

Ovulation Predictor Kits

These kits are available and monitor urinary hormone levels. The computer detects 6–10 days each month when intercourse should be avoided.

Lactational Amenorrhea Method Women who are exclusively breastfeeding, are amenorrheic, and have a baby under the age of 6 months have an extremely low risk of pregnancy. Women in this situation can rely on lactational amenorrhea as a contraceptive method but should start using another method once supplemental foods are introduced for the baby, once 6 months have passed since delivery, or if menstruation returns. The uptake and success of this method depend on the pattern and duration of breastfeeding

Family Planning/Contraception

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and, in many developed countries, women introduce formula milk and solid food at an early stage.

Withdrawal

Female sterilization with clips

This is the oldest method of contraception, first described in the Bible. Withdrawal (or coitus interruptus) involves withdrawing the erect penis from the vagina before ejaculation occurs, thus avoiding the passage of sperm into the female genital tract. The method requires discipline on the part of the male and can be reasonably effective if the man can recognize the imminence of ejaculation. Pre-ejaculatory secretions containing sperm may escape from the urethra before withdrawal.

Sterilization Procedures

Vasectomy procedure

Female Sterilization Female sterilization involves a surgical procedure to occlude the Fallopian tubes thereby preventing sperm reaching and fertilizing the ovum. It must be performed by trained health-care professionals and can be carried out under local or general anesthesia. The choice of technique and type of anesthesia are often dictated by local availability of equipment and training of personnel more than by patient preference.

Timing of the Procedure The procedure can be performed at any time in the menstrual cycle, although care should be taken to ensure that the woman is not at risk of having conceived just before the procedure. Immediate postpartum sterilization can be performed and may be the only option available in developing countries or remote communities. Postabortion sterilization can also be undertaken, but this is associated with a higher rate of regret and is therefore generally best deferred until the woman has an opportunity to plan her reproductive future at a less stressful time.

Techniques Various methods can be used to block the Fallopian tubes (Figure 6). Clips made of metal and plastic, silastic rings, diathermy, and laser ablation are all in common use. The Fallopian tubes can also be surgically divided with excision of a small portion of tube. A female sterilization procedure can be carried out by both laparoscopy and mini-laparotomy. Laparoscopy is usually done under general anesthesia but can be done under spinal or local anesthesia. Mini-laparotomy involves a 2–3 cm suprapubic incision and avoids the need for expensive laparoscopy equipment. It is the procedure of choice in the immediate postpartum period when the uterus is large. Essure is a nonsurgical sterilization technique that is available in North America and some European countries. Under hysteroscopic guidance, a metal coil is inserted into each Fallopian tube via a slim catheter. Scar tissue develops around the coils and results in occlusion of the Fallopian tubes. It takes 3 months to ensure occlusion of the tubes and initial failure rates appear very low.

Figure 6 Female sterilization and vasectomy. Source: Glasier, A., Gebbie, A. (Eds.), 2008. Handbook of Family Planning and Reproductive Healthcare, fifth ed. Churchill Livingstone, Edinburgh, UK.

Clinical Management Women undergoing sterilization must be carefully counseled about the irreversibility of the procedure and the very small failure rate. A consent form explaining these important points and requiring the woman’s signature is recommended. Reversal of female sterilization is technically possible but success rates vary according to the type of procedure performed initially. Successful reversal rates are highest when the tubes have been occluded with clips or rings. Reversal procedures are technically complex and expensive operations. Failure of female sterilization is associated with an increased risk of ectopic pregnancy; therefore, women with symptoms of pregnancy following sterilization must seek medical advice to exclude an ectopic pregnancy.

Male Sterilization Male sterilization (vasectomy) involves division or occlusion of both vasa deferentia and is a more effective procedure than female sterilization. It is also much safer and simpler to perform and is undertaken under local anesthesia in most men.

Technique The standard technique involves making a single midline or two incisions, one on each side, to expose the vas. The vas on each side is then divided surgically or occluded by clips or diathermy (see Figure 6). No-scalpel vasectomy uses a special instrument to puncture the skin and expose the vas. It is quicker and less traumatic to the surrounding tissues so is associated with less bruising and discomfort.

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Clinical Management Signed consent is usually obtained for the procedure, explaining the permanent nature of vasectomy and its very small failure rate. In contrast to female sterilization, vasectomy is not effective immediately and it takes around 3 months to clear sperm from the vas beyond the site of the division or occlusion. Contraception must be continued during this time and until two consecutive semen samples have been found to be devoid of sperm. Uncommonly, men may experience chronic pain following vasectomy which may be the result of sperm granulomas developing as a local inflammatory response at the cut ends of the vas. Late canalization of the vas deferens can occasionally occur many years following vasectomy but is rare. Some studies have suggested an association between vasectomy and subsequent development of both testicular and prostatic cancer. This has not been substantiated and these small studies have not influenced clinical practice.

Emergency Contraception Emergency contraception is a back-up method used following unprotected intercourse or when another method has failed. It is commonly used when condoms have burst, but can also be used when contraceptive pills have been omitted.

Hormonal Emergency Contraception The most modern regimen involves a single dose of 1.5 mg of the hormone levonorgestrel up to 72 h following the unprotected episode of intercourse (some practitioners recommend it up to 120 h but efficacy is highest when taken in the first 24 h following intercourse and declines over time). Side effects are uncommon. It is available in more than 100 countries on medical prescription and also over-the-counter in some countries. The mode of action of hormonal emergency contraception is not clear but disruption of ovulation is the most likely mechanism. Hormonal emergency contraception probably only prevents around three-quarters of pregnancies that would otherwise have occurred so should not be used as a sole method of contraception. The older Yuzpe regimen using combined contraceptive pills involved giving two doses, each of ethinylestradiol (100 mg) and levonorgestrel (0.5 mg), 12 h apart and was associated with a significant degree of nausea and vomiting. In China, the antiprogestogen mifepristone is marketed as an additional emergency contraceptive.

Postcoital Intrauterine Device A copper-bearing IUD can be inserted following unprotected intercourse and appears to be highly effective in preventing pregnancy. The effectiveness of the levonorgestrel-releasing system (LNG-IUS) when inserted postcoitally has not yet been studied and hence this device should not be used for this indication. A device can be inserted up to 5 days after the anticipated day of ovulation, despite multiple episodes of unprotected intercourse, without fear of causing abortion. The device can be removed following the next menstrual period or can remain in situ as the ongoing method of

contraception. Women should be carefully assessed for risk of STI prior to insertion of a postcoital IUD.

Conclusion A range of methods exists that allow couples to regulate their fertility. While permanent sterilization is available for both men and women, there are only a few reversible methods for use by men, namely condoms and withdrawal, and both are among the less effective methods of contraception. For women, a range of reversible methods allows a choice between barriers, intrauterine contraceptives, and hormonal methods, with or without estrogen, and deliverable by a variety of routes (oral, injectable, etc.). All methods are very safe for healthy women and a robust classification of medical eligibility helps providers choose suitable methods for women with preexisting medical conditions. Method choice is influenced by a long list of factors but is vital to successful use of contraception. While methods vary in their effectiveness, and while those that rely little or not at all on compliance are the most effective, correct, consistent, and continued use is most likely when people use the method they find most acceptable. Use of contraception allows couples (and individuals) to choose whether, and when, to have children and contributes enormously to sexual and reproductive health. In a recent article, Cleland et al. (2006) described family planning as being: unique among medical interventions in the breadth of its potential benefits: reduction of poverty, and maternal and child mortality; empowerment of women by lightening the burden of excessive childbearing; and enhancement of environmental sustainability by stabilising the population of the planet. Cleland et al. (2006: p. 1810).

See also: Gender Aspects of Sexual and Reproductive Health; Infertility, An Overview; Reproductive Rights; Sexual and Reproductive Health: Overview.

References Beral, V., Hermon, C., Kay, C., et al., 1999. Mortality associated with oral contraceptive use: 25-year follow up of cohort of 46,000 women from Royal College of General Practitioners’ oral contraceptive study. Br. Med. J. 318, 96–100. Cleland, J., Bernstein, S., Ezeh, A., et al., 2006. Family planning: the unfinished agenda. Lancet 368, 1810–1827. Collaborative Group on Hormonal Factors in Breast Cancer, 1996. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data of 53,297 women with breast cancer and 100, 239 women without breast cancer from 54 epidemiological studies. Lancet 347, 1713–1727. International Collaboration of Epidemiological Studies of Cervical Cancer, 2007. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 370, 1609–1621.

Further Reading Glasier, A. (Ed.), 2006. Contraception and hormone replacement therapy. Med. Int. 34 (1), 1–34.

Family Planning/Contraception Glasier, A., Gebbie, A. (Eds.), 2008. Handbook of Family Planning and Reproductive Healthcare, fifth ed. Churchill Livingstone, Edinburgh, UK. Glasier, A., Winikoff, B., 2005. Fast Facts Contraception, second ed. Health Press, Oxford, UK. Hatcher, R.A., Trussell, J., Stewart, F., et al., 2004. Contraceptive technology, eighteenth revised ed. Ardent Media, New York. Mishell, D. (Ed.), 2007. Contraception, 75 (Suppl. 1), pp. S1–S117. Population Reference, 2004. Bureau transitions in world population. Popul. Bull. 59, 1–40. Trussell, J., 2004. Contraceptive efficacy. In: Hatcher, R.A., Trussell, J., Stewart, F., et al. (Eds.), Contraceptive Technology, eighteenth revised ed. Ardent Media, New York, pp. 773–845. World Health Organization Department of Reproductive Health and Research (WHO/RHR) and Johns Hopkins Bloomberg School of Public Health/Center for Communications Programs (CCP), INFP Project, 2007. Family Planning: A Global Handbook for Providers. CCP and WHO, Baltimore, MD and Geneva, Switzerland. World Health Organization, 1998. Cardiovascular Disease and Steroid Hormone Contraception. Technical Report Series 877. World Health Organization, Geneva, Switzerland.

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World Health Organization, 2004. Medical Eligibility Criteria for Contraceptive Use, third ed. World Health Organization, Geneva, Switzerland. World Health Organization, 2005. Selected Practice Recommendations for Contraceptive Use, second ed. World Health Organization, Geneva, Switzerland.

Relevant Websites http://www.ffprhc.org.uk – Faculty of Family Planning and Reproductive Healthcare in the UK. http://www.infoforhealth.org/cire/cire_pub.pl – The INFP Project and Continuous Identification of Research Evidence (CIRE) System. http://www.popcouncil.org – Population Council in the United States. http://www.who.int/reproductive-health/publications/MEC/index – World Health Organization Medical Eligibility Criteria for Contraceptive Use (WHOMEC). http://www.who.int/reproductive-health/publications/spr/index – World Health Organization Selected Practice Recommendations for Contraceptive Use.

Famine Marc-Andre´ Prost, London School of Hygiene and Tropical Medicine, London, UK Alex de Waal, World Peace Foundation, Fletcher School of Law and Diplomacy, Tufts University, Medford, MA, USA Ó 2017 Elsevier Inc. All rights reserved.

Introduction

Hunger, Starvation, and Famine: Definition

As the twenty-first century dawns, humanity possesses unprecedented wealth. The last two centuries have seen the wealth of the nations expanding ninefold while population has grown only sixfold. For the first time in history, the world has the capability of eliminating famine. However, wealth and power are distributed with dramatic inequality. Famine, though much reduced globally, remains a recurrent threat for communities affected by armed conflict, particularly in Africa. In the 1950s, the fight against hunger moved from being a charitable endeavor to a global project. In large part, this was thanks to the establishment of specialist agencies of the United Nations (UN) and aid budgets in richer nations, while the growth of nongovernmental humanitarian agencies reflected growing concern over the problem among the general public in the most affluent countries. Increasing global food availability through productivity was then seen in short as the solution for hunger and famine eradication. In the mid-twentieth century the global issue was framed as a population challenge to food supply: there was worry that the Earth might not be able to feed 10 or 15 billion human beings. However, rapid population growth has coincided with dramatic reductions in great and calamitous famines. In absolute terms, the second half of the twentieth century saw unprecedented progress in reducing global famine. By the end of the century, famine was eradicated from most of Eurasia including the three countries that had witnessed the vast majority of nineteenth- and twentiethcentury famine deaths, namely China, India, and Russia. However, in 2004 the Food and Agriculture Organization of the UN estimated that 834 million people in developing countries still lacked sufficient access to food to meet their nutritional requirements, an absolute decrease of just 140 million in 35 years. Meanwhile, famines persist today in Africa and parts of the Middle East, chiefly as a result of armed conflict, albeit registering as disasters that kill only a fraction of the millions who died routinely in the calamities of earlier years. While famine remains in the poorest and most conflictprone countries, the problems of malnutrition are much more widely spread. The global burden of malnutrition increasingly includes obesity as well as the traditional manifestation of hunger, namely stunting, marasmus, and kwashiorkor. Equitable development and poverty eradication make up the heart of the struggle against chronic malnutrition, but efforts to overcome famine encompass a host of political challenges, notably ending civil wars in which belligerents use starvation as a weapon of war. As the nature of famine changes so too do the measures necessary to defeat it.

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Starvation is . people going without adequate food, while famine is a particularly virulent manifestation of [starvation] causing widespread death. Sen (1981: p. 1).

There are underlying principles that differentiate famine from starvation, that is, in their most common ‘English’ sense (in Sen’s definition), one being that starvation refers to the individual as opposed to famine-affected populations, and the other being the time frame over which they occur (Figure 1). An individual starves in a biological sense and experiences famine as a wider social and economic phenomenon. An individual may experience starvation in the absence of famine in the community or society to which he or she belongs, even amid generalized prosperity: there is no geographical definition to individual starvation. Conversely, the occurrence of a famine

Figure 1 Starving boy with a calabash in the hunt for food. Reproduced with permission from Tom Stoddart, Getty Images.

International Encyclopedia of Public Health, 2nd edition, Volume 3

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Famine does not by any means imply that every individual in the affected area is starving. Famine is defined by location but does not afflict evenly within the affected area. Even mass starvation is a selective phenomenon. The second differentiation is the time dimension. Famine is an acute phenomenon, bound by time, for which one can identify a beginning and an end. Famine relief is an urgent business. Chronic starvation and hunger by contrast exist over long periods of time within societies and do not possess clear beginnings and ends. The two are related as an endemic disease while famine is related as an epidemic. A triggering event, whether a natural disaster (drought, flood, pest invasion, or crop failure) or the product of an economic or political system (war, deliberate policy of a government, speculation), can provoke a sudden collapse in the ability of the poor and vulnerable to secure enough food, plunging a large category of a population into famine. Typically, such disaster also exposes underlying trends that have rendered the population vulnerable to such a shock: the etiology of the famine can be traced back to well in advance of the triggering event. Most representations of famines in history relate to cataclysmic events best described in terms of excess death attributable directly or indirectly to starvation and disease. As many as 30 million people may have died in China during the Great Leap Forward (1958–61), up to 4.8 million died during Holodomor (Ukrainian famine of 1932–33), between 500 000 and 2 million during the famous Irish Potato Famine (1845–49) and Kalhana’s records of the 1917–18 Kashmir famine reports that “one could scarcely see the water in the Vistasa, entirely covered as the river was with corpses. . The land became densely covered with bones in all directions until it was like one great burial ground” (Sen, 1981: p. 39). Such representations of famine have powerful echoes of biblical apocalypse and other variants of metaphysical determinism. A secular version of this fatalism was first theorized by Thomas Malthus in his Essay on the Principle of Population, first published in 1798. The British philosopher argued that since the natural tendency of populations was to grow faster than their food supply, famine, war, and epidemics were inevitable events acting as ‘checks’ on population levels, that is, people had no control over famine occurrence and the inexorable outcome was mass deaths (Figure 2). Although repeatedly disproven by history, Malthus’ idea continues to exert a powerful grip on the collective imagination. Amartya Sen’s seminal work Poverty and Famines (1981) was the most significant advance in famine theorizing since Malthus. He shifted the debate from global food availability to local food accessibility at individual level. His ‘entitlement theory’ was centrally organized around the concept that famines occur not because there is not enough food but because people do not have enough access to it (i.e., lack of entitlement to food). It provided a robust explanation for why the poorest are, often, the worst affected in times of famine. Rangasami and later de Waal have challenged the conceptualization of famine as mass deaths through starvation embedded in both Malthus’ and Sen’s theories. De Waal argued that lingering Malthusian influence has led us to consider only extreme cases of famines, while also encouraging a tendency to treat famine as failures for which science can cater to with

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Figure 2 ‘Famine’ (1989) by Viktor Zarets’kyi (1925–90). Oil on canvas. The painting represents Holdomor, the Great Ukraine Famine of 1932–33.

technological fixes. He reminded us that, according to him, famines were foremost social experiences better measured through changes in food availability and increased food insecurity, and that death is not a means of defining famine but merely a possible outcome, obviously the worst.

Famine: Past and Future Trends The size of any animal population is constrained by the available sources of food, and it is reasonable to assume that this was the case for human populations in prehistoric times and, more recently, among hunter-gatherer societies. Demographic responses to famines show that human populations evolved so as to be maximally resilient to such stress. Famine deaths are concentrated among the very young and the elderly, and mortality is lowest among young women. Canceled or postponed births are comparable in number to excess deaths. The female mortality advantage during famine is well documented and logical although the mechanisms to account for it are not fully explained. This selective impact means that a famineimpacted population is best placed for a postfamine fertility rebound. In modern history, famines have never represented a Malthusian type of shock that massively reduces population size. Historical evidence indicates that famines rarely reduce overall population size by as much as 10 percentage points. The largest famine of the twentieth century, which was the Great Leap Forward famine in China during 1958–61, is estimated to have killed 30 million people and reduced births by a further 30 million, amounting to a gross impact of about 10% of China’s population, with certain areas faring significantly worse. Nonetheless, within a few years the Chinese population had regained and surpassed its prefamine size.

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Famine

Famine was a recurrent feature of agrarian societies in Europe and Asia during the early modern period. The last widespread subsistence crisis in Europe occurred in 1815–16, though there were serious famines in individual countries in the remainder of the century, notably in Russia. The Irish famines of the 1840s caused some of the highest rates of population decline of any recorded peacetime disasters in history, the majority of this due to out-migration in the aftermath of the famines. In Asia, famines became more common throughout the nineteenth century. Possibly the most severe sequence of famines in modern times took place during 1880–1900, due to a combination of climatic anomalies (a large El Niño/ Southern Oscillation event leading to failures of the monsoon rains), and the social, economic, and political impacts of imperial conquest and associated warfare, which led to the dismantling of indigenous famine response and relief systems and the collapse of livelihoods dependent on trade and the local cotton industries. Watts (Michael Watts, social historian) has called these ‘late Victorian Holocausts.’ Especially severe famines struck India and China, as well as a huge arc of eastern Africa from Eritrea to South Africa, the latter caused in part by a rinderpest epizootic that destroyed cattle herds. There was also severe deprivation in northeast Brazil. During the twentieth century, famines and episodes of forced mass starvation are estimated to have killed 97 million people, fully 30 million of those during the 1958–61 China famine. The listing includes ‘great’ famines (those that killed 100 000 people or more) and ‘calamitous’ famines (that killed 1 million or more). Among the other largest famines of the century included Bengal in 1943 (an estimated 3 million excess deaths) and the 1928 famine in northern China. (We should note that statistics for famine mortality usually consist of the median figure from a range of estimates, sometimes widely variant. India is unusual in that it has excellent demographic data that can allow more accurate estimation.) Among the worst famines are four from the Soviet Union, including the famine caused by the civil war in 1920–22, the Ukrainian famine of 1932–33, the siege of Leningrad during World War II and a crisis that struck at the

end of the war (Figure 3). Episodes of forced mass starvation include the Nazi ‘hunger plan’ that aimed to reduce the population of eastern Europe by 30 million (in the event, causing ‘only’ an estimated 4.2 million deaths) (Snyder, 2012) and Pol Pot’s ‘Year Zero’ in Cambodia (in which 1.75 million starved) (Kiernan, 2008). Africa suffered famines during the first three quarters of the twentieth century. Colonial conquest and repression in the first 2 decades involved the deliberate destruction of livelihoods of groups who resisted and, in the case of the Herero of southwest Africa (Namibia), starvation as an act of genocide. A wideranging Sahelian drought in 1913, and further sequences of droughts in the 1940s and 1970s, brought famine to different parts of the continent. Ethiopia was the worst hit of these countries, with the poorest northern provinces also suffering drought-related famines in the 1950s and 1960s. However, in scale and numbers killed, none of these famines ranked alongside the great Asian and Russian famines of those decades. The last European famines occurred during and after World War II, including the Hunger Winter in the Netherlands in 1944 and the much larger disasters in the Soviet Union. The advent of peace and the end of the titanic, Communist, social engineering projects such as forced collectivization meant that European populations enjoyed an unprecedented era of food security. While the return of civil war to the Balkans in the 1990s was not marked by significant famine, the Russian assaults on Chechnya led to serious if underreported humanitarian crisis, including starvation in the city of Grozny. The elimination of famine from almost all parts of Asia during the second half of the twentieth century will rank as the single most important development in the history of famine. Throughout recorded history, Asia’s agrarian societies have suffered the largest, most frequent, and most deadly famines. In the final quarter of the twentieth century, only two Asian countries suffered famines that killed large numbers of people. One was Cambodia under the Khmer Rouge (1975– 78), during which time about 3 million people are estimated to have perished on account of overwork, disease, and starvation. The second was North Korea during the 1990s, due to the precipitous decline of the country’s economy under

Figure 3 Death toll from famines associated with armed conflict and political repression, 1870–2015. Source: World Peace Foundation, ‘Mass Famine,’ http://www.fletcher.tufts.edu/World-Peace-Foundation/Program/Research/Mass-Atrocities-Research-Program/Mass-Famine.

Famine Communist dictatorship. These two cases, along with Mao’s Great Leap Forward catastrophe, represent the product of utopian social experiments by totalitarian regimes, gone tragically awry. No African famines rival historic European and Asian calamities in scale. It is tempting to conclude that massive famines are now an anachronism. Some caution is, sadly, in order. Wars have led to humanitarian crises in Iraq (1991), Afghanistan (throughout the decade), the Darfur region of Sudan (2004–05), and Somalia (2011–12). During the 1990s, the sanctions imposed on Iraq led to a disastrous decline in the quality of health care and a sharp increase in child mortality. The efficient food rationing system of the Ba’ath regime prevented what would conventionally have been called a famine. In 2015–16, armed conflicts were causing famine in South Sudan and Yemen, and major humanitarian crisis in parts of Syria. While famine has been conquered in Asia, it has persisted in Africa. The sole African famine to have killed sufficient people to count among the worst 10 of the twentieth century was the Ethiopian famine of 1983–85, which killed between 400 000 and 1 million. This famine was the product of war, drought, and failed agricultural policies, exacerbated by official refusal to recognize the crisis until very late. The famine in Sudan at the same time, caused by drought, economic crisis, and a government denial that any problem existed, killed an estimated 250 000 people, and the contemporaneous drought in the west African Sahel is also believed to have led to excess mortality. During the late 1980s and 1990s, most African famines were caused by warfare, notably in southern Sudan, Angola, Mozambique, Somalia, Liberia, Sierra Leone, and the Democratic Republic of Congo. The terminology preferred by aid agencies is humanitarian crisis, but they are in fact war famines under a different name. In situations in which civilian populations have been subjected to deliberate starvation, death rates have sometimes been very high indeed. In the first decade of the twenty-first century, comparable crises have erupted in Darfur (Sudan) and Ivory Coast. Meanwhile, the formerly food-surplus country of Zimbabwe has plunged into a vortex of decline, brought about by misgovernment, confiscation of commercial farms, and mass eviction of peri-urban populations, causing that country to face severe food crisis. Famines related to drought and rural poverty have not ceased. In 2002–03, Ethiopia faced its largest-ever food emergency, with 13 million people estimated to need relief assistance on account of crop failures consequent on drought, exacerbated by a sharp decline in the country’s livestock exports and coffee revenues. Shortly afterward, Niger also faced drought and calls for emergency assistance. Also at this time, a widespread drought in southern Africa led to very large numbers of people needing food assistance in Mozambique, Zambia, Malawi, and Zimbabwe. Malawi suffered several food crises in quick succession. A contributory factor in these crises has been the HIV/AIDS epidemic, which has undermined the resilience and capacity to cope of sections of the rural populace. Judging by the number of events classified as ‘famine,’ one might conclude that famines are becoming more common. However, it is important to note that since the late 1980s,

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peacetime famines in Africa have not led to significant excess mortality. There is little evidence for raised death rates in the southern African drought of 2002–03. The Ethiopian drought of the same year was marked by localities in which child mortality was elevated, but among the general population, the evidence suggests that death rates did not rise. The reasons for this include widespread programs for vaccinating children, improved public health (especially water supplies), food rations distributed to rural areas that inhibit distress migration and the public health disruption that accompanies such migration and congregation in relief camps, and the improvement in technologies for supplementary and therapeutic feeding of malnourished children. It would be fair to say that in a contemporary peacetime famine, public health and relief technologies can prevent excess mortality. However, interventions have been much less successful at addressing the socioeconomic causes of famine. The Ethiopian drought of 2015 affected almost one quarter of the country with 18 million people in need of food aid. However, a rapid and well-funded government response means that the country’s largest-ever food emergency is not causing elevated mortality – a remarkable improvement on the disastrous situation 30 years earlier.

Causation of Famines Theories of famine date from Malthus’ Essay on the Principle of Population, which theorized that food production could only increase arithmetically while population grew geometrically, leading inexorably to a situation in which the population of the world would outrun the available food, with the result that ‘gigantic inevitable famine’ would cut the number of people to a level commensurate with the food supply. Although no historical famine has arisen from such causes or has shown the levels of mortality needed to confirm to this framework, Malthus’ theory has proved extraordinarily influential. There are several variants to supply-side or food availability theories of famine causation. There is Malthus’ own population theory, which is usually refined so as to relate human population numbers to the capacity of a certain territory to produce food, or commodities and services that can be exchanged for food. In the nineteenth century, British administrators and politicians argued that India and Ireland were ‘overpopulated,’ and thus they adopted laissez-faire policies of allowing ‘natural’ population checks to operate, saying that these were in the best, long-term interests of those countries. ‘Overpopulation’ recurs as a popular explanation for the vulnerability of Sahelian Africa and Ethiopia to famine today. However, it fails to explain when and where food crises occur, and why those countries’ populations continue to grow even while famines decline. A more persuasive variant of supply-side explanations focuses on fluctuations in food supply and particularly precipitate falls in availability, due to environmental changes, drought, or other disruptions to food production or importation. Under this explanation, if the normal food supply for a society is disrupted, famine is a likely consequence. Explanations further focus on why societies are vulnerable in this way,

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on account of low agricultural production, insufficient food reserves, exposure to production shocks such as droughts, or economic policies that fail to provide sufficient incentives for farmers to grow surpluses and bring them to market. The logical corollary of supply-side theories of famine causation is that famine prevention is primarily a matter of increasing food supplies through better agricultural techniques, along with more efficient marketing systems. From the middle of the nineteenth century, population theories of famine and supply-side explanations in general have been critiqued by socialists and by Irish and Indian nationalists. They argued that contemporary famines were less the result of insufficient or backward technology and more directly the outcome of colonial conquest and subjugation, which disrupted existing means of production and transfer, reducing erstwhile self-sufficient populations to penury. Indian nationalists mocked the way in which under the ‘civilizing mission’ of the British Raj, the subcontinent had faced more frequent and severe famines than ever before. When famines became a source of political instability – both because of the threat posed by unemployed and hungry laborers, and because of the political ammunition they provided to militant nationalists and their allies in the metropolis – the imperial government belatedly introduced systematic relief measures. At the center of the Indian Famine Codes was the provision of employment for the destitute. Implicitly, the system conceded that the cause of famine was not failures in production but because large numbers of people were too poor to buy food. This approach prefigured the most significant reevaluation of famine causation since Malthus, namely Amartya Sen’s entitlement theory. Despite its name this is not a theory of legal or moral entitlement to food but instead a demand-side explanation of why people go hungry – when they are unable to command sufficient income to buy the food necessary to sustain life, either from their own production, from selling their labor, or from exchanging commodities for food. Sen’s analysis was strongly influenced by the Bengal famine of 1943, which he experienced as a child. That famine struck despite no significant decrease in food availability in Bengal, and selectively hit certain occupational categories, particularly wage laborers. Entitlement theory explains how an adverse shift in the exchange ratio between labor or other commodities and food can suddenly mean that entire occupational groups will starve. In the case of Bengal, this happened because of general wartime inflation that pushed up the price of food, but not wages, combined with restrictions on the movement of food into Bengal at a time of a minor supply disruption that led to speculative buying of food that in turn pushed up the price. Sen writes, “Famine is the phenomenon of some people not having enough food to eat. It is not the phenomenon of their being not enough food to eat” (Sen, 1981: p. 1). Sen also applied his entitlement theory to the famines of the 1970s. In the case of Ethiopia in 1973, market imperfections, especially the underdeveloped and fragmented nature of the rural markets in northern Ethiopia, contributed to a situation in which tens of thousands were left destitute and starving, while the famine-affected provinces exported food. In the case of the west Africa Sahel during 1970–73, livestock herders saw their entitlements to staple foods crash, not only through

an increase in the price of food grains but also through a simultaneous drop in market prices for animals. Four major critiques have been leveled at Sen’s entitlement theory. One is the empirical claim that famines are caused by food shortages. Sen notes that many famines are indeed associated with sharp declines in food availability (the Sahel being one such instance), but notes, first, that other famines occur with plentiful food availability or no such decline, and second, food shortage theories fail to explain who starves and why. Second is the Marxist critique, first and most cogently leveled by Amrita Rangasami, who argued that Sen focuses only on the final, starvation phase of famine, and overlooks the essential previous stages in which a vulnerable population is reduced to a state of penury and vulnerability, by losing its land tenure rights, the autonomy of its livelihoods, and the markets for its produce. Without looking at the longer-term prior processes whereby people are left poor and vulnerable, Rangasami argues, Sen is missing the key reason why famine occurs. A third critique is more of an elaboration, arguing that Sen’s approach takes the case of the assetless wage laborer as its paradigm and does not analyze the more complex livelihoods of rural people, especially in Africa, who have diverse sources of income and food, and who struggle to sustain essential assets such as land and livestock even amid hunger and famine. This critique has contributed to the ‘livelihoods framework’ for analyzing vulnerability to famine, coping with famine, and sustainable rural development. There is a fourth and final critique: entitlement theory, purporting to explain why people starve, overlooks an important finding, that is, that the majority of famine deaths are caused by outbreaks of infectious disease. Different and more epidemiologically sophisticated models are required to explain patterns of famine mortality. Amartya Sen’s second and distinct contribution to famine theory was the observation that famines do not occur in countries with democratically elected governments and a free press. However, the ‘liberal democracy prevents famine’ hypothesis is oversimplistic. In cases in which a democracy is at war (e.g., Sudan during 1985–89) or in crisis (Bangladesh, 1974) or the country is exceptionally poor and government is extremely constrained (Malawi, 2001–05), adjustments are needed. But the counterpart claim – that famine occurs under totalitarian, unaccountable, and secretive governments – is amply demonstrated. The most hideous famines of the twentieth century, including the Ukraine in 1932–33, China in 1958–61, Cambodia in 1975–78, Ethiopia in 1983–85, and North Korea in the 1990s, have occurred under Communist dictatorships that are either wholly indifferent to the lives of their citizens or criminally intent on destroying them in large number. Overall, the great majority of famine deaths since the 1870s have occurred during war, colonial conquest, or active political repression (mostly totalitarian dictatorship). The elimination of famines from Europe and their nearelimination from Asia coincides with the end of total wars of conquest and the demise of Communist regimes. In the paradigmatic case for entitlement theory – Bengal – famine was caused in part by the economic distortions introduced by mobilization for war. Entitlement theory is, however, essentially a theory of peacetime famine. In the last 20 years, the ways in which wars cause famine have come into focus,

Famine notably in the context of intractable and complex humanitarian emergencies in the Horn of Africa. For as long as wars have been fought, they have caused famines. Armies have provisioned themselves off the land, reducing local inhabitants to starvation, or have used scorched earth as a tactic, denying food to their enemies. Sieges and blockades have been favored weapons in long campaigns, using famine as a weapon. Wars typically disrupt trade, destroy livelihoods, and make it impossible for farmers to till their land. In modern times, the most common and deadly faminecreating mechanism has been counterinsurgency campaigns that operate on the maxim of trying to drain the sea to catch the fish. Such campaigns include measures for population control and relocation, restrictions on movement and marketing, especially with regard to food, along with military offensives aimed at rebel-controlled areas. The squeezing or complete destruction of livelihoods that these campaigns entail means that they are efficient at reducing populations to famine. Colonial counterinsurgencies in Algeria, Indo-China, and southern Africa repeatedly created famine, and their postcolonial successors have done the same in Ethiopia in 1983–85, southern Sudan repeatedly from 1985 to 1999, and tragically again in independent South Sudan since 2014, Mozambique, Angola, Afghanistan, and in the former Iraqi government’s campaigns against the Kurds and the Marsh Arabs. Denial and manipulation of relief is an element in counterinsurgency that has been artfully used by many governments. Selectively providing relief is not only a means of controlling a desperate population and rewarding local clients, but also provides good propaganda and can serve as a smokescreen behind which famine-creating actions are pursued. A particular variant of counterinsurgency that is prone to creating famine is the cheap option of sponsoring a selfsupporting militia. This method has been used by the Sudan government since the mid-1980s, and the militia in question have looted and burned villages, seized land, and livestock, and killed and raped, creating famine among civilian populations suspected of supporting their adversaries. Famine is also a convenient way of emptying land so that it can be used for commercial agriculture, oil exploration, or resettlement of incoming communities. In several cases, most recently in Darfur, human rights organizations have alleged that these faminecreating strategies amount to genocide. More widely, the decay of centralized states and centrally financed armies has led to a proliferation of ‘new’ wars, both in Africa and in certain other parts of the world (Afghanistan, the Balkans, Colombia). In these wars, at least some of the belligerents are self-financing and quasi-commercial, preying on local civilian populations. A new twist on war famines has occurred with the U.S. government imposing legal restrictions on humanitarian agencies providing any support, material or moral, direct or unwitting, to entities classified as ‘terrorist.’ This contributed to a slow emergency response to the Somali famine of 2011 (Maxwell and Majid, 2015) and has restricted humanitarian operations in parts of Syria controlled by militant groups. Why do nonwar famines persist in an age of unprecedented global prosperity including large-scale transfers of free or subsidized food? These ‘new’ famines are diverse, some caused by

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the anachronism of regressive dictatorships (North Korea, Zimbabwe) and others by the multiple and overlapping vulnerabilities of the world’s poorest populations (Malawi, Ethiopia). In this respect, international financial institutions’ structural adjustment policies significantly weakened governments’ mechanisms for famine prevention and mitigation. The tying of loan agreements to structural reforms including currency devaluation, the commercialization of strategic food reserves, and the elimination of subsidies and welfare programs undermined social protection mechanisms, even while increasing the incomes of those farmers well placed to supply urban markets. Food crises in Zimbabwe in 1990 (De Waal, 1997) and Malawi in 2002 (Devereux et al., 2002) were caused in part by the evisceration of state-run food security mechanisms in compliance with the International Monetary Fund strictures. New vulnerabilities to famine have also emerged, related to the collapse of public food distribution systems (Iraq), highprevalence HIV/AIDS epidemics among poor communities (southern Africa), and perhaps most significant of all for the future, climate change. It is possible that large-scale disruption to food production systems in poor countries due to changing weather patterns, an increase in ‘natural’ disasters associated with an increase in extreme climatic events, and the flooding of arable land due to rising sea levels will create both more acute humanitarian crises globally and also greater structural vulnerability to famine in places such as sub-Saharan Africa, Bangladesh, and northeast Brazil. The next generation of famines may generate new interest in Malthusian theories. Sen’s entitlement theory of famine, his liberal democracy theory of famine prevention, and his wider ‘capabilities’ approach to economics, which stresses the quality of life, come together in a vision that sees economic systems as a matter of moral choice, not of fate or iron laws. Thus, it is not inevitable that people starve. Rather, it is because the most powerful members of society have erected social, economic, and political systems that cause them to do so.

Impact of Famine and the Human Adaptability to Starvation Famine occurs in populations vulnerable to food insecurity experiencing a sometime minor triggering event that pushes them over the edge from poverty to starvation. Inasmuch as this increased vulnerability is the result of social processes, the resorting to coping or adaptive mechanisms typically induces even greater vulnerability in the long term and diminishes the ability of famine-affected populations to face the next crisis. The immediate public health consequences of famine – death and malnutrition – are usually outweighed by the protracted economic impact on households’ assets and activities and the profound modification of community networks. In addition famine, like other types of crises, brings benefit to those well placed to take advantage of the suffering and vulnerability of others. Famine is an engine of social and economic change.

Malnutrition, Diseases, and Death Increased mortality is usually, although not always, the most salient consequence of a severe food crisis. In analyzing famine

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mortality patterns, the relative contribution of migration, disruption of traditional social and economic systems, conflict, dietary changes, disease epidemics, and malnutrition differ greatly from one place to another and one difficult to untangle. The relationship between acute malnutrition and the risk of death has been extensively studied and is now well established in both famine and nonfamine situations. In reviewing the evidence from several African and Asian famines, Young and Jaspars (1995b) came to the conclusion that the risk of dying increases exponentially with the severity of acute malnutrition with a threshold effect corresponding to the cut-off for severe malnutrition (i.e., less than 3 z-score weight-for-height/ length). They noted, however, that the relative risk of dying for a given cut-off was a changing one according to social and environmental conditions. They stressed the importance of the health environment in explaining different patterns of famine mortality and the important contribution of less apparent micronutrient deficiencies in relation to increased susceptibility to infections (Figure 4). Seaman (1993) highlighted the role of infectious disease epidemics rather than the direct effect of starvation in Indian famines. According to Seaman, the peak in mortality was not concomitant with the lowest level of food availability (at household level) but happens when rains return first and foremost due to malaria epidemics. This was also reported by Sen in his description of the 1943 Bengal famine: “The death rate reached its peak [only when] the most acute period of starvation had by then passed; epidemics were raging in a faminedevastated country” (Sen, 1981: 55). The role played by epidemic diseases in Asian famines may have lessons for modern African famines. However, the quality of the vital registration systems in Asia that has allowed such analyses contrasts with the near absence of African demographic data. The resilience of famines on the continent calls

for humility in our understanding of causal mechanisms leading to excess mortality and what can be done, and how, to avoid it. Evidence suggests that displaced populations suffer greater mortality rates than nondisplaced, famine-affected populations (see Figure 5). It has been argued that it is likely due to an increase in transmissibility of infectious diseases in overcrowding conditions rather than an increased susceptibility to infections provoked by a poor diet. As a matter of fact the transmission probability of infectious diseases is necessarily increased in displaced population camps where overcrowding multiplies the possibility of effective contact and is further exacerbated by deteriorating hygiene conditions. The physical exhaustion and changes in dietary habits that follow forced migration weaken people and enhance susceptibility to infections. The association of these parameters creates ideal conditions for disease outbreaks (Figure 5). Hence there is strong need to embrace a synergistic approach to malnutrition, infection, and death in famine conditions that has important programmatic implications for famine relief interventions.

Societal Impact of Famines In times of famine, malnutrition and mortality – when it occurs – are the result of disrupted traditional livelihood systems. Obviously the debilitating effect of malnutrition and the demographic gap resulting from excess mortality have immediate economic consequences for affected communities as they affect the labor force available to resume income-generating activities once the bulk of the crisis has passed. However, this may be overcome relatively quickly. China had regained its population level in just a few years following the 1958–61 famine.

Figure 4 Nutritional status, malnutrition, and death in famine: a conceptual framework. Reproduced with permission from Young, H., Jaspars, S., 1995. Nutrition Matters: People, Food and Famine. Intermediate Technology Publication, London.

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Figure 5 Relation between mortality and prevalence of wasting in shelter population and traditional societies in southern Ethiopia. Reproduced with permission from Lindtjorn, B., 1990. Famine in southern Ethiopia 1985–6: population structure, nutritional state, and incidence of death among children. Br. Med. J. 301, 1126.

In the face of growing food insecurity, affected households will first adopt coping or adaptive options – sometimes referred to as insurance or risk-absorption strategies – aimed at minimizing the risk of long-term, adverse impact on their livelihood until available options narrow. Then individuals will resort to distress measures, that is, crisis or risk-taking strategies aimed at saving their lives, sometime at the cost of household disintegration. The nature of these coping strategies, the timing of, and order in which they are implemented is nested in the local cultural and physical environment as much as the precrisis characteristics of the households. Hence the sequence in which responses to degrading living conditions are being implemented is not an absolute one.

Within a community, households stand at different points in terms of wealth and competencies. Responses to food insecurity will vary according to households’ available assets – physical, social, financial, political, and access to natural resources – and capabilities as represented in Figure 6. Coping strategies may be successful when they allow people to retain capabilities and assets, and become detrimental when they lead to a downward vortex of impoverishment and/or a dependency on nonlocal resources. Some coping strategies are listed in Table 1. Alternative options may first be chosen for their ability to preserve livelihood. These first strategies including income sources diversification – crop, livestock, petty trade, craft – stocking,

Figure 6 The sustainable livelihoods framework. Adapted from DFID sustainable livelihood framework in Carney, D., Drinkwater, M., Rusinow, T., Neefjes, K., Wanmali, S., Singh, N., 1999. Livelihoods approaches compared. Department for International Development (DFID), London. http://www. livelihoods.org/info/docs/lacv3.pdf (accessed February 2008).

110 Table 1 crises

Famine Example of strategies used by households during food

Adaptive, coping, or insurance strategies Related to main activity Crop diversification Restructuring of livestock holdings for more drought-resistant animals Selling small livestock Drawing on stores Income source diversification Sharing food/incomes (community support) Selling nonproductive assets Starting petty trade or handiwork Producing and selling charcoal, gathering firewood Wage laboring/piecework Borrowing food/money from relatives/professionals Labor migration Changes in dietary patterns Eating less-preferred food Reducing consumption per meal Gathering of wild foods Distress or crisis strategies Food related Reducing the number of meals Relying on wild/famine foods Begging and stealing Nonfood related Distress migration Selling productive assets Selling/mortgaging land or house Placing children Abandoning elder household members Prostitution

and saving allow the household to resume rapidly the activities that constitute the basis of its livelihood once better days return. The next stage, as the crisis goes on, implies impoverishment and loss of long-term entitlement. The household starts to draw down on its physical and financial assets (food stocks and savings, sell off nonproductive and productive assets). Food consumption patterns change – reduced number of daily meals, reduced consumption per meal, eating less-preferred food – and household members may migrate for work in higher proportion. In the last famine stage, households’ options are reduced to the extreme. The collapse of social rules and normal living mechanisms lead to the adoption of distress mechanisms such as selling last assets (land, home, and clothes), mass migration to distant relatives or relief camps to seek assistance for those who still have enough energy to walk, selling children, or abandoning elderly members of the household. The stigma attached to some distress strategies can result in the degradation of social links that are the cement of social cohesion in traditional societies. The erosion of social values and the undermining of authority structures can be as profound an impact as the pauperization of whole categories of the society. These impacts greatly shape the political and economic future of such communities and typically leave them not only economically vulnerable to further famine, but also prone to conflict and social unrest.

Victims and Beneficiaries Ethiopian households who experienced the 2003 famine reported: “those who were rich can survive the famine and buy livestock and property at cheaper prices from the hungry” (Stevenson and Foley, 2004: p. 4). The benefit induced to one or more sections of the community generally increases deprivation and destitution for the victims. The process entails that the rich and the powerful, who may also suffer during famine (loss of livestock, crops), capitalize and thrive during the postfamine period for having survived better (Figure 7). Sen highlighted the role of “speculative withdrawal [of paddy] and panic purchase encouraged by administrative chaos” (Sen, 1981: p. 76) in the process leading to the Great Bengal Famine. He demonstrated the transfer of exchange entitlement from wage laborers to military, civil defense workers, and the near totality of the Calcutta (urban) population who were benefiting from subsidized prices and could therefore exercise strong demand pressure on food. These transfer mechanisms and wealth redistribution are as much a cause as a consequence of famines. Social relations are power relations, and the redistribution of wealth and power resulting from a severe crisis modifies and shapes the social, political, and economic landscape of communities. In India, the Bengal famine provided political weapons to overthrow the colonial power on the basis of its lack of consideration for the people. In sub-Saharan Africa the weakness of state accountability in most famine-prone countries formed the basis of the political unrest the continent suffered in the last decades. It provided, and still does, a fertile ground for the perpetration of famines as a mean to gain or retain power and get richer. It also suggests an explanation for the singular resilience of famines on this continent, and the return of starvation to the Middle East, after the disappearance of famine from Asia.

The Imprint of Starvation on Humanity Beyond societal and population coping strategies, the human body has developed powerful mechanisms to increase the likelihood of survival during starvation. Darwin himself noted the

Figure 7 A crawling boy whose food has just been stolen by man in the white robe. Reproduced with permission from Tom Stoddart, Getty Images.

Famine likelihood of famines being instruments of natural selection. Hence the present generation is the result of our forebears surviving thousands of starvation episodes, a process during which the traits of the least adaptable have been removed from the common population pool. Modifications to reproductive function during starvation have been well investigated. Historical data from the Dutch Hunger Winter of 1944–45 and the 1958–61 Chinese famine indicate both a reduction in fertility and an increase in miscarriage and stillbirths. In the case of the Chinese famine, fertility reduction may even have had a greater demographic impact on population size than the actual loss of lives through starvation and disease. The effect of reduced energy intake on fertility can be seen on seasonal pattern of births among subsistence farmers in Africa and elsewhere. The lowest birth rate was observed in Gambian rural women 9 months after the nadir of the hungry season. Ansel Key’s notable Minnesota experiment (Kalm and Semba, 2005) was conducted – among other things – to optimize rehabilitation of men and women who were about to be liberated from Nazi concentration and prisoner of war camps. This experiment, part of the wartime American research on the metabolic adaptation to starvation, remains today as the most comprehensive collection of data on the subject. In the face of semistarvation, an array of energy-sparing mechanisms is activated. The metabolic rate is dramatically decreased. The fuel used to generate the energy necessary to perform housekeeping tasks shifts from glucose (glycogen) to lipids as the body starts to burn fat stores. Once fat stores are depleted, lean tissues are used to generate energy leading to wasting (marasmus). Other vital functions such as immunity are affected by sparing mechanisms. Evidence suggests that the high energy–requiring cellmediated immune response is suppressed during starvation. The resulting susceptibility to infections partly explains why disease epidemics constitute the bulk of deaths during famine episodes. Neel’s concept of thrifty genes (Neel, 1962), elaborated on when he was studying the effect of maternal diabetes on fetal growth in 1960, remains the base of our understanding of the fast-growing obesity epidemics. In his theory, genes selected initially to optimally respond to starvation ill-equip us to cope with the current pattern of fat, sugar, and salt intake. However, nearly 50 years later, no such thrifty gene has been identified to validate Neel’s hypothesis. Furthermore, as all humanity as been subject to selection by famine, this genetic selection would not explain the marked gender variability that exists in regard to obesity rates observed in some developing countries. It remains that evidence exists (Hales and Barker, 2001) that poor nutrition in early life induces permanent changes to the metabolic response to a higher-fat-content diet later in life, including reduced capacity for insulin secretion and insulin resistance involved in the development of type 2 diabetes.

Is Famine Preventable and Predictable? Famines have been virtually eliminated from Asia since the Bangladesh and Cambodia disasters in the 1970s, with the notable exception of North Korea. Although it would be perilous to assume famine cannot happen again on this

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continent, the Asian success provides good arguments for advocating renewed efforts for Africa. However, there is a discrepancy between the root causes of famine on both continents. Africa presents singular social and political characteristics. Successfully implemented policies in India and elsewhere in Asia have not been effective in eradicating famine from Africa.

Early Warning Systems Crippling famines in the 1970s and 1980s in sub-Saharan Africa persuaded policy-makers of the necessity of developing effective strategies to detect impending disasters. The aim was to inform in a timely manner governments and donors of the nature and extent of the response needed. Drèze and Sen, not denying the usefulness of such early warning systems (EWS), reminded us that countries that have been successful in preventing famine or at least excess mortality from famine (India, Botswana, Cape Verde) have not relied on a formal system but rather on a variety of information sources ranging from official and unofficial reports to newspaper articles. Nonetheless, these systems have proved relatively effective in alerting countries and decision-makers of impending food crisis and contribute to preventing large-scale disasters. Important failures of EWS have been well documented and include in recent years Malawi in 2002 and Niger in 2005. It should be noted that many famines occur not because of a lack of prior knowledge of a worsening situation but because there is a lack of interest and political will from major donors until it reaches the ‘point of conscientisation’ – generally death and malnutrition on a large scale. There is a wide variety of methods in data collection, collation, and analyses in EWS. The primary aim is to estimate food availability and derive needs in terms of commercial imports or food aid. Most countries in Africa and elsewhere now have satellite-based estimation of domestic cereal production that allows them to draw up annual cereal balance sheets. Caveats abound: balance sheets estimate availability only at the national level, do little to include informal trading, and are concerned only with cereals, thus sidelining important other foods such as tubers, roots, and animal products. These systems have been complemented by approaches to identify more localized food-insecure areas and population groups generally relying on decentralized governmental structures and based on a wider range of indicators (health, economic, nutrition, agro-meteorological) used to build a composite vulnerability index. These are easy to implement and relatively cost-effective approaches but are hindered by low quality and reliability of data and lengthy delays in information transmission. Livelihood approaches have recently been being applied successfully in some countries, in particular in the Horn of Africa. They concentrate on measuring food access at household level rather than availability and on getting an understanding of how people make their living and how they cope with variations in their food or exchange entitlement. Data are collected in a variety of ways (nationwide assessments, local surveys, routine data collection, satellite-based estimations, etc.) by a variety of actors including governmental bodies, international organizations, and international or national nongovernmental organizations (NGOs). The main constraints

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include coordination, validity of data, and analysis of this diverse and large amount of information to produce reliable, independent, and accountable information in a timely manner. A singular success for a food crisis EWS was the response to the Ethiopian drought in 2015. The national monitoring system accurately measured the impact of a rainfall failure associated with the El Niño fluctuation. After an initial hesitation, the Ethiopian government responded promptly by mobilizing $700 million for relief and appealing to international donors for a matching amount. Although this mobilization placed severe strains on Ethiopia’s budget, it filled the gap that existed due to the inevitably slow response by foreign donors and prevented excess mortality. Ultimately, the effectiveness of EWS resides in their ability to generate a consensus on the severity of a situation to trigger timely, coordinated, and effective interventions. Strong bias of decision-makers and the wider public in donor countries that pay attention to ‘late’ emotive indicators imply that these interventions are generally aimed at mitigating the impact rather than preventing a crisis. Prevention strategies rely heavily on the political will of national governments and their ability to deliver which, in modern sub-Saharan Africa, is still a wish in many countries.

Prevention and Mitigation Strategies Sen theorized that the most powerful antifamine strategy is democratization and state accountability. He argues that there can never be a famine in a functioning democracy as the threat on political leadership preempts government response over any other considerations. Hence, for many, the eradication of famines is beyond the scope of public health. Swift (1993) presented a thoughtful analysis of famine prevention strategies comparing what he called the successful Indian model to the failing African model. In his view, the collapse of traditional coping mechanisms largely attributable to liberalization, globalization, and population growth have been effectively replaced in the Indian model by “statesponsored anti-famine policies and safety nets” (Swift, 1993: p. 1). The Indian tradition of government-led interventions in time of famine stretches from the promulgation of the Famine Code in 1880 to the postcolonial Scarcity Manual. According to Drèze and Sen, the pillars of the Indian success reside on public work programs and employment guarantees, subsidized food prices through public distribution systems (public stocks of grains), and control of artificial market pricing. They add that, for the threat of famine to be eliminated, endemic poverty has to be eradicated. Swift argues that the Indian success also owes to structural reforms (increased food availability – Green Revolution), improved infrastructures and communications, better implementation capabilities from central and local governments, state accountability, and finally peace and security. This has not happened in Africa where failing or neopatrimonial states have been unable to provide a viable alternative to severely undermined customary coping strategies. As both a cause and a consequence, many African nations and governments, with the complacency and sometime the complicity of the international community, have increased their dependency on external expertise and interventions (skilled human

resources, logistic supply, infrastructures rehabilitation, medicine, food aid, agriculture, etc.) that have undermined their ability – and willingness – to internally cope with crisis situations. Ethiopia, as the biggest recipient of food aid in Africa, symbolizes this situation. Kheler (Stevenson and Foley, 2004) estimated that the country had received an average 700 000 tons of food aid every year for the last 15 years. Despite this effort, 5 million people are in need of food aid in any 1 year, 3 million when the country enjoys bumper harvests, but up to 10 to 15 million can be expected in bad years, as was the case in 2002–03. Externally funded emergency relief operations now constitute the bulk of food security and famine prevention and mitigation strategies (Figure 8). In terms of public health, strategies are fairly limited in their diversity. Their aim is to limit the spread of infectious diseases – as primary killers – and rehabilitate the nutritional status through feeding programs. Food aid is the first commodity provided in such operations mainly through the World Food Programme (WFP). Intervention designs include targeted feeding programs (therapeutic and supplementary feeding, distribution to vulnerable groups such as HIVpositives, widows, and orphans, school feeding programs, etc.), blanket feeding programs (general distributions), food for employment schemes or food as a protection against the consumption of staple seeds during distributions. The main problem with food aid is that most of it is tied to import from donor countries and this massive release of free, imported food tends to distort the market by discouraging local producers thus further reducing resilience capacities to face crises. The European Union, the second largest donor of food aid, has adopted a ‘local purchase’ policy since 1996 to prevent distortions and promote cash transfers to local economies. There have been efforts to persuade the United States to follow suit, which continue to be impeded by the nexus between the agricultural lobbies in Congress and some relief agencies that depend heavily on food aid. Health-related measures comprise routine vaccination and emergency immunization programs, infectious disease vector control, including improving access to safe water, and promoting sanitation. Preventing human gatherings, such as of displaced populations or in feeding centers, can be effective

Figure 8 A UN plane dropping food. Reproduced with permission from Tom Stoddart, Getty Images.

Famine but practically it is seldom attainable. Controversially, ‘voluntary’ resettlement policies were implemented by the Ethiopian government following the famines of the 1980s and 1990s. Other programs may aim at improving food availability and diversity (irrigation, soil conservation, crop diversification, and animal production), improving food accessibility (income source diversification, training, microcredit, cash transfer through employment, etc.), or strengthening the health system and health services. Most of them are implemented at a local level by national or international NGOs funded externally and generally not during the acute phase of the crisis.

Famine Eradication in the Context of Climate Change Clearly, what has proved to be highly successful in Asia and India in particular does not work for Africa, which is plagued by a lack of infrastructure, poor planning capacities, an absence of state accountability, and endemic insecurity. The technologized response provided to growing food insecurity and famine threat has called for increasing dependency and further retreat from accountability of African governments. The growing threat of climate change sheds a new light on food availability that is persistently below requirements in sub-Saharan Africa. The fourth assessment report on climate change released by the Intergovernmental Panel on Climate Change (IPCC) (2007) removed the remaining doubts about the role of human activity in current patterns of global warming. Since then the evidence of man-made climate change has further stacked up, with indications that the major impacts will kick in during the middle decades of the twenty-first century. How are famine-prone countries likely to be affected? Many of the countries most vulnerable to climate change are African and Asian countries that have historically been vulnerable to acute food insecurity, including Bangladesh and Ethiopia. According to the IPCC, decreases in precipitations by as much as 20% are likely in most subtropical regions. Hence it is those countries already most affected by dry weather that will become even more drought-prone (Devereux and Edwards, 2004). This will occur in countries relying heavily on subsistence farming and pastoralism with very little room for maneuver if agriculture is undermined. The slow, steady process of climate change in subtropical areas could be coupled with abrupt changes and trigger more famine, insecurity, and mass migration. There is an urgent need to find political and technological ways to pull fragile economies away from dependency on natural resources or face without failing the responsibility to assist and relieve human suffering in a growing number of humanitarian catastrophes.

See also: Ethnic Conflict and Public Health; Global Issues: Urban Health in Developing Countries; Health and Human Rights: Overview; Population Growth; Relief Operations.

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References Carney, D., Drinkwater, M., Rusinow, T., Neefjes, K., Wanmali, S., Singh, N., 1999. Livelihoods Approaches Compared. Department for International Development (DFID), London. http://www.livelihoods.org/info/docs/lacv3.pdf (accessed February 2008). Devereux, S., Edwards, J., 2004. Climate change and food security. Inst. Dev. Stud. Bull. 35 (3), 22–29. Devereux, J., Howe, P., Biong Dieng, L. (Eds.), 2002. The “New Famines”, vol. 33. Institute for Development Studies Bulletin, pp. 1–11 (4). De Waal, A., 1997. Famine Crimes: Politics and the Disaster Relief Industry in Africa. James Currey, London. Hales, N.C., Barker, D.J.P., 2001. The thrifty phenotype hypothesis. Br. Med. Bull. 60, 5–20. Intergovernmental Panel on Climate Change (IPCC), 2007. Climate Change 2007: The Physical Science Basis: Working Group 1 Contribution to the Fourth Assessment Report of the IPCC. Cambridge University Press, Cambridge, UK. Kalm, L.M., Semba, R.D., 2005. They starved so that others be better fed: remembering Ancel Keys and the Minnesota experiment. J. Nutr. 135 (6), 1347–1352. Kiernan, B., 2008. The Pol Pot Regime: Race, Power, and Genocide in Cambodia under the Khmer Rouge, 1975–79, third ed. Yale University Press, New Haven, CT. Lindtjorn, B., 1990. Famine in southern Ethiopia 1985–6: population structure, nutritional state, and incidence of death among children. Br. Med. J. 301, 1123–1127. Neel, J.U., 1962. Diabetes mellitus: a ‘thrifty’ gene rendered detrimental by progress. Am. J. Hum. Genet. 14, 353–362. Seaman, J., 1993. Famine mortality in Africa. Inst. Dev. Stud. Bull. 24 (4), 27–32. Snyder, T., 2012. Bloodlands: Europe between Hitler and Stalin. Basic Books, New York. Stevenson, F., Foley, M. (Eds.), 2004. Famine Response, Humanitarian Exchange, vol. 27, pp. 2–24. Swift, J., 1993. Understanding and preventing famine and famine mortality. Inst. Dev. Stud. Bull. 24 (4), 1–27. Sen, A., 1981. Poverty and Famines: An Essay on Entitlement and Deprivation. Clarendon Press, Oxford, UK. Young, H., Jaspars, S., 1995a. Nutrition Matters: People, Food and Famine. Intermediate Technology Publication, London. Young, H., Jaspars, S., 1995b. Nutrition, disease and death in times of famine. Disasters 19 (2), 94–109.

Further Reading Arnold, D., 1988. Famine: Social Crisis and Historical Change. Blackwell, London. Becker, J., 1996. Hungry Ghosts: Mao’s Secret Famine. Owl Books, New York. Davis, M., 2001. Late Victorian Holocausts: El Nino Famines and the Making of the Third World Verso, London. Devereux, S. (Ed.), 2006. The New Famines: Why Famines Persist in an Era of Globalization. Routledge, London. De Waal, A., 2005. Famine That Kills: Darfur, Sudan, rev. ed. Oxford University Press, New York. Drèze, J., Sen, A., 1989. Hunger and Public Action. Oxford University Press, Oxford, UK. Dyson, T., ÓGráda, C. (Eds.), 2002. Famine Demography: Perspectives from the Past and Present. Oxford University Press, Oxford, UK. Keen, D., 1994. The Benefits of Famine: A Political Economy of Famine and Relief in Southwestern Sudan. Princeton University Press, Princeton, NJ. Ó Gráda, C., 2015. Eating People Is Wrong, and Other Essays on Famine, Its Past and Its Future. Princeton University Press, Princeton. Webb, P., von Braun, J., 1994. Famine and Food Security in Ethiopia. Lessons for Africa. Wiley, Chichester, UK.

Fatty Acids Mohammed H Moghadasian, Canadian Centre for Agri-Food Research in Health and Medicine, University of Manitoba, Winnipeg, MB, Canada Fereidoon Shahidi, Memorial University of Newfoundland, St. John’s, NL, Canada Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Fereidoon Shahidi and S.P.J. Namal Senanayake, volume 2, pp. 594–603, Ó 2008, Elsevier Inc.

Lipids are a class of nutrients primarily composed of carbon, hydrogen, and oxygen atoms; these energy-yielding nutrients are hydrophobic in nature. Nutritionally, they are a major source of energy (9 kcal g
1 or 37 kJ g
1) and carry fatsoluble vitamins (A, D, E, and K) throughout the body. They are equally important sources of essential fatty acids that cannot be made by the body. Essential fatty acids include linoleic acid (C18:2 n-6) and alpha-linolenic acid (C18:3 n-3) and are required for normal growth and development plus physiologic function of body systems. In addition, lipids enhance the foods we eat by providing texture and consistency, imparting flavor, and contributing to the feeling of satiety after eating. Lipids are also important functionally in the preparation of many food products. They may act as tenderizing agents, assist in aeration, transmit flavors and colors, and supply a heating medium for food preparation. Fats and oils are present naturally in many foods, such as dairy products, meats, poultry, fish, and nuts, as well as baked goods, margarines, dressings, and sauces. The current Dietary Guidelines from developed countries advocate the consumption of a wide variety of foods in moderation combined with a physical exercise regimen. The 2015 Dietary Guidelines for Americans (see Relevant Website) recommend a total fat intake between 20% and 35% of calories for adults to meet daily energy and nutritional needs. Intake of fat outside this range is not recommended for most individuals because of potential adverse effects on achieving recommended nutrient intake and on risk factors for chronic diseases. The Institute of Medicine confirms this advice by recommending that Americans should receive 45–65% of their calories from carbohydrates, 20–35% from fat, and 10–35% from protein, while including at least 1 h of moderate exercise per day. Such dietary advice emphasizes moderation and variety regarding the intake of all nutrients in the total diet. This concept allows considerable flexibility in the selection of foods as long as an appropriate balance is maintained between total calorie intake and calories expended. The U.S. Department of Agriculture (2005) food guidance system recommends fats and oils from foods such as vegetable oils, nuts, and some fish because of their healthful qualities. To understand the nutritional and functional significance of fats and oils, it is important to understand their chemical composition. Fatty acids form the basic chemical structure of lipids. One hundred milligrams of fat or oil will yield approximately 95 mg of fatty acids. Both the physical and chemical characteristics of fats and oils are influenced greatly by the types and proportions of the component fatty acids and the way in which these are positioned on the glycerol molecule. Fatty acids are saturated and unsaturated carbon chains usually with an even number of carbon atoms and a single carboxyl group.

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Fatty acids are classified as saturated and unsaturated fatty acids, the latter being further subdivided into monounsaturated (MUFA) and polyunsaturated fatty acids (PUFAs) (Figure 1).

Saturated Fatty Acids and Health Chemically speaking, saturated fatty acids contain only single carbon–carbon bonds in the aliphatic chain and all other available bonds are taken up by hydrogen atoms (Figure 2). They are the least reactive chemically. The melting point of saturated fatty acids increases with chain length. For instance, capric acid and longer chain saturated fatty acids are solid at room temperature. The most common saturated fatty acids in animal and plant tissues are straight-chain compounds with 12, 14, 16, and 18 carbon atoms. Saturated fatty acids are predominantly found in butter, margarine, shortening, and coconut and palm oils, as well as foods of animal origin. Fatty acids containing 4 to 14 carbon atoms occur in milk fat and in some vegetable oils. For example, cow’s milk fat contains butyric acid at a level of approximately 4%. In addition, fatty acids containing 6 to 12 carbon atoms are also present in small quantities. The short-chain fatty acids are usually retained in butter and in other milk fat–based products. Tropical fruit oils, such as those from coconut and palm kernel, contain very high amounts (approximately 50%) of a saturated fatty acid called lauric acid. These oils also contain significant amounts of caprylic, capric, and myristic acids. Palmitic acid is the most widely occurring saturated fatty acid. It is found in almost all vegetable oils, as well as in fish oils and body fat of land animals. The common sources of palmitic acid include palm oil, cottonseed oil, lard, and tallow. Stearic acid is less common compared to palmitic acid. However, it is a major component of cocoa butter. This fatty acid may be produced by hydrogenation of 18carbon-atom chain fatty acids such as oleic, linoleic, and linoleic acids. Saturated fatty acids are important as sources of energy and as components that make up cell membranes. They are not ‘essential’ because the human body can synthesize its own saturated fatty acids. Saturated fats, when consumed in excess, are reported to raise total serum cholesterol levels. This includes both low-density lipoprotein (LDL) cholesterol (so-called bad cholesterol) and high-density lipoprotein (HDL) cholesterol (so-called good cholesterol). Elevated serum levels of LDL cholesterol may increase the risk for cardiovascular disease (CVD). Some food choices in this group are high in saturated fat. These include fatty beef, lamb, pork, regular ground beef, and majority of processed foods including regular sausages, hot dogs, bacon, regular

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Lipids

Saturated fats animal fats (butter, lard)

Unsaturated fats

Monounsaturated fats

Omega-9 fatty acids Olive oil Almonds Peanuts Avocados

Figure 1

Polyunsaturated fats

Omega-3 fatty acids Fish Algae Shellfish Soybean Flaxseed Walnut Canola

Omega-6 fatty acids Sunflower oil Corn oil Safflower oil Borage oil Evening primrose oil Fungal oil

Classification of lipids and fatty acids.

n-6 PUFAs

n-3 PUFAs

18:2n-6

18:3n-3 ∆ 6-desaturase

18:3n-6

18:4n-3

Elongase PGE1

20:3n-6

20:4n-3

∆ 5-desaturase

PGE2 PGI2 TXA2 LT4

20:4n-6

20:5n-3

PGE3, PGI3, TXA3, LT5

Elongase 22:4n-6

22:5n-3

Elongase 24:5n-3 ∆6-desaturase

∆4- desaturase β -oxidation

22:5n-6

22:6n-3

24:6n-3

Figure 2 Classical omega-3 and omega-6 fatty acid synthesis pathways. PUFA, polyunsaturated fatty acid. Source: Senanayake, S.P.J.N., 2000. Enzyme-Assisted Synthesis of Structured Lipids Containing Long-Chain Omega-3 and Omega-6 Polyunsaturated Fatty Acids (Ph.D. thesis). Memorial University of Newfoundland, Canada.

bologna, and salami, among others. To help keep blood cholesterol levels healthy, it is important to limit the amount of these foods we consume. However, rarely is any consideration given to the fact that short-chain saturated fatty acids

are metabolized differently than other fats. The American Heart Association’s Nutrition Committee recommends the amount of saturated fat intake to be less than 7% of total calorie intake.

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Monounsaturated Fatty Acids and Health Fatty acids containing one or more carbon–carbon double bonds are termed ‘unsaturated.’ When the fatty acids contain one carbon–carbon double bond in the aliphatic chain, they are called monounsaturated. In general, these fats are liquid at room temperature, but start to solidify at refrigerator temperature. MUFAs are synthesized within the human body. A major nutritionally important MUFA is oleic acid. Examples of dietary sources of MUFAs include olive and canola oil, avocados, peanuts, nuts, and seeds. Olive oil is rich in MUFAs and is a major ingredient of the Greek, southern Italian, and Spanish culinary traditions. Because MUFAs are present in relatively high amounts in the traditional Mediterranean diet, mainly due to high intake of olives and olive oil, and because regions consuming this diet generally have lower rates of CVD, it has been speculated that MUFAs are cardioprotective. Furthermore, recent studies have reported a significant negative association between regular consumption of Mediterranean diet and cancer and other chronic disease risk factors. When consumed as a substitute for butter or lard, olive oil appears to lower ‘bad’ cholesterol (LDL cholesterol) levels in blood, raise ‘good’ cholesterol (HDL cholesterol), and reduce the risk of heart attack. This may also help explain why CVD death rates have been reported to be lower among habitants of the Mediterranean region. Their diets are higher in vegetables, fruits, and whole grain products than the typical U.S. diet. Furthermore, antioxidants in olive oil, fruits, and vegetables may protect body cells and tissues from damage by oxidation – a process that could set the stage for heart disease. MUFAs may also have other health benefits. In a study of 3442 Italian women’s dietary habits, those who ate large amounts of olive oil (about 1.5 tablespoons) daily reduced their risk for ovarian cancer by 30%. A survey of 5632 elderly participants, called the Italian Longitudinal Study on Aging (ILSA) showed that the higher an individual’s MUFA consumption is, the lower the likelihood for developing age-related cognitive decline – a mild deterioration in memory. However, these findings are still preliminary. The rate of cancer among Mediterranean populations seems to be also significantly lower than among the rest of the world. There is some preliminary evidence to suggest that these lower rates of cancer, particularly breast cancer, may also be at least in part due to olive oil consumption, as oleic acid (a component of olive oil) has shown the potential to prevent breast cancer in laboratory studies. However, this evidence is still preliminary. In the United States, it is currently recommended that MUFA and PUFA sources should be consumed more frequently than foods rich in saturated fat, trans fat, – but within the restriction of 20–35% of total calories from fat.

eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). In particular, ALA is known as an essential fatty acid, meaning that our body cannot synthesize it. However, humans may synthesize EPA and DHA in very small amounts from ALA. The main dietary sources of ALA are flaxseed oil, canola oil, soybean oil, and walnuts, while sea foods, particularly fatty fish such as salmon and some species of fish from Northern lakes, are good sources of EPA and DHA. The body can use all three of these omega-3 fatty acids to help perform different functions. Research indicates that EPA is important in promoting the development of prenatal and infant cardiac and circulatory systems. DHA, however, seems to receive more attention and great compliments from the scientific community with regard to health during pregnancy and infant nutrition. It is suggested that 500–1800 mg (0.5–1.8 g) per day of EPA and/or DHA may reduce the risk of death from heart disease. However, insufficient information is available to set a safe upper limit for omega-3 fatty acids. The Food and Drug Administration (FDA) suggests that up to 3000 mg per day of EPA þ DHA is generally recognized as safe. Excessive consumption of omega-3 fatty acids may have negative effects on the immune system and may inhibit blood clotting, so supplementation should only be considered with caution. The U.S. Institute of Medicine has established adequate intakes for ALA and linoleic acid (1.1–1.6 g day
1 and 11–17 g day
1, respectively, for adults) but not for EPA and DHA. The recommended intake of omega-3 fatty acids in diets for adults by the American Heart Association is provided in Table 1. Most American diets provide at least 10 times more omega6 (another type of PUFA) than omega-3 fatty acids. Omega-6 essential fatty acid linoleic acid is found in many vegetable oils (sunflower, corn, safflower, etc.), cereals, snack foods, and baked goods. There is now general scientific agreement that individuals should consume more omega-3 and less omega-6 fatty acids for good health. It is not definitely known, however, whether a desirable ratio of omega-6 to omega-3 fatty acids exists for the diet or to what extent high intakes of

Table 1 Recommend intakes of omega-3 fatty acids in diets for adults by the American Heart Association Population

Recommendation

Individuals with no documented coronary heart disease

Eat a variety of (preferably fatty) fish at least twice a week. Include oils and foods rich in alpha-linolenic acid (flaxseed, canola, and soybean oils; flaxseed and walnuts) Consume about 1 g of EPA þ DHA per day, preferably from fatty fish. EPA þ DHA supplements could be considered in consultation with a physician 2–4 g of EPA þ DHA per day provided as capsules under a physician’s care

Patients with documented coronary heart disease

What Are Omega-3 Fatty Acids? Omega-3 fatty acids are a type of PUFAs containing more than two double bonds. They differ from other fatty acids because of the location of the first double bond in the aliphatic chain. The omega-3 fatty acids that are most important nutritionally are alpha-linolenic acid (ALA),

Patients who need to lower triacylglycerols

Modified from Kris-Etherton, P.M., Harris, W.S., Appel, L.J., 2002. Fish consumption, fish oil, omega-3 fatty acids, and cardiovas-cular disease. Circulation 106, 2747–2757.

Fatty Acids omega-6 fatty acids interferes with any benefits of omega-3 fatty acid consumption. The Third National Health and Nutrition Examination Survey examined the intakes of omega-3 fatty acids in the United States and found that men consumed significantly less ALA than women, adults consumed more than children, and those with a history of CVD consumed less than those without CVD (when energy intake was taken into account in the analysis). On any given day, only 25% of the population reported consuming any EPA or DHA. Average daily intakes were 14 g linoleic acid, 1.33 g ALA, 0.04 g EPA, and 0.07 g DHA.

Omega-3 Fatty Acids and Public Health Early epidemiological studies published in the late 1970s noted relatively low cardiovascular mortality in populations such as the Inuit with high fish and other seafood consumption. The apparent health benefits of fish are explained, at least in part, by the EPA and DHA they contain. Since these early studies, hundreds of clinical trials have been conducted to evaluate the effects of EPA and DHA from marine sources on cardiovascular health and disease. The possible health benefits of omega-3 fatty acids are listed in Table 2. Several epidemiological studies have examined the relationship between fish intake and stroke incidence. The association between fish consumption and stroke incidence was assessed by so-called Cox proportional hazards models. In one study, the unadjusted hazard ratio of men who consumed an average of 20 g day
1 of fish was 0.49 compared with those who consumed less. Likewise, in a follow-up study, white females who consumed fish more than once per week had an ageadjusted stroke incidence that was only half that of women who reported not consuming fish. These studies suggest that consumption of at least one portion of fish per week may be associated with a reduced stroke incidence. Research has also examined the role of omega-3 fatty acids in relation to omega-6 fatty acids. Some researchers believe one of the reasons why Americans suffer from high rates of CVD may be due to an imbalance in the ratio of omega-3 to omega-6 fatty acids. The optimal ratio of dietary omega-6 to omega-3 fatty acids is suggested to be 2–4:1. However, in many developed countries this ratio is up to 15:1. Therefore, many health promoting organizations recommend an increase in omega-3 fat intake for promoting quality of life in general population. High ratio of omega-6 to omega-3 fat may be associated with

Table 2

Health benefits of omega-3 fatty acids

Decrease triacylglycerol levels Help prevent blood from clotting and sticking to artery walls Lower blood pressure Reduce inflammation Decrease the risk of sudden death and abnormal heart rates Prevent hardening of the arteries Help to lower the risk for blocked blood vessels and heart attacks Improve overall heart health Adapted from Kris-Etherton, P.M., Harris, W.S., Appel, L.J., 2002. Fish consumption, fish oil, omega-3 fatty acids, and cardiovas-cular disease. Circulation 106, 2747–2757.

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the incidence of several disorders. These include CVD, cancer, and mental disorders. For example, depression is a common form of mental affliction and affects about 7% of the American adult population or some 15 million American adults in any given year. The U.S. National Institute of Mental Health estimates that about 4% of adolescents also get seriously depressed. Depression affects a person’s ability to work, sleep, eat, and experience pleasure, and it can be disabling. It is more common in women than men, particularly after childbirth. Depression is least common in countries where people eat the most fish, such as Japan, Iceland, and Korea, while countries with low fish consumption have the highest rates. They include the United States, Canada, and West Germany. People with depression often have low levels of EPA and DHA in their tissues compared with healthy individuals, but it is not clear what this means. Several studies have reported positive outcomes in depressed patients who took EPA along with their usual medication. Low doses of EPA (1–2 g day
1) were more effective than high-dose levels, and EPA appears to be more effective than DHA. However, these encouraging findings must consider that some studies found no benefits with EPA. Moreover, almost all studies have been carried out with small numbers of patients. That means we still need firmer results from larger studies under strictly controlled conditions.

Fatty Acids for Infant Nutrition Fatty acids supply the energy consumed in cellular growth at certain stages of life, particularly during infancy. DHA and arachidonic acid (ARA) have been identified as important structural components of the highly specialized membrane lipids of the human central nervous system, with phospholipids of brain gray matter containing high proportions of DHA. DHA is also the major long-chain polyunsaturated fatty acid (LC PUFA) in the outer segments of the retina’s rods and cones in the eyes. In addition, DHA and ARA are found in breast milk. Given their role as essential fatty acids and their importance in central nervous system (especially brain and eye) development, both have been added to infant formula in the United States since 2002. The levels of ARA found in breast milk are fairly consistent worldwide; however, DHA levels show considerable variability and appear to be linked to maternal dietary intake. DHA- and ARAsupplemented infant formula are now available in most countries, including North America, South America, Europe, Australia, New Zealand, and Asia. The rationale is that formulas enhanced with DHA and ARA may improve visual and mental development outcomes in formula-fed babies, more similar to that of their breastfed counterparts. The U.S. FDA has stated that it has no objections to the addition of DHA and ARA to formula for term infants. The British Nutrition Foundation, the Food and Agriculture Organization of the United Nations/World Health Organization (FAO/ WHO), and the International Society for the Study of Fatty Acids and Lipids (ISSFAL) all recommend supplementation of premature infant formulas with both DHA and ARA. FAO/ WHO reviewed all the available scientific literature on DHA and ARA supplementation and recommended that all

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full-term infant formulas may provide 20 mg DHA per kg day
1 and 40 mg ARA per kg day
1 (0.3% DHA and 0.6% ARA, assuming consumption of 6.5 g fat per kg day
1). The optimal fatty acid profile of infant formula has not been determined. Experts agree that infant formulas should be designed to approximate the fatty acid composition of breast milk and include omega-3 fatty acids such as DHA. Infants may have a unique need for certain fatty acids, particularly DHA and ARA, in addition to essential fatty acids. Worldwide, DHA concentrations in breast milk range from 0.07% to greater than 1.0% of the total fatty acids, with a mean of about 0.34%. ARA concentrations are greater in magnitude and lower in variability, averaging 0.53%. Given the importance of all omega-3 fatty acids in the diets of infants, the Institute of Medicine set an adequate intake of 0.5 g of omega-3 fatty acids per day during the first 12 months of life. The omega-6 to omega-3 ratio of infant formula may especially be important. DHA is the most abundant omega-3 fatty acid in the brain and the retina of the eye, representing about 97% and 93% of all omega-3 fatty acids in the brain and eyes, respectively. DHA is key to the developing brain, accumulating in vast amounts during infant development and during the first few years of life. DHA is a central component of the nervous system and promotes neurological development, particularly with regard to the eyes and to fundamental cognitive function. The brain grows rapidly during the last months of gestation and throughout the first years of life. This growth spurt is a time of rapid DHA accumulation in the brain. An infant’s ability to produce DHA may be inconsistent and inefficient. Infant blood DHA levels decrease significantly following birth unless the infant receives DHA either through breast milk or DHAsupplemented infant formula. Studies have examined the impact of dietary DHA and ARA on visual function of infants. A 1-year study measured the red blood cell fatty acid composition and visual function of 108 infants over 52 weeks’ time. Twenty-nine of the infants were breast-fed and the rest were fed either plain infant formula or formula supplemented with DHA and/or ARA. It was found that the fatty acid makeup and visual function were similar between the breastfed- and fatty acid–supplemented groups, but were inferior in the nonsupplemented formula group (Birch et al., 1998). Studies suggest that a baby born to a mother with high levels of DHA in her system will more likely have advanced cognitive abilities and an increased attention span (a fundamental nonverbal indicator of intelligence in very early childhood). These effects have been measured up to age 4, suggesting that there are long-term benefits of DHA consumption during pregnancy and nursing. Another study tested over 70 mothers and their babies between 4 and 8 months of age. The study tested for visual acuity and visual-cognitive learning ability by showing infants pictures and measuring reactions. Results indicated that babies born to mothers with elevated DHA levels had increased visual ‘skills’ and abilities. Infants who were breast-fed and then weaned to formula supplemented with DHA and ARA demonstrated more mature visual acuity than those breastfed infants weaned to nonsupplemented formula. Infants fed DHA-supplemented formula exhibited better visual acuity than that of the nonsupplemented infants (equivalent to 1.5 lines on the eye chart), and similar to that of breastfed infants. One study

showed that infants fed formula supplemented with DHA (0.36%) and ARA (0.72%) had fewer episodes of bronchiolitis and bronchitis at age 5, 7, and 9 months compared to infants fed nonsupplemented formula. Infants fed formula supplemented with DHA and ARA had significantly lower blood pressure compared to infants fed nonsupplemented formula, similar to that of breastfed infants. Because blood pressure tends to track from childhood into adult life, it has been suggested that early intake of DHA may reduce the risk of CVD later in life. Compared to conventional formula feeding, breastfeeding has been found to produce long-lasting improvements in cognitive ability and educational achievement. The analysis of the data has determined that DHA and ARA contents of breast milk are at least partially responsible for this difference. One study found an IQ advantage of preterm infants fed breast milk by tube compared to a nonsupplemented formula-fed group, indicating an effect beyond the actual act of breastfeeding. There have also been several studies that have compared regular infant formula to formula supplemented with DHA and ARA as to effect on mental development. These studies have found infants receiving DHA- and ARA-enriched formula to have greater cognitive ability than infants fed nonsupplemented formula. Term infants fed formula supplemented with DHA (0.36%) and ARA (0.72%) scored 7 points higher on the Bayley Mental Development Index at 18 months than those fed nonsupplemented formula. In a follow-up study of those same children at age 4, visual acuity and verbal IQ scores were higher in those children who had received supplemented formula compared with those who received formula lacking DHA and ARA. The effect of DHA and ARA in infant formula on problem solving at 10 months of age was evaluated. Forty-four healthy, full-term newborns were included in this study. Starting shortly after birth, half the babies received a standard infant formula, while the others received the same formula supplemented with DHA and ARA. The fat supplement was derived from milk fat, vegetable oils, and egg lipids. When tested at 10 months, both groups had normal physical development and were equally able to solve simple mental problems. However, faced with a more complex mental challenge, those taking DHA-supplemented formula did better, and their advantage was statistically significant. The accretion of DHA and ARA by the fetal brain during the last trimester of gestation is essential; therefore, infants born prematurely are at an increased risk of having a decreased level of these two fatty acids. Autopsy studies of term infants who died during the first year of life have also shown such PUFA differences in the brains and retinas of infants fed formulas not supplemented with DHA. Studies of fatty acids in autopsied sudden-infant-death syndrome (SIDS) infants showed reductions in DHA of around 10% in those fed conventional formula compared to those fed breast milk. All of the above studies support the importance of DHA and ARA for normal neural development. In the United States, approximately 3600 deaths each year were attributed to SIDS from 1992 to 1999. However, there have been no reports of an increase in SIDS-related deaths in countries where formulas supplemented with a source of DHA and ARA had been used for several years.

Fatty Acids Breast milk is the optimal infant food. Breast milk contains the long-chain PUFAs DHA and ARA. Recommendations have been made by several expert groups for infant formulas containing DHA and ARA. Many studies, as discussed previously, have demonstrated improved mental development for infants fed DHA- and ARA-supplemented formula compared to those receiving nonsupplemented formula. These benefits extend well beyond the period of supplementation and continue into childhood. Infants rapidly accumulate DHA from their mother during the last months (third trimester) of gestation. Infants born prematurely do not have time to accumulate DHA to the same level as their full-term counterparts. When fed formula supplemented with DHA and ARA, preterm infants achieved normal growth in terms of weight, length, and head circumference and showed improved visual and mental development compared to the infants fed formula not supplemented with DHA and ARA. No concerns have been reported by physicians worldwide who have monitored the administration of formulas supplemented with DHA and ARA to low-birth weight infants. Studies with stable isotopes indicated that preterm and term infants can convert linoleic acid to ARA and ALA to DHA. However, sufficient synthesis to enable tissue accretion is limited at birth because of immature enzyme systems.

Omega-3 Fatty Acids and Maternal Health Scientific research continues to expand our knowledge of nutrition in pregnancy, and perhaps the most important recent development in this field is the role played by omega-3 fatty acids in the development of a healthy baby. Omega-3 fatty acids are stored by the body and brain of the mother, and the nutritional benefits of dietary omega-3 fatty acids will be passed from mother to fetus during pregnancy through the placenta. During pregnancy, however, if the diet does not contain sufficient omega-3 fatty acids, the fetus may begin to utilize omega-3 fatty acids from the mother’s internal stores in the brain. This can cause a long-term deficit of omega-3 fatty acids if omega-3 fatty acids are not regularly consumed from food and/or supplement sources. This deficiency in omega-3 fatty acids intake is compounded by the fact that after a woman’s first pregnancy, her maternal stores become depleted. Women need to favor their own health and healthy pregnancies by having healthy eating habits. For that reason, foods rich in omega-3 fatty acids, particularly DHA and EPA, should be included. Before pregnancy, consuming seafood or other foods with these fatty acids will ensure their availability from the earliest stages of pregnancy through term. After giving birth, maintaining good nutrition meets the demands of breastfeeding and helps replenish nutrients reduced during pregnancy. Women who have had one or more children have less EPA and DHA available for another pregnancy. It has been shown that women who have had several children have less DHA in their tissues than women having their first baby. Unless these losses are replaced by consuming fish and shellfish or other sources of EPA and DHA, less DHA will be available for other pregnancies. The health benefits of omega-3 fatty acids are, of course, not restricted to fetal and early-childhood development. One of the

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serious medical complications of pregnancy is preeclampsia/ eclampsia, also known as toxemia. This complication complicates approximately 5–10% of all pregnancies and is a common cause of maternal mortality, premature delivery (preterm labor), fetal growth retardation, and perinatal mortality. Women with lower dietary intake of omega-3 fatty acids have much more risk of developing preeclampsia. Equally important, higher levels of omega-3 fatty acids may reduce the odds of postpartum depression and regulate a newborn’s sleep patterns. An even more important benefit is the role of omega-3 fatty acids in preventing preterm labor and delivery. Women with lower amounts of omega-3 fatty acids have a higher risk of preterm labor, and supplementation with this nutrient has been shown to decrease the risk of this often catastrophic pregnancy complication. Fortunately, there are now easy ways to supplement a pregnant woman’s diet with these nutrients. One might think that eating more fish would be a simple, natural way to obtain more omega-3 fatty acids. However, due to increased mercury pollution, the levels of mercury in fish may occasionally be too high. The FDA has issued advisories that limit the amount of fish that is safe for pregnant woman, nursing mothers, and young children to consume. Specifically, shark, swordfish, king mackerel, and tilefish are not considered safe for pregnant women. However, consumption of salmon, pollock, shrimp, and catfish as well as small-size fish are recommended by the FDA. Also, canned ‘light’ tuna can be taken in moderation. Mercury is a potent neural toxin and may be responsible for cognitive delays and other types of brain damage. Developing babies are the most vulnerable to this type of toxin. Many authorities recommend that pregnant and nursing women consume fatty fish two to three times weekly and/or add a minimal amount of flaxseed oil to their diets to insure adequate intake of omega-3 fatty acids, as the usual diet often contains sufficient amount of omega-6 fatty acids. Health Canada recommends that women eat adequate amounts of essential fatty acids while they are pregnant to meet the needs of the fetus. Different groups have given various recommendations for total omega-3 fatty acids during pregnancy, ranging from 0.5% to 1.3% of daily calories. One group specifically recommends that women who are pregnant or breastfeeding should get at least 300 mg day
1 of DHA. A safer option may be supplements containing omega-3 fatty acids. In addition to the algal oil and fish oil capsules sold in health food stores, there are other brands of prenatal supplements contain DHA. Omega-3 fatty acids are also available in supplemented infant formula. For breastfeeding mothers, supplementation would be recommended so the nutrients can pass to the baby in the breast milk. Research into the role of omega-3 fatty acids is continuing, and all of the benefits may not be known for years, especially given the long time required to study the effects of brain development. However, the data so far seem to be encouraging, indicating a benefit for both mother and baby at this critical time of life.

Public Health Risks of Trans-Fatty Acids Chemically, unsaturated fatty acids could be found in either cis or trans isomer forms. In trans-fatty acid molecules, the hydrogen atoms bonded to double-bonded carbon atoms

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(characteristic of all unsaturated fats) are in the trans (opposite sides, E configuration) rather than the cis (the same side; Z configuration) arrangement. This results in a less kinked shape for the carbon chain, more like the straight chain of a fully saturated fatty acid. Trans-fatty acids are primarily formed when vegetable oils are processed to make them more solid or more stable oils. This process is referred to as partial hydrogenation. The unsaturated fatty acids of vegetable oils are typically in the cis form. When an oil is partially hydrogenated, some trans-fatty acids are formed. Additionally, some double bonds move along the fatty acid chain, so that a group of cis and trans isomers are formed. Trans-fatty acids may also be formed during heating and frying of oils at high temperatures. Hydrogenation is used to convert liquid oils into solid fats, providing the attributes of texture, mouth feel, and eating quality desired by consumers in baked, fried, or processed foods. Hydrogenation is also performed to enhance the keeping quality of many foods. Partially hydrogenated oils protect against oxidative rancidity, thus preserving freshness and extending the shelf life of foods containing them. It is important to note that hydrogenation results in a number of changes in the acyl chain of the fatty acid moiety, all of which can impact physiological parameters: conversion of cis to trans double bonds, saturation of double bonds, and migration of double bonds along the acyl chain resulting in multiple positional isomers. Another method of formation of trans-fatty acids is through microorganisms in the rumen of ruminant animals; such trans fats are also known as ‘naturally occurring’ trans fats that seem to have beneficial health effects. The main source of trans-fatty acids in the diet comes from partially hydrogenated vegetable oils; however, up to 20% of the trans fats in the U.S. diet is consumed as products of ruminant animals (i.e., beef, dairy, and lamb products). Several countries have now strict regulations for either production of foods without trans fat or labeling the amount of trans fat which generally is not recommended to be more than 1% of total calorie intake. Trans-fatty acids are rare in nature. They are only created in the rumen of animals such as cows and sheep and are only found in small amounts in milk, cheese, beef, and lamb. Some of the unsaturated fatty acids ingested by ruminants are partially hydrogenated by microorganism in the rumen. Thus, as a consequence, milk fat, dairy products, beef fat, and mutton fat also contain cis and trans fatty acid isomers, although the proportions are somewhat different. The levels found are about 2–9%, and such conjugated trans-fatty acids are found to have certain benefits, contrary to those created industrially in fats and oils due to processing and exposure to high temperatures. In ruminants the main component of the trans-fatty acid is trans-vaccenic acid, while in processed fats it is elaidic acid. Partially hydrogenated vegetable oils have been an increasingly significant part of the human diet for about 100 years, and some deleterious effects of trans fat consumption are scientifically accepted, forming the basis of the health guidelines discussed above. Unlike other dietary fats, trans fats are neither required nor generally beneficial for health and, in fact, the consumption of most trans fats increases one’s risk of coronary heart disease by raising levels of LDL cholesterol and lowering levels of HDL cholesterol. Health authorities worldwide recommend that consumption of trans fat be reduced to trace amounts. Trans fats from partially hydrogenated oils are

generally considered to be more of a health risk than those from naturally occurring oils. The exact biochemical methods by which trans fats produce specific health problems are a topic of continuing research. The most prevalent theory is that the human lipase enzyme is specific to the cis configuration. This enzyme can hydrolyze the cis double bond, resulting in two lower molecular weight fatty acids that can be further metabolized. The human lipase enzyme is ineffective with the trans configuration, so trans fat remains in the bloodstream for a much longer period of time and is more prone to arterial deposition and subsequent plaque formation. While the mechanisms through which trans fats contribute to coronary heart disease are fairly well understood, the mechanism for trans fat’s effect on diabetes is still under investigation. There are suggestions that the negative consequences of trans fat consumption go beyond the cardiovascular risk. In general, there is much less scientific consensus that eating trans fat specifically increases the risk of other chronic health problems such as obesity, diabetes, and cancer. Research indicates that trans fat may increase weight gain and abdominal fat, despite a similar caloric intake. Although obesity is frequently linked to trans fat in the popular media, this is generally in the context of eating too many calories; there is no scientific consensus connecting trans fat and obesity. There is a growing concern that the risk of type 2 diabetes increases with trans fat consumption. However, consensus has not been reached. For example, one study found that risk is higher for those in the highest quartile of trans fat consumption. Another study has found no diabetes risk once other factors such as total fat intake and body mass index (a number calculated from a person’s weight and height) were accounted for. There is no scientific consensus that consumption of trans fats significantly increases cancer risks across the board. However, some studies have found connections between trans fat and prostate cancer.

Conjugated Linoleic Acid and Health Conjugated linoleic acid (CLA) is a collective term given to a group of positional and geometric isomers of linoleic acid in which the double bonds are conjugated, instead of being in the typical methylene-interrupted configuration. The conjugated double bonds occur at carbon atoms 10 and 12 or 9 and 11, with all possible cis and trans combinations. Although conjugation of double bonds occurs as part of free radical-mediated oxidation of linoleic acid, CLA is a true isomer of linoleic acid, in that it does not possess an additional oxygen. CLA is found primarily in the meat and dairy products of ruminants (Table 3). CLA comes in two isomers: the c9,t11 isomer (rumenic acid), which appears responsible for improving muscle growth; and the t10,c12 isomer, which primarily prevents lipogenesis (storage of fat in adipose tissue). Most supplements sold in stores contain a 50:50 mix of both isomers. CLA is a trans fat which may provide some health benefits. Unlike most trans-fatty acids found in the human diet, CLA occurs naturally, produced by microorganisms in the forestomach of ruminants. Vaccenic acid is an isomer of CLA available in ruminants’ fat. Nutritional studies based on animal models have demonstrated a variety of beneficial health effects from dietary ingestion of CLA, including antiobesity, anticarcinogenic,

Fatty Acids Table 3 Conjugated linoleic acid (CLA) content of various foods Food Vegetable oils Safflower oil Sunflower oil Meats/fish Chicken Pork Salmon Egg yolk Fresh ground beef Veal Lamb Dairy products 2% milk Butterfat Butter Sour cream Cultured buttermilk Condensed milk Homogenized milk Plain yogurt Low-fat yogurt Frozen yogurt Ice cream

Table 4

mg CLA per g fat 0.7 0.4 0.9 0.6 0.3 0.6 4.3 2.7 5.8 4.1 6.1 4.7 4.6 5.4 7.0 5.5 4.8 4.4 2.8 3.6

Health benefits of conjugated linoleic acids

Reduce the risk of cancer Increase metabolic rate Enhance muscle growth Lower normal cholesterol and triacylglycerol levels Decrease abdominal fat Help make it easier to control weight Help maintain normal insulin levels Reduce food-induced allergic reactions Enhance immune system

antiatherogenic, and antidiabetic effects (Table 4). Many studies on CLA in humans show a tendency for reduced body fat, particularly abdominal fat, changes in serum total lipids, and decreased whole-body glucose uptake. The maximum reduction in body fat mass was achieved with a 3.4 g daily dose. CLA may have anticancer property. Some studies have reported beneficial effects of CLA against tumors, including cancers of the skin, breast, prostate, and colon. However, data from well-controlled large-scaled human trials are still missing.

See also: Cholesterol and Lipids; Vitamin A Deficiency and Its Prevention.

Further Reading Berrino, F., 2016. Mediterranean diet and its association with reduced invasive breast cancer risk, 2016 Published online January 21 JAMA Oncol. E1–E2. Best, K.P., Gold, M., Kennedy, D., Martin, J., Makrides, M., 2016. Omega-3 longchain PUFA intake during pregnancy and allergic disease outcomes in the offspring: a systematic review and meta-analysis of observational studies and randomized controlled trials. Am. J. Clin. Nutr. 103 (1), 128–143.

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Birch, E.E., Hoffman, D.R., Uauy, R., et al., 1998. Visual acuity and the essentiality of docosahexaenoic acid and arachidonic acid in the diet of term infants. Pediatr. Res. 44, 201–209. Birch, E.E., Garfield, S., Hoffman, D.R., Uauy, R., Birch, D.G., 2000. A randomized controlled trial of early dietary supply of long-chain polyunsaturated fatty acids and mental development in term infants. Dev. Med. Child Neurol. 42, 174–181. British Nutrition Foundation, 1992. Recommendation for Intakes of Unsaturated Fatty Acids. Unsaturated Fatty Acids: Nutritional and Physiological Significance. Chapman and Hull, London, pp. 152–163. Chaddha, A., Eagle, K.A., December 1, 2015. Omega-3 fatty acids and heart health. Circulation 132 (22), e350-2. Dietary Guidelines Advisory Committee, 2005. Dietary Guidelines for Americans. U.S. Department of Health and Human Services and U.S. Department of Agriculture, Washington, DC. Food and Agriculture Organization of the United Nations/World Health Organization, 1994. Expert Committee: Fats and Oil in Human Nutrition. Food and Nutrition Paper. WHO, Rome, Italy. Gebauer, S.K., Destaillats, F., Dionisi, F., Krauss, R.M., Baer, D.J., 2015. Vaccenic acid and trans fatty acid isomers from partially hydrogenated oil both adversely affect LDL cholesterol: a double-blind, randomized controlled trial. Am. J. Clin. Nutr. 102 (6), 1339–1346. Golay, P.A., Dong, Y., 2015. Determination of labeled fatty acids content in milk products, infant formula, and adult/pediatric nutritional formula by capillary gas chromatography: single-laboratory validation, first action 2012.13. J. AOAC Int. 98 (6), 1679–1696. Institute of Medicine, 2002. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. National Academies Press, Washington, DC. International Society for the Study of Fatty Acids, 1994. Recommendations for the essential fatty acid requirements for infant formulae. ISSFAL Newsl. 1, 4–5. Katan, M.B., 2000. Trans fatty acids and plasma lipoproteins. Nutr. Rev. 58, 188–191. Kessler, R.C., Chiu, W.T., Demler, O., Walters, E.E., 2005. Prevalence, severity and comorbidity of 12-month DSM-IV disorders in the national comorbidity survey replication. Arch. Gen. Psychiatry 62, 617–627. Kris-Etherton, P.M., Nicolosi, R.J., 1995. Trans Fatty Acids and Coronary Heart Disease Risk. International Life Sciences Institute, Washington, DC. Kris-Etherton, P.M., Harris, W.S., Appel, L.J., 2002. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 106, 2747–2757. Lucas, A., Morley, R., Cole, T.J., Lister, G., Leeson-Payne, C., 1992. Breast milk and subsequent intelligence quotient in children born preterm. Lancet 339 (8788), 261–264. Malloy, M.H., Freeman, D.H., 2004. Age at death, season, and day of death as indicators of the effect of the back to sleep program on sudden infant death syndrome in the United States, 1992–1999. Arch. Pediatr. Adolesc. Med. 158, 359–365. Moghadasian, M.H., Moghadasian, P., Le, K., Hydamaka, A., Zahradka, P., 2015. Lipid analyses of four types of fish from Manitoba lakes. EC Nutr. 1, 41–48. Mozaffarian, D., January 8, 2016. Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review. Circulation pii: CIRCULATIONAHA.115.018585. [Epub ahead of print]. Praagman, J., Beulens, J.W., Alssema, M., Zock, P.L., Wanders, A.J., Sluijs, I., van der Schouw, Y.T., 2016. The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort. Am. J. Clin. Nutr. 103 (2), 356–365. de Souza, R.J., Mente, A., Maroleanu, A., Cozma, A.I., Ha, V., Kishibe, T., Uleryk, E., Budylowski, P., Schünemann, H., Beyene, J., Anand, S.S., August 11, 2015. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ 351, h3978. Senanayake, S.P.J.N., Fichtali, J., 2006. Single-cell oils as sources of nutraceutical and specialty lipids: processing technologies and applications. In: Shahidi, F. (Ed.), Nutraceutical and Specialty Lipids and Their Co-products. CRC Press, Boca Raton, FL, pp. 251–280. Senanayake, S.P.J.N., Shahidi, F., 2001. Modified oils containing highly unsaturated fatty acids and their stability. In: Shahidi, F., Finley, J.W. (Eds.), Omega-3 Fatty Acids: Chemistry, Nutrition and Health Effects. American Chemical Society, Washington, DC, pp. 162–173.

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Senanayake, S.P.J.N., Shahidi, F., 2005. Dietary fat substitutes. In: Shahidi, F. (Ed.), Bailey’s Industrial Oil and Fat Products, sixth ed., vol. 3. John Wiley & Sons, Indianapolis, IN, pp. 503–534. Senanayake, S.P.J.N., 2000. Enzyme-Assisted Synthesis of Structured Lipids Containing Long-Chain Omega-3 and Omega-6 Polyunsaturated Fatty Acids. Ph.D. thesis). Memorial University of Newfoundland, Canada. Shahidi, F., Senanayake, S.P.J.N., 2006. Nutraceutical and specialty lipids. In: Shahidi, F. (Ed.), Nutraceutical and Specialty Lipids and Their Co-products. CRC Press, Boca Raton, FL, pp. 1–25. Shahidi, F., Senanayake, S.P.J.N., 2007. Fat replacers. In: Kirk-Othmer Encyclopedia of Chemical Technology. John Wiley & Sons, Indianapolis, IN. http://www.heart.org/ HEARTORG/Conditions/Cholesterol/PreventionTreatmentofHighCholesterol/Know-YourFats, October 26, 2015. Smuts, C.M., Huang, M., Mundy, D., Plasse, T., Major, S., Carlson, S.E., 2003. A randomized trial of docosahexaenoic acid supplementation during the third trimester of pregnancy. Obstet. Gynocol. 101 (3), 469–479. Sofi, F., Cesari, F., Abbate, R., Gensini, G.F., Casini, A., September 11, 2008. Adherence to Mediterranean diet and health status: meta-analysis. BMJ 337, a1344.

Toledo, E., Salas-Salvadó, J., Donat-Vargas, C., Buil-Cosiales, P., Estruch, R., Ros, E., Corella, D., Fitó, M., Hu, F.B., Arós, F., Gómez-Gracia, E., Romaguera, D., OrtegaCalvo, M., Serra-Majem, L., Pintó, X., Schröder, H., Basora, J., Sorlí, J.V., Bulló, M., Serra-Mir, M., Martínez-González, M.A., November 1, 2015. Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED trial: a randomized clinical trial. JAMA Intern. Med. 175 (11), 1752–1760. Valls-Pedret, C., Sala-Vila, A., Serra-Mir, M., Corella, D., de la Torre, R., MartínezGonzález, M.Á., Martínez-Lapiscina, E.H., Fitó, M., Pérez-Heras, A., SalasSalvadó, J., Estruch, R., Ros, E., 2015. Mediterranean diet and age-related cognitive decline: a randomized clinical trial. JAMA Intern. Med. 175 (7), 1094–1103.

Relevant Website http://www.health.gov/dietaryguidelines/2015/guidelines – Dietary Guidelines (last accessed 09.06.16.).

Female Reproductive Physiology/Function Horacio B Croxatto, Chilean Institute for Reproductive Medicine, Santiago, Chile Ó 2017 Elsevier Inc. All rights reserved.

Introduction The organs most involved in reproduction in the female are made up of the genital tract and ovaries located in the lower part of the abdomen, the hypothalamus, and pituitary gland located at the base of the brain and the breasts (Figure 1 and Figure 2). The female reproductive system is formed during embryonic and fetal development, reaching incomplete development at the time of birth. Further growth and acquisition of full functional capacity is attained after puberty, which unfolds between 9 and 13 years of age. At puberty, the hypothalamic-pituitary-ovarian-uterine axis is activated and ovarian and endometrial cycles (Figure 3) become manifest by the occurrence of menstruation with a monthly periodicity. The first menstruation (or menarche) marks the onset of the fertile segment of a woman’s life or reproductive years, in which women can conceive and give birth to one or more children. The number of oocytes (female

gametes) present in the ovaries at birth is limited to a few hundred thousand or less and their number decreases thereafter continuously through a resorption process known as atresia. As a consequence, around the age of 50 years, the pool of oocytes becomes exhausted, ovarian and endometrial cycles cease to occur, and reproductive capacity wanes after the last menstruation (or menopause).

Menstruation and the Menstrual Cycle The vast majority of vertebrates exhibit reproductive cyclicity as they can bear offspring repeatedly, but with a periodicity that is entrained with environmental phenomena determined by the Earth’s rotation and yearly circling around the sun. Other than parturition or egg-laying, an outstanding external signal of reproductive cyclicity is the female’s behavior in response to male attempts to copulate. In most species, the female

Fallopian tube Isthmic segment

Ampullary segment

Ovarian ligament

Uterine body Ovary Fimbria

Endometrium Cervix

Uterine cavity Myometrium Cervical canal

Vagina

Ovaries and genital tract Figure 1 The female genital tract encompassing the ovaries, fallopian tubes, uterus, and vagina. A partial frontal section allows appreciating the cavity of the tubular organs and the way they are connected.

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GnRH secreting neurons

Oxytocin and vasopressin secreting neurons

Artery Hypothalamicpituitary axis

Primary capillary plexus Portal vessels Anterior pituitary

Posterior pituitary

Secondary capillary plexus Artery Vein draining anterior pituitary hormones

Vein draining posterior pituitary hormones

Figure 2 Components of the hypothalamic-pituitary axis most relevant to the reproductive process. Some neurons, which have their cell bodies located in hypothalamic nuclei, project their axons toward the primary capillary plexus of the hypothalamic-pituitary portal system where they deliver their hormonal secretions, notably GnRH. GnRH circulates down the portal vessels that resolve into the secondary capillary plexus in the anterior pituitary lobe. Here GnRH diffuses out of the capillaries and acts on the gonadotrophs, stimulating the secretion of the gonadotrophic hormones. Other hypothalamic neurons extend their axons all the way down into the posterior lobe of the pituitary where they release vasopressin and oxytocin, which are involved in parturition and milk ejection, respectively.

Ovary Follicular phase

Ovulation

Luteal phase

Estradiol concentration in serum Progesterone concentration in serum

Endometrium

Menstruation 0

Proliferative phase 5

Secretory phase

10 15 20 Days of the menstrual cycle

25

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Figure 3 The upper part of this figure illustrates the phases of an ovarian cycle: the growth of a follicle in the ovary ending in ovulation and transformation into a corpus luteum that grows and then regresses and wanes. The middle part shows the oscillations in the blood serum concentration of estradiol and progesterone along the ovarian cycle. The lower part illustrates the phases of the endometrial cycle, beginning with menstruation. Increasing levels of estradiol secreted by the leading follicle as it grows stimulate cell proliferation and increasing thickness in the endometrium. The corpus luteum secretes both estradiol and progesterone in amounts proportional to its development. Progesterone stimulates glandular secretion and acquisition of receptivity to the blastocyst in the endometrium. Demise of the corpus luteum and associated decrease in estradiol and progesterone levels cause the onset of menstruation and of a new ovarian and endometrial cycle.

Female Reproductive Physiology/Function does not allow copulation except for a short period of hours or a few days preceding ovulation (the release of one or more oocytes from the ovary), enhancing in this way the probability of becoming pregnant. With the exception of the human and a few other species, mating is precisely timed to optimize the likelihood of conception (union of male and female gametes) and therefore reproduction. This female receptive behavior toward mating is known as heat or estrus, hence the cycle in these animals is called the estrous cycle. This stereotyped receptive behavior toward mating is practically absent in the human female since women engage in sexual intercourse at any time of the menstrual cycle, during pregnancy, during lactational amenorrhea, and after the menopause. As a consequence, the vast majority of acts of sexual intercourse in the human are nonreproductive, affording only pleasant, uniting, and recreational experiences to the couple, without the invariable reproductive aim characteristic of most other animals. The most prominent external sign of cyclicity during the reproductive years of the human female is menses or menstruation, which is blood mixed with tissue sloughed off from the superficial or functional layer of the endometrium (internal lining of the womb), being expelled through the vagina to the exterior. Thus, the cycle in women is called the menstrual cycle. Menses occur from menarche until menopause more or less regularly with a periodicity approaching the lunar cycle, and are temporarily suppressed during pregnancy and breastfeeding. While the occurrence of menstruation allows a woman to assume she is fertile, a delay in its occurrence, beyond its expected timing during the reproductive years in cycling, sexually active women, usually indicates that she has become pregnant. At the time of impending menstruation or during menses, many women can experience a variety of unpleasant changes in mood and/or bodily sensations within a wide range of intensities, conditioned by the hormonal oscillations that cause menstruation. This, together with the sanitary requirements imposed by several days of vaginal bleeding, makes most women experience this monthly sign of cyclicity of their reproductive function with great awareness, although its importance and meaning varies considerably among them. Furthermore, different cultures assign a special meaning to menstruation and impose various rules on women that affect their social behavior or marital relationships while the bleeding episode is taking place. On the other hand, vaginal bleeding does not always reflect menstruation since there are diverse pathological conditions that are associated with blood loss from the endometrium or other segments of the female genital tract. Menstruation is the culmination and external sign of the end of a nonconceptional cycle. It is immediately followed by the endometrial proliferative phase in which cells multiply to rebuild the functional layer that was sloughed off during menstruation (see Figure 3). The deeper or basal layer of the endometrium remaining after menstruation is no more than 3 mm in thickness and develops into a fully grown layer of up to 12–15 mm or more in about 2 weeks through stimulation by the increasing levels of estradiol (female hormone produced by the ovary) in blood. This proliferative phase is followed by a secretory phase in which tissue differentiation and remodeling and endometrial glandular secretion predominate under the influence of progesterone (another ovarian

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hormone) in preparation for nesting a fertilized egg (or zygote), if it should happen to be formed and arrive into the uterus in that cycle. The secretory phase also entails building the necessary mechanisms to produce menstruation if no zygote is formed during that cycle. Recurrent sloughing off and rebuilding of the endometrium constitutes the endometrial cycle and takes place continuously for years until conception or the menopause occur. This process is not autonomous and is heavily dependent on estradiol and progesterone secreted by the ovary, therefore the endometrial cycle is precisely synchronized with the ovarian cycle (see Figure 3). Ovarian cycles are absent and ovarian hormone production is minimal or nil before puberty, during pregnancy and lactation, and after the menopause. An outstanding feature of the menstrual cycle is its variability within and between women, not only in the intervals between menses but in their duration, in the timing of ovulation, and the blood levels attained by the hormones involved and several other parameters. The days of the cycle are usually counted taking the first day of menstruation as the first day of the cycle. Only for didactic purposes, it is generally said that the menstrual cycle lasts 28 days and ovulation takes place on day 14 of the cycle. However, the normal cycle length varies from 21 to 35 days and follicular rupture can take place as early as day 10 or as late as day 22.

The Ovarian Cycle The ovary plays a central role in female reproductive cyclicity and the menstrual cycle. Usually, the full ovarian cycle occurs in one of the two ovaries while the other exhibits incomplete waves of follicular growth for one or more cycles until the fully active side is reversed in a nonpredictable fashion. At the onset of each ovarian cycle, small antral follicles (tiny spheres containing each an oocyte and a fluid-filled cavity) grow rapidly stimulated by the gonadotropic hormones secreted by the anterior pituitary gland (Figure 4). Eventually, one of them becomes the leading or dominant follicle, which continues to grow to become a mature or Graafian follicle. A transient surge of the gonadotropic hormones in blood triggers the ovulatory process only in the mature follicle, leading to its rupture, release of the oocyte it contains and its transformation into a corpus luteum. The life span of the corpus luteum is self-limited to approximately 2 weeks, unless a developing zygote signals its presence. Functional demise of the corpus luteum allows both menstruation and the beginning of a new ovarian cycle. The fundamental structures that sustain ovarian cyclicity come from a pool of thousands of primordial follicles, from which cohorts of about two dozen start growing every day in an autonomous manner. After a few months, nearly half a dozen reach the stage of antral follicle with a diameter of 2–5 mm while the rest undergo atresia at various stages of their development and disappear. The wall of antral follicles is formed by two layers of cells (Figure 5). The outermost layer is called the theca layer and is richly vascularized and innervated. The innermost layer, called granulosa, lacks vascular irrigation and innervation and is in direct contact with antral fluid. It is separated from the theca, by a thin homogeneous lamina

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Primary oocyte (diploid)

Follicle Mature follicle Ovary

Ovulation

Secondary oocyte (haploid) Corpus luteum Figure 4 Life history of the follicle from a primary follicle destined to ovulate until ovulation, formation of a corpus luteum, and its demise in the ovary. See Figure 5 for the time frame of each stage and what happens to accompanying follicles of the same cohort.

Internal theca cells

Granulosa Follicular cells fluid Oocyte Cumulus cells

Basal membrane

Mature follicle

Capillary network Figure 5

A cross-section of a mature follicle.

(basal membrane). Usually, each follicle contains a single oocyte that is immersed in the granulosa. The granulosa cells surrounding the oocyte form the cumulus oophorus during the ovulatory process. Figure 5 shows a cross-section of a mature follicle illustrates the layers forming its wall. From the outside to the inside: the external layer of cells forms the theca externa and interna. The

theca externa is adjacent to the ovarian stroma (not shown). The theca interna is richly vascularized and innervated. A basal membrane separates the theca interna from the granulosa that lacks blood irrigation and innervation. The granulosa consists of several layers of cells housing a single oocyte and surrounding a cavity filled with follicular fluid. The cells immediately surrounding the oocyte (cumulus cells) behave differently from the rest of granulosa cells (mural granulosa). At ovulation a mucinous material accumulates between them forming the cumulus oophorus; they detach from the wall of the follicle and are released from the follicle surrounding the oocyte at ovulation. Theca cells respond primarily to LH-secreting androgens, whereas granulosa cells respond to FSH transforming the androgens into estrogens. At each transition from the end of one cycle to the beginning of the next, there is an elevation of the folliclestimulating hormone (FSH), a gonadotropic hormone in the circulation which acts to accelerate growth of the small antral follicles that began to develop months earlier. These follicles enter into a sort of competition until one of them becomes dominant and the others stop growing and undergo atresia. The dominant follicle continues growing by multiplication of its cells and accumulation of fluid in its cavity until reaching about 20 mm in diameter in 10–15 days. During this phase, the dominant follicle secretes increasing quantities of estradiol, resulting in an exponential rise in the blood level of this hormone until it surpasses a critical level that triggers a massive and transient release of the gonadotropic hormones, luteinizing hormone (LH) and FSH, from the pituitary gland. This surge of gonadotropic hormones acting on the mature follicle initiates the ovulatory process that will culminate 36 h later in follicular rupture and release of the oocyte into a space that can be reached by spermatozoa to accomplish fertilization.

Female Reproductive Physiology/Function The ovulatory process is a complex series of parallel, synchronous, and, to some extent, independent changes affecting almost every component of the mature Graafian follicle. A crucial process is the resumption of oocyte meiosis that leads to extrusion of the first polar body (a small daughter cell resulting from oocyte division) containing one chromosome of each pair and, thus, the reduction of the number of maternal chromosomes within the oocyte to a single set. Another key process is the expansion of the intercellular matrix uniting the granulosa cells that surround the oocyte, to form the cumulus oophorus that detaches from the follicle wall so it can be extruded from the follicle at the time of follicular rupture and voiding. A third process is the activation of enzymes that erode the intercellular matrix of the follicle wall and allow the apex of the follicle to yield to the slightly positive pressure of the antral fluid, which is maintained throughout the entire process by the sustained contraction of the outer thecal cells at the base of the follicle. Both the granulosa and thecal cells begin a process called luteinization that entails major changes in steroid-synthesizing machinery leading to decreased synthesis of estradiol and increased synthesis of progesterone. The large amounts of progesterone to be produced in the following days impose increased energetic demands by these cells so granulosa cells secrete angiogenic factors that lead to disruption of the basal membrane and growth of newly formed blood capillary vessels into the luteinizing granulosa layer. Finally, the wall of the follicle ruptures at the apex, the follicle contracts, and the antral fluid containing the cumulus oophorus is voided toward the peritoneal cavity or directly to the fimbria of the Fallopian tube. Altogether these processes constitute ovulation. Luteinized theca and granulosa cells remaining in the ruptured follicle reorganize to form the corpus luteum. They grow substantially in size, accumulate large amounts of lipids required for steroid hormone synthesis and, in the course of 1 week, they constitute the corpus luteum, a compact body in the superficial layer of the ovary that replaces the ruptured follicle (see Figure 4). During the second week after ovulation, the corpus luteum starts regressing and produces less and less progesterone and estradiol, which results in decreasing circulating levels of these hormones up to the point where the endometrium, lacking this hormonal support, starts to break down and menstruation ensues. The reduction in the circulating level of ovarian hormones weakens their negative feedback on gonadotropin secretion, allowing a transient small elevation of FSH that recruits a new cohort of antral follicles for initiating the next ovarian cycle. The alternation of dominant follicle and corpus luteum as the predominant structure in the ovary gives rise to the denomination of follicular phase and luteal phase, respectively, to refer to these two phases of the ovarian cycle. These structural ovarian changes are accompanied by changes in the rate of secretion and blood levels of steroid and protein hormones produced by the ovary. The length of the follicular phase is more variable than that of the luteal phase and accounts for most of the variability in the length of the menstrual cycle observed within and between women. The length of the luteal phase, taking as the first day the day in which the echographic image of the leading follicle shows it has collapsed, and as the last day the day preceding the onset

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of menstruation, varies from 9 to 16 days being 13–15 days in nearly 70% of the cycles.

The Endometrial Cycle As the dominant follicle grows and secretes increasing amounts of estradiol, the cells located in the basal layer of the endometrium proliferate, endometrial glands and surface epithelium are reconstructed, and blood vessels grow again side by side with the endometrial glands. At the time of ovulation, endometrial thickness is 12–15 mm and, as progesterone secretion by the corpus luteum increases, endometrial glands begin to secrete their products and the luminal epithelium (single cell layer that covers the endometrial surface) exhibits transient swellings known as pinopodes. By the seventh day of exposure to elevated progesterone, the endometrium becomes receptive to embryo implantation and remains so for a few days, a period known as the window of implantation or receptive phase. The success of embryo implantation depends on blastocyst (a developmental stage of the zygote able to attach to the endometrium) quality and endometrial receptivity. The latter depends on progesterone which, acting through its receptors on an estrogen-primed endometrium, changes the transcription rate of target genes. Hence, endometrial receptivity is associated with either enhanced or decreased expression of certain repertoires of genes in comparison with prereceptive stages of the endometrium. A morphological correlate of this receptivity is the predecidual transformation of the cells surrounding the endometrial blood vessels. The absence of a blastocyst in the mid-luteal phase allows luteolysis (breakdown of the corpus luteum) to proceed and menstruation to start a week later.

The Conceptional Cycle The cycle in which a pregnancy begins is referred to as the conceptional cycle. In such a cycle, menstruation does not take place 2 weeks after ovulation as it does in an infertile cycle because the corpus luteum does not regress but continues to produce progesterone, thus menstruation does not occur. The conceptional cycle ends normally 9 months later with parturition, followed by lactational amenorrhea until menstrual cyclicity resumes. Ten percent or more of conceptional cycles will end prematurely due to death of the conceptus (developing zygote), the embryo or the fetus, or other causes, but before the product of conception is viable outside the womb. Loss of the embryo or fetus in these circumstances is referred to as abortion (or clinically often as ‘miscarriage’). In addition, a variable number of conceptuses (estimated at 20–50%) die during or soon after they implant in the endometrium and menstruation may occur at the normal time or somewhat delayed without the woman being aware of this failed implantation. The ovarian and endometrial cycles of the menstrual and the conceptional cycles do not differ until after ovulation, except for possible subtle changes in response to sexual intercourse and the presence of seminal plasma components and spermatozoa that interact with the epithelial cells lining the inner surface of the genital tract. The major differences between

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both cycles, before the delay in menses occurs, take place after ovulation and particularly at the time of implantation and thereafter. A sequence of several fundamental processes is required for the natural occurrence of a conceptional cycle. The first two events are sexual intercourse and ovulation; the former must be close to, but not after, ovulation. They must be followed by the encounter of the gametes, oocyte, and spermatozoon, usually in the ampullary segment of the Fallopian tube (Figure 6), where fertilization takes place leading to the formation of a single cell, the zygote, representing the beginning of a new individual. This is followed by development of the zygote up to the morula stage, its transport to the uterine cavity where it continues to develop up to the blastocyst stage, which is the stage at which it is capable of implanting in the endometrium. Following fertilization within the ampullary segment of the fallopian tube, the zygote develops within this organ up to the early morula stage composed of 8–12 cells in the course of 3 days at the end of which it passes into the uterine cavity. In the following 3 days the morula develops into a blastocyst inside the uterus. At the end of this period the blastocyst expands, looses the zona pellucida, and begins to implant in the endometrium. Implantation of the blastocyst starts in the middle of the luteal phase when progesterone secretion by the corpus luteum is at its peak. As implantation begins, the trophoblastic cells of the blastocyst begin to secrete increasing amounts of the hormone chorionic gonadotropin (hCG), which passes into the mother’s bloodstream. Acting upon the corpus luteum, hCG prevents its involution and keeps it secreting high levels of progesterone and estradiol. In this manner, the hormonal support of the endometrium is maintained and menstruation is prevented so that the implanted blastocyst can continue its development in the endometrium.

Gamete Encounter and Fertilization The vast majority of acts of sexual intercourse do not generate a pregnancy in fertile couples who are not using any means to avoid it, indicating that the reproductive process in the human has rather low efficiency in comparison with other domestic and wild species in which almost every mating is

followed by pregnancy. There are several reasons for this difference, one of them being that ovulation takes place in one of the 21–35 days of the menstrual cycle and intercourse can occur multiple times randomly distributed along that period and by chance not close enough to ovulation to allow the encounter of fresh gametes. By carefully monitoring the day of ovulation and days of intercourse in 625 cycles of 221 women seeking to become pregnant, Wilcox et al. (1995) were able to establish that a single act of sexual intercourse can generate a conceptional cycle if it takes place on the day of ovulation or in any of the 5 preceding days. These 6 days of the menstrual cycle are designated as the fertile period of the menstrual cycle. The probability of generating a conceptional cycle is highest when intercourse occurs on the last 3 days of the fertile period, when it is close to 35%. Wilcox et al. (1998) also established that 30% of conceptional cycles identified by detection of hCG in the urine ended before the pregnancy was clinically recognized. Since menstruation in such cycles occurs at about the expected time, women are not aware of these early conception losses and perceive the cycle as a normal, nonconceptional menstrual cycle. Spermatozoa can survive in the genital tract of women and retain their fertilizing potential up to 5 days after intercourse. On the other hand, the oocyte needs to be fertilized within the first few hours after ovulation to generate a viable, healthy zygote with full developmental capacity. This explains why the fertile period is limited to 6 days asymmetrically distributed relative to the day of ovulation. Ovulation is preceded by high estradiol and low progesterone levels in the circulation. Therefore, the endocrine milieu prevailing during the fertile period is optimal for the production of abundant, clear, more watery and less viscous cervical mucus that fills the cervical canal and is easily penetrable by spermatozoa. When a man ejaculates during coitus, semen containing several 100 million spermatozoa is delivered to the vagina. If this occurs during the fertile period, sperm cells will easily pass into cervical mucus extruding from the external opening of the cervical canal. In fact, several hundred thousand spermatozoa will do so within the first hour and most of them will colonize the cervical crypts where they can remain viable for days, forming a sperm reservoir. In a short-lived first phase, some sperm cells are passively transported within minutes to

Morulae

2- and 4-cell embryos

Zygote

Uterine cavity Ovary Blastocysts

Fertilization Oocyte

Figure 6

Preimplantation development of the zygote.

Female Reproductive Physiology/Function the Fallopian tube while the others actively migrate from the cervical reservoir to the Fallopian tube continuously over the next hours and days. Animal experiments have demonstrated that passively transported sperm do not have the capacity to fertilize and that the fertilizing sperm come from the active phase. Noncapacitated spermatozoa (not yet ready to fertilize an oocyte) reaching the Fallopian tubes bind for hours to the epithelial cells lining the lumen and subsequently are released in a capacitated state. Capacitated spermatozoa can readily fertilize an oocyte, but they soon lose viability if ovulation has not taken place. Fresh spermatozoa coming from the cervical reservoir can repeat this cycle until ovulation takes place or for a maximum of 5 days after intercourse. Once a capacitated sperm cell penetrates the cumulus oophorus, it binds to the proteinaceous layer covering the oocyte, called zona pellucida. Here it loses part of the outer cell membrane allowing the release of various enzymes (acrosome reaction) that help the sperm drilling a pathway through the zona until it reaches the oocyte cell-membrane. Again, the sperm binds to this membrane and fuses its own membrane with it. The sperm head carrying one set of paternal chromosomes then comes inside the oocyte cytoplasm. Meanwhile, the oocyte undergoes several processes in response to sperm signaling. It releases components (cortical granules) that turn the zona pellucida impenetrable to further spermatozoa, completes the second meiotic division keeping only one half of the maternal genome (haploid condition) and becomes denuded from cumulus cells. At this stage, the chromosomes of the oocyte and those of the fertilizing spermatozoa are separately contained in membrane-bound structures called pronuclei. Afterward they come together so that the fertilized oocyte now contains the full endowment of chromosomes (diploid condition) becoming a single cell zygote, which represents the beginning of a new individual of the species.

Development and Transport of the Zygote to the Site of Implantation The zygote develops steadily by successive divisions of its initial mass without accruing additional living matter. Thus, each division gives rise to equal-size daughter cells of smaller and

smaller size. Initially, this happens inside the Fallopian tube up to approximately the 12-cell stage or morula in the course of 3 days (see Figure 6). During this time, the developing zygote resides within the ampullary segment of the Fallopian tube and, by the end of the third day, it is transported through the isthmic segment into the endometrial cavity where it continues to divide. A fluid-filled cavity develops at the center of the developing zygote and enlarges, giving rise to a developmental stage known as blastocyst that continues to grow in size by fluid accumulation. At the same time, the blastocyst cells differentiate into two classes. The most numerous cells, called trophoblast cells, line the outer surface, and the less numerous, a cluster of 10–20 cells, is called the inner cell mass and lies inside, adjacent to one section of the trophoblast. At about the seventh day after fertilization, the blastocyst comprises some 200 cells, 10% of which correspond to the inner cell mass that will actually give rise to the embryo while the rest will form the placenta. At this stage, due to fluid accumulation, the volume of the blastocyst is at least twice as large as the oocyte from which it originated; the blastocyst then hatches from the zona pellucida and is ready to initiate implantation (Figure 7). Following menstruation, cells of the basal layer proliferate, rebuilding the spongy and compact layer where glands and spiral arteries grow. Following ovulation and fertilization on day 14, the zygote begins its preimplantation development and the newly formed corpus luteum starts producing increasing amounts of progesterone that induce glandular secretion and receptivity to the embryo in the endometrium. By day 21 the blastocyst has attained full development and begins to implant. At the same time it produces chorionic gonadotrophin that passes into the mother’s bloodstream and acts upon the corpus luteum to sustain progesterone secretion and avoid menstruation. The endometrial stroma undergoes decidualization to contain the invading trophoblast. By day 30 the blastocyst has turned into an embryo that is entirely immersed in the endometrium. Trophoblast cells have differentiated in two cell lineages that interact with endometrial blood vessels to build the placenta, a nurturing system for the embryo whose postimplantation development is now ongoing.

Implanted embryo Implantation begins Gland Spiral artery Compact layer Spongy layer Basal layer

Menstrual phase Follicular phase 0

Figure 7

5

10

15 Days

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Progestational phase 20

25

Schematic illustration of the first 30 days of an endometrial cycle in a conceptional cycle.

Gravid phase 30

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Implantation The particular distribution of the two cell types that constitute the blastocyst confers polarity to its structure. Trophoblast cells covering the inner cell mass attach to the epithelial cells lining the endometrial cavity and eventually their cytoplasmic projections penetrate between the epithelial cells, cross the basal membrane underlying the epithelial cells and begin to invade deeper endometrial layers. The conceptus immerses into the endometrium and becomes separated from the uterine cavity by the reconstructed epithelial lining (see Figure 7). This is followed by the establishment of a complex interphase between the embryo itself and the mother, allowing the exchange of nutrients and many other substances required for further development of the embryo in the months to follow. The placenta is the main component of this interphase and is derived from the trophoblast. The endometrium itself changes into a structure known as decidua that can support the placenta while at the same time limiting the invasiveness of the cells derived from the trophoblast. An important adaptation of the maternal side modulates the local immune system to prevent embryo rejection. The mother’s immune system would otherwise recognize as nonself the embryonic proteins encoded by paternal-inherited genes and this would mobilize an allograft rejection. In fact, failure of this protective mechanism is thought to be responsible for a proportion of early embryo wastage. As the conceptus establishes conduits to access maternal nutrient supplies, new living matter can be synthesized and real growth begins, resulting in a new phase of embryonic development where cells can keep their size after each division and new cell types can emerge that associate temporally and spatially in varying manners thereby forming the rudimentary organs that eventually shape the body. Once these organs are in place, fetal growth ensues until the fetus reaches enough maturity to trigger the onset of parturition and continue living outside the womb.

Regulation of the Hypothalamic-Pituitary-Ovarian Axis The three organs forming the hypothalamic-pituitary-ovarian axis communicate with each other mainly by means of chemical signals that are the hormones they produce that travel from one organ to the other via the bloodstream. The hypothalamus located at the base of the brain contains neurons that produce a peptide composed of 10 amino acids known as gonadotropin-releasing hormone (GnRH). This molecule is secreted directly into the primary blood capillary plexus of the hypothalamic-pituitary portal system through which it reaches the pituitary gland in high concentrations (see Figure 2). This portal system conveys blood from the median eminence of the hypothalamus directly into the anterior lobe of the pituitary gland (adenohypophysis) where it resolves into a secondary blood capillary plexus, allowing hypothalamic hormones to reach the adenohypophysis without being diluted in the general circulation. As in men, GnRH is released in a pulsatile fashion, with an interpulse interval varying within the range of 60–120 min. Specialized cells within the adenohypophysis known as

gonadotrops synthesize and secrete the FSH and LH in response to GnRH pulses. Both gonadotropins consist of two subunits, designated a and b, linked together by disulfide bonds. The a-subunit is common to other glycoprotein hormones while the b-subunit is more specific. Nevertheless, the b-subunit of LH is highly homologous to the b-subunit of hCG. Both pituitary gonadotropins are released into the blood in response to GnRH, although there are other factors that modulate this response so that under certain conditions, the patterns of their secretion differ to some extent. Each GnRH pulse generates a gonadotropin pulse, being more pronounced in LH than in FSH. FSH, acting on granulosa cells of antral follicles, stimulates the secretion of several growth-promoting factors and the expression of aromatase, an enzyme that converts androgens into estrogens. As a consequence, follicular growth is accompanied by increasing secretion of estradiol (see Figure 3). LH, in turn, through its action on thecal cells stimulates the synthesis of androgens (male-type hormones) that in part diffuse into the bloodstream, but also into the granulosa cells where they are converted into estrogens. As blood estradiol levels rise during the follicular phase, they exert negative feedback on gonadotropin secretion, keeping the response of the ovary in check so that usually only one follicle matures in each cycle. When the level of estradiol in blood surpasses a certain critical level, the negative feedback turns into positive feedback: pulsatile activity of GnRH neurons increases and the pituitary gonadotropic cells become highly sensitive to GnRH’s stimulatory action resulting in a massive discharge of both gonadotropins, which causes a transitory increase in the blood concentrations of both hormones. The rise in gonadotropins is far more noticeable for LH than FSH. It is known as the preovulatory gonadotropin discharge, midcycle gonadotropin surge, or LH peak, and is responsible for selectively triggering the ovulatory process in the mature follicle. Both hormones return to their basal level approximately 48 h after the beginning of the discharge. At the onset of luteinization induced by the LH peak, estradiol secretion drops at the same time as progesterone secretion begins to increase. Thereafter, the blood concentrations of both steroids increase progressively until the mid-luteal phase when they start decreasing again during the second half of this phase if no conceptus has signaled its presence. During the luteal phase, the combined effect of elevated estradiol and progesterone keeps the frequency of GnRH and gonadotropin pulses at a reduced rate and no follicular recruitment takes place. When the corpus luteum begins to involute and eventually ceases to produce the two steroid hormones, gonadotropins are released from their negative feedback and their basal levels rise leading to the initiation of a new follicular phase. Apart from sex steroids, peptide hormones – some of them produced by the ovaries – contribute to the regulation of gonadotropin secretion. Among them, inhibins, activins, and follistatin are functionally involved in the regulation of FSH secretion. Inhibins (both the A and B types) are produced by granulosa cells and inhibit selectively the secretion of FSH. Activins (of which there are A and B types too) are also produced by granulosa cells, as well as by cells of several other organs including the pituitary gland, but, in contrast to inhibins, activins stimulate the secretion of FSH. Follistatin is a protein

Female Reproductive Physiology/Function produced in the pituitary gland that binds activins and prevents their stimulatory effect on the FSH-secreting gonadotropic cells. It is likely that activins and follistatin produced locally in the pituitary are at least as important for FSH regulation as their circulating levels. Another peptide hormone produced by granulosa cells is Müllerian inhibiting substance (MIS) (also known as antiMüllerian hormone). In male fetuses it is produced by Sertoli cells of the testicles and it suppresses Müllerian duct development. In the female it is produced after birth by primordial, preantral, and very early antral follicles and its function is to restrain primordial follicles from entering into FSH-dependent growth. MIS serum levels are stable throughout the menstrual cycle and begin to decrease with age as the primordial follicle pool shrinks. Its synthesis ceases when these structures disappear in the menopause.

Conclusion Knowledge and understanding of the normal, human female reproductive process has grown considerably in the last century aided by animal experimentation, clinical research, and technological developments that allow measuring minute amounts of hormones in body fluids, tracing their action in cells, and measuring cell responses under a variety of conditions. The reproductive process across mammals bears many features in common and the reproductive process in the human female has, if any, very few distinguishing features from the rest of mammals. The wealth of basic knowledge acquired has allowed bringing into practice diagnostic and therapeutic procedures for improving sexual and reproductive health. Moreover, methods to control fertility at times when childbearing is unwanted or to allow infertile couples to have babies have become possible and are now widespread and generally successful.

See also: Family Planning/Contraception; Gynecological Morbidity; Infertility, An Overview.

References Wilcox, A.J., Weinberg, C.R., Baird, D.D., 1995. Timing of sexual intercourse in relation to ovulation effects on the probability of conception, survival of the pregnancy, and sex of the baby. N. Engl. J. Med. 333, 1517–1521. Wilcox, A.J., Weinberg, C.R., Baird, D.D., 1998. Post ovulatory ageing of the oocyte and embryo failure. Hum. Reprod. 13, 394–397.

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Further Reading Bischof, P., Campana, A., 1996. A model for implantation of the human blastocyst and early placentation. Hum. Reprod. Update 2, 262–270. Burrows, T.D., King, A., Loke, Y.W., 1996. Trophoblast migration during human placental implantation. Hum. Reprod. Update 2, 307–321. Croxatto, H.B., 1995. Gamete transport. In: Adashi, E.Y., Rock, J.A., Rosenwaks, Z. (Eds.), Reproductive Endocrinology, Surgery, and Technology, vol. 1. Lippincott-Raven, Philadelphia, PA, pp. 385–402. Dimitriadis, E., White, C.A., Jones, R.L., Salamonsen, L.A., 2005. Cytokines, chemokines and growth factors in endometrium related to implantation. Hum. Reprod. Update 11, 613–630. Evans, J.P., 2002. The molecular basis of sperm-oocyte membrane interactions during mammalian fertilization. Hum. Reprod. Update 8, 297–311. Giudice, L.C., 2004. Microarray expression profiling reveals candidate genes for human uterine receptivity. Am. J. Pharmacogenomics 4, 299–312. Goldfien, A., Monroe, S.E., 1997. Ovaries. In: Greenspan, F.S., Strewler, G.J. (Eds.), Basic and Clinical Endocrinology, fifth ed. Appleton and Lange, Stamford, CT, pp. 434–574. Hotchkiss, J., Knobil, E., 1993. The menstrual cycle and its neuroendocrine control. In: Knobil, E., Neill, J.D., Greenwald, G.S., Markert, C.L., Pfaff, D.W. (Eds.), The Physiology of Reproduction, vol. 1. Raven Press, New York, pp. 711–750. Luisi, S., Florio, P., Reis, F.M., Petraglia, F., 2005. Inhibins in female and male reproductive physiology: role in gametogenesis, conception, implantation and early pregnancy. Hum. Reprod. Update 11, 123–135. Messinis, I.E., 2006. Ovarian feedback, mechanism of action and possible clinical implications. Hum. Reprod. Update 12, 557–571. Norman, R., Phillipson, G., 1998. The normal menstrual cycle; changes throughout life. In: Fraser, I.S., Jansen, R.P.S., Lobo, R.A., Whitehead, M.I., Mishell Jr., D.R. (Eds.), Estrogens and Progestogens in Clinical Practice. Churchill Livingstone, London, pp. 105–118. Seifer, D.B., Maclaughlin, D.T., 2007. Mullerian inhibiting substance is an ovarian growth factor of emerging clinical significance. Fertil. Steril. 88, 539–546. Sirios, J., Sayasith, K., Brown, K.A., et al., 2004. Cyclooxygenase-2 and its role in ovulation: a 2004 account. Hum. Reprod. Update 10, 373–385. Suarez, S.S., Pacey, A.A., 2006. Sperm transport in the female reproductive tract. Hum. Reprod. Update 12, 23–37. Veenstra van Nieuwenhoven, A.L., Heineman, M.J., Faas, M.M., 2003. The immunology of successful pregnancy. Hum. Reprod. Update 9, 347–357. Yanagimachi, R., 2003. Fertilization and development initiation in orthodox and unorthodox ways: from normal fertilization to cloning. Adv. Biophys. 37, 49–89. Yanagimachi, R., 2005. Male gamete contributions to the embryo. Ann. N.Y. Acad. Sci. 1061, 203–207.

Relevant Websites http://www.web-books.com/eLibrary/Medicine/Physiology/Reproductive/Female.htm – Female Reproductive System. http://www.en.wikibooks.org/wiki/Human_Physiology/The_female_reproductive_system – Human Physiology/The Female Reproductive System. http://www.biology.clc.uc.edu/courses/bio105/sexual.htm – Reproductive Physiology, Conception, Prenatal Development. http://www.educypedia.be/education/reproductivesystem.htm – Reproductive System, Male and Female Reproductive Anatomy.

Fetal Growth Restriction: Causes and Outcomes Susan M Sayers, Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia Paul AL Lancaster, Menzies Centre for Health Policy, University of Sydney, Sydney, NSW, Australia Clare L Whitehead, University of Melbourne, Melbourne, VIC, Australia Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Susan M. Sayers, Paul A.L. Lancaster, pp. 613–621, Ó 2008, Elsevier Inc.

Introduction Fetal growth restriction (FGR) describes a pathological inhibition of fetal growth resulting in the fetus failing to reach its growth potential. It is considered one of the major complications of pregnancy with fetuses that fail to meet their growth potential at 5–10 fold increased risk of fetal death. The diagnosis of FGR is challenging as no single definition exists and there is considerable overlap between small but healthy fetuses, and those that are small and sick. In the developed world the commonest definition is a failure to reach a set growth threshold, frequently the 10th centile for gestational age. Whereas in the developing world, the gestation is frequently unknown and babies less than 2500 g at birth are grouped as low birth weight without any differentiation. Ideally, fetal growth restriction should be one of the main national indicators of pregnancy outcome, together with maternal, fetal, neonatal, and infant death rates. Instead, because information about the duration of pregnancy is not available in many developing countries, low birth weight is recommended as the key outcome by the World Health Organization (WHO). Among the estimated 130–140 million births in the world each year, about 32 million infants (weigh less than 2500 g at birth (Table 1). Of those about 30–40% have fetal growth restriction at term gestation. The fetal growth restriction status at lower gestational ages is not known on population levels, although it is known that a great majority of extreme preterm infants who survive are born growth restricted as well. In developed countries, the low birth weight infants are more likely to be born preterm (less than 37 weeks’ gestation) rather than

Table 1

growth restricted but in developing countries where low birth weight rates are over 10% it is predominantly due to fetal growth restriction. The likelihood that a significant proportion of chronic diseases in adult life such as diabetes, hypertension, and coronary heart disease in both developed and developing countries may be due to fetal growth restriction has given new impetus to improving our knowledge of its causes and prevention. The possible mechanisms whereby derangements of physiological and metabolic pathways cause fetal growth restriction have been extensively studied for many decades. Observations of variations in size at birth around the world, the impact on pregnant women of ‘natural experiments’ such as the siege of Leningrad and the Dutch famine in the Second World War, and the outcomes of growth-restricted fetuses after birth have all stimulated further epidemiological, clinical, and laboratory studies of fetal growth restriction. The rapid increase in birth weight by several hundred grams in Japan in the decades after the Second World War provided strong evidence that a significant change in maternal risk factors was responsible. Improved living conditions and better maternal nutrition seemed the most likely reasons. Although more than 90% of the world’s births occur in developing countries the proportion of low birth weight is not evenly distributed across these regions. About half the total births are in South Asia, mainly India and neighboring countries, and in East Asia and the Pacific. However, low birth weight is four times more common in South Asia (29%) than in East Asia (7%) (Table 1). Across Africa and the Middle East, where there are more than a third of the world’s births, 13–15% are low birth weight, which is double that in the

Estimates of low birth weight in regions and countries of the world

Country/region

Estimated annual number of births (thousands)

Percentage of infants with low birth weight (less than 2500 g)

Industrialized countries Developing countries Least developed countries World Sub-Saharan Africa Eastern and Southern Africa West and Central Africa Middle East and North Africa South Asia East Asia and Pacific Latin America and Caribbean CEE/CIS

10 848 120 128 28 258 133 449 28 715 13 575 15 140 9743 37 077 29 820 11 651 5595

7 16 19 15 14 13 15 15 29 7 9 9

Reproduced from UNICEF, 2006. The State of the World’s Children 2007. Women and Children. The Double Dividend of Gender Equality. UNICEF, New York, (derived from the published statistical tables).

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Fetal Growth Restriction: Causes and Outcomes industrialized countries and East Asia. Within individual countries, many studies have consistently shown that mothers in higher socioeconomic groups are less likely to have an infant of low birth weight.

Concepts about the Relationship between Birth Weight and Gestational Age Gestational age indicates the duration of pregnancy, dated from the first day of the last menstrual period, whereas birth weight is the final achieved weight of the infant on completion of the pregnancy. Estimates of gestational age may be doubtful in a considerable proportion of pregnancies, either because of uncertainty about the date of the last menstrual period, abnormalities of fetal growth during pregnancy, or because mothers attend late or not at all for their antenatal care. Although gestational age increases continuously throughout pregnancy, by convention, gestational age is frequently referred to as being in the first, second, or third trimester rather than reported as completed single weeks. While birth weight is readily measured, assessing gestational age accurately has proved to be much more difficult. It was not until the early twentieth century that the Finnish pediatrician, Arvo Ylppö, first proposed that small infants at birth should be designated as premature, based on a birth weight of 2500 g or less (Ylppö, 1919). Initially fetal growth during pregnancy was assessed indirectly by serial measurements of maternal weight, fundal height of the uterus, and abdominal girth. Various maternal hormonal and biochemical parameters, and fetal X-rays, were used to assess fetal maturity and well-being. It was only in the 1960s that direct visualization of the fetus became possible when the evolving technique of clinical ultrasound was first used on pregnant women. Measurements of the biparietal diameter of the fetal skull were made in large numbers of pregnant women whose menstrual cycles had been regular, of normal duration, and in which the date of the last menstrual period was reliably known. These measurements at successive stages of pregnancy were then used to establish population values against which gestational age could be reliably assessed. As ultrasound could be safely used in early pregnancy, serial measurements could then be made at intervals to determine whether the pattern of fetal growth was normal or otherwise. Birth weight percentile charts were introduced to assess whether an individual infant with known birth weight and gestational age was appropriately grown (Lubchenco, 1976). Terms such as small-for-dates and large-for-dates became widely used to describe infants whose size at birth deviated from the normal value, especially those who were deemed to be growth-restricted. Concurrently, it was increasingly recognized that low birth weight/premature infants are not a homogeneous group but rather a group in which some are born preterm and others are low birth weight because of poor fetal growth (Gruenwald, 1974). For those who are less familiar with concepts related to growth from conception to birth at term some 270 days later, a better understanding of fetal growth can be gained by

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comparing this with the features of the postnatal growth of newborn infants from birth to adult size and maturity. Here, an individual’s progress can be more readily observed directly and changes in height, weight, head circumference, and other indices can be measured serially, then compared with population normal values obtained at the same age. Unless these concepts are well understood, the mainly unseen growth of the fetus remains mysterious to many! As in postnatal life, a change in growth velocity or a drop to a lower percentile during intrauterine growth often suggests an adverse outcome. For example, a fetus consistently on the 75th percentile in serial measurements during pregnancy may be adversely affected by the onset of maternal hypertension in the third trimester of pregnancy and have a much reduced birth weight, say, on the 50th percentile. Such an infant will not usually be considered as growth-restricted because the birth weight is well above the cut-off weight designating small-forgestational age. Yet this infant will be liable to some of the adverse outcomes of other more obviously growth-restricted infants. The severity of the eventual outcome is influenced by the duration in pregnancy of the underlying cause and by the degree of fetal distress during the peripartum period, which can reflect a compromised supply of essential nutrients to the fetus.

Terminology and Definitions No other topic in perinatal medicine has been so bedeviled by confusing terminology and definitions as small size at birth and fetal growth restriction. Similar problems are confronted in defining hypertensive disease of pregnancy, when terms such as pregnancy-induced hypertension, toxemia of pregnancy, preeclampsia, preexisting or gestational hypertension are often used interchangeably for the same condition. Many clinicians, nurses, and other health professionals tend to cling tenaciously to terms first used during their period of training. The WHO defines newborn infants with low birth weight as the percentage of live born infants with birth weight less than 2500 g in a given time period. Low birth weight may be subdivided into very low birth weight (less than 1500 g) and extremely low birth weight (less than 1000 g). Preterm (less than 37 weeks’ gestation), term (37–41 completed weeks), and post-term (42 weeks or more) describe the duration of pregnancy. In practice, the statistical definitions of the lower limits for gestational age and birth weight are often modified by some legal requirement within each country. The terms prematurity and post-maturity have been superseded by these more concise, less ambiguous definitions. Dysmaturity, which described an infant’s abnormal appearance at birth and suggested a compromised nutrient supply-line in utero, has also been discarded. Accurate information on fetal growth restriction is difficult to obtain in populations in which gestational age is not reliably known. Fetal growth during pregnancy is an ongoing, dynamic process and it is preferable to be specific that it is the fetus that is affected rather than using the more nebulous term intrauterine growth restriction. ‘Intrauterine under nutrition’ may often be the true underlying cause of fetal growth restriction,

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and emphasizes an important preventable cause, especially in developing countries, but other causes may be apparent only after birth. Fetal growth restriction may have an onset early in pregnancy, for example, in fetuses with multiple malformations or congenital infections, or become apparent in the later stages of pregnancy, especially in twins and in other multiple pregnancies with more than two fetuses. Selecting which percentile should be used to designate the extremes of growth has proved to be problematical. Obviously birth weight and other parameters of growth may be due to genetic factors or to some pathological cause. As these measurements broadly have a normal distribution around mean values, some infants in the lower percentile range are small because their parents, usually the mother, have small stature. In a statistical sense, the distribution of percentiles around the median value at each week of gestational age, rather than around the mean, is more appropriate. Birth weights do not have a normal distribution about the mean because relatively more infants are growth restricted than are large-for-gestational age. In general, the greater the deviation from the median or mean, the more likely is a severe nutritional or other pathological cause. Nevertheless, there are genetically or constitutionally small infants with birth weights in the lower percentiles referred to small for gestational age or SGA that have a low risk of complications. This distinction between constitutionally and pathologically small infants may be based on the presence or absence of distinct signs of pathological processes inhibiting growth such as clear evidence of placental insufficiency. Fetal growth restriction may originate early in gestation and these infants are usually growth restricted in a symmetric fashion with weight, length and head circumference all affected. However when fetal growth restriction is due to uteroplacental insufficiency with poor transfer of nutrients and oxygen in the second and third trimester of pregnancy the resultant growth restriction is asymmetrical. Head growth is spared to the greatest extent and to a lesser extent the length. At birth those with asymmetrical restriction have lower glycogen stores and a low ponderal index compared to those with symmetrical restriction.

Birth Weight for Gestational Age Reference Standards Accurate data sets needed to generate birth weight–gestational age percentile charts are difficult to produce and maintain. Just as there has been much debate about terms and definitions, there is often also disagreement about the most appropriate standards to use. National or regional standards based on nutritionally deprived mothers and infants fail to highlight such preventable problems (Lancaster, 1989). Although birth weight is a simple and easy measurement, the quality of birth weight measurements may be affected by the time interval from birth. Weight should be measured preferably within the first hour of life before significant postnatal weight loss has occurred. Many observers show digit preference by recording birth weight rounded to 0 or the nearest 100 g value. National statistics are usually obtained from the birth weight data of viable newborns born in hospital and community clinics. However, in developing countries many babies are born at home and sometimes the proportion of babies weighed at birth is low. Hence available data are likely to come from

health institutions servicing a small privileged minority. There is lack of international uniformity in assessing signs of life and viability and, apart from birth size, local factors such as place of delivery medical costs, maternity benefits, and burial costs may affect the decision to define a birth as live born. Accurate gestational age estimations are essential particularly if the common misclassification of small growthrestricted babies as preterm babies is to be avoided. Gestational age is estimated by a variety of methods according to the resources available. In developed populations, the estimated gestational age is based on maternal recall of the last menstrual period (LMP), often in association with an early fetal ultrasound measurement. In areas of limited resources, LMP recall and fundal height measurements are more likely to be used. Postnatal clinical examinations are used in the absence of or to verify estimations derived from antenatal sources. Nevertheless gestational age estimations are not infrequently unreliable. Large data sets with adequate numbers to produce percentiles in each gestational age interval are likely to have gestational age misclassifications resulting in major biases. Smaller, more accurate hospital-based data sets may fail to have adequate numbers in the lower gestational age intervals and require supplementation from other data sets. Furthermore, to remain representative of the population, it is recommended that data sets should be updated at least every 10 years due to changing populations, lifestyles, and living conditions. Understandably, populations with limited resources may not be able to produce, analyze, and maintain large, accurate representative data sets. In many countries, a sizable proportion of infants with a birth weight between the 3rd and 10th percentile do not have a pathological cause and may be small for familial reasons. Fetal growth restriction is then best defined as a birth weight below the 3rd percentile for each week of gestational age, recognizing that others may use the 5th or 10th percentile, or sometimes 2 standard deviations below the mean. In practice, especially in developing countries where fetal growth restriction is much more common, using the 10th percentile as the cut-off is more appropriate. This approach is based on assumptions that the 10th percentile is a valid cut-off point for identifying infants at higher risk and that the increased risk is constant over different gestational age intervals. For some fetal growth charts, the 10th percentile cut-off in all gestational age intervals underestimates higher risk while others overestimate it (Boulet et al., 2006). But in general, the risk of fetal and neonatal morbidity increases as the centile drops, and remains increased for all fetuses less than 10th centile even if many of these are constitutionally small. Importantly as most data contributing to representative data sets are collected after birth, all curves up to 36 weeks of gestational age are, by necessity, taken from abnormal material. There is considerable error in this method, since babies born preterm do not represent the healthy population of babies that otherwise remain in utero. More accurate fetal weigh charts are those that are based on ultrasound estimates of fetal weight. More complex attempts to develop birth weight for gestational age standards have included three-dimensional contour lines of birth weight–gestational age distributions by race, sex, and metropolitan status (Hoffman, 1974) and individualized growth assessments based on predicted second-trimester growth trajectories.

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Figure 1 An example of a birth weight for gestational age percentile chart. The weights of liveborn Caucasian infants at gestational ages 24–42 weeks graphed as percentiles and published for the first time. Reproduced from Lubchenco, L., Hansman, L.O., Dressler, C., Boyd, M., 1963. Intrauterine growth as estimated from liveborn birth-weight data 24–42 weeks of gestation. Pediatrics 32, 793–800.

Separate percentile charts have been recommended for subpopulations if there is a unique and intrinsic advantage such as perinatal survival rates associated with the gestational age–specific categories. As girls have better survival than boys at a given weight for gestation, separate charts according to gender are biologically justified. However there is little justification for separate charts based on racial/ethnic differences likely to be secondary to socioeconomic and lifestyle behaviors rather than fundamental biological differences (Roberts and Lancaster, 1999). Perinatal outcomes are worse in certain ethnic groups and there are concerns that correcting for ethnicity may mean some of these babies are missed by including ethnicity in these charts. Customized growth charts have been proposed to improve the sensitivity of identifying fetal growth restricted fetuses. In developing countries where ultrasound access remains limited, customized charts developed to plot fundal height measurements, improve the antenatal detection of fetal growth restriction from 25% to 50% compared to non-customized charts. Similarly customized growth charts of ultrasound estimates of fetal weight improve the detection of fetal growth restriction. Identification of fetal growth restriction by customized growth potential compared with fetal growth restriction defined by a population standard showed higher risk for pregnancy complications including neonatal morbidity and mortality

(Gardosi and Francis, 2009) However, currently there are no controlled trials to assess whether improvement in the detection of growth restriction occurs with customized charts. Future research in large trials is needed to investigate the benefits and harms (including perinatal mortality) of using such charts in different settings. An example of a birth weight for gestational age percentile chart is shown in Figure 1.

Causes of Fetal Growth Restriction Traditionally, the causes of fetal growth restriction are subdivided into maternal, placental, and fetal (Table 2). Those of maternal and placental origin relate to insufficient gas exchange or delivery of nutrients to the fetus to allow it to thrive in utero. Causes affecting the fetus are familial, genetic, and chromosomal abnormalities, or congenital infections. For approximately 30% of fetal growth restriction, no cause can be identified. In developing populations maternal poverty and undernutrition are the prime causes of growth restriction in the fetus. Furthermore if restricted fetal growth is exacerbated by poor living conditions, lack of maternal education, and inadequate nutrition in childhood, successive generations are likely to be affected, making it more difficult to interrupt this vicious cycle.

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Table 2

Maternal, placental, and fetal factors related to fetal growth restriction

Maternal

Placental

Fetal

Undernutrition: low pre-pregnant weight, short stature, poor gestational weight gain, anemia, Obesity extremes of maternal age Malaria Substance abuse and drug ingestion: Smoking, alcohol, cocaine, phenytoin, heroin, warfarin

Abnormal uteroplacental vasculature: abnormal trophoblast invasion, multiple infarcts, abruption placenta Malaria Damage due to thrombophilias: homocysteinuria

Congenital: Trisomy 21, Trisomy 18, Trisomy 13, Turners syndrome, various deletions

Hypertensive conditions: chronic hypertension, pregnancy-induced hypertension, pre-eclampsia, eclampsia Chronic maternal disease: diabetes mellitus, renal disease, hypoxic lung disease, heart disease, hemoglobinopathies, thrombophilia, thyroid disease, asthma Prior history of fetal growth restriction: sibling, maternal High altitude

Chronic villitis

Structural anomalies Infections: syphilis, cytomegalovirus, toxoplasmosis, rubella, hepatitis B, herpes simplex virus, human immunodeficiency virus Multiple pregnancies

Placental mesenchyme dysplasia

Modified from Lin, C., Santoloaya, J., 1998. Currents concepts of fetal growth restriction: Part 1. Causes, classification and pathophysiology. Obstet. Gynecol. 92 (6), 1044–1055.

When these underlying causes are more widely recognized, the economic benefits of reducing low birth weight in developing countries will be unarguably clearer (Alderman and Behrman, 2006). In contrast, in developed countries obesity aside from being associated with large babies is one of the leading modifiable causes of fetal growth restriction and stillbirth.

Maternal Maternal under nutrition, defined as a BM< 18.5 kg m 2.is widely prevalent in Africa south-east Asia, Latin America and the Caribbean with rates in some countries as high as 20%. Undernutrition may occur in combination or singly as low pre-pregnant weight due to inadequate nutritional status before conception, short stature primarily due to undernutrition and infection during childhood, and low gestational weight gain (GWG) due to inadequate diet during pregnancy and rapid succession of pregnancies. The classical natural experiment on the effects of maternal undernutrition on birth weight relate to the Dutch famine of 1945 when a strict food embargo occurred during the last 6 months of World War II. The restriction of caloric intake of pregnant women to approximately 30% of the recommended daily allowance was associated with an 8–9% decrease in birth weights of babies (Smith, 1947). However, it is the combination of a low pre-pregnant weight and a poor gestational weight gain that carries the greatest risk of delivering a growth restricted baby, so for undernourished women in drought or other times of nutritional stress the effects of low pre-pregnant weight are even greater. Even for well-nourished women the calculated relative risk for fetal growth restriction is approximately two times higher if gestational weight gain is less than 7 kg (Kramer, 1987). Malaria is a major determinant of fetal growth restriction in developing populations where there is endemic disease.

In sub-Saharan Africa one in four women has evidence of placental infection at the time of delivery. In areas of high malaria transmission, malaria-associated low birth weight approximately doubles if women have placental malaria, the greatest effect occurring in primigravida women. In developed populations cigarette smoking is a major cause of fetal growth restriction with smoking increasing the risk up to 3.5-fold. Smoking effects are dose related and may be dependent on the time of smoking in pregnancy, with effects increasing with maternal age. Other factors that, like smoking, affect oxygen-carrying capacity include hemoglobinopathies, maternal cyanotic heart disease, and severe maternal hypoxic lung disease. Maternal anemia, often due to malnutrition or malaria, also affects the oxygen carrying capacity and is strongly associated with fetal growth restriction. In developed populations, placental dysfunction is the commonest cause of growth restriction, Placental insufficiency may manifest later in pregnancy with isolated growth restriction, but often as a spectrum of placental disease which includes hypertensive disease (gestational hypertension and preeclampsia), abruption and stillbirth. Preexisting hypertension and diabetes may predispose women to these placental complications. Interestingly, preterm fetal growth restriction often occurs in the presence of hypertensive disease, whereas growth restriction at term more frequently occurs in normotensive women. Of concern is the increasing rates of obesity in the developed world which is increasing the number of women entering pregnancy with preexisting medical conditions that predispose them to growth restriction, but where the ability to detect the small babies may be limited by maternal size. Other maternal causes of fetal growth restriction include the pregnancies of growing adolescents in whom nutrients are used preferentially to promote maternal growth at the expense of the fetus. In contrast, older mothers are also more at risk of fetal growth restriction, perhaps due to increased presence of other maternal medical conditions. High-altitude living, associated

Fetal Growth Restriction: Causes and Outcomes with diminished oxygen saturation and maternal circulatory adjustments, also limit fetal growth. Fetal growth restriction is up to 10 times more frequent in twin deliveries because these and other multiple pregnancies can be affected by uneven placental distribution, poor placental implantation, and twin-to-twin transfusion. The risk of fetal growth restriction is increased with primiparity and grand multiparity and, in the absence of other specific pregnancy complications, there is a strong tendency for fetal growth restriction births to be repeated. Having a previous growth restricted fetuses is the strongest predictor of a subsequent affected pregnancy. Intergenerational effects also occur with fetal growth restricted mothers more likely to have fetal-growth restricted babies. Alcohol consumption affects fetal growth and, separate from the fetal alcohol syndrome abnormalities, heavy maternal alcohol consumption, cocaine, methamphetamine, heroin use, and medications such as warfarin and phenytoin have all been linked to fetal growth restriction. Multiple substance abuse carries the greatest risk of growth restriction.

Placental Abnormalities of placental structure and function are major causes of fetal growth restriction in developed populations. Adequate placental function is essential to provide the developing fetus with the oxygen and nutrition it requires to maintain growth. Placental function relies on adequate placental invasion in early pregnancy and appropriate maternal adaptations as gestation progresses. Early in pregnancy the outer layer of the placenta invades the maternal blood vessels. In normal pregnancies this converts the maternal arteries from low flow, high resistance vessels to high flow, low resistance vessels. This adaptation allows the placenta to be bathed in maternal blood and the transfer of oxygen and nutrients to occur. However in growth restricted pregnancies this adaption may not occur leading to shallow invasion of the uterus associated with a lack of available oxygen to the developing placenta. Subsequently the placenta may become infarcted or prone to chronic inflammation and as a result, the placenta is often smaller, thinner, and lighter. Normally as pregnancy progresses, there is reduced blood flow to the placenta and an increased resistance of blood flow through the placenta to the fetus. The growth of the fetus gradually declines and the fetus adapts to this adverse environment by redirecting blood flow to vital organs. In severe preterm growth restriction, as much as 70% of the placenta may have ceased functioning, and if unrecognized such a fetus rapidly succumbs to hypoxia and fetal death. Increased susceptibility to blood coagulation due to maternal blood-clotting disorders, such as factor V Leiden mutation and hyperhomocysteinuria, may contribute to thrombus and infarct pathology.

Fetal The fetal origins of fetal growth restriction relate to genetic and infective causes. Disorders due to increased chromosomes (e.g., trisomy 21 – Down syndrome, trisomy 13, and trisomy 18) and chromosomal reductions (e.g., Turner’s syndrome) and

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deletions (e.g., Cri du Chat syndrome) are all associated with fetal growth restriction. Single gene effects are rare but autosomal recessive metabolic diseases are consistently reported to have smaller babies. Polygenic effects may be expressed through a wide spectrum of congenital malformations associated with fetal growth restriction. The congenital infections of syphilis, rubella, toxoplasmosis, cytomegalovirus, herpes simplex virus, varicella-zoster, and human immunodeficiency virus have all been implicated with fetal growth restriction. The mechanisms of reduced growth are thought to be due to infection of the vascular endothelium and limitation of cell multiplication. Like so many other aspects of human pregnancy and care of the newborn, much has been learned about fetal growth by testing hypotheses experimentally in other species. For example, in the classic studies of the 1930s, heavy, powerful shire horses were crossbred with much smaller Shetland ponies. It was shown that maternal size was a crucial factor in limiting the size of the fetus at birth, thereby enabling easier pelvic descent and avoiding disproportion and obstructed labor and delivery (Walton and Hammond, 1938). This was subsequently confirmed by indirect studies in humans and became known as ‘maternal constraint’ of fetal growth (Ounsted and Ounsted, 1973). These early experiments represent the effect of what we now know as genetic imprinting. It is an important survival mechanism to ensure safe delivery of the fetus for the maternal determinants of growth to have precedence over the paternal determinants. To do this, the paternal genes must be ‘switched off’. This is achieved by epigenetic mechanisms, whereby particular genes are tagged and their action suppressed by the addition of this tag. Certain growth genes which are turned on and off have been studied in detail, and when they are turned off inappropriately may lead to severe fetal growth restriction.

Consequences of Fetal Growth Restriction The disadvantages of fetal growth restriction continue over the entire life course. In early life there are increased fetal, neonatal, and infant death rates. During childhood there is poor postnatal growth and impaired neurodevelopment and immune function and in adult life growing epidemiological evidence suggests that fetal responses to a deprived intrauterine environment may underlie the development of many chronic adult diseases. Fetal growth restriction is associated with higher stillbirth rates, neonatal mortality and morbidity, and infant mortality rates in preterm, term, and post-term infants (Yu and Upadhyay, 2004; Katz et al., 2013). Sixty-five percent of babies dying on their first day of life are growth restricted. Compared to appropriately grown neonates in the neonatal period, fetal growth restricted babies are more prone to develop asphyxia and, as a result, meconium aspiration syndrome is more common. Many growth restricted infants have a characteristic appearance soon after birth of dry peeling skin and deficient subcutaneous tissue. Hypothermia (low temperature) is likely in these babies because of the greater surface area relative to weight and depleted subcutaneous fat and brown fat stores. Up to 25% may develop hypoglycemia (low blood sugar), partly due to diminished glycogen stores and poor adipose

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Figure 2 Fetal growth restriction. Australian Aboriginal infants of the same gestational age: the smaller baby is severely growth restricted.

tissue. Hypocalcemia (low serum calcium levels) is more common. In approximately 15% of fetal growth restricted babies, polycythemia (abnormally large number of red blood cells in the circulatory system occurs as a result of erythropoietin production in response to chronic intrauterine hypoxia and this condition adds to the hypoglycemia and hyperbilirubinemia seen in fetal growth restriction. Asphyxia also results in a diversion of blood flow from mesenteric vessels to the brain and, together with the hyperviscosity accompanying polycythemia, contributes to the development of necrotizing enterocolitis. Figure 2 is an example of a growth restricted baby compared to one with normal growth. Growth restricted children have a high incidence of failure to thrive. Many fetal-growth restricted babies, particularly those born at term, experience some catch-up growth. However, prospective studies that carefully define fetal growth restriction indicate that despite partial catch-up growth during the first 1–2 years of life fetal growth restricted babies continue to have a smaller body size compared with children who were not growth restricted in fetal life. It is estimated that about a fifth of stunted children in developing countries were born with growth restriction By age 17–19 years, studies from both developed and developing populations show fetal-growth restricted subjects about 5 cm less in height and 5 kg less in weight than those who were not fetal growth restricted (Sayers et al., 2011) Babies born both fetal growth restricted and preterm appear to have limited or no catch-up during the first years. Also, while studies are not conclusive, there is a trend for babies with symmetrical fetal-growth restriction to have poorer growth outcomes compared to asymmetrical fetal growth restriction. Compared to children who were appropriately grown babies, children who were fetal growth restricted, exhibit more neurodevelopmental impairments including cerebral palsy, cognitive defects, clumsiness, and behavioral problems associated with attention deficit disorders, and hyperactivity (Yanney and Marlow, 2004). School failure is more likely among fetal growth restricted children. A study focusing on the neuropsychological profile of 10 year old children who

had fetal growth restriction at birth compared to those normally grown noted a reduction in IQ and specific difficulties in creative problem solving, attention, and executive functions, visual motor organization and higher order verbal skills. These domains are related to frontal lobe function and several observations support the concept that this area of the brain is especially vulnerable to fetal nutrient deficiency in the third trimester. Impairment of immunological functions has been reported in a small number of studies, showing evidence of poor lymphocyte function and decreased IgG (immunoglobulin) production. In addition cohort studies from the Gambia have demonstrated that being born in the hungry season is associated with reduced thymus size and function and in Pakistan and the Philippines, correlations between birth weight and functional responses to vaccines administered in adolescence have been described. Such observations have not been described universally and more research is needed to elicit the pathways between fetal nutritional deprivation and later immune function and resistance to infection. Other organs systems directly affected by the inadequate nutrient building blocks associated with growth restriction are the renal, liver, pancreas and respiratory systems. Compared with those of normal size at birth, those with growth restriction have decreased nephron numbers with increased nephron size suggesting that in these circumstances the existing glomeruli undergo compensatory hypertrophy to sustain adequate kidney function. This adaptation may led to loss of nephrons and accelerate decline in renal function. In adults that have been low birth weight, there is an increased prevalence of microalbuminuria and proteinuria and a greater severity and progression of renal diseases. Poor respiratory function in adulthood following fetal growth restriction is a reasonably consistent finding but the extent to which later growth might compensate for the effects of intrauterine adversity is less clear. Animal experiments with maternal undernutrition have demonstrated altered liver structure with decreased insulin sensitivity and for both animal and humans decreased beta cells with decreased insulin secretion has been demonstrated in those with growth restriction. There is now increasing epidemiological evidence of the relationship of fetal growth restriction (mostly represented by low birth weight) to later chronic adult disease associated with premature adult mortality. Initial retrospective observations linked lower birth weights in old birth records in Hertfordshire, UK, to adult coronary heart disease mortality. Since that time numerous studies in different populations have related lower birth weights to later adverse outcomes. These include reduced ‘human capital’ with shorter stature, lower lean body mass, and poorer cognition educational achievement, work capacity, income and reproductive performance, with increased risk factors for later higher blood pressure and insulin resistance (Victora et al., 2008) as well as central adiposity, stress responses, reduced glucose tolerance, lung function, glomerular filtration rate and immune function. These conditions are associated with an increase of the clinical diseases of type 2 diabetes, coronary heart disease, chronic renal disease and chronic lung disease and increased all-cause and cardiovascular mortality (Fall, 2013).

Fetal Growth Restriction: Causes and Outcomes The concept of early life events affecting later health and disease is now well established but the mechanisms involved are not clear. In a nutritionally deprived environment survival is enhanced by limited growth of the fetus accompanied by protection of brain growth. This occurs through dynamic physiological processes involving enzyme systems and endocrine pathways with alterations of blood supply from abdominal and musculoskeletal systems to the brain. These adaptations may lead to permanent structural and physiological effects. These permanent phenomena may develop through epigenetic mechanisms by which changes to the genome alter gene expression but do not alter the primary DNA sequence of the gene. Within cells, three systems are now known to interact with each other to alter gene expression: DNA methylation, histone modifications, and RNA-associated silencing (McKay and Mathers, 2011). Hence through these mechanisms one genotype may give rise to a range of phenotypes in response to different environmental conditions during development. A mismatch between the intrauterine and postnatal nutritional environment appears to be a consistent finding contributing to the development of cardio-metabolic chronic diseases (Gluckman et al., 2007). The highest risks of adverse metabolic and cardiovascular outcomes occur when low birth weight is associated with higher child or adult body mass. Rapid postnatal growth of babies is associated with an enhanced risk for obesity, diabetes, hypertension cardiovascular disease, and osteopenia in later life. The finding of higher risk with the interaction of low birth weight and higher child and adult body mass has important public health implications. This nutritional profile is characteristic of populations undergoing nutritional transition. Countries with rapid economic development experience shifts in diet and physical activity that favor over-nutrition which in combination with low birth weight increases the risk of chronic disease. Importantly while compensatory catch-up growth has been encouraged in these developing populations it may be more prudent to avoid rapid postnatal weight gain, thereby balancing immediate short term growth gains with consideration of the future nutritional environment over the whole life span. However, current evidence suggests that rapid growth may be possible within the first 2 years without incurring adverse long term consequences (Adair et al., 2013). There is now compelling experimental animal evidence that indicates that the adverse effects of fetal growth restriction off-spring can be carried on through subsequent generations most likely through epigenetic changes. Evidence for the role of the specific environmental factors and epigenetic changes in the placenta are now emerging, but larger studies are required to determine if these findings can be replicated in different populations.

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growth, but will also impact on maternal and neonatal morbidity. The existing primary prevention programs relating to fetal growth restriction are based mainly on specific health-care interventions during antenatal care. However some of the most powerful influences on pregnancy and subsequent infant health are related to the health and well-being of the mother long before the beginning of pregnancy. As many pregnancies are unplanned and/or presentation to antenatal care delayed there has been a recent focus on a life course approach to maternal health with a continuum of care beginning during adolescence in the preconception period and continuing through the reproductive years.

Preconception Despite an increasing advocacy for preconception care there are currently no studies describing the implementation and evaluation of a holistic approach delivering preconception care as a complete program. Evaluations of interventions focusing on single risk factors are reported (Dean et al., 2012). For delaying the age at the first pregnancy, a combination of multiple interventions, especially contraception with education have been effective and successful programs to prevent repeat teenage pregnancies all include teaching parenting skills and encouragement to complete education with medical care. Quality family planning services are essential and have successfully supported women to determine how many children they have and importantly helped them space their children at least 18–24 months apart. Smoking interventions in the preconception period have been shown to be effective. Immunization prior to pregnancy for rubella and varicella may prevent some perinatal infections. In addition, vaccination against pneumococcus, Haemophilus influenza and viral influenza may improve fetal growth by reducing maternal respiratory illness. Research studies optimizing maternal nutrition prior to conception remain very limited. A multi-centered, individually randomized, controlled trial of a preconception nutrition intervention is currently underway in Guatemala, India, Pakistan, and the Democratic Republic of the Congo. Positive results of this trial will have a huge impact in shifting nutritional improvements to all females of child bearing age. However currently overall there is still a relatively short list of core interventions with substantial evidence of effectiveness in the preconception period and considerable further research is necessary to determine effective programs (Temel et al., 2013).

Antenatal

Prevention of Fetal Growth Restriction Ideally, on a global scale, prevention should focus on successfully breaking the cycle of generations of growth-restricted babies by implementing major public health measures that aim to end poverty and the desolate socioeconomic conditions that contribute to child and maternal starvation and infections. Such measures have the benefit of not only improving fetal

Systematic reviews of randomized controlled trials (RCTs) are the most objective way to evaluate the effectiveness of the antenatal health-care interventions targeting fetal growth restriction. However, methodological issues concerning rigorous randomization, reliable assessment of gestational age, and adequate sample size and confounders have meant there are fewer studies from developing populations included in these reviews. Cochrane Reviews are systematic reviews of

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primary research in human health care and health policy, and are internationally recognized as the highest standard in evidence-based health care. A 2012 Cochrane review of randomized controlled trials of antenatal dietary advice and supplementation to increase energy and protein intake of pregnant women (Ota et al., 2012 showed that the infants born to mothers receiving balanced protein energy supplementation during pregnancy (where protein accounts for < 25% of the total energy content) tended to be heavier than those born to non-supplemented mothers with clear increases in mean birth weight evident in 11 trials of 5385 women and fewer growth restricted births in seven trials of 4408 women however the impact on the long-term health of the babies benefiting from supplementation remains uncertain. Providing nutritional advice alone resulted in an increase in the mother’s protein intake, but did not translate into having a significant effect on growth restricted birth outcomes and most importantly one trial of high protein supplementation involving 1051 mothers showed no benefit to the mothers and possible harm to the baby. In addition isocaloric protein supplementations (i.e., balanced supplements in which the protein replaces an equal quantity of other nutrients, e.g., macronutrients, fat and carbohydrate) in two trials involving 184 women showed no benefit for women or their babies. Aside from these randomized controlled studies, an important nonrandomized study of supplementation during two consecutive pregnancies and the intervening lactation period showed even higher increases in mean birth weight. This suggests that the likelihood of improving birth weight in the chronically undernourished would be greater with longer-standing interventions. These findings confirm a previous overview of nutritional interventions during pregnancy for the prevention or treatment of fetal growth restriction. This overview, based on searches for Cochrane systematic reviews and RCTs published up to 2002, reported a systematic review of 13 trials of balanced protein energy supplementation in pregnancy, of which six reported fetal growth restriction. Data from these six trials on more than 4000 women showed that balanced protein energy supplementation given to women during pregnancy reduced the risk of fetal growth restriction by 30% (Merialdi et al., 2003). Although the change in mean birth weight was small, it translated into relatively large reductions in the rate of fetal growth restriction. For example, a Gambian study that obtained an increase in mean birth weight of 136 g showed a reduction in low birth weight by 35%. In many developing populations multiple micronutrient deficiencies occur that are exacerbated by pregnancy. A Cochrane review of multiple micronutrient supplementation in pregnant women assessed 23 trials and reported an 11–13% reduction in FGR births. Up till now, single micronutrient supplementation interventions have not been shown to affect size at birth. A Cochrane review of daily iron supplementation women during pregnancy reported a 19% reduction in the incidence of low birth weight. However methodological concerns overshadow the findings that magnesium supplementation reduced fetal growth restriction by 30% in three trials of 1700 women.

Calcium has been shown to be of benefit but may be limited to those populations where there is low dietary calcium intake. Smoking cessation has been shown to reduce the occurrence of low birth weight. Observational data suggest that even partial reduction in smoking can have positive effects on birth weight. In general behavioral strategies have been more effective in reducing smoking than just giving advice and increases in mean birth weights have been highest in groups who were most successful in totally stopping smoking. Prevention and treatment of maternal infection is vital to prevent low birth weight babies. A systematic review of antimalarial chemoprophylaxis use in endemic areas included 11 trials with data available on 3000 women. Although the studies were of variable designs overall, antimalarial chemoprophylaxis was associated with higher maternal hemoglobin levels and increases in birth weights. The effects were more marked in primigravida who are known to be most susceptible to infection. More research is needed to determine the optimum timing and combinations of drugs administered. Antenatal screening for syphilis and treatment with penicillin can reduce syphilis related stillbirths by 82%, many due in part to growth restriction. Antibiotic treatment for asymptomatic bacteriuria has been shown to reduce the incidence of low birth weight by 44%. Antiviral treatment for HIV also improves fetal growth as well as reducing rates of transmission. Antiplatelet drugs reduce the incidence of growth restriction in high risk women. The difficulty arises in deciding which women may benefit from such treatment because they are most useful if started prior to 16 weeks gestation. Aspirin is cheap and easily accessible, and heparin has also been proposed but only in trial settings.

Management of Fetal Growth Restriction The first step in the management of growth restricted fetuses is to identify those fetuses that are truly at risk for adverse outcomes. This requires exclusion of small fetuses that are normally grown. It is also useful to identify those in whom fetal growth restriction is due to an underlying condition in which management will not greatly alter the outcome (e.g., chromosomal abnormalities, viral infections). Currently there is a lack of known therapeutic interventions to improve placental function and stimulate fetal growth so the management of fetal growth restriction relies on careful monitoring of fetal well-being and the planned delivery of the fetus when the risk of fetal death is greater than that of neonatal death and morbidity. Antenatal surveillance of fetal well-being is resource dependent. In resource poor settings assessment of fetal well-being may be confined to the monitoring of standardized fundal height measures, fetal movements, and listening to the fetal heart. Although a WHO collaborative study suggests a single measurement of weight gain from pre-pregnancy to 16–28 weeks is the most practical screening test for FGR in resource poor settings. Measurement of fundal height has been the main approach for detection of fetal size throughout the world. But it is subject to significant inter and intra observer variability and using this method up to 85% of growth-restricted fetuses may be missed. Fetal movement

Fetal Growth Restriction: Causes and Outcomes counting is useful as when a fetus is hypoxic it minimizes unnecessary movements, diverting blood to vital organs such as the heart and brain. Maternal perception of a reduction in the movements of the fetus may alert the health provider to the presence of a growth restricted fetus that requires further investigation. In pregnancies where the fetus is known to be small, a reduction in movements may be a warning of imminent fetal demise. In resource richer settings ultrasound measures can increase the identification of growth restriction. Ideally more than one ultrasound should be performed, at least 2 weeks apart and the growth trajectory assessed as well as the estimated centile. However, this is not always practical. Ultrasound assessment of fetal weight is calculated using measurements of the head (biparietal diameter and head circumference), abdominal circumference and femur length. Many calculations have been proposed of which the Hadlock equation is most frequently used. The estimated fetal weight can then be plotted on either a population or customized growth chart (as above). Targeted ultrasound in high-risk pregnancies or when growth restriction is predicted improves detection rates. Although routine third trimester ultrasound has not been shown to improve perinatal outcomes. Doppler assessment of fetal and placenta vessels is particularity useful in differentiating between constitutionally small fetuses and those with pathological growth restriction due to placental dysfunction. Doppler assessment of the maternal uterine arteries in the first but predominately second trimester, are elevated and notched in pregnancies where the placental has failed to invade adequately. This may be a predictive tool but when these changes persist into the third trimester can be a useful tool to confirm the placental origin of growth restriction. For various fetal vessels there is a high level of evidence (level one) that measurement of blood flow by Doppler improves perinatal outcomes. Umbilical artery resistance represents placental resistance, and if 60–70% of the placenta is infarcted and non-functioning, there is very high resistance in the umbilical artery. When loss or reversal of blood flow occurs in this vessel in diastole it is likely the fetus is becoming hypoxic and acidotic. In addition when the fetus is becoming hypoxic, blood flow is directed to the brain. Middle cerebral artery blood flow can measure this brain sparing effect. Finally, the ductus venosus is responsible for redirecting blood flow from the liver to the heart in a compromised fetus. When there is a loss of forward flow in this vessel the fetus is already acidemic, and if undelivered is likely to succumb to fetal death shortly. Thus measurement of the blood flow in these vessels allows clinicians to not only confirm the presence of fetal growth restriction, but allows them to determine if delivery is required to save the fetus. Delivery must always be balanced against the risks of prematurity and therefore the use of such assessments are only appropriate when the resources are available to care for a preterm infant delivered as a result. There is a fear that in low resource settings, this may lead to increased rates of prematurity without improving long term survival. Cardiotocography (CTG), or fetal heart rate analysis in response to movement and contractions, is used widely. However, difficulties of interpreting the patterns are challenging and user dependent. Outside labour, abnormal fetal

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heart rate patterns often occur only when urgent delivery is needed to prevent fetal death and therefore limit its application. Similarly a poor score in the composite biophysical profile including CTG, ultrasound measures of amniotic fluid volume recorded as the amniotic fluid index, fetal tone, movement, and breathing activity may also occur only when delivery is urgent. There is no evidence to show CTG or the biophysical profile improves perinatal outcomes. Combinations of fetal biometry, heart rate patterns, arterial and venous blood flow measures, and biophysical variables allow the most comprehensive evaluation of fetal well-being. A new approach is the development of blood based biomarkers to predict fetal growth restriction and help determine the presence and severity of restriction. In Downs Syndrome differing amounts of placental hormone expression has been shown in the maternal blood which may also be useful in predicting adverse pregnancy outcomes. In a research setting, fetal RNA appears to more accurately identify and predict pregnancies at risk of growth restriction than other currently available biomarkers. It may also be useful in determining the degree of hypoxia present in small babies and so help clinicians with the timing of delivery. These preliminary findings are currently being explored in much larger clinical trials (Whitehead et al., 2013). But currently these tests are not sensitive enough to be recommended for routine clinical practice. The most important aspect of prenatal management is that the timing and mode of delivery be individualized for the fetus at risk. Two randomized controlled trials attempt to describe the optimum time to deliver, with a large European trial completed but to date unpublished. The DIGITAT trial randomized women with suspected fetal growth restriction to either delivery or expectant management. There was minimal difference in perinatal outcomes in either group, but fewer babies were born 9000 QALYs, whereas seven were less than 900 QALYs. Foodborne diseases occur at great economic costs. As an example, in the United States, the economic burden of 14

pathogens accounting for 95% of illnesses and hospitalizations and 98% of deaths due to identifiable pathogens was estimated by Hoffman et al. to be $14.0 billion (range: $4.4–$33.0 billion) in cost of illness and a loss of 61 000 QALYs (range:19 000– 145 000 QALYs) per year (Hoffmann et al., 2012). Five agents account for approximately 90% of the economic cost: nontyphoidal Salmonella ($3.3 billion; 17 000 QALYs), Campylobacter spp. ($1.7 billion; 13 300 QALYs), L. monocytogenes ($2.6 billion; 9400 QALYs), T. gondii ($3 billion; 11 000 QALYs), and norovirus ($2 billion; 5000 QALYs).

Foodborne Disease Surveillance Foodborne disease surveillance information can be used to detect and investigate foodborne outbreaks, halt ongoing disease transmission, prevent future outbreaks, guide future food safety prevention, intervention, and control activities, and evaluate the progress and success of such activities. The United States has one of the most comprehensive foodborne disease surveillance programs in the world with surveillance carried out by the coordinated efforts of multiple surveillance systems at the CDC. The following section examines three core surveillance systems, the National Molecular Subtyping

Foodborne Diseases Network for Foodborne Disease Surveillance (PulseNet), the Foodborne Disease Active Surveillance Network (FoodNet), and the Foodborne Disease Outbreak Surveillance System (FDOSS), to illustrate how foodborne disease surveillance can function to provide information on the origins, extent, and attribution of foodborne diseases that can be used to keep the food supply safe.

National Molecular Subtyping Network for Foodborne Disease Surveillance PulseNet is a passive surveillance molecular subtyping network of 83 federal, state, and local public health laboratories that was created in 1996 to facilitate the identification of and response to dispersed outbreaks caused by bacterial pathogens originating from widely distributed foods (CDC, 2016g). PulseNet is based on the presumption that individuals infected with a foodborne pathogen of the same genetic strain most probably acquired that pathogen from the same food source. On this basis, participating laboratories upload subtype data obtained from clinical samples to a CDC DNA fingerprint database in real time, and the data are analyzed to identify molecular subtype clusters that may represent common source outbreaks. Thus, PulseNet can detect widespread outbreaks and differentiate between sporadic and outbreak-associated cases of foodborne illness occurring at the same time. PulseNet uses pulsed-field gel electrophoresis of DNA restriction fragments as the current ‘gold standard’ method of DNA fingerprinting. However, it is transitioning to wholegenome sequencing (WGS) fingerprinting methods as new high-throughput sequencing technologies (a.k.a. nextgeneration sequencing (NGS) technologies) allow for timely, cost-effective sequencing of complete microbial genomes. The key advantage of WGS over more traditional fingerprinting methods is that the enormous amount of data generated on individual isolates enables much more comprehensive analysis and comparison of isolates. A notable early mobilization of WGS for foodborne disease surveillance took place during the investigation of the 2011 Shiga toxin–producing E. coli O104:H4 outbreak in Europe. During this outbreak, the release of real-time, open-source data from multiple sequencing platforms for crowdsource analysis by groups in multiple countries allowed for the rapid identification, within 1 week, of the outbreak strain as belonging to a distinct lineage of enteroaggregative E. coli that had acquired genes for Shiga toxin 2, antibiotic resistance, and other virulence factors (Deng et al., 2016). Two years later, PulseNet initiated routine application of WGS to detect Listeria outbreaks as part of a multiple agency initiative (the Listeria WGS Project) seeking to perform realtime WGS on all patient, food, and environmental isolates of L. monocytogenes (Jackson et al., 2016). The initiative proved successful as evidenced by an increase in both the detection of clusters of listeriosis and the number of solved outbreaks, and a reduction in the average size of detected clusters as a result of earlier detection and investigation. PulseNet is now expanding the use of WGS to investigate outbreaks caused by Campylobacter, E. coli, and Salmonella, and, in 2014, it launched the “Transforming Public Health Microbiology – PulseNet and Beyond” project which aims to consolidate most foodborne pathogen identification and characterization activities into

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a single, fast, and efficient WGS process (CDC, 2016g). The project is part of CDC’s Advanced Molecular Detection and Response to Infectious Disease Outbreaks (AMD) initiative that seeks to combine NGS pathogen identification technologies with enhanced bioinformatics capabilities and advanced epidemiology to improve understanding, prevention, and control of infectious diseases (CDC, 2016a). Globalization of international food trade has created the need for a foodborne disease surveillance system that can detect outbreaks created by the distribution of food products worldwide. In 1999, the initiation of collaboration between CDC’s PulseNet and its counterpart in Canada marked the inception of PulseNet International which now consists of a network of PulseNet systems in Africa, the Asia Pacific, Canada, Europe, Latin America and the Caribbean, the Middle East, and the United States (Swaminathan et al., 2006) (CDC, 2016h). The objective of PulseNet International is “to participate in the investigation of outbreaks of foodborne infections and to facilitate early recognition of foodborne disease clusters that may represent common source outbreaks through molecular surveillance of infections at the global level by: partnering with reference laboratories throughout the world, building capacity for molecular surveillance of foodborne infections, collaborating on the development, validation and implementation of internationally standardized subtyping methods to be used in the networks, [and] performing collaborative studies on the geographic distribution and spread of different clones of foodborne pathogens” (CDC, 2016h).

Foodborne Disease Active Surveillance Network Launched in 1995, the FoodNet conducts active, populationbased surveillance for laboratory-confirmed infections of nine pathogens commonly transmitted through food and for hemolytic uremic syndrome (HUS) (Henao et al., 2015; CDC, 2016c). The network consists of 10 sites covering a surveillance area of 58 million persons (15% of the US population). Its primary objectives include monitoring trends in the incidence of specific, major foodborne illnesses (both sporadic and outbreak) over time, determining the burden of foodborne illness in the United States, and attributing the burden of foodborne illnesses to specific sources and settings. The information generated by these activities is used by multiple government, industry, and private stakeholders to prioritize and evaluate food policy and safety efforts and monitor progress toward national health objectives (Scallan, 2007; CDC, 2016c).

Foodborne Disease Outbreak Surveillance System FDOSS is a passive surveillance system that monitors the agents, foods, and settings responsible for foodborne disease outbreaks across the United States (CDC, 2016e; Gould et al., 2013). It depends on state and local health departments voluntarily reporting relevant data (e.g., location, magnitude, demographics, agent, vehicle, contributing factors, public health response) on outbreaks they investigate to the CDC through the electronic National Outbreak Reporting System (NORS) (CDC, 2016f). The FDOSS database, containing information on foodborne outbreaks reported to CDC since 1998, can be searched through the public access, web-based platform,

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Foodborne Diseases

Foodborne Outbreak Online Database (FOOD) (CDC, 2016d). Analysis of FDOSS data can be used to assess changes in food commodities commonly associated with outbreaks that might occur following changes in food safety practices, food consumption patterns, or food preparation practices and, thus, identify food commodities and preparation settings as potential targets for effective intervention (Gould et al., 2013).

New Culture-Independent Diagnostic Tests Since a substantial proportion of foodborne disease outbreaks do not have a specific pathogen identified, there has been increasing focus on the development of novel diagnostic tests for enteric infections that do not rely on standard microbiological culture and isolation techniques and can provide diagnoses more rapidly and inexpensively. Some of these tests directly detect bacterial toxins such as Shiga toxin, while other tests use enzyme immunoassays for pathogen detection (Braden and Tauxe, 2013). While these tests do not obviate the need for culture and susceptibility testing, since precise species identification (DNA fingerprinting) and antibiotic resistance profiles are important for public health surveillance to detect outbreaks and monitor trends, they nevertheless provide important additional tools to facilitate foodborne disease diagnosis (Iwamoto et al., 2015; Huang et al., 2016). In a similar manner, the aforementioned strategies such as WGS may include specific gene markers for antimicrobial resistance and virulence markers that may help to improve detection and source tracking in multistate or multicountry outbreaks (Deng et al., 2016).

Different Types of Foodborne Illnesses Infectious gastroenteritis is the most common foodborne disease and may be complicated by sequelae days to months after an initial foodborne infection. There are also many other foodborne diseases with various symptoms and degrees of seriousness that are caused by microbes or chemical toxins.

food. Campylobacteriosis, salmonellosis, and shigellosis are some of the more frequent types of bacterial gastroenteritis. In addition, a number of different strains of E. coli are responsible for acute diarrhea. Common bacterial pathogens and their clinical features are shown in Table 4. Campylobacterosis is caused by Campylobacter jejuni and is one of the most common bacterial diarrheal illnesses in both developed and underdeveloped countries. In developed countries, the incidence of reported laboratory-diagnosed cases ranges from 12 per 100 000 population in the United States to 390 per 100 000 population in New Zealand. The number of cases in the community is higher than those reported through laboratory-based surveillance, so the overall burden is presumed to be much greater. It is likely that incidence may be higher in less developed countries. Campylobacter normally lives in the intestines of healthy birds, and the main identified sources of infection are undercooked poultry, contaminated water, raw milk, and contact with infected animals. Salmonellosis is caused by infection with S. enterica, which occurs in the intestines of birds, reptiles, and mammals. Salmonella enterica is divided into over 2000 epidemiologically distinct serotypes. Animal feces containing these bacteria contaminate soils and waterways, leading to contamination of human food. Salmonella replicates in food that is not refrigerated, and outbreaks of foodborne disease affecting many people from one food source are common, especially during warm weather. Some European countries, such as Norway, Denmark, and Sweden, have very low rates of Salmonella infections due to robust control measures in animal flocks and herds. Campylobacter and Salmonella are thought to be about 80–90% foodborne, with the remainder of cases acquired from water, animals, and the general environment. Shigellosis is caused by Shigella spp., which is mostly spread directly from person to person. The incidence of shigellosis is higher in less developed countries. It is easily spread from food contaminated by infected food handlers and by water contaminated by sewage. About 10% of cases are thought to be foodborne.

Viral Gastroenteritis Foodborne infectious gastroenteritis is caused by an array of different bacteria, parasites, and viruses; the characteristics of some common pathogens are shown in Table 4. Gastroenteritis is usually short-lived, 1–10 days, with loose stools, stomach cramps, fever, and vomiting. The nature, duration, and severity of symptoms vary with the causative pathogen. Illnesses caused by microbial pathogens may result from ingesting toxins formed by bacteria growing in food, from toxin produced in the intestine after ingestion, or by true infection where the pathogen itself invades the gastrointestinal tract and causes inflammation. Generally speaking, the incubation period will be shorter, when preformed toxin is involved, and longest, when infection occurs.

Viral pathogens that can be transmitted via food include norovirus, adenoviruses, and rotavirus. Adenoviruses and rotavirus are very common in young children, but only about 5% of cases are estimated to be transmitted via food. Norovirus is one of the most common viruses transmitted by food. It is an RNA calicivirus, previously called Norwalk-like virus or small round structured virus. The virus only replicates in humans and is predominantly spread from person to person with 10– 40% of norovirus infections being foodborne. Norovirus in human sewage can contaminate fruits, vegetables, and oysters and result in large outbreaks. In the United States, norovirus has been demonstrated to be a major cause of foodborne outbreaks in the last decade with food preparation in restaurants having been implicated in about two-thirds of outbreaks (Hall et al., 2014).

Bacterial Gastroenteritis

Parasitic Gastroenteritis

Infectious Gastroenteritis

There are about 20 known bacterial agents that may cause gastroenteritis and are potentially transmitted via contaminated

Cryptosporidiosis, cyclosporiasis, and giardiasis are caused by the protozoal microorganisms Cryptosporidium parvum,

Table 4

Clinical and epidemiological characteristics of common foodborne pathogens

Organism

Common vehicles

Median incubation period (hours)b

Clinical features a

Median duration of illness (days)b

Sources of diagnostic material

Bacillus cereus (emetic form) Bacillus cereus (diarrheal form) Bacillus anthracis Campylobacter jejuni Clostridium perfringens Clostridium botulinum

Fried rice, vanilla sauce, cream

2 (1–24)

N, V, C, D

0.4 (0.2–0.5)

Vomitus, stool, or food

Vanilla sauce, meatballs, beef, chicken

9 (6–14)

D, C, N, V

1 (1–2)

Vomitus, stool, or food

Beef, other livestock Milk, chicken, pet animals, beef Beef, turkey, chicken Canned and preserved foods

48 (24–188) 48 (24–240) 12 (8–22) 24 (6–36)

Poorly defined (2–7) 7 (2–30) 1 (0.3–3)

Blood, food Stool or rectal swab Stool or rectal swab Food, food contact surfaces

Salad, beef

24 (8–14)

N, V, B, C, F D, F, C, B, H, M, N, V D, C (N, V, F rare) Double/blurred vision, drooping eyelids, slurred speech, muscle weakness D, C, N, H, F, M

3 (1–4)

Stool or rectal swab, food source

Salami, sprouts, milk, apple cider

3–4 (1–10)

Milk, vegetables, coleslaw, dairy products, poultry, beef, soft cheese Ham, pork, canned beef, cream-filled pastry

Enterotoxigenic Escherichia coli Enterohemorrhagic Escherichia coli Listeria monocytogenes

Stool or rectal swab, food source

Not well defined

Stool or rectal swab; blood, CSF

3 (1–6)

V, N, C, D, F (rare)

1 (0.3–2)

24 (5–72)

D, C, N, V, F, H, B (rare), enteric fever

3 (0.5–14)

24 (7–168)

C, F, D, B, H, N, V

3 (0.5–14)

12 (2–18)

D, C, N, V, H, F (25%), B (rare)

3 (2–10)

Vibrio vulnificus

Seafood; rarely salt water or salted vegetables Seafood (particularly oysters)

? (12–72)

?(2–8 days)

Yersinia enterocolitica

Chocolate or milk, pork

? 72 (2–144)

7 (2–30)

Stool from food preparer

Norovirus Toxoplasma gondii

Fruits and vegetables; raw shellfish Meat (lamb, pork, beef); cat feces contaminated garden fruits and vegetables Pork

33 (12–48) ? (5–23 days)

D, F, N, V, cellulitis, CNS symptoms, septic shock B (rare), F, C, D, V, pharyngitis, arthritis, mesenteric adenitis, rashes C, D, F, G, M, N, V F, H, M; CNS and ocular symptoms in immunocompromised

Stool, vomitus; food or food contact surfaces; nasal, hand, or purulent lesions from food preparer Stool or rectal swab from patients and food preparation workers; raw food Stool or rectal swab from patients and food preparation workers; food Stool or rectal swab; food, food contact surfaces; seawater Stool, blood, cutaneous lesions

33 (12–48 h) ? (few weeks to months)

Stool Blood, CNS, tissue sections

Disease continues until death of tapeworm

Stool or rectal swab

Staphylococcus aureus Salmonella spp. Shigella spp. Vibrio parahaemolyticus

Taenia solium

Eggs, meat, poultry, tomatoes, cantaloupe Milk, salads (potato, tuna, turkey)

(8–10 weeks)

C, N, D, constipation

? ¼ unknown. a B, Bloody diarrhea; C, crampy abdominal pain; D, diarrhea; F, fever; H, headache; M, myalgias; N, nausea; V, vomiting. b ranges are given in parentheses. Table is modified from CDC, 2016. CDC Estimates of Foodborne Illness in the United States: CDC 2011 Estimates [Online]. Available: http://www.cdc.gov/foodborneburden/2011-foodborne-estimates.html (accessed 29.06.16.); which was constructed with data derived from Scallan, E., Griffin, P.M., Angulo, F.J., Tauxe, R.V., Hoekstra, R.M., 2011. Foodborne illness acquired in the United States – unspecified agents. Emerg. Infect. Dis. 17, 16–22.

Foodborne Diseases

5 (5–7)

? (9–48)

F, M, D, C, B, F, hemolytic uremic syndrome D, F, C, M, N, V,

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Cryptosporidium hominis, Cyclospora cayetanensis, and Giardia lamblia, respectively. Infections are generally mild but can be prolonged, lasting weeks. Most illnesses are transmitted from another infected person or animal or via contaminated water, with foodborne transmission occurring less frequently. Both cryptosporidiosis and giardiasis are common, and it is estimated that Cryptosporidium infection accounts for up to 5% of diarrheal disease in developed countries and between 3% and 20% in developing regions. Worldwide, Giardia infection accounts for 1–30% of diarrheal illness, depending on the region and age group. There are a variety of other important parasitic diseases that have gastroenteritis as a major symptom, including amebiasis and trematode infections, among others.

Other Illnesses (Nongastroenteritis) Sequelae of acute illnesses can occur weeks or even months after an initial acute foodborne illness in a few susceptible people. Major sequelae that can follow bacterial gastroenteritis include HUS, reactive arthritis, irritable bowel syndrome (IBS), and Guillain-Barré syndrome. Other acute nongastroenteritis illnesses can also be transmitted by food. Microbial pathogens, helminths, prions, and chemicals can cause acute illnesses including listeriosis, hepatitis A, toxoplasmosis, a variety of helminth infections, and variant Creutzfeldt-Jakob disease (vCJD). Illnesses due to chemicals can be caused by naturally occurring toxins and man-made chemical waste products and pesticides.

Sequelae

HUS may develop in people suffering gastroenteritis caused by organisms that produce Shiga toxins, such as enterohemorrhagic E. coli (EHEC), Shigella dysenteriae, and Citrobacter freundii. HUS is characterized by destruction of blood cells and acute renal failure, often requiring dialysis for several days until the kidneys recover. The illness is more severe in children, and there may be significant associated mortality. Shiga toxin–producing E. coli (STEC) infections are thought to be about 50% foodborne, with some cases acquired directly from animals. Reactive arthritis, a nonpurulent joint inflammation, may be triggered by gastrointestinal or urethral infections. It can develop some weeks after foodborne gastroenteritis due to Salmonella, Yersinia, or Campylobacter. Joint pains and low back pain are common, and fever and weight loss can also occur. The arthritis is fairly mild in most cases, but can occasionally be severe. The illness lasts weeks to months and is most common in middle age. People who have a particular genetic disposition identified by a positive blood test for HLA-B27 are more likely to develop reactive arthritis. IBS is characterized by abdominal pain and irregular bowel movements. The bowel is thought to be oversensitive, and IBS can be triggered by stress, diet, or previous infection with foodborne Campylobacter, Salmonella, or Yersinia. It is estimated that about 7% of bacterial gastroenteritis cases lead to IBS. The illness may be lifelong, with active periods lasting for days to months, and periods of remission. Guillain-Barré syndrome is an autoimmune disease that affects the nervous system. Campylobacter is one trigger that causes this illness, accounting for about 20% of GuillainBarré cases. First symptoms include weakness or tingling in

the legs, which spreads to the upper body, usually over a number of days. Paralysis of respiratory muscles can occur, and this can lead to an inability to breathe and death if the patient is not supported in hospital. The disease is more common in older people, and in developed countries, approximately 8% of those affected die. Most often the illness lasts from a few weeks to months, but in about 20% of cases, residual weakness in some muscles can remain as a permanent disability.

Other Infectious Illnesses (Nongastroenteritis)

Listeriosis is caused by L. monocytogenes, a bacterium that can cause a serious invasive illness with septicemia or meningitis in immunocompromised people and the elderly. The casefatality rate may be as high as 30%. Listeria monocytogenes may also cause abortion, stillbirths, and neonatal meningitis in utero in pregnant women despite the mother showing little or no symptoms. It is thought to be exclusively transmitted through foods, including unpasteurized dairy products. Unusually, this organism can replicate at the low temperatures found in refrigerators. Hepatitis A is an infection of the liver with hepatitis A virus that ranges in severity from subclinical to severe liver disease. Adults tend to be more severely affected with anicteric, asymptomatic infections being common in children. The virus is mostly spread from person to person by the fecal–oral route, with contamination of food accounting for about 10% of cases. Toxoplasmosis is caused by a cellular parasite, T. gondii. The cat is the primary host in the parasitic life cycle, and the illness is spread by contact with contaminated cat feces or ingestion of raw infected meat (such as ‘steak tartare’) or water. Cysts may occur in muscle, heart, brain, eyes, or other organs and may reactivate years later if an individual becomes immunocompromised. Approximately 35% of cases of toxoplasmosis are considered foodborne. Helminth infections are a major cause of morbidity that lead to malnutrition and general debilitation, particularly among people in less developed countries. There are three types of foodborne helminth infections: nematodes (roundworms), cestodes (tapeworms), and trematodes (flukes). Nematodes are nonsegmented helminths and have a bilateral symmetry; cestodes have a flat ribbonlike body; and trematodes are leaf shaped and are covered with a resistant cuticle. Infection by helminths, such as Fasciola spp., Paragonimus spp., Clonorchis spp., and Heterophyes spp., can occur through the ingestion of raw and undercooked infected fish, crustaceans, and plants. Infections with Clonorchis spp. are associated with increased incidence of cholangiocarcinoma (Lun et al., 2005). The life cycle of these parasites is often complex, but usually involves fish and mollusks. Many infections are easily treated using antiparasitic agents. Foodborne transmission of roundworm and hookworm eggs can occur when fresh night soil (human excrement collected night) from infected is used to fertilize green-leaf vegetables that are subsequently eaten without adequate washing. Creutzfeldt-Jakob disease (CJD) is a human transmissible spongiform encephalopathy that causes spongy degeneration of the brain with severe and fatal neurological signs and symptoms. In 1996, pathologists identified a variant (vCJD) that affected younger patients and had a more rapid course of illness

Foodborne Diseases (Diack et al., 2014). Similarities between the agent causing vCJD and that causing bovine spongiform encephalopathy found in cattle suggest that humans have acquired the illness from contaminated beef. The agents causing the disease are thought to be prions, small protein particles that can replicate. The first case of variant CJD was found in the United Kingdom in 1996, and subsequently 177 cases were identified in that country up to 2014, and 55 cases in 11 different countries in other parts of the world.

Illnesses due to Chemicals

Chemical toxins found in food can lead to both acute and chronic illnesses. The toxins can be either naturally occurring or man-made. Examples of common naturally occurring toxins include ciguatoxins and histamines from fish and mycotoxins produced in plants. Ciguatera poisoning can be caused by eating large reef fish that have come from coral reefs where algae contain ciguatoxins that subsequently bioaccumulate in larger predatory fish higher in the food chain. The illness is found in the Pacific and Indian oceans and the Caribbean. Scombrotoxicosis is associated with eating fish containing high levels of histamine. Most commonly this occurs in fish such as tuna and mackerel that have been poorly handled during processing, which potentiates histamine toxicity. Outbreaks of histamine poisoning occur throughout the Pacific. Both ciguatera and scombrotoxicosis are 100% foodborne and cause neurological symptoms that can be serious. Naturally occurring mycotoxins include aflatoxins that are produced by fungi growing in stored grains and nuts in hot humid conditions. These are carcinogenic and hepatotoxic. Anthropogenic chemical contaminants of food include heavy metals such as mercury, arsenic, cadmium, and lead, dioxins, and pesticides, among others. Methylmercury is the result of methylation of inorganic mercury produced by combustion power plants and waste incinerators. Methylation occurs due to the action of sediment bacteria in waterways, and methylmercury accumulates higher in the food chain in large fish that may be eaten by humans. It is a neurotoxin and affects development of the brain in the fetus and young child and can cause seizures and cerebral palsy, blindness, deafness, and mental retardation. Postnatal exposure can be from breast milk if the mother has high levels of methylmercury. Cadmium is used in industry, especially for the production of batteries. It is released into the environment as an air pollutant and in waste water that can contaminate food, the main route of ingestion. Cadmium accumulates in the body over years and causes damage to the kidneys. Lead can be introduced into food by improperly glazed pots used for cooking and food storage. People can also be affected by inhalation and absorption of lead through the skin. Lead is neurotoxic and in particular can affect early neurological development. It affects the brain, causing attention-deficit disorder and other learning disabilities, poor motor coordination, and poor language development, as well as anemia. Excretion is very slow and can take years. Dioxins, dibenzofurans, and polychlorinated biphenyls (PCBs) are related by-products from industrial processing that can enter the food chain. Dioxins are the result of open burning of waste products, and particles can settle onto plants that are then eaten by animals. Dioxins are absorbed into animal fat,

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and concentration increases through bioaccumulation while moving up the food chain. Foods likely to contain dioxins are those that contain fat, such as dairy products, meat and meat products, fish, eggs, breast milk, and infant formula. When people eat food contaminated with dioxins, they remain in the body’s fat stores and can affect the nervous, reproductive, and immune systems. People exposed to very high levels of dioxins have a higher risk of developing a variety of cancers later in life. Pesticides are used on food crops, and some can be harmful to humans. To reduce the risk of contamination of food, there is often a recommended waiting period after application of a pesticide before harvest of the crop. The application of such recommendations varies from country to country, and in developing countries there may be little control. Some pesticides accumulate higher in the food chain and so may reach toxic levels in animals even if the original plant application was within safe limits. Pesticides work in different ways and as a consequence can cause different illnesses in humans. Some affect human enzymes, including organophosphates and carbonate insecticides, which inhibit the enzyme cholinesterase and can cause serious neurotoxicity.

Prevention of Foodborne Illness In recent years, risk-based programs, such as hazard analysis critical control points (HACCP), have been developed. HACCP requires the identification of points where possible hazards in food production could occur and developing methods for controlling the hazards (Table 5). These critical points are monitored, often by industry, and any deficiencies in the system are corrected as needed. These risk-based programs apply to all businesses in the food supply chain, from primary production to those serving foods. The WHO and Food and Agriculture Organization have jointly created the Codex Alimentarius Commission, an international standard-setting body for foods. Codex uses riskbased frameworks to prepare standards, guidelines, and other texts to improve safety in food business and trade (WHO, FAO, 2016). Educating people who prepare food commercially and in the home is a vital part of preventing foodborne disease. The WHO and other agencies have prepared health Table 5 Principles of hazard analysis and critical control point safety procedures 1. Identify potential hazards associated with food, such as microbes and chemicals, and means to control them 2. Identify critical points in food production where the potential hazard can be controlled (e.g., on the farm, packaging) 3. Establish preventive measures with critical limits for each control point (e.g., minimum cooking temperature and time) 4. Monitor critical points 5. Take corrective actions when a critical limit has not been met (e.g., disposing of food if the minimum temperature has not been achieved) 6. Verify that the system is working properly (e.g., verify that time and temperature devices are working properly) 7. Maintain proper records of procedures

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promotion materials to promote food safety during preparation of meals. The five key messages are to keep equipment clean, to separate raw and cooked foods, to cook food thoroughly, to keep food at safe temperatures, and to use safe water and raw materials.

HIV/AIDS of the Central Nervous System; Intestinal Infections: Overview; Protozoan Diseases: Cryptosporidiosis, Giardiasis, and Other Intestinal Protozoan Diseases; Protozoan Diseases: Toxoplasmosis; Salmonella; Shigellosis; Transmissible Spongiform Encephalopathies; Typhoid Fever; Viral Diarrhea; Waterborne Diseases.

Control of Foodborne Disease Outbreaks Many countries conduct surveillance of foodborne disease by requesting doctors and laboratories to report certain cases to health departments. These usually include infections due to Campylobacter, Salmonella, EHEC, L. monocytogenes, and others. These data are analyzed regularly for trends and clustering of cases that may indicate outbreaks of illness due to food potentially affecting many people. Recognition of outbreaks should ideally trigger an investigation by a public health team. Investigations involve collection of stool samples from sick people to identify the microorganism, laboratory testing of food samples, and tracing back of food items to determine the origin of the contamination. With the globalization of the food supply for many countries in the past decade, outbreaks have been identified that affect people over wide geographical areas and time periods (McEntire, 2013). Foods that have a long shelf life and are distributed internationally can result in outbreaks that span multiple continents and last for many months or years. Thorough investigation of foodborne disease outbreaks is important to identify and eliminate the source of infection and develop policy to prevent further disease. One example is the interventions that were implemented subsequent to large Salmonella outbreaks due to infected chickens and eggs. Vaccination and culling programs in infected chicken flocks in the United Kingdom and the United States reported marked decrease in human infections (Braden, 2006). Similarly, human vaccination programs have resulted in significant declines in hepatitis A infection in countries such as the United States (Ogholikhan and Schwarz, 2016).

Conclusions Foodborne disease is common in both developing and developed countries. The most frequent type of illness is infectious gastroenteritis, but other illnesses also occur. Prevention of contamination of food involves effort at all points in the food supply chain, from primary producer to consumer. Surveillance and control of foodborne disease outbreaks remains a priority in an era of globalization.

See also: Agricultural Health and Safety; Antimicrobial Resistance in a One Health and One World Perspective – Mechanisms and Solutions; Bacterial Infections: Overview; Botulism; Brucellosis; Cadmium; Carcinogens, Environmental; Cholera and Other Vibrioses; Drinking Water and Sanitation; Epidemic Investigation; Escherichia coli; Gastrointestinal Disorders: Overview; Helminthic Diseases: Foodborne Trematode Infections; Helminthic Diseases: Intestinal Nematode Infections; Helminthic Diseases: Trichinellosis and Other Helminthic Tissue Helminthic Infections; Hepatitis, Viral;

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Relevant Websites http://www.atsdr.cdc.gov/ – Agency for Toxic Substances and Disease Registry (ATSDR) (last accessed on 27.07.16.). http://www.cdc.gov/ncezid/dfwed/index.html – CDC: Division of Foodborne, Waterborne, and Environmental Diseases (DFWED) (last accessed on 27.07.16.). http://www.cdc.gov/foodsafety/index.html – CDC and Food Safety (last accessed on 27.07.16.). https://www.efsa.europa.eu/en/about/howwework – European Food Safety Authority (last accessed on 27.07.16.). http://www.fao.org/home/en/ – Food and Agriculture Organization (FAO) (last accessed on 27.07.16.). http://www.fda.gov/Food/default.html – Food and Drug Administration (FDA) (last accessed on 27.07.16.). http://www.cdc.gov/foodsafety/diseases/index.html – Foodborne Illness A-Z (last accessed on 27.07.16.). http://www.cdc.gov/foodborneburden/surveillance-systems.html – Foodborne Illness Surveillance Systems (last accessed on 27.07.16.). https://www.foodsafety.gov/ – Food Safety Governmment (last accessed on 27.07.16.). http://www.who.int/gfn/en/ – Global Foodborne Infections Network (GFN) (last accessed on 04.08.16.). http://www.fsis.usda.gov/wps/portal/fsis/home – United States Department of Agriculture/Food Safety and Inspection Service (USDA/FSIS) (last accessed on 27.07.16.). http://www.who.int/foodsafety/en/ – World Health Organization: Food safety (last accessed on 27.07.16.).

Forced Migration and Health Pascale Allotey, Monash University, Selangor, Malaysia Sharuna Verghis, Health Equity Initiatives, Kuala Lumpur, Malaysia Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by P. Allotey, M. Markovic, volume 2, pp. 653–659, Ó 2008, Elsevier Inc.

Introduction Fueled by the forces of trade and globalization, global movements of people are arguably both normal and an essential component of current economic and social lives of most countries. Recent figures show that over 214 million (3.1%) of the world’s population are migrants (International Organization for Migration, n.d.), that is, they live outside their countries of origin. Most migration is voluntary, motivated, regardless of status, by the individual’s need to seek better opportunities; economic advantage, better education, better quality of life, greater freedoms. The choice is also influenced by broader social and political structures in both sending and receiving countries. For many, however, migration is involuntary. About 7.6% of all migrants are forced migrants (International Organization for Migration, n.d.). They are compelled to leave their homes by events over which they have little control, and migrate because of an imperative for survival; to protect their lives and the lives of their families. Forced migration can be categorized by the events that lead to the displacement. These include civil strife, armed conflict, generalized violence, massive violation of human and minority rights and natural and man-made disasters. They may also be categorized by the location of the displaced persons; internally displaced persons remain within their national borders but are nonetheless unable to return to their homes, or it may be international, within neighboring countries in the region or to countries that are far removed in culture and distance from their countries of origin. Between the broad categories of voluntary and involuntary migration, there are less well defined drivers of migration where the notion of choice is more fluid. For instance, extreme poverty that threatens survival and livelihoods provides an imperative to flee. A global study of forced migration suggested that there are a number of variables that can be considered in a cost–benefit analysis model to predict the point at which the cost of staying far outweighs any benefits. The variables include social, cultural, physical, emotional, and environmental stability and ability to engage in the broader political life of the community (Moore and Shellman, 2002). A further (although heavily contested) category of forced migrants are people who are trafficked for various forms of indentured labor, some through coercion, others through deception, again highlighting the complexity of choice in the decision to migrate. Migration categories are primarily of administrative relevance. However, understanding them is critical because they inherently describe a legal status that determines the duration and conditions of residence in a host country and give an important indication of the journeys undertaken in the process of migration, the resulting exposure to health risks, and in the country of settlement, entitlements and access to goods and services such as health care. In this article, we discuss the health effects of forced migration, focusing on the main

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subpopulations of forced migrants: refugees, asylum seekers, internally displaced persons, environmental displacees, and trafficked persons. We also highlight the international efforts to mitigate the effects of forced migration.

Forced Migrants: Definitions Refugees Thousands of people were displaced after the Second World War, living within a context where governments were unwilling or unable to enforce laws and protect their basic rights. In recognition of their need for protection, the United Nations General Assembly established the Office of the United Nations High Commissioner for Refugees (UNHCR) in 1950. Under the International Refugee Convention of 1951 and the Protocol of 1967(UNHCR, 1951, 1967), the key characteristics of refugees are: They are outside their countries of origin. They have a well-founded fear of persecution (have experienced or are likely to experience) should they return. l The persecution is on the grounds of race, religion, nationality, membership of a particular social group, or political opinion. l They are unable or unwilling to seek the protection of their country of origin. l l

The 1951 Convention and 1967 Protocol provide the foundations in international and refugee law for the protection and the rights of refugees. Member states of the United Nations who have ratified the Convention and Protocol undertake to protect refugees and respect the principle of nonrefoulement, a principle in international law which prevents countries from sending refugees back to situations which would threaten their freedom or life. Working with host nations and other humanitarian agencies, the UNHCR provides the administrative, legal, and humanitarian support in the event of a large-scale refugee exodus. In addition, individuals and smaller groups of people facing persecution can apply for protection through the UNHCR, drawing on the legal protections and guidelines available through international law and treaties. Voluntary repatriation, local integration, and resettlement to a third country in situations where it is impossible for a person to go back home or remain in the host country, are the three durable solutions that UNHCR attempts to secure for refugees. The ideal protection from the UNHCR perspective is to facilitate repatriation to the country of origin. Between 2002 and 2012, 7.2 million refugees were repatriated while 836 500 were resettled. In 2012, 98 600 were repatriated to Afghanistan, 82 300 to Iraq, 72 900 to Cote d’Ivoire, 71 900 to the Democratic Republic of Congo and 68 600 to the Syrian Arab Republic (United Nations High Commissioner for Refugees, 2013b). However, repatriation

International Encyclopedia of Public Health, 2nd edition, Volume 3

http://dx.doi.org/10.1016/B978-0-12-803678-5.00163-6

Forced Migration and Health can only be achieved when the initial circumstances that led to the flight are no longer a threat. Most refugees are therefore initially hosted in countries proximal to the crises. The advantage of this temporary solution is that neighboring countries offer a broadly similar social and cultural milieu, minimizing problems with adaptation. There is of course a small risk of unrest spreading through the region as resources can become increasingly stretched to accommodate the often large influx of refugees. However, the expectation is that international assistance will mitigate any potential crisis. Finally, UNHCR may facilitate refugees’ resettlement in a third country if there is little likelihood of repatriation in the short term. The UNHCR monitors refugee flows and provides annual statistical updates on global trends on their website. According to the agency’s Global Trends Report 2012 (United Nations High Commissioner for Refugees, 2013b), global forced displacement touched a new all-time high since 1994 with 45.2 million people displaced in 2012. About 23 000 people per day were forced to migrate due to conflict and persecution. The number of refugees varies extensively between regions depending on new or ongoing crises. The escalating conflicts in Syria and Mali contributed to the increased number of displaced people in 2012. Refugee women constitute about 48% of the refugee population. Further, 80% of forced migrants live in developing countries with Pakistan hosting the highest number of refugees. Additionally, about half of the world’s refugees are urban refugees (United Nations High Commissioner for Refugees, 2013b), who unlike camp-based refugees do not receive systematic assistance from UNHCR and the international community. Although most urban refugees in the past were men, the current composition of urban refugees include large numbers of women, children, and older persons (United Nations High Commissioner for Refugees, 2009). With regard to applications for asylum, Germany, followed by the United States of America, were the top two recipient countries of asylum claims in 2013 (United Nations High Commissioner for Refugees, 2013a). In the same period, in relation to resettlement, about 20% of refugees resettled in countries in North America, Australasia, and Europe (United Nations High Commissioner for Refugees, 2013b). Despite the UNHCR’s long and successful history, many argue that the 1951 definition of a refugee, which was temporally appropriate, is no longer adequate to encompass the wider range of issues resulting in forced migration. There is a greater subtlety to human rights violations and the interpretations of legislative frame-works are highly context-dependent. For instance, applications for refugee status have been made on the basis of the rights violations of the Chinese government’s one-child policy. Another example is the need to escape harmful cultural practices such as female genital cutting to which women from some parts of Africa are subjected. In addition, large-scale civil unrest resulting, for instance, from events in Iraq and Afghanistan, has caused massive displacements; however, under the Refugee Convention, the displaced persons are not specifically targeted for persecution and many have been refused protection by potential host countries because they are not genuine refugees. The challenges that arise from the increasing complexities of forced migration have overwhelmed

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the international protection system and have given rise to large numbers of asylum seekers.

Asylum Seekers An asylum seeker is a person who is outside their country of origin and has applied to another country for legal recognition as a refugee under the guidelines of the UNHCR. The right to seek asylum is enshrined in international law and with improvements in access to information, there has been a global spread of knowledge about human rights. On the other hand, the increase in the numbers of asylum seekers has been the cause of much political dissent and media discussion in receiving countries. In 2006, 596 000 first-instance or appeal-asylum or refugee-status applications were submitted in 151 countries directly to governments or UNHCR offices. There is a broad perception that asylum seekers represent the potential for abuse of the refugee protection system because their claims of persecution may not be legitimate. Consequently, the interpretation and application of refugee protection laws in many potential host nations has become increasingly rigid and restrictive (UNHCR, 2007).

Internally Displaced Persons An internally displaced person has been forced to flee their home or place of normal residence but remains within the national border. Internally displaced persons often face the same circumstances faced by refugees and asylum seekers, except they have not yet crossed an internationally recognized border. A major cause of internal displacement is wars, which are often characterized by low intensity but protracted internal conflicts that target civilians. Recent larger-scale wars such as in Iraq and Afghanistan have occurred within cities with little distinction made between combatants and noncombatants. Civilian war-time casualties have increased from 65% at the end of World War II to 90% in the wars over the last decade. In the 1990s internal conflicts have claimed in excess of 5 million lives. Civilians escaping wars in Sri Lanka, Angola, and Sudan have lived for more than 20 years as internally displaced persons, grappling with poverty and insecurity. Recent estimates of internally displaced persons suggest that there are 28.8 million (United Nations High Commissioner for Refugees, 2013b); there are more internally displaced persons than there are refugees. It could be argued that internally displaced persons are in a greater position of vulnerability because of the lack of protection; the very same governments whose actions may have caused their persecution and displacement are responsible for their protection. The mandate of the UNHCR does not cover internally displaced persons. However, 17.7 million IDPs were supported by the UNHCR (United Nations High Commissioner for Refugees, 2013b). In recognition of the gravity of the plight of internally displaced persons, a position was created for a representative of the UN Secretary General on Internally Displaced Persons in 1992. The mandate of the representative was to address this vacuum of responsibility. Guiding Principles on Internal Displacement were drafted to assist in the protection of the rights of internally displaced persons and assign responsibility to states and international bodies to ensure their care. Though not legally binding,

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the guiding principles support the authority of the internally displaced against the conditions that cause their displacement.

Protracted Displacement and Irregular Movements The best outcome for internally displaced persons and refugees is achieved if the crisis is short-lived with a quick resolution that enables them to return to their homes. Health considerations in those instances are based largely on the challenges and opportunities in rebuilding and restoring health-care infrastructure following repatriation. These situations may often benefit from the injection of assistance from the international community during the acute crisis. However, the movement of a refugee often extends beyond the country of first asylum. Often, countries of first asylum are countries of transit for refugees because they fail to offer effective protection. For example, about 38% of all refugees live in the Asia Pacific region (United Nations High Commissioner for Refugees, 2011), where the majority of the countries lack a normative and legal framework for refugee protection (United Nations High Commissioner for Refugees, 2012). The lack of legal protection and the lack of recognition of the right to asylum in these countries creates tremendous challenges for asylum seekers including inadequate access to basic necessities, harassment by enforcement authorities including risks of arrest and detention, and the risk of refoulement (Jesuit Refugee Service, 2012). The introduction of mandatory detention of asylum seekers pending the review of their asylum claim, including incarceration in immigration detention centers, has been associated with adverse mental health and psychosocial impacts on adults, families, and children (Silove et al., 2007). Asylum seekers in this phase of forced migration also encounter many barriers in obtaining health care including legal/policy directives prohibiting and/or restricting their access to health care (Jacobsen, 2006; Kagan, 2007; Women’s Refugee Commission, 2011). Frequently, forced migrants endure harsh conditions as described above for protracted periods of time. Protracted refugee settings are places where 25 000 or more refugees of the same nationality have lived in exile for over 5 years, unable to take advantage of any of the three durable solutions (repatriation, integration, or resettlement) offered by UNHCR (United Nations High Commissioner for Refugees, 2013b). Prolonged encampment of refugee populations in places like Kakuma in Kenya have been home to displaced persons from Southern Sudan, Somalia, Burundi, Congo, Eritrea, and Uganda for over 20 years. The situation in Palestine offers another stark example of protracted exile. Additionally, IDPs and urban refugees are also known to experience protracted displacement. About 6.2 million refugees are said to live in protracted exile in 25 countries (United Nations High Commissioner for Refugees, 2013b). Onward movements of such forced migrants lacking a durable solution in countries of first asylum are to be distinguished from the concept of “irregular movements” of refugees which have been defined as the “phenomenon of refugees, whether they have been formally identified as such or not (asylum-seekers), who move in an irregular manner from countries in which they have already found protection, in order to seek asylum or permanent resettlement elsewhere” (United Nations High Commissioner for Refugees, 1989).

In practice however, the narratives on “irregular movements” are rooted in divergent and contested political perspectives. For example, on the one hand, the boat arrivals of asylum seekers to Australian shores have been characterized as a phenomenon driven by ineffective protection and protracted displacement in countries of first asylum. These discourses have also put the spotlight on the multifarious risks experienced by such persons in need of international protection. These are not limited to dangerous journeys through treacherous waters, being smuggled, and being vulnerable to human trafficking. In relation to maritime arrivals, it is estimated that about 17 000 persons risked their lives in rickety boats to reach Australia in 2012, while about 21 000 fled into the Bay of Bengal and another 500 are estimated to have perished at sea after their boats capsized or broke down. As such the United Nations, has called the Indian ocean, “one of the deadliest regions of the world” (Brown, 2013). On the other hand, state led discourses have cast the issue as a problem of human smuggling and irregular migration and have engendered state policies of interception, interdiction, and extensive bilateral and regional cooperation with countries of origin and transit on border management. The Pacific Solution, the Indonesia Solution, the Malaysia Plan, and most recently the Cambodia Agreement are examples of Australia’s bilateral and regional cooperation to deter asylum seekers arriving by boat. These policies have triggered debate about Australia’s contravention of its legal obligations under the 1951 Refugee Convention.

Environmental Displacees Environmental displacees are people who are forced out of their homes as a result of floods, famine, volcanic eruptions, earthquakes, landslides, and other environmental disasters. A subcategory of these are those displaced by development projects that so drastically alter their environments to make continued residence untenable. Examples include the building of dams (e.g., the Three Gorges Dam across the Yangtze), roads, mines, deforestation, and pollution that arises from industry. The World Bank estimates that approximately 10 million people are displaced from their homes every year to accommodate such projects (Cernea and McDowell, 2000). Other examples of man-made disasters that result in forced migration include industrial nuclear accidents that have left survivors without homes or livelihoods. The number of environmental displacees is estimated at double the numbers of refugees. Most end up as internally displaced persons.

Human Trafficking and Smuggling Human trafficking and smuggling focus on the context of the migration journey rather than on reasons for displacement. However, circumstances of people who are trafficked or smuggled are often not dissimilar to other forced migrants. When the forces that compel forced migration are up against the barriers created by limited opportunities for legal migration, human trafficking and smuggling are a predictable though undesirable result. Human trafficking involves the illegal trading and movement of mostly women and children in economically

Forced Migration and Health exploitative situations. It is defined by the UN Convention on Transnational Organized Crime (UN TOC) as:

. the recruitment, transportation, transfer, harboring or receipt of persons, by means of the threat or use of force or other forms of coercion, of abduction, of fraud, of deception, of the abuse of power or of a position of vulnerability or of the giving or receiving of payments or benefits to achieve the consent of a person having control over another person, for the purpose of exploitation. Exploitation shall include, at a minimum, the exploitation of the prostitution of others or other forms of sexual exploitation, forced labor or services, slavery or practices similar to slavery, servitude or the removal of organs. . The consent of a victim of trafficking in persons to the intended exploitation . shall be irrelevant where any of the means set forth (above) have been used. The recruitment, transportation, transfers . of a child for the purpose of exploitation shall be considered ‘‘trafficking in persons’’ even if this does not involve any of the means set forth (above). United Nations (2000: p. 2).

The trafficked are usually expected to engage in forced domestic labor, sex work, false marriages, and indentured labor. There is an increasing market in the sex industry supported through tourism and a market in children trafficked for adoption. It can therefore be argued that trafficked persons are forced migrants as a result of their lack of choice. A trafficked person, under International Law, is considered a victim of coercion, abduction, fraud, or deception; consent is lacking or defective and therefore irrelevant. States party to the Protocol to Prevent, Suppress and Punish Trafficking in Persons are therefore mandated to provide temporary or permanent protection to trafficked persons. People smuggling is tightly bound with human trafficking. Most trafficked persons are smuggled into a country, although this is not always the case. Smuggling, in the context of migration, refers to consensual transactions where the transporter and the transported agree to circumvent immigration control for mutually advantageous reasons. The UN TOC Smuggling Protocol defines smuggling of migrants as: the procurement, in order to obtain, directly or indirectly, a financial or other material benefit, of the illegal entry of a person into a State Party of which the person is not a national or a permanent resident (Article 3).

The critical elements of the definition are the illegal border crossing by the smuggled person and the financial gain of the smuggler. Under this definition, people smuggling reflects a commercial rather than exploitative transaction, although like most illegal transactions it is difficult to argue that the partners are equal. Smuggling is considered a crime against the state; unlike trafficking which is a crime against the person. This is an important distinction because on apprehension, the smuggled person, as a party to an illegal transaction is considered a criminal regardless of the often exploitative conditions of the transaction. The rights and treatment of these illegal migrants are therefore highly political and contentious issues in the area of migration and health. Notwithstanding the crime, smuggled persons are also entitled to be treated with dignity and in the event of detention, under the provisions of the Geneva Convention (USCR, 2003).

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There are strong arguments against characterizing people smuggled as forced migrants. Nonetheless, as described in the next section, it is difficult to ignore the range of circumstances that would compel individuals to undertake the hazardous journeys involved in people smuggling. The majority of people smuggled into countries like Australia, for instance, are asylum seekers who claim that they are unable to access the overwhelmed international protection system and are therefore compelled to employ the services of people smugglers. Trafficking and smuggling are significantly underreported, so available data are based on rough estimates. According to the United Nations, women and girls comprise 76% of all trafficked persons worldwide, with the proportion of trafficked girls increasing between 2007 and 2010. The proportion of trafficked children also increased by 7% between the periods 2003–06 and 2007 and 2010. Almost half of all trafficking in persons is intraregional. Trafficked persons in South and East Asia, the Pacific, Africa, Eastern subregions, Europe, and Central Asia are most often from within the region. However, countries in the Middle East, North America and Western and Central Europe detect trafficked persons from other regions and subregions (United Nations Office on Drugs and Crime, 2012). The potential for exploitation and human rights violations through these illegal ventures is necessarily high because of the lack of legal status of the people being smuggled. In addition, the journeys are often fraught with danger in order to circumvent existing immigration and other legal controls. Trafficking is currently one of the most lucrative high-return, low-risk crimes (estimated to be US$5–7 billion per annum) for both the recruiters and the traffickers.

Stateless Persons Article 1(1) of the 1954 Convention relating to the Status of Stateless Persons (1954 Convention) defines a stateless person as, “a person who is not considered as a national by any State under the operation of its law.” Palestinians, the Bedouins of Kuwait, Roma in Eastern Europe, Saami in Scandinavia, and Kurds in Northern Iraq are examples of stateless persons. Stateless persons are categorized into the de jure stateless and the de facto stateless. The de jure stateless lack a legal nationality. The Rohingyas of Myanmar who were stripped of their citizenship in 1982 by the Myanmar government are a case in point. A de facto stateless person has legal nationality but is one who is unable, or for valid reasons, unwilling to avail the consular and diplomatic protection of his/her country, including return to the State of nationality (United Nations High Commissioner for Refugees, 2010). For example, the nonrecognition of Somali travel documents creates situations where deportation is indefinitely postponed and/or visas are not issued (De Chickera, 2010). Stateless persons are unable to acquire and/or prove their nationality due to legal, administrative, procedural, and/or practical barriers. Migrants with undetermined nationality also fall under the category of stateless persons. Administrative records of governments of 72 countries indicate that there were about 3.3 million stateless persons in 2012. However, UNHCR estimates the numbers of stateless persons globally to be about 10 million (United Nations High Commissioner for Refugees, 2013b).

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Forced Migration and Health

Health and Forced Migration Forced migration and displacement have health implications for the various categories of migrants as well as for the receiving or host countries. For the receiving country there is an increased demand on health-care resources to monitor public health measures for disease control and to address the health needs of the new migrants. The health needs are both physical and mental resulting from: preexisting (preflight) health conditions, morbidities arising from the events leading up to displacement such as injuries or environmental exposure, health burdens from the journey or stressors that are a result of the resettlement process. These are discussed in the following sections.

Humanitarian Crisis and Health Forced migration invokes images of large-scale complex humanitarian crises, massive population displacements, poor hygiene and vulnerability of temporary shelters and refugee camps, and the collapse of public health infrastructure. These are dealt with in detail in the article on humanitarian responses to complex emergencies. This is a critical aspect of forced migration and health, and the area that receives the most media coverage and international assistance.

The Forced Migration Journey The circumstances and events described previously provide some indication of the health risks and preexisting vulnerabilities of forced migrants regardless of category. It is important to note that the vulnerabilities of forced migrants reflect the social determinants of health and inequalities in broader population health. In broad terms, those with higher levels of income have a greater capacity to access systems of protection or to flee in less hazardous circumstances. Most persons of concern therefore are those who are likely to have faced poverty, experienced violence on a personal or collective level, have been exposed to injury or pollution, have had poor access to health services, and have been exposed to a range of communicable diseases. Important challenges have emerged in the assessment of morbidity and mortality related to forced migration in general and conflict in particular. While injury and fatality from direct trauma are easier to ascertain, deaths that result from malnutrition, infectious diseases and poor, unhealthy conditions under which the journey of forced migration occurs are more difficult to quantify. The direct health effects of conflict are well documented and range from physical injury to poor mental health outcomes (Allotey et al., 2007; Allotey and Zwi, 2006).

Preflight, Flight, and Transit There is an extensive body of literature compiled by researchers, and humanitarian and human rights organizations, on the incidents of torture and trauma and other forms of persecution that many experience before the opportunity to flee presents. In addition, there is a loss of social networks and cultural institutions, a sense of place, permanence and predictability, and trust in the ability of the state to protect.

Children and the elderly face the highest mortality rates in the flight to safety. Resources of basic food and shelter are usually limited and risks are further exacerbated by poor conditions and lack of emergency care. Health risks increase for a number of reasons. First, detrimental health impacts of forced migration exist in situations when the flight to the temporary or permanent refugee is unsafe and vulnerable populations end up being the victims of pirates and people smugglers, at risk of abuse and exploitation. The crude mortality rate has been found to at least double normal baseline in the population before the events that lead up to displacement. Second, the flight may be associated with traumatic events experienced en route to safety. For example, a study on Cambodian refugees in the United States revealed that 90% experienced near-death due to starvation, and the same proportion had a family member or friend murdered (Marshall et al., 2005). Health concerns in these situations are a major challenge to public health; there is a general lack of interest from the international community once the acute crisis period is over, and consequently, a lack of governance, health service infrastructure, and health programs. In countries of transit too, the complexity of protection challenges create tremendous health and human security risks for refugees. The corresponding global health challenges present a complex mix of clinical, public health, humanitarian, ethical, political, social, and financial issues for States, health practitioners, international agencies, and community-based organizations that work with these populations. Research funded by the Special Program for Research and Training in Tropical Diseases (TDR) highlighted the increase in diseases such as malaria and the spread of virulent strains of tuberculosis and other infectious diseases. Further, major sexual and reproductive health problems have been identified and the safety and security of women who do not have the protection of a male relative is of particular concern. The risks of sexual exploitation have also been identified (UNHCR, 2006). Mental health problems (Martin and Taylor, 2012; Muhwezi and Sam, 2004) and chronic diseases (Spiegel, 2010) are also widely prevalent in this stage of forced migration. The resolution of these issues is dependent on lasting solutions to the original crisis. In the interim, they experience many barriers to accessing health care and the social determinants of health.

The Destination and Resettlement Refugees are a widely diverse population originating from countries across the world and displaced by varying crises. Their demographic profiles are as diverse as the profiles found in host populations across socioeconomic status, gender, age, education, and religion. Ultimately, individual refugees would therefore present with their unique set of circumstances. Lack of familiarity with mainstream health services, lack of proficiency in the language of the host community, cultural differences, poverty and marginalization, combined with previous experiences of physical or psychological trauma, all contribute to social and health disadvantage and vulnerabilities of refugees. Added to these are the normal migration stresses of settling in a new country (often not of choice); finding acceptable food, shelter, education, and employment. Rediscovering safety,

Forced Migration and Health developing social networks and a sense of stability and trust in people and their environment are critical in the early years and the importance of policies in host countries to facilitate this process cannot be overemphasized (Beiser, 1999; Allotey et al., 2007). The health of resettling refugees is an ongoing concern. Problems with resettlement such as continuing social isolation, perceived discrimination, and unemployment, further add to psychiatric disorders. There are important gender differences, although the findings are not always consistent across countries and refugee groups. In broad terms, female refugees report more mental and other chronic health symptoms. However, studies in some resettling refugee communities suggest that particularly when unemployed, mental health outcomes may be worse for refugee men than women. This is manifest for instance in the dynamics of gender-based violence in refugee communities. Qualitative studies have also highlighted gender-based strategies for coping and resilience in refugee women. There is a clear need for similar work to be carried out with refugee men. Research on the experiences of refugees within the health services highlights the complex interaction of their previous and current experiences with other social determinants of health and disease. Torture and trauma experiences can leave permanent physical and mental scars that influence their ability to trust those around them and to interpret what to others are unremarkable social interactions. Problems have been identified, for instance, in promoting the uptake of regular cervical screening in refugee women who have had previous experiences of brutal sexual assault. Patients undergoing dental treatment have displayed behaviors characterized as a severe overreaction when the reaction had resulted from a triggered memory of torture experiences involving their teeth being pulled out. Similar reactions have been reported from refugees undergoing EEG and ECG investigations who have previously been tortured by electrocution. In addition, patients often present with symptoms that mask underlying psychological distress. Mental health is prominent in the area of forced migration and health. Research suggests that refugees have a higher prevalence of the following psychiatric illnesses: Posttraumatic stress disorder, depressive disorders, anxiety disorder, somatization disorders, brief reactive psychosis, and adjustment reactions. However, there are often differences in opinion about the diagnosis of these conditions as a result of questions of cross-cultural validation. In addition, there may be questions of possible exaggeration in self-reported assessments, particularly if the diagnosis has the potential to influence the outcome of a refugee claim (Summerfield, 2001; Allotey et al., 2007). In spite of the tendency to focus on these vulnerabilities, however, it is important to note that while the level of trauma and the effects of this on health cannot be underestimated, the survivors who resettle in third countries often show a remarkable degree of resilience. As discussed in the section on protracted displacement, the increase in the number of forced migrants of various categories has been concurrent with an increasing reluctance from countries, even those that are signatories to the Refugee Convention, to respond to the resettlement needs of displaced persons. Many countries have tightened their immigration

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controls and asylum seekers often end up in mandatory detention; this policy contributes to othering refugees and their marginalization (Grove and Zwi, 2006; Grove et al., 2007). Government policies of detaining forced migrants who attempt to enter the country of immigrants illegally have negative health outcomes. Research has shown that the history of detention and the temporary protection status both contributed independently of all other factors (e.g., age, gender, preimmigration trauma) to risk of ongoing posttraumatic stress disorder, depression, and mental health-related disability. While the detention of asylum seekers receives the most political and media coverage, a large majority of asylum seekers live in the community while their claims are being processed. The support they receive is largely dependent on the policy of national governments toward asylum seekers; this determines their ability to seek employment and gain financial independence, and access to health, education, and welfare.

Human Trafficking and Health There are a number of health problems specific to trafficking and smuggling. Because they have to pay back a debt to traffickers and smugglers, undocumented migrants frequently find themselves confined to sweatshops, factories, or are forced into prostitution or begging. Research indicates that persons who have experienced human trafficking suffer from a range of medical problems including neurological, gastrointestinal, cardiovascular, and musculoskeletal problems, besides skin infections and sexual and reproductive health problems (Decker et al., 2009; Gushulak and MacPherson, 2000; Zimmerman et al., 2006). With regard to mental health, depression, anxiety, posttraumatic stress disorder (PTSD) are commonly observed among those who have experienced human trafficking (Gajic-Veljanoski and Stewart, 2007; Tsutsumi et al., 2008) with severe mental distress causing cognitive impairment (Zimmerman et al., 2006). HIV rates in women trafficked for prostitution are at least as high as the rates among prostitutes in general based on research from Burma and Cambodia. Where sex workers are organized for their own protection, infections have been found to be better controlled compared to prostitution controlled by organized crime. Because of their irregular status, they do not have access to legal assistance and medical care. With regard to forced labor, the IL reports that at least 12.3 million people are victims of forced labor globally, and about 2.4 million of these people have been trafficked (International Labor Organization, 2005). Research with refugees who have been trafficked and coerced into forced labor shows high levels of mental health morbidity (Health Equity Initiatives, 2011).

Statelessness and Health The body of literature on stateless people and health is not as extensive as refugee health. However, available evidence reveals that stateless persons experience several barriers in accessing health care, employment, and education. Restrictions to physical mobility because of the lack of

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documentation is another barrier to accessing health care and other social services. These factors contribute to health problems among stateless persons. For example, the European Roma experience high mortality risks than the non-Roma and Roma children experience greater health risk factors, low birth weight than non-Roma children (Cook et al., 2013). Additionally, there is a significant prevalence of tuberculosis and HIV (Casals et al., 2011) among the Roma in whom urinary tract infections have been associated with poor environmental conditions and hygiene (Sivic et al., 2013). Similarly, the stateless hill tribes of Thailand experience high rates of HIV, tuberculosis, and lymphatic filariasis (Suwanvanichkij, 2008)

and providing health care for asylum seekers (Gaudion and Allotey, 2009). Ethical dilemmas for health workers also abound in immigration detention centers where they may be witnesses to poor, inhumane, and degrading treatment of asylum seekers and/or be under pressure to neither diagnose nor treat medical conditions that would prevent deportation because of the associated risks of transmission of infection during transit or the unavailability of treatment in the country of origin (Allotey et al., 2007). Another role-conflict facing health care providers in their role as care providers is in relation to the financing of health care of asylum seekers where health maintenance organizations (HMOs) demanding cost efficacy of treatment limit treatment options (Kurth E et al., 2010).

Public Health in Host Countries The growth of public health as a discipline is strongly tied with the management of communicable disease and epidemics that spread as a result of mobile populations. Early public health interventions were based on the control of infectious diseases through the isolation of new arrivals of humans and goods, the precursors to quarantine and other public health regulations. Therefore, the traditional focus on communicable disease screening prearrival, or on-arrival for infectious diseases remains critical. There is no denying that travel and migration have helped to spread contagious diseases. Tuberculosis remains of primary concern in migration and health. Others include malaria, hepatitis C, and HIV. Screening has been responsive to global trends. Screening potential migrants on the basis of health profiles is a common practice and traditionally was instituted primarily for public health safety but also to enable referral of migrants for health care. However, there are humanitarian questions to be raised when the results of screening are used to exclude forced migrants despite resource implications. Approximately 60 countries currently screen potential migrants (voluntary and involuntary and visitors) for HIV. It is clear, however, that the health issues from a population perspective are more complex than just communicable disease control. There are ongoing debates about the resource implications of hosting vulnerable populations. Paradoxically, the international assistance provided in integration programs for forced migrants in resource-poor settings has resulted in better health outcomes for the displaced persons than the residents. There have been instances in Central and Eastern Africa where this has been a source of further conflict.

Conclusion In conclusion, the majority of people moving today are doing so to counter poverty, lack of opportunities, conflict, exploitation and environmental circumstances often beyond their control. As a population group, they epitomize many of concepts articulated in the social determinants of health that result in poor health outcomes; minority ethnic groups, poverty, unemployment, social exclusion, poor preexisting health, and the list goes on. This notwithstanding, the prioritization of the health concerns, particularly for populations of refugees and asylum seekers, is highly political and seen as the responsibility of international bodies that are concerned with humanitarianism and human rights and less so by individual states. Current global insecurities have further curtailed the spirit of humanitarianism that was embodied by the Refugee Convention. The essential elements of modern public health theory and practice are its emphasis on collective responsibility for health and the prime role of the state in protecting and promoting the public’s health; a focus on whole populations; an emphasis on prevention; and a concern for the underlying socioeconomic determinants of health and social inequalities (Beaglehole and Bonita, 2009). With the ongoing global events, forced migration will continue to be a significant issue affecting the lives of millions. Public health has a critical role to play in alleviating the health burden of forced migrants through the production of knowledge and capitalizing on opportunities to make a real difference.

See also: Humanitarian Response to Complex Emergencies and Natural Disasters; Populations at Special Health Risk: Migrants.

Ethical Dilemmas in the Care of Refugees and Asylum Seekers The complexity of the context of asylum described above also raises ethical challenges in the assessment and provision of care to asylum seekers. A prominent ethical challenge that health care professionals encounter relates to role-conflict in the assessment of asylum claims. The role-conflict is in relation to their professional roles as physicians and care providers and expected role as gate keepers pressure to provide evidence that supports the rejection of asylum claims (Allotey et al., 2007). At other times, linking immigration status to health care entitlements creates barriers to obtaining

References Allotey, P., Pickles, H., Johnston, V., 2007. Duties to refugees and asylum seeders in host country medical systems. In: Ashcroft, R., Dawson, A., Draper, H., Mcmillan, J. (Eds.), Principles of Health Care Ethic, second ed. John Wiley, London, pp. 663–670. Allotey, P., Zwi, A., 2006. People movement. In: Kawachi, I., Wassman, S. (Eds.), Globalisation and Health. Challenges and Prospects. Oxford University Press, New York. Beaglehole, R., Bonita, R. (Eds.), 2009. Global Public Health: A New Era. Oxford University Press, New York.

Forced Migration and Health Beiser, M., 1999. Strangers at the Gate: The Boat People’s First Ten Years in Canada. University of Toronto Press, Toronto, Canada. Brown, H., 2013. UNHCR Says More Refugees Seeking Asylum in SE Asia. [podcast on the Internet]. ABC Radio, Australia [updated 2013 April 2; cited 2014 June 2]. Available from: http://www.radioaustralia.net.au/international/radio/program/asiapacific/unhcr-says-more-refugees-seeking-asylum-in-se-asia/1110356 [Online]. Casals, M., Pila, P., Langohr, K., Millet, J.-P., Caylà, J.A., Roma Population Working Group, 2011. Incidence of infectious diseases and survival among the Roma population: a longitudinal cohort study. Eur. J. Public Health 22 (2), 262–266. Cernea, M., Mcdowell, C., 2000. Risks and Reconstruction: Experiences of Resettlers and Refugees. World Bank, Washington, DC. Cook, B., Wayne, G.F., Valentine, A., Lessios, A., Yeh, E., 2013. Revisiting the evidence on health and health care disparities among the Roma: a systematic review 2003–2012. Int. J. Public Health 58, 885–911. De Chickera, A., 2010. Unravelling Anomaly: Detention, Discrimination and the Protection Needs of Stateless Persons. Equal Rights Trust, London. Decker, M.R., Oram, S., Gupta, J., Silverman, J.G., 2009. Forced prostitution and trafficking for sexual exploitation among women and girls in situations of migration and conflict: review and recommendations for reproductive health care personnel. In: Martin, S.F., Tirman, J. (Eds.), Women, Migration, and Conflict: Breaking a Deadly Cycle. Springer, Dordrecht, Heidelberg, London, New York, pp. 63–86. Gajic-Veljanoski, O., Stewart, D.E., 2007. Women trafficked into prostitution: determinants, human rights and health needs. Transcult. Psychiatry 44, 338–358. Gaudion, A., Allotey, P., 2009. In the bag: meeting the needs of pregnant women and new parents in exile. Pract. Midwife 12, 20–23. Grove, N., Zwi, A., Allotey, P., 2007. Othering of refugees. Social exclusion and public health. In: Douglas, J., Earle, S., Handsley, S., Lloyd, C., Spurr, S. (Eds.), A Reader in Promoting Public Health. Sage Publications and the Open University, London, pp. 213–224. Grove, N.J., Zwi, A.B., 2006. Our health and theirs: forced migration, othering, and public health. Soc. Sci. Med. 62, 1931–1942. Gushulak, B.D., Macpherson, D.W., 2000. Health issues associated with the smuggling and trafficking of migrants. J. Immigr. Health 2, 67. Health Equity Initiatives, 2011. Forced Labor, Human Trafficking and Mental Health. The Experiences of Refugees and Asylum Seekers in Malaysia. HEI, Kuala Lumpur. International Labour Organization, 2005. A Global Alliance against Forced Labour. Report of the Director-General, 93rd Session, Report I (B). ILO, Geneva. International Organization For Migration, n.d. Facts & Figures on World Migration. IOM. [Online] Available: http://www.iom.sk/en/about-migration/facts-figures (accessed 22.05.14.). Jacobsen, K., September 2006. Refugees and asylum seekers in urban areas: a livelihoods perspective. J. Refugee Stud. 19, 273–286. Jesuit Refugee Service, 2012. The Search: Protection Space in Malaysia, Thailand, Indonesia, Cambodia and the Philippines. JRS Asia Pacific, Thailand. Kagan, M., 2007. Legal refugee recognition in the urban south: formal v. de facto refugee status. Refuge 24, 11–26. Kurth, E., Jaeger, F.N., Zemp, E., Tschudin, S., Bischoff, A., 2010. Reproductive health care for asylum-seeking women – a challenge for health professionals. BMC Public Health 10, 659. Marshall, G.N., Schell, T.L., Elliott, M.N., Berthold, S.M., Chun, C.A., 2005. Mental health of Cambodian refugees 2 decades after resettlement in the United States. JAMA 294, 571–579. Martin, S.F., Taylor, A., 2012. Urban Refugees in Amman: Mainstreaming of Healthcare. Institute for the Study of International Migration and Center for Contemporary Arab Studies, Georgetown University, Washington, DC. Moore, W., Shellman, S., 2002. Fear of Persecution: A Global Study of Forced Migration. Department of Political Science, Florida State University, Tallahassee, FL. Muhwezi, W., Sam, D., 2004. Adaptation of urban refugees in Uganda: a study of their socio-cultural and psychological well being in Kampala city. J. Psychol. Africa 14, 37–46. Silove, D., Austin, P., Steel, Z., 2007. No refuge from terror: the impact of detention on the mental health of trauma-affected refugees seeking asylum in Australia. Transcult. Psychiatry 44, 359–393. Sivic, S., Huremovic, A., Djerzic, H., 2013. Social exclusion as a determining health factor of the Roma population. Med. Arch. 67, 60–62. Spiegel, P., 2010. Urban refugee health: meeting the challenges. Forced Migr. Rev. 34, 22–23. Summerfield, D., 2001. The invention of post-traumatic stress disorder and the social usefulness of a psychiatric category. BMJ 322, 95–98. Suwanvanichkij, V., 2008. Displacement and disease: the Shan exodus and infectious disease implications for Thailand. Confl. Health 2, 4.

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Tsutsumi, A., Izutsu, T., Poudyal, A.K., Kato, S., Marui, E., 2008. Mental health of female survivors of human trafficking in Nepal. Soc. Sci. Med. 66, 1841–1847. UNHCR, 1951. United Nations Convention Relating to the Status of Refugees, Article 1(a) 2. United Nations High Commissioner for Refugees, Geneva, Switzerland. UNHCR, 1967. Protocol Relation to the Status of Refugees. United Nations High Commissioner for Refugees, Geneva, Switzerland. UNHCR, 2006. The State of the World’s Refugees 2006: Human Displacement in the New Millennium. Oxford University Press, Oxford, UK. UNHCR, 2007. Global Trends: Refugees, Asylum-Seekers, Returnees, Internally Displaced and Stateless Persons. Division of Operational Services Field Information and Coordination Support Section [Online] Available: http://www.unhcr.org/ 4852366f2.html (accessed 22.05.14.). United Nations High Commissioner For Refugees, 1989. Problem of Refugees and Asylum-Seekers Who Move in an Irregular Manner from a Country in Which They Had Already Found Protection. EXCOM Conclusions No. 58 (XL) – 1989. UNHCR. United Nations, 15 November 2000. United Nations Convention against Transnational Organized Crimes (with protocols). United Nations, New York [Online]. Retrieved 1 February 2016. http://www.legal.un.org/avl/ha/unctoc/unctoc.html. United Nations High Commissioner For Refugees, 2009. UNHCR policy on refugee protection and solutions in urban areas: September 2009. Int. J. Refugee Law 21, 823–850. United Nations High Commissioner For Refugees, 2010. The Concept of Stateless Persons under International Law. Summary Conclusions. Expert meeting. The concept of stateless persons under international law. Prato, Italy. United Nations High Commissioner For Refugees, 2011. The Global Report 2010. UNHCR, Geneva [Online] Available: http://www.unhcr.org/4dfa11499.html (accessed 02.02.13.). United Nations High Commissioner For Refugees 2012 September 21, October 2012. Update on UNHCR’s Operations in Asia and the Pacific. Executive Committee of the High Commissioner’s Programme. Sixty-third Session. Geneva, pp. 1–5. United Nations High Commissioner For Refugees, 2013a. Asylum Trends 2013. Levels and Trends in Industrialized Countries. UNHCR, Geneva [Online] Available: http:// www.unhcr.org/5329b15a9.html (accessed 27.05.14.). United Nations High Commissioner For Refugees, 2013b. UNHCR Global Trends 2012: Displacement, the New 21st Century Challenge. UNHCR, Geneva [Online] Available: http://www.refworld.org/docid/51c169d84.html (accessed 27.05.14.). United Nations Office On Drugs And Crime, 2012. Global Report on Trafficking in Persons 2012. United Nations Publication, Vienna. Sales No. E.13.IV.1. USCR, 2003. Trafficking in Persons: A Country by Country Report on a Contemporary Form of Slavery. Refugee reports 24. Women’s Refugee Commission, 2011. The Living Ain’t Easy. Urban Refugees in Kampala, New York. Zimmerman, C., Hossain, M., Yun, K., Roche, B., Morison, L., Watts, C., 2006. Stolen Smiles: The Physical and Psychological Health Consequences of Women and Adolescents Trafficked in Europe. The London School of Hygiene & Tropical Medicine, London.

Further Reading Crisp, J., 2000. Who has counted the refugees? UNHCR and the politics of numbers. Providence, RI: Thomas J. Watson Jr., In: Lubkemann, S.C., Minear, L., Weiss, T.G. (Eds.), Humanitarian Action: Social Science Connections Occasional Paper #37. Institute for International Studies, Brown University, pp. 33–62. Harrell-Bond, B., 1986. Imposing Aid: Emergency Assistance to Refugees. Oxford University Press, Oxford. Norwegian Refugee Council And Global Idp Project, 2002. Internally Displaced People: A Global Survey, second ed. Earthscan, London. Un High Commissioner For Refugees (UNHCR), June 30, 1999. “Who Has Counted the Refugees?” UNHCR and the Politics of Numbers. ISSN: 1020-7473 [Online] Available: http://www.refworld.org/docid/4ff58e4b2.html (accessed 03.06.14.). United Nations High Commissioner For Refugees, 2012. Regional Operations Profile – Asia and the Pacific. UNHCR [Online] Available: http://www.unhcr.org/pages/ 4a02d8ec6.html (accessed 11.01.11.). Zolberg, A., Suhrke, A., Aguayo, S., 1989. Escape from Violence: Conflict and the Refugee Crisis in the Developing World. Oxford University Press, New York.

Relevant Websites http://www.forcedmigration.org/ – Forced Migration Online. http://www.fmreview.org/ – Forced Migration Review, the Journal of the Refugee Studies Centre. http://www.iasfm.org/ – International Association for the Study of Forced Migration.

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http://www.iom.int – International Organization for Migration. http://www.rsc.ox.ac.uk/ – Refugee Studies Centre Working Paper Series. http://www.reliefweb.int/ – Relief Web Provides Time-Critical Information on Complex Emergencies and Natural Disasters. http://www.unhcr.org – The United Nations High Commissioner for Refugees (UNHCR).

http://www.unhcr.org.uk/info/briefings/basic_facts/definitions.html – The United Nations High Commissioner for Refugees (UNHCR) Basic Definitions. http://www.reliefweb.int/ocha_ol/pub/idp_gp/idp.html – United Nations Office for the Coordination of Humanitarian Affairs, Guiding Principles on Internal Displacement.

Foundations in Public Health Ethics Bruce Jennings, Center for Humans and Nature, New York, NY, USA Ó 2017 Elsevier Inc. All rights reserved.

Introduction Public health inherently involves the use of power to restructure institutions, reallocate resources, and change behavior. Public health ethics, therefore, encompasses questions of political morality as well as those of individual choice and professional practice. The paradigmatic political and moral questions of public health are the questions of liberty, justice, and democracy. (1) The liberty question: What justifies the use of power to promote health and prevent disease? In particular, what restrictions can and should be placed on individual freedom in order to further the health interests of either the individual in question, some group of other individuals, or society as a whole? (2) The justice question: How should public health affect the distribution of the benefits of health, the burdens of disease, and health risks in a society? (3) The democracy question: With what level of public engagement and citizen and community participation should public health policies and interventions be informed? The foundations of public health ethics include three elements that operate on different levels of explicitness and abstraction. First, there is the broader ideological or political theoretic context within which discourse concerning public health takes place. Second, there are various styles of ethical discourse or perspectives from which public health is viewed ethically. Finally, there are various principles that have been put forward by public health ethicists to guide the design and implementation of public health policies and programs. In this article, each of these three elements will be reviewed and discussed.

Ideological Foundations: Public Health Ethics and Political Theory Public health has emerged during the past 200 years as a product of many historical forces. Central among these are the maturation of the modern state; the industrial and postindustrial phases of capitalism; changing environmental, workplace, and lifestyle factors that affect the health of populations and individuals; the development of social systems highly urbanized and stratified by class, race, and ethnicity; the growth of medical scientific knowledge (including the development of effective vaccines and other pharmaceuticals); and, finally, the growing body of observational and statistical knowledge, from epidemiology and other fields, concerning the nature of health risks and the distribution of disease and dysfunction on a population basis. These factors have created new kinds of public health threats and problems, and this body of knowledge has pointed to new kinds of interventions. The steady hallmark of public health has been a focus on social and behavioral change. Public health has promoted social change in the direction of greater social and economic equality and greater access to the resources and conditions necessary for widespread health and the health of the least well off, for example, sanitary living conditions, adequate

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medical care, and measures to limit risk and exposure to conditions that undermine health. None of these issues is free from normative challenge or from the requirement of public normative justification. Here we cannot rely on an understanding of science and epidemiology alone. These controversies are rarely settled solely on the basis of the best available scientific understanding (Cooke, 1991; Wildavsky, 1995). They involve the preexisting traditions, patterns, and conditions of normative argumentation and legitimation. What are these patterns? The following offers a map of the prevailing array of ethical and political theories that interact and contest with one another in the discourse of political morality and in the justification and legitimation of public policy. The terminology employed in this article has mainly been developed within, and is drawn from, English-language philosophical literature. However, the basic concepts underlying the typology offered here are widely shared in the world today. While it would be a mistake to ignore differences in nuance and emphasis among different political cultures, there is now a global discourse of political ethics centering on the values of freedom, democracy, human rights, and social justice (Laborde, 2002). The foundations of public health ethics are deeply rooted in this global discourse of ethics. Figure 1 presents one scheme for classifying the main types of ethical and political theories that play a role in the normative argument within and about public health (Jennings, 2003). This represents the universe of normative discourse with which those in public health need to be familiar. A few caveats should be noted before discussing these types further. In the case of both ethical theory (moral philosophy) and political theory, the configurations highlighted here are not the only ones that could be mentioned. Moreover, theoretical and philosophical orientations have been grouped together that, while having a certain family resemblance with one another, especially in contrast with other theoretical approaches, nonetheless have important internal differences. Partisans of any particular theory will object to such a grouping. Thus contractarian, neo-Kantian, and rights-based ethical theories are presented as one configuration, despite many important differences within and among them. For the purposes of this discussion, we can gloss over these differences. There are three basic types of ethical theory at work in contemporary moral discourse and in most discussions of ethical issues in public health. The first is utilitarianism, with its many standards of evaluation (pleasure, happiness, utility) and its varieties of form (whether it is applied to individual acts or to general rules or patterns of behavior; whether the evaluation uses averaged or weighted units). It is not surprising that utilitarianism should remain a significant aspect of public moral discourse. Its consequentialist orientation is appealing in a largely materialistic, empirically minded, and pragmatic cultural milieu. It seems to offer the most rigorous, even quantitative, approach to normative questions, and this comports well with fields such as economics, policy analysis, and some portions of public health that have roughly the same normative

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Figure 1 Aspects of ethical and political theory in public health. Adapted from Jennings, B., 2003. Frameworks for ethics in public health. Acta Bioethica IX (2), 165–176, with permission.

and epistemic biases. It offers something like a lingua franca among policy makers for the purposes of determining largescale policy or distributional issues (Goodin, 1995). The second main cluster of ethical theories, contractarianism, has coexisted uneasily with utilitarianism since the late eighteenth century and has been given a new invigoration in recent decades by many new theories of justice, notably that developed by John Rawls (Daniels, 2008; Faden and Powers, 2006). These contractarian theorists have not only developed a new and quite sophisticated version of the contractarian theoretical apparatus, they have also developed a powerful critique of contemporary utilitarianism by essentially showing that utilitarian accounts of justice were unable to take seriously the differences among individuals, or the unique moral value of each individual (Rawls, 1999). The keystone of this type of theory is that it grounds the justification of moral argument on the notion that any moral claim must be reasonably acceptable to a group of free and equal individuals deliberating on the basis of certain norms of reason and open discourse. Respect for the freedom and equal moral worth of each individual may be expressed in a slightly different way by an enumeration of fundamental political, social, and human rights that are shared by all persons. This is justified not on the basis of the (good) consequences of recognizing those rights, but on the basis of their intrinsic value and rightness. The third formation of ethical theories that must be taken into consideration is a disparate class of so-called communitarian orientations. Communitarian ethics arose to some extent in reaction to what was perceived as the excessively individualistic character of contractarian ethics and the excessively hedonic nature of the utilitarian conception of social relations. Communitarians charge that contractarians and utilitarians make individuals seem to be free-standing and sui generis beings, without connection to others or society and without formation through the medium of a preexisting culture or tradition. Contractarians are critical of utilitarians for taking the individual to be little more than a utility-maximizing strategic player in a social competition where the overall outcome – not the individual players – matters. In a similar vein, communitarians fault both the utilitarians and the contractarians for having an inadequate conception of the human

person and for paying insufficient attention to the moral importance of the fabric that binds human beings together in a mutually beneficial, caring, and nurturing society. Communitarians have also been critical of an emphasis on the rights (claims, powers, and privileges of a person against society) of individuals without a corresponding emphasis on the responsibilities of individuals to the society or community to which they belong (Mulhall and Swift, 1996). It is not difficult to understand why communitarian ethics can take on both a kind of left-leaning egalitarian and participatory democratic turn as well as a more culturally conservative and authoritarian turn. One orientation strongly committed to social change and cultural transformation, feminist philosophy and the feminist movement, has been an important source of communitarian ethics. Within this perspective, important recent work has been devoted to developing a ‘relational’ conception of the person and of core ethical principles such as liberty and autonomy (Baylis et al., 2008; Gergen, 2009; Haliburton, 2014; Jennings, 2009; Mackenzie and Stoljar, 2000; Nedelsky, 2013). Progressive communitarianism holds that, although persons are shaped by culture and relationships, prevailing relationships can be changed. Moreover, those cultural traditions, distributions of power, and relationships that are discriminatory and oppressive to certain types or classes of people should be transformed, not for the sake of greater individual liberation and autonomy in some abstract sense, but for the sake of better, more humanly self-fulfilling patterns of relationships and sharing of power. By the same token, an emphasis on the need of the individual for stability, order, and cultural roots, coupled with a sense of the limitations of human reason (either as a motivating factor in human conduct or as a faculty that can successfully design and guide deliberate social change) can take communitarianism in a much more conservative and authoritarian direction. In this it has affinities with the conservative (aristocratic) heritage, with the civic republican tradition (given its emphasis on individual duty, virtue, and common morality), and with the world view of religious orthodoxy and fundamentalism. For its part, communicative ethics, growing largely from the tradition of German critical theory in the work of Jürgen

Foundations in Public Health Ethics Habermas and others, is perhaps best situated midway between contractarianism and communitarianism. It can be quite formalistic in character (Habermas, 1990), but communicative ethics, akin in this respect to theories of deliberative democracy, focuses on real-world social discourse and deliberation as the basic justifying grounds for ethical argument (Benhabib and Dallmayr, 1990). Turning to political theory, it is not so easy to group various approaches into three clusters. The basic starting point for understanding political theory in relationship to public health is that commonly both public argument and political conflict over ideology and policy have taken place within the broad tradition of political and philosophical liberalism. Since 1945, leading work in political theory has shifted away from the debate between liberalism and its authoritarian left- and right-wing opponents to be replaced with disagreements within liberal and capitalist ideology itself. Thus the classification in Figure 1 suggests a large range of variations within liberalism, with a left-communitarian-style emphasis on a more participatory form of democracy on the one hand, and a rightcommunitarian-style cultural conservatism, on the other. These two forms of communitarianism, rather than an old communist left or a fascist right, make up what amounts to the main challenges to mainstream liberalism today. Within the spectrum of liberalism broadly construed (including large portions of what is ordinarily called conservatism or neo-liberalism), we have variants that are close to being socialist and collectivist in nature and grow mainly out of the utilitarian tradition. A somewhat more moderate strain, egalitarian liberalism, is also of the left in that it favors the use of national state power to promote a more equal distribution of wealth and power in the society. This conception of justice requires primary attention to the interests of the least advantaged and the close regulation of corporate and private economic activity to mitigate deleterious environmental, social, and health effects. It draws theoretical justification from the individualistically oriented theorists of freedom, justice, equality, and human rights that comprise the contractarian approach. Rounding out the liberal spectrum is libertarian liberalism, which favors maximal freedom of individual choice with a minimum of governmental power or coercion. Institutions that bring about social order and cooperation on the basis of unplanned and uncoordinated actions and choices of free individuals (e.g., the market model in theory) are preferred by libertarians over the achievement of social order and the public interest via governmental regulation and the exercise of the police power or the paternalistic authority of the state. Liberalism of all types tends to presuppose an institutional framework of representative democracy, the rule of law, freedom of speech and political organization, and competitive elections. Liberalism and democracy were not always thought to be mutually compatible, but today they are joined at the hip at least in Western political thinking. Perhaps the most theoretically innovative and interesting challenge to this liberal paradigm arises from forms of democratic theory that are not satisfied with current institutions of electoral politics and representative, interest group democracy. One such form that is close to egalitarian liberalism in many ways, but which nonetheless demands a more direct, active role in both political argument

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and in civic and political life, is known as deliberative or discursive democracy (Dryzek, 2000). It also has a great deal in common with left-communitarianism, as was noted above. Another major type of political theory that rivals liberalism, and has a long pedigree in the history of Western political theory, is known as civic republicanism. With intellectual roots that can be traced back to classical political thought in ancient Greece and Rome, republicanism was rekindled during the Italian Renaissance, and later played a key role in the English, American, and French revolutions in the seventeenth and eighteenth centuries (Pocock, 1975). In American history, for example, republicanism was an important ideological foundation for revolution and governing the country during its first 100 years (Sandel, 1996). It was not until the period of the Industrial Revolution in the late nineteenth century that more individualistic public philosophies – such as Lockean liberalism, libertarianism, natural rights theories, and the more materialistic and economically oriented versions of utilitarianism – drove republicanism into abeyance. With its sense of the common good and its emphasis on public service and civic virtue, civic republicanism is proving to be a theoretical vocabulary of renewed vitality in recent years. It is a straightforward ally of communitarianism and deliberative democracy in many settings. It has direct pertinence to policy and practice in public health (Jennings, 2007). Finally, no schema of contemporary political thought would be complete without mention of the kind of cultural conservatism that is so powerfully associated with religious fundamentalism. Stronger in the U.S. than elsewhere in the West, this movement has not taken on a guise of collectivism in the manner of national socialism or fascism. Instead, for the most part this movement has embraced economic and political liberalism combined with restrictive communitarian and anti-libertarian goals of cultural and sexual traditionalism. In contrast, fundamentalism in some parts of the non-Western world involves more profound basic conflicts with liberalism (Nussbaum, 2007). It is not possible to construct a one-on-one mapping of ethical theories with political theories. The lines drawn on Figure 1 are meant to indicate that there is a two-way pattern of influence between political and ethical thinking, and that each configuration of political theory can draw from several different sources within ethical theory. In On Liberty, for example, John Stuart Mill develops a position closely akin to libertarian liberalism on the basis of a utilitarian metatheory, while Robert Nozick (1974) grounds his libertarianism on rights-theory and contractarianism. Similarly, contractarianism provides the theoretical underpinnings for both egalitarian liberalism and some aspects of deliberative democracy. The main disagreement between these two camps would not be over fundamental values and principles, but over the most effective means to formulate policy and to build support for it in a democratic process (the democrats prefer actual deliberation over hypothetical deliberation). On the other hand, deliberative democrats and civic republicans draw much in common from the insights of communitarianism about the moral and human importance of relationships of solidarity and shared commitment, cultural tradition, and a sense of community. Yet they may differ considerably about the importance and the practicality of direct grassroots

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participation in deliberation and policy making. The republican tradition has never insisted on direct democracy; indeed it is more characteristic of republicans to look toward governance by elites or experts, tempered perhaps by representative democracy and constitutional and other judicial protections. This is because the goal of civic republicanism is not active participation in shared decision making per se (public citizenship), but rather the preservation of the public morality and a sense of duty and responsibility among private citizens whose behavioral support and restraint are necessary to achieve public goals and to realize the common good. Space does not permit a full discussion of how these ideological currents affect the normative discourse of public health. It must suffice to mention a few areas where these currents are particularly salient. One important area of normative controversy in public health is in health promotion and disease prevention. Such programs inevitably raise questions about the responsibility of individuals to live healthy lives; about the role of government in coercing health-related behavior or in developing educational programs; about the use of incentives, economic or otherwise, to promote good health; and about the relative importance for society of pursuing good health, particularly in a culture that prizes autonomy and does not always look fondly on government intervention (Dawson and Verweij, 2007). A second area of public health controversy centers around the goal of risk reduction. Risks to the health of the public are many, and many methods are used to reduce or eliminate them. Almost every one of them can pose one or more ethical problems. The concept of risk itself is seemingly impossible to define in value-neutral terms and is inherently controversial. Even more ethically charged is the question of what level or degree of risk is socially acceptable, who should decide, and how exposure to risk should be distributed across the affected population. Routine public health practice involves a number of interventions and policies designed to prevent harm to individuals and to lower health risks within the population. These include various forms of public health surveillance – screening and testing – on different age groups, many of which are legally mandatory and paternalistic or are administered in a way that does not follow the requirements of informed consent. Epidemiological research may not always follow strict ethical protocols on the rights of human subjects, and the collection of health information may sometimes put the researcher in a position of having information that a specific individual might have an interest in knowing. The responsibilities of the public health researcher regarding individual notification and the protection of personal privacy and confidentiality are not yet clearly set out as a matter of consensus within the profession. Like the prevention of harm to others, individual privacy is a lightning rod for the conflicts and tensions between individual liberties and the common good that the main ethical and political theories of our time attempt to adjudicate and set in order. Finally, there is the issue of structural and socioeconomic disparities in health status. Equitable access to decent health care and reduction in health status disparities have been longsought goals in many democratic societies. The appropriate role for the public health community in seeking greater justice in health care, and the balance between its fact-finding and educational role versus an historically strong advocacy mission remain

unresolved questions. To what extent, if any, ought the field adopt a politically partisan posture? (Shrader-Frechette, 2002).

Styles of Practical Ethical Discourse These questions lead us to a second element in the foundations of public health ethics: The orientations and styles of practical or applied ethical analysis. As before, we need some rough typology or conceptual map to guide further research and interpretation in the normative study of public health. This has not been thoroughly explored in the literature (Callahan and Jennings, 2002). The following terminology and system of classification is one way of thinking about ethical discourse. There are four basic styles in public health ethics: (1) Professional ethics, (2) advocacy ethics, (3) applied ethics, and (4) critical ethics (Table 1).

Professional Ethics The study of professional ethics tends to seek out the values and standards that have been developed by the practitioners and leaders of a given profession over a long period of time and to identify those values that seem most salient and inherent in the profession itself. Applied to public health, this perspective entails identifying the central mission of the profession (e.g., protection and promotion of the health of all members of society) and building up a body of ethical principles and standards that would protect the trust and legitimacy that the Table 1

Orientations in public health ethics

Professional ethics l l l l l l

Distinctive history and tradition Ethical knowledge assimilated to practical knowledge Special obligations and permissions Sense of elite duty and public trust Virtue oriented Role oriented

Advocacy ethics l Social goal-centered (health, healthy population) Pragmatic and political Ethical discourse self-evident; unreasonable to question; unnecessary to dwell on underlying justifications l Sense of populist benefit, representational voice, service to the oppressed l l

Applied ethics Situation- or case-oriented Draws upon general ethical theory l Ethical knowledge distinct from practical knowledge l Decision making not character l l

Obligations added, not distinct Sense of detached, impersonal analytic reasoning process and skills Critical ethics l Tends to blend ethics with more general social and historical inquiry l Uses tradition suspiciously l Identifies tacit ideological blind spots and social interests in mainstream ethical theory l l

Sense of progressive or developmental emancipatory possibilities l Ethical justification grounded in an ideal discursive process rather than a particular value theory or a notion of impartial reason l

Foundations in Public Health Ethics profession should maintain. Like all professionals, public health officials exercise considerable power over the lives of others, and the way they use that power makes a substantial difference in the quality of those lives. The perspective of professional ethics seeks to express the virtues that practitioners ought to possess and the rules they ought to follow if they are to be permitted by society to exercise such power and authority. A difficulty in using this approach for public health is the questionable, tenuous status of public health as a single, unified profession. In some ways, it appears to be less a profession and more a field to which a number of professions contribute. The power of the professional ethics approach usually comes from the fact that students and practitioners feel that they have taken on a special role-duty or calling when they enter the profession. This ethos and sensibility is not always present in public health at the moment.

Advocacy Ethics If there is a characteristic ethical orientation within the field of public health today, it is probably less theoretical or academic than practical and issue-oriented. The ethical persuasion most lively in the field is a stance of advocacy for those social goals and reforms that public health professionals believe would enhance the general health and well-being, especially of those least well off in society. Such advocacy is in keeping with the natural priorities of those who devote their careers to improving public health. It has a strong orientation toward equality and social justice, for so much of the research and expertise in public health throughout its history has focused on showing how social deprivation, inequality, poverty, and powerlessness are directly linked to poor health and the burden of disease. In recent years, a growing international movement in support of human rights has exerted an important influence in public health (Mann et al., 1999). This has moved public health ethics in its advocacy mode toward an agenda of social and welfare rights designed to provide resources and to empower individuals and groups and not just to protect the so-called negative or political rights of the individual against intrusion or harm. The problem raised by this perspective on ethics is the flip side of its passion and commitment. Precisely because it backs the professional service agenda of the field of public health, it has only a limited ability to provide a critical perspective on norms and orientations that are taken for granted in the field. As an ethical approach, it aims more toward action than persuasion. There is little to calm and reassure those outside the field who may question the legitimacy of public health’s use of its governmental or social power. By definition, an advocacy position is not primarily based on detached rational persuasion. To look beyond the advocacy ethics of public health we need to find an orientation no less critical of powerful interests, but one more committed to careful and inclusive deliberation; an orientation that tries to set aside specific moral commitments and political agendas on behalf of gaining some broader perspective in the moral questions at issue.

Applied Ethics Another approach to public health ethics comes from the field that has emerged in recent years as applied or practical ethics.

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Bioethics and public health ethics are significant within this domain of ethics. The applied ethics perspective differs from the professional ethics perspective principally in that it adopts a point of view from outside the history and values of the profession. From this more general moral and social point of view, applied ethics seeks to devise general principles that can then be applied to real world examples of professional conduct or decision making. These principles and their application are designed to give professionals guidance and to give clients and the general public standards to use in assessing professional conduct. Thus in applied ethics there is a tendency to reason abstractly and to draw from general ethical theories, rather than from the folkways and knowledge base of the professions. The emphasis tends to be on professional conduct rather than on the virtues of professional character. One difficulty in using the applied ethics approach is that it has been individualistic and client-rights-oriented. It works most effectively, therefore, in what might be called clientcentered as opposed to public professions. For professions such as public health, the obligations and service pertain to a set of institutions, to a particular structure or arrangement of social relationships, and to the overlapping interests of large groups of people. When collective nouns, such as the public, society, the community, children, or persons at risk for diabetes, feature in the ethical obligations and principles of a given field, the applied ethics perspective has difficulty formulating ethical guidance that is philosophically coherent and practically useful. The same could be said when collective values (such as the common good or the public interest) are at the center of ethical controversies in the field, as they surely are – and must be – in public health.

Critical Ethics Finally, there is a perspective that can be called critical ethics, for it has some affinities with the eclectic and synthetic theoretical orientation of the German tradition of social thought called critical theory (Benhabib and Dallmayr, 1990). In many ways, it attempts to combine the strengths of the other perspectives mentioned. Like professional ethics, it is historically informed and practically oriented toward the specific real-world and real-time problems of public health, but like applied ethics it brings larger social values and historical trends to bear in its understanding of the current situation of public health and the moral problems faced. These problems are not only the result of the behavior of certain disease organisms or of particular individuals. They are also the result of institutional arrangements and prevailing structures of cultural attitudes and social power. At one level, public health has always known this larger critique and has always stressed it; but of late, in its actual programmatic behavior, public health has neglected the project of institutional change and focused on the individual as the object of education, health promotion efforts, and lifestyle change. The perspective of critical ethics has much in common with the egalitarian and human-rights-oriented discourse of advocacy ethics in public health. One advantage critical ethics may have is that it calls upon the discussion of ethics and public health policy to be genuinely public or civic endeavors. Critical ethics does not pursue the advocacy of a well-intentioned elite

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on behalf of needy clients, but rather seeks forums and programs of meaningful participation, open deliberation, and civic problem solving and capacity building. Some of the best examples of public health practice, from this point of view, grow out of efforts to support communities as places of mutual support, respect, and self-esteem, thereby reinforcing health promoting behaviors among their individual members.

Frameworks of Ethical Principles for Public Health Each of the stances or orientations represented in the normative discourse of public health today tends to present ethical arguments and justifications by reference to general claims most commonly referred to as ethical principles, rules, or guidelines. Such principles usually take the form of statements with action verbs modified by compounds of obligation (shall, must, ought, or should) or permission (may). These statements refer to prescribed or proscribed actions, outcomes of actions, states of affairs or relationships between persons, the distribution of resources, benefits or burdens, and the like. It is often difficult to distinguish between a moral principle and the formulation of a moral right. Sometimes such principles refer to the intention or motivation standing behind an action or informing a relationship. There is no universal definition of an ethical principle, and such statements may occur at different levels of generality and perform different logical functions within an ethical theory or ethical argument or analysis. In ethics today, the most universal and abstract statements are apt to be called moral laws, somewhat more specific and bounded statements with narrower areas of application are called principles, and the most concrete and specific moral injunctions are referred to as moral rules. But this usage is by no means universal. Some moral philosophers have a deductive conception of moral argument and justification in which laws engender principles, which in turn engender rules. Others argue that valid principles and rules can be stipulated even though we have no widely agreed upon set of moral laws, or which may be compatible with two or more different accounts of the moral law. Hence the fields of applied and professional ethics may work in some detachment from any particular ethical theory or moral philosophy (or moral theology for that matter). There has been some controversy over the approach known as principlism in applied and professional ethics. Rather than see ethics as involving the application of general rule-like imperatives, some argue that ethics should instead involve practical judgments concerning relationship or character. These favor an approach to ethics in terms of virtue or locating moral situations in larger narrative frameworks and case scenarios. Still others point out that ethical reasoning is less often deductive (reasoning from general principles to particular decisions or actions) than analogical in form. That is, ethical reasoning involves moving from well-understood, modal life situations to less familiar situations that we assimilate to the well understood moral paradigm cases. This approach to ethics has been called casuistry, and it represents an alternative to the application of moral principles (Jonsen and Toulmin, 1988). Nonetheless, it is fair to say that most work in applied and professional ethics in the past 25 years or so has been

done by reference to ethical principles and rights. Public health ethics, thus far, is no exception to this. The stances of advocacy and applied ethics have dominated public health ethics during this period, and they are the most readily compatible with ethical principlism. Part of the reason for this surely has to do with the success of this approach in the cognate field of bioethics. There the influence of academic ethicists (philosophers, lawyers, social scientists, and some professional practitioners) in clinical and policy settings was greatly enhanced by the appeal of easily grasped and logically cogent lists or frameworks of ethical principles. Codes of professional ethics are most often documents stating principles as well. In bioethics, the rise of arguments centered on principles was stimulated by the influence of the so-called Belmont Report of the U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issued in 1979. This has become the basis for ethical regulations governing the use of human subjects in research both in the U.S. and worldwide. Also important as a model for public health ethics was the reception in clinical medicine and medical education of Tom Beauchamp and James Childress, Principles of Biomedical Ethics, first published in 1979 and reissued in five expanded editions to date (2001). These works canonized the four principles of (1) respect for persons or autonomy, (2) beneficence, (3) nonmaleficence, and (4) justice or equity. The development of ethical discourse in public health by reference to the formulation of various principles is evidenced by a growing body of literature devoted to this aim (see Further Reading). James Childress himself is now actively working with colleagues in the field of public health ethics and brings his careful philosophical and conceptual attention to the study of the foundations and frameworks of public health ethics. An accurate overview of the discussion to date is given by a brief consideration of the formulation of principles in three contributions to this literature: The code of ethics for public health developed by the Public Health Leadership Society (PHLS, 2002), the work on principles of public health ethics by Nancy Kass, and the work of James Childress and his colleagues. I begin with the statement of principles offered by the PHLS (2002), which is reproduced in Table 2. It articulates 12 should statements, some of which refer to objectives and substantive outcomes, some refer to process and the values served by ethical process, such as respect, dignity, recognition, inclusion, and accountability. These principles are interesting in that they address not just the individuals who work in public health, but the field or practice of public health as a whole as itself a moral agent – and as subject to the duties set forth in the principles. They also focus on the effects of policies and programs and on the effects of the particular ways in which such policies are implemented. Good intentions by public health practitioners count for little in this moral landscape. Actual impacts and outcomes must be assessed and evaluated as good policies can be administered so badly (oppressively, arrogantly, disrespectfully) that their moral justifications are undermined. The ethical framework offered by the PHLS is also noteworthy because it contains an internal tension that sets public health apart from clinical medicine both in terms of the principles that are prioritized and in terms of the ways each principle

Foundations in Public Health Ethics Table 2

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Public Health Leadership Society, principles of the ethical practice of public health

1. Public health should address principally the fundamental causes of disease and requirements for health, aiming to prevent adverse health outcomes 2. Public health should achieve community health in a way that respects the rights of individuals in the community 3. Public health policies, programs, and priorities should be developed and evaluated through processes that ensure an opportunity for input from community members 4. Public health should advocate and work for the empowerment of disenfranchised community members, aiming to ensure that the basic resources and conditions necessary for health are accessible to all 5. Public health should seek the information needed to implement effective policies and programs that protect and promote health 6. Public health institutions should provide communities with the information they have that is needed for decisions on policies or programs and should obtain the community’s consent for their implementation 7. Public health institutions should act in a timely manner on the information they have within the resources and the mandate given to them by the public 8. Public health programs and policies should incorporate a variety of approaches that anticipate and respect diverse values, beliefs, and cultures in the community 9. Public health programs and policies should be implemented in a manner that most enhances the physical and social environment 10. Public health institutions should protect the confidentiality of information that can bring harm to an individual or community if made public. Exceptions must be justified on the basis of the high likelihood of significant harm to the individual or others 11. Public health institutions should ensure the professional competence of their employees 12. Public health institutions and their employees should engage in collaborations and affiliations in ways that build the public’s trust and the institution’s effectiveness Reproduced from Public Health Leadership Society, 2002. http://www.phls.org/home/section/3-26/, with permission.

is interpreted. This tension has to do with the inherently collective and population-based nature of public health information, analysis, and interventions, on the one hand, and the highly individualistic, libertarian, and rights-oriented political culture of advanced Western societies, on the other. While mindful of the rights of individuals (a stipulation that is mentioned only once), this framework is oriented toward communities, their empowerment, flourishing, and internal equality. The PHLS framework of principles is, in effect, a professional code of ethics and has been endorsed as such by the American Public Health Association. The framework of principles developed by Nancy Kass (2001) explicitly distinguishes itself from a code of ethics and offers instead what she calls “. an analytic tool, designed to help public health professionals consider the ethics implications of proposed interventions, policy proposals, research initiatives, and programs” (Kass, 2001: p. 117). This framework is comprised of six questions that should be asked in an ethical evaluation of any public health policy or practice. These are: 1. 2. 3. 4.

What are the public health goals of the proposed program? How effective is the program in achieving its stated goals? What are the known or potential burdens of the program? Can the burdens be minimized? Are there alternative approaches? 5. Is the program implemented fairly? 6. How can the benefits and burdens of a program be fairly balanced? Although phrased as questions, it is not difficult to convert these considerations into declaratory statements of principle. Among them are: beneficence and effectiveness (2); beneficence and nonmaleficence (3 and 4); justice (5 and 6); and beneficence and accountability (1 and 3). Conversely, it is not difficult to convert statements of principle into the form of questions to be posed during the course of ethical argument and evaluation. Indeed, this may be one of the best ways to interpret ethical principles and their discursive function. Principles should be understood as questions posed

rather than as commands issued. The appropriate response to an ethical command is not the give and take of further dialogue, but mute obedience. Interpreting principles as evaluative questions pushes us in the direction of a more dialogic encounter in which and through which principles are specified and their implications for action explored. The meaning of ethical principles, one might say, is not given prior to this dialogic, interpretive process but is constituted by it. The complicating factor in this account is that the very possibility of dialogue presupposes at least some degree of orderly, peaceful, and cooperative life made possible by the prior functioning of ethical (social and cultural) norms. If ethical principles are constituted by ongoing dialogue, they are also the presupposition of such dialogue. This complex structure and function of ethical principles is what Rawls refers to as reflexive equilibrium and what Habermas explores through the theoretical model of an ideal speech situation. The lasting value of a framework such as that developed by Kass, however, is the richness and insight with which these questions are interpreted and fleshed out. In a commentary on each question, Kass demonstrates that the real contribution of public health ethics lies not with its tools or forms, but with the substantive human interests, both personal and social, that inform the ingredients that would comprise good answers to these questions in a program assessment exercise. Finally, a sizable team led by James Childress (and including Nancy Kass) made an important contribution to the foundations of public health ethics with an article titled ‘Public health ethics: mapping the terrain’ (Childress et al., 2002). This article identifies what it calls general moral considerations for public health ethics. These are: 1. producing benefits, 2. avoiding, preventing, and removing harms, 3. producing the maximal balance of benefits over harms and other costs, 4. distributing benefits and burdens fairly (distributive justice),

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5. ensuring public participation, especially by affected parties (procedural justice), 6. respecting autonomous choices and actions, including liberty of action, 7. protecting privacy and confidentiality, 8. keeping promises and commitments, 9. disclosing information as well as speaking honestly and truthfully (transparency), 10. building and maintaining trust. This framework clearly encompasses the four principles influential in bioethics: autonomy (6–9), beneficence (1, 3), nonmaleficence (2), and justice (4, 5). It expands on these concepts in interesting ways in the context of public health. For example, it recognizes that respect for persons includes liberty, privacy, and access to information necessary to make informed choices. It also includes a democratic dimension to the usual stipulation concerning distributive justice. This is parallel to the PHLS emphasis on inclusive and fair process. Finally, the framework underscores the importance of promise keeping and trust, recognizing that as complex as the physician–patient relationship may be, the relationship between public health and the communities it serves is a no less dynamic, complex, and essential one. The ethical practice of public health must be committed to sustain that relationship of legitimacy and trust. This analysis does not simply lay out a scheme of principles and offer interpretive commentary on them, it also provides a sophisticated analysis of how such concepts may be used in ethical discourse concerning public health. There are two dimensions to the use of a framework of principles: The scope of the principles and their relative moral weight. The scope dimension pertains to the actual behavioral and programmatic requirements that a principle imposes in a public health context. Respecting autonomy does not always entail providing an opportunity for informed consent. Respecting the principle of avoiding harm does not always mean that the interests of certain individuals and groups may not be overridden in order to achieve other values and goals. Truth telling does not always mean providing a mass of undifferentiated information out of context so that private individuals will be rendered neither more informed and thoughtful nor more secure and reassured thereby. The dimension of moral weight pertains to resolving conflicts among the various principles and prioritizing them. Again, this takes us directly into the specifics and details on the ground in a public health program or community intervention. Ethical theory does not provide any basis for an absolute prioritization of principles such as these. Even fundamental human rights are not absolute when they conflict with other equally fundamental rights. At best, broader categories or thresholds (e.g., fundamental/nonfundamental; primary/ secondary) can be devised to provide guidance in resolving practical dilemmas and conflicts. Childress et al. propose a set of subsidiary principles, tie-breakers, so to speak, for use here. These criteria are effectiveness, proportionality, necessity, least infringement, and public justification. Here the basic idea is that if tragic ethical choices between important principles or fundamental values must be made, and if important rights and interests must sometimes be overridden, then public health measures that do so should undergo tests of strict scrutiny.

No important interests of one or a few should be sacrificed for the sake of programs that are not effective, are overly restrictive and burdensome given their objective, are not necessary, or involve surplus loss of liberty compared to reasonable alternative policies. In addition, where rational analysis and assessment alone may fail, the final arbiter of conflicts among principles must be the court of public judgment and justification. More needs to be said about this last consideration. We need to follow this type of analysis with a much better understanding of how an effective participatory and deliberative form of democracy could be made practical in our societies. What form of public education is required of citizens? What type of motivation would lead to genuine deliberation and not simply special interest advocacy? What kinds of institutional forms would facilitate more grassroots participation and discussion of key public health (and other social) issues? Other approaches to public health ethics, particularly in areas such as the control of infectious disease and in disaster ethics and public health emergency preparedness, are addressing these questions. They are arguing that public must address complex meanings and motivations in order to bring about behavioral change and institutional restructuring. Healthy behavior resides in the context of healthy communities and in the lived experience of individuals whose actions are oriented toward relationships, communal practices, and value narratives. For example, in their study of infectious disease control, Battin et al. (2009) argue that public health response take into account a complex web of historical, cultural, and emotional meanings given to the forces of nature and the biological fragility of the human body. Human beings are caught up in a biological web that contains both beneficial symbiotic and pathogenic microorganisms. Our bodies and activities are integral parts of the mobility and life cycle of these microorganisms, and hence we are what Battin and colleagues refer to as ‘way station’ selves. This identifies the moral ambiguity inherent in the biology of infectious disease – namely, that individuals may be both victims to be cared for and carriers of the pathogens, or ‘vectors,’ who must be controlled. Care and control, concern and coercion, are two sides of the same coin in an infectious disease emergency. They argue that the deductive application of general principles will provide little guidance in these contexts in which historically and culturally informed and nuanced interpretation of behavior and emotional motivation are required. Another ecological perspective on public health ethics is contained in the recent work of Jennings and Arras (2016). Like the approach used by Battin et al., they emphasize an ecological perspective, but in a different way. Rather than see public health practice in terms of a dialectic between culture, the biology of infectious disease, and social control of human bodies, Jennings and Arras view public health as a ‘civic practice’ of building communities of inclusive social justice and health. From a civic perspective, public health is something that citizens ought to engage in and support out of a sense of membership and solidarity, or common self-interest. Membership perceives that everyone is a part of a community of common interest and common vulnerability. Solidarity perceives that we have a responsibility for others and for the health of our shared community as a whole.

Foundations in Public Health Ethics

Conclusion The different types of analysis contained in the literature on ethical frameworks and principles distinguish between the ethics of public health (how it frames and analyzes the ethical problems it encounters), and the ethics within public health (how its practitioners understand their role, their values, and the criteria for judging the ethical perspective they bring to bear on their professional work). Many problems will require moving back and forth between the two levels. At the same time, there may well be a tension between the general values of society (e.g., its individualism) and the special values of public health (e.g., its population rather than individual orientation). In these and other contributions to the recent literature to the new public health ethics, the legacies of liberalism (both libertarian and egalitarian) and utilitarianism are manifest. But so too are the increasing echoes of democratic values and aspirations. Public health is moving beyond its past – which too often was marked by racism, elitism, paternalistic expertise, and arrogant social engineering – and into a more dialogic, cooperative, and community-rooted mode of social change and health intervention. The new public health ethics reflects that critically democratic or civic temperament, but also has the foundational and conceptual resources to promote and ignite it.

See also: Codes of Ethics in Public Health; Environmental Justice and Health; Ethics and Health Promotion; Ethics of Immunization; Ethics of Infectious Disease Control; Ethics of Public Health Research: Moral Obligations to Communities; Ethics of Screening; Foundations in Public Health Law; Health and Human Rights: Overview.

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Jennings, B., 2003. Frameworks for ethics in public health. Acta Bioethica IX (2), 165–176. Jennings, B., 2007. Public health and civic republicanism. In: Dawson, A., Verweij, M. (Eds.), Ethics, Prevention, and Public Health. Oxford University Press, Oxford, UK, pp. 30–58. Jennings, B., 2009. Public health and liberty. Public Health Ethics 2 (2), 123–134. Jennings, B., Arras, J.D., 2016. Ethical aspects of emergency preparedness and response. In: Jennings, B., Arras, J.D., Barrett, D., Ellis, B. (Eds.), Emergency Ethics: Public Health Preparedness and Response. Oxford University Press, New York, pp. 1–103. Jonsen, A.R., Toulmin, S., 1988. The Abuse of Casuistry. University of California Press, Berkeley, CA. Kass, N.E., 2001. An ethics framework for public health. Am. J. Public Health 91 (11), 1776–1782. Laborde, C. (Ed.), 2002. Rawls in Europe. Special Issue. Eur. J. Political Theory 1 (2), 181–198. Mackenzie, C., Stoljar, N. (Eds.), 2000. Relational Autonomy: Feminist Perspectives on Autonomy, Agency, and the Social Self. Oxford University Press, New York. Mann, J.M., Gruskin, S., Grodin, M.A., Annas, G.J. (Eds.), 1999. Health and Human Rights. Routledge, New York. Mulhall, S., Swift, A., 1996. Liberals and Communitarians, second ed. Blackwell, Oxford, UK. Nedelsky, J., 2013. Law’s Relations: A Relational Theory of Self, Autonomy, and Law. Oxford University Press, New York. Nozick, R., 1974. Anarchy, State, and Utopia. Basic Books, New York. Nussbaum, M., 2007. The Clash within: Democracy, Religious Violence, and India’s Future. Harvard University Press, Cambridge, MA. Pocock, J.G.A., 1975. The Machiavellian Moment: Florentine Political Thought and the Atlantic Republican Tradition. Princeton University Press, Princeton, NJ. Public Health Leadership Society (PHLS), 2002. Principles of the Ethical Practice of Public Health, Version 2.2. Available on the web at: http://www.phls.org (accessed September 2007). Rawls, J., 1999 [1971]. A Theory of Justice, revised ed. Harvard University Press, Cambridge, MA. Sandel, M., 1996. Democracy and Its Discontents. Harvard University Press, Cambridge, MA. Shrader-Frechette, K., 2002. Environmental Justice: Creating Equality, Reclaiming Democracy. Oxford University Press, New York. Wildavsky, A., 1995. But Is It True? A Citizen’s Guide to Environmental Health and Safety Issues. Harvard University Press, Cambridge, MA.

References Battin, M.P., Francis, L.P., Jacobson, J.A., Smith, C.B., 2009. The Patient as Victim and Vector: Ethics and Infectious Disease. Oxford University Press, New York. Baylis, F., Kenny, N.P., Sherwin, S., 2008. A relational account of public health ethics. Public Health Ethics 1 (3), 196–209. Benhabib, S., Dallmayr, F. (Eds.), 1990. The Communicative Ethics Controversy. MIT Press, Cambridge, MA. Callahan, D., Jennings, B., 2002. Ethics and public health: forging a strong relationship. Am. J. Public Health 92 (2), 169–176. Childress, J.F., Faden, R.R., Gaare, R.D., et al., 2002. Public health ethics: mapping the terrain. J. Law Med. Ethics 30 (2), 170–178. Cooke, R.M., 1991. Experts in Uncertainty: Opinion and Subjective Probability in Science. Oxford University Press, New York. Daniels, N., 2008. Just Health: Meeting Health Needs Fairly. Cambridge University Press, New York. Dawson, A., Verweij, M. (Eds.), 2007. Ethics, Prevention and Public Health. Oxford University Press, Oxford, UK. Dryzek, J., 2000. Deliberative Democracy and Beyond. Oxford University Press, New York. Faden, R., Powers, M., 2006. Social Justice: The Moral Foundations of Public Health and Health Policy. Oxford University Press, New York. Gergen, K.J., 2009. Relational Being: Beyond Self and Community. Oxford University Press, New York. Goodin, R., 1995. Utilitarianism as a Public Philosophy. Cambridge University Press, Cambridge, UK. Habermas, J., 1990. Moral Consciousness and Communicative Action. MIT Press, Cambridge, MA. Haliburton, R., 2014. Autonomy and the Situated Self: A Challenge to Bioethics. Lexington Books, Lanham, MD.

Further Reading Beauchamp, T., Childress, J.F., 2012. Principles of Biomedical Ethics, seventh ed. Oxford University Press, New York. Bayer, R., Fairchild, A.L., 2004. The genesis of public health ethics. Bioethics 18 (6), 473–492. Dawson, A. (Ed.), 2011. Public Health Ethics: Key Concepts in Policy and Practice. Cambridge University Press, Cambridge, UK. Gostin, L.O., 2008. Public Health Law: Power, Duty, Restraint, second ed. University of California Press, Berkeley, CA. Holland, S., 2015. Public Health Ethics, second ed. Polity Press, Cambridge, UK. Mill, J.S., 1971 [1859]. On Liberty. Bobbs–Merrell, Indianapolis, IN. Singer, P. (Ed.), 1991. A Companion to Ethics. Blackwell, Oxford, UK. Thomas, J.C., Sage, M., Dillenberg, J., Guillory, V.J., 2002. A code of ethics for public health. Am. J. Public Health 92 (7), 1057–1059.

Relevant Websites www.apha.org – American Public Health Association. www.asph.org – Association of Schools of Public Health. Society for Public Health Education. www.sophe.org – The Center for Law and the Public’s Health at Georgetown and the Johns. www.publichealthlaw.net – Georgetown and Johns Hopkins Universities. www.thehastingscenter.org – The Hastings Center. www.phls.org – Public Health Leadership Society.

Foundations in Public Health Law Lawrence O Gostin, Benjamin E Berkman, and John Kraemer, Georgetown University, Washington, DC, USA Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 2, pp. 670–676.

Government’s principal obligation is to ensure the health and welfare of its population. It does so through the enactment and enforcement of laws designed to create the conditions necessary for citizens to lead healthy, safe lives. This article explores the ways in which law can be used as a tool for improving the health of a society by creating public health authorities, defining their powers, and denoting the means by which those powers can be used. However, before we begin, we first offer a definition of public health law, focusing on the characteristics that make it different from other areas of law.

Definition and Characteristics of Public Health Law Public health has to do with the safety and well-being of populations. Contrast this to the field of medicine, which is primarily concerned with the health of individual patients. In medicine, doctors must do what is best for their individual patient. Public health takes a wider perspective, focusing on what must be done to improve and maintain the health of a collective group. Inherent in this approach is the reality that sometimes the government will require that individual rights be sacrificed for the greater good; people must forgo individual freedom, privacy, and autonomy in order to benefit their community. With this in mind, we define public health law as follows: Public health law is the study of the legal powers and duties of the state, in collaboration with its partners (e.g., health care, business, the community, the media, and academe), to assure the conditions for people to be healthy (e.g., to identify, prevent, and ameliorate risks to health in the population) and the limitations on the power of the state to constrain the autonomy, privacy, liberty, proprietary, or other legally protected interests of individuals for the common good. The prime objective of public health law is to pursue the highest possible level of physical and mental health in the population, consistent with the values of social justice. Gostin (2007b).

This multifaceted definition focuses on five essential characteristics of public health law. 1. Government – The primary responsibility of safeguarding the public’s health falls to government, as it is best situated to act in the interest of the populace (Institute of Medicine, 2002). 2. Populations – Public health’s goal is to improve the health and well-being of a group rather than individual patients. 3. Relationships – Public health is concerned with the relationship between the state and the population. Sometimes this relationship justifies the government’s imposition of burdens on individuals in order to promote the population’s greater good.

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4. Services – Public health improves the welfare of a group by providing population-based services grounded in the scientific methodologies of public health (e.g., biostatistics and epidemiology). 5. Power – In order to promote the public’s health, the government must possess certain powers to regulate and control individuals and businesses. Since public health often requires individual sacrifice, the government cannot rely on requests for voluntary cooperation; an ample, yet clearly delineated power to coerce is required. Law is the mechanism through which government can fulfill its obligation to protect the public’s health. In the next section, we outline seven models of legal intervention. In each model, the law (through constitutions, legislation, regulation, or the courts) gives government the power to influence human behavior. Of course, although law creates the governmental power to safeguard the public’s health, this same law can serve as a restraint on that power, ensuring that government acts appropriately and maintaining an appropriate balance between individual rights and the population’s health. The third section discusses the ways in which law can limit government action. The fourth section explores the challenges associated with reforming public health law in the face of evolving conceptions of the powers, duties, and restraints necessary for government to protect the public’s health.

Law as a Tool to Protect the Public’s Health The Power to Tax and Spend One of the fundamental governmental powers, often contained in a constitution, is the ability to tax and spend. In its simplest form, the power to spend is relevant because it allows government to devote resources toward vital public health infrastructure. Government must hire and train a public health workforce, create information and communication systems, conduct disease surveillance, maintain laboratory facilities, and establish the capacity to respond to public health emergencies (Centers for Disease Control and Prevention, 2002). This direct spending can also have an indirect effect on health through the government’s placement of health-related restriction or conditions on the receipt of public funds. For example, the receipt of local road construction money could be conditioned on the implementation of safety requirements, such as a lower speed limit. The power to tax can also be used as a tool to indirectly influence the behavior of individuals and businesses. Taxes on unhealthy or harmful behaviors serve as a disincentive to engage in those activities. Many governments tax risky behaviors, such as smoking, in an effort to make it less attractive. This type of monetary disincentive can be a powerful means of influencing unhealthy behaviors, especially among young

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Foundations in Public Health Law people. Tax relief can also be used as a positive incentive for engaging in healthful behaviors. For example, a tax rebate or deduction can be offered for purchasing health insurance or for income devoted toward medical expenses.

The Power to Alter the Flow of Information Information influences the health-related choices that people make. Government can influence the informational environment, thus encouraging healthy behaviors and discouraging harmful ones. The government can engage in direct information dissemination, through the use of educational campaigns. They can impose product labeling rules, requiring the inclusion of important information such as health warnings, nutritional information, or safe use instructions. Government can also impose outright bans on certain forms of advertising, especially for information that is misleading or that promotes unreasonably harmful products (e.g., tobacco, alcohol). Of course, by regulating or banning certain kinds of commercial speech, government is restricting businesses’ freedom of expression. In many countries, the right to free speech is a core social value. However, there is a difference between expressing one’s social or political views and engaging in commercial speech for profit. Many liberal democracies do not protect commercial speech because it is not vital for the promotion of a vibrant democracy.

The Power to Alter the Built Environment The environment in which one lives can have an immense impact on health. Public health has long been engaged in interventions designed to improve the health-promoting qualities of our built environment, through the government’s use of laws and regulations. Government has regulated workplace safety to reduce injuries. Cities have required that housing comply with specific fire and building codes. The spread of infectious disease has been impeded through the creation of sanitation systems and the implementation of zoning rules. Government has also restricted the production and use of harmful environmental agents such as lead paint, asbestos, and pollution. Developed countries are seeing an epidemiological shift away from infectious disease, toward chronic health problems such as cancer, cardiovascular disease, diabetes, asthma, and depression. As the disease distribution changes, government can still use its power to alter the built environment as a tool to promote physical and mental health by reducing the incidence of chronic disease. City planners can include parks and playgrounds that encourage active lifestyles. Government can facilitate access to nutritional foods by encouraging the production of supermarkets in previously underserved areas. Laws can restrict the use of harmful products, such as cigarettes and alcohol; for example, many jurisdictions have banned smoking in all public spaces (Perdue et al., 2003).

The Power to Alter the Socioeconomic Environment Research indicates a clear correlation between socioeconomic status (SES) and health (Rogot et al., 1992). Populations with the fewest financial, educational, and occupational

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resources generally are the least healthy. Some have even suggested that countries with the largest gap between the rich and the poor will have lower health status compared to similar countries in which wealth is distributed more evenly. Although we cannot completely explain the complex relationship between SES and health, one can make a strong argument that social justice is good for our health. Regardless of the specific interrelationship between SES and health, people of low SES are subject to a disproportionate number of harms: reduced access to material goods (food, shelter, and health care), a toxic physical environment, psychosocial stressors (financial, occupational, and social insecurity), and social contexts that promote risky behaviors. Government can work to alleviate these specific determinants of morbidity and premature mortality, keeping in mind that social equality might be the ultimate way to promote the health of an entire population (Lynch et al., 2004).

The Power to Directly Regulate Persons, Professions, and Businesses Government has the power to regulate individuals, professions, and businesses by creating clear, enforceable rules designed to protect the health and safety of workers, consumers, and the population at large. On the individual level, regulation can reduce injuries and death by controlling individual behavior. For example, in most places, it is illegal to drive without a seatbelt (or helmet) or while under the influence of drugs or alcohol. On the professional level, governments regulate the quality and standards of practice by requiring licenses and permits to enter a field. In the area of health, this power is used to regulate doctors’ licenses, as well as to certify hospitals and nursing homes. Inspection and regulation of businesses can help create safer work environments, limit toxic emissions, and ensure safer consumer products. For example, the FDA closely regulates the production of influenza vaccines through inspections and testing in order to prevent contaminated products from reaching the market. Of course, the regulation of businesses for public health purposes is controversial. Although there are clear public health benefits achieved through regulation of commercial enterprises, many have argued for the benefits of open competition and unfettered entrepreneurship. Yet effective public health policy requires some level of government restraint on businesses in order to avoid the potential threats that would result from unbridled commercialism.

Indirect Regulation through the Tort System The tort system aims to hold individuals and businesses civilly accountable for engaging in dangerous or harmful activities. The effects of a tort system are threefold. First, the threat of being held liable can deter individuals and businesses from engaging in unreasonably dangerous or harmful activities. Second, victims who have been harmed through no fault of their own can be compensated for their injury. Finally, the tort system encourages innovation. Since the system holds an actor responsible for the harm caused by his or her dangerous activity, there is an incentive to find ways to make it safer, or less harmful.

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In the public health realm, civil litigation can redress many kinds of public health problems. Companies that pollute, or use toxic substances, can be held liable for the environmental damage and adverse health effects that they have caused. Similarly, companies that produce inherently dangerous products (e.g., firearms, tobacco) or defectively produced goods can be forced to compensate victims injured by their merchandise. For example, in 1998, tobacco companies reached a settlement with American States totaling $206 billion over the next 27 years. Similarly, there has been a recent series of cases against firearms producers, with plaintiffs arguing that the companies should be held liable for producing an inherently dangerous product (Lytton, 2005).

Deregulation: Removing Laws that Negatively Affect the Public’s Health Although law gives government the power to protect the public’s health, law can also serve as an impediment to this goal. In such cases, deregulation can be a useful tool. Politically popular policies, such as banning needle exchange, can actually increase the spread of HIV infections. Similarly, the criminalization of sexual acts performed by HIV-positive individuals (without disclosure) can serve as a disincentive to get tested or seek medical treatment. Deregulation can be controversial because it often requires the removal of superficially popular laws that get their support from moral or ethical arguments. Needle exchange bans and HIV-specific criminal penalties represent society’s moral condemnation of disapproved behaviors (Gostin, 2004). Since public health is concerned with reducing morbidity and mortality by using scientifically based techniques, interventions can often appear to conflict with a society’s set of morals. However, it is important for public health officials to examine the real health effects of public policies and to push for their deregulation when evidence demonstrates an unintended consequence.

Law as a Limit on Government Power Protecting the public’s health is not possible without constraining a wide range of private activities that pose unacceptable risks. The legal tools discussed above infringe on a number of values that occupy a core place in many societies. Public health can require the government to infringe on privacy, restrict speech, and limit movement and autonomy (e.g., quarantine, isolation, vaccination). Given the importance of the public’s health, government must have the power to restrict individual rights and freedoms in the interest of the collective good. However, government must do so consistently with constitutional and statutory constraints on state action. This section discusses how legal frameworks can ensure that government does not abuse its power; law can make sure that government uses its coercive powers only when necessary and appropriate. Any theory of public health law presents a paradox. Government, on the one hand, is compelled by its role as the elected representative of the community to act affirmatively to promote the health of the people. To many, this role requires vigorous measures to control obvious health risks. On the other

hand, government cannot unduly assault individuals’ rights in the name of communal goods. Health regulation that overreaches, in that it achieves a minimal health benefit with disproportionate human burdens, is not tolerated in a society based on the rule of law and is antithetical to ethical considerations. Consequently, scholars and practitioners often perceive a tension between the claim of the community to reduce obvious health risks and the claim of individuals to be free from government interference. This perceived conflict might be agonizing in some cases and absent in others. Thus, public health law must always pose the questions: does a coercive intervention truly reduce aggregate health risks, and what, if any, less intrusive interventions might reduce those risks as well or better? Respect for the rights of individuals and fairness toward groups of all races, religions, and cultures remains at the heart of public health law.

Substantive Restrictions Public health powers are permissible only if they are exercised in conformity with five standards: public health necessity, reasonable means, proportionality, harm avoidance, and fairness (Childress et al., 2002). These standards, while permissive of public health intervention, nevertheless require a deliberative governmental process to safeguard liberty. If these standards are followed, they often result in a requirement that public health authorities use the least restrictive effective means necessary to protect the public from legitimate dangers.

Public Health Necessity

Public health powers are exercised under the theory that they are necessary to prevent an avoidable harm. Some courts have required that police powers go no farther than that which is reasonably necessary to protect the public. Early meanings of the term ‘necessity’ are consistent with the exercise of police powers: to ‘necessitate’ was to force or compel a person to do that which he would prefer not to do, and the ‘necessaries’ were those things without which life could not be maintained. Government, in order to justify the use of compulsion, therefore, must act only in the face of a demonstrable health threat. The standard of public health necessity requires, at a minimum, that the subject of the compulsory intervention must actually pose a threat to the community.

Reasonable Means

Under the public health necessity standard, government may act only in response to a demonstrable threat to the community. The methods used, moreover, must be designed to prevent or ameliorate that threat. Courts have adopted a means/ends test that required a reasonable relationship between the public health intervention and the achievement of a legitimate public health objective. Even though the objective of the legislature may be valid and beneficent, the methods adopted must have a real relationship to protection of the public’s health.

Proportionality

The public health objective may be valid in the sense that a risk to the public exists, and the means may be reasonably likely to achieve that goal. Still, a public health regulation is legally troublesome if the human burden imposed is wholly

Foundations in Public Health Law disproportionate to the expected benefit. “[T]he police power of a State,” said Justice Harlan in the foundational American case of Jacobson v. Massachusetts, “may be exerted in such circumstances or by regulations so arbitrary and oppressive in particular cases as to justify the interference of the courts to prevent wrong . and oppression.” Public health authorities have a responsibility not to overreach in ways that unnecessarily invade personal spheres of autonomy. This suggests a requirement for a reasonable balance between the public good to be achieved and the degree of personal invasion. If the intervention is gratuitously onerous or unfair it may overstep constitutional boundaries.

Harm Avoidance

Those who pose a risk to the community can be required to submit to compulsory measures for the common good. The control measure itself, however, should not pose a health risk to its subject. The legality of vaccinating a fit person against a contagious disease is very different than that of vaccinating someone who is medically contraindicated. Likewise, quarantine is not permissible if it creates conditions likely to spread disease or if it is conducted without regard to the basic needs of people being detained. Courts have required safe and habitable environments for persons subject to detention to protect the public’s health on the theory that public health powers are designed to promote well-being, not to punish the individual.

Fairness

The courts require that public health measures be implemented in a fair way. Interventions cannot target particular classes of people – members of a race, religion, ethnicity, for example – without a compelling reason. The law can discriminate among people in two ways. First, the law can expressly make distinctions among persons or groups. This kind of discrimination is called a facial classification because the distinction among people is ‘on the face’ of the statute. For example, a statute that requires searches of persons of Middle-Eastern descent facially discriminates on the basis of national origin. Second, the law can be ‘facially neutral’ in that it applies a general standard to all people. Statutes of general applicability, nonetheless, often disproportionately affect particular persons or groups. For instance, a law that requires prenatal screening in all communities with a specified high prevalence of HIV infection will have a disparate impact on minority and low-income populations. The courts will not necessarily find that a law of general applicability violates equal protection even if a demonstrably inequitable effect on vulnerable groups exists. If a law is facially neutral, the disproportionately burdened class must demonstrate that the government’s actual purpose was to discriminate against that group, which can be exceedingly difficult to prove. If a law expressly discriminates or if a facially neutral law adversely affects persons or groups and the government intends to discriminate, an equal protection problem exists. Contrary to popular belief, however, government is not obliged to treat all people identically. Instead, government is required to treat like cases alike but is permitted to treat unlike cases dissimilarly. Virtually any public health policy establishes a class of people that receives a benefit or burden and a class that does

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not. For example, case isolation is only applied to the class of infectious people. The critical inquiry is whether a sufficient justification exists for the distinction among classes. Put another way, do public health authorities have a valid reason for distinguishing among people and, if so, how substantial is that reason? Medicare eligibility, for example, is based on a person’s age, but the government has a plausible reason for offering the benefit to the elderly and excluding others. However, quarantining a particular ethnic group in an area where disease is endemic has no justification.

Procedural Due Process Fair procedures are required if an individual or business suffers a deprivation of property or liberty. However, this does not decide the question of exactly what kinds of procedures the government must provide. Due process is a flexible concept that varies with the particular situation. In deciding which procedures are required, courts should balance several factors. First, the courts should consider the nature of the private interests affected. The more intrusive or coercive the state intervention, the more rigorous the procedural safeguards. In cases of plenary deprivation of liberty, such as civil commitment of a person with mental illness or tuberculosis, the state must provide the full panoply of procedures – notice, counsel, impartial hearing, cross-examination, written decision, and appeal. The justification for rigorous procedural protections is found in the fundamental invasion of liberty occasioned by long-term detention. Second, the courts should consider the risk of an erroneous deprivation and the probable value, if any, of additional or substitute procedural safeguards. Here, the courts are concerned with the value of procedures as a method of protecting against erroneous decision making. If the court feels that an informal process is likely to lead to a ‘correct’ result, it will not require procedural formalities that it regards as unnecessary. Third, the courts should consider the fiscal and administrative burdens in providing additional procedures and the extent to which the government’s interests would be undermined. Most mental health or public health statutes permit an expedited form of due process in cases of emergency. Reduced due process is justified by the fact that the state’s interests in rapid confinement of immediately dangerous persons would be undermined by elaborate, time-consuming procedures. In sum, in ascertaining the procedures that are constitutionally required, the courts should weigh three factors: the extent of the deprivation of liberty or property, the risk of an erroneous decision, and the burdens that additional procedures will entail. Thus, the procedures in any given circumstance depend on the public health context and vary from case to case. The process required can range from a full-blown hearing to an informal, nonadversarial review.

Accountability and Transparency In a republic, public health measures are legitimate only when they reflect transparent legislative decisions. Public health activities in a democracy cannot be organized, funded, or implemented without the assent of the people. It is government

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that possesses the sole authority to empower, regulate, or carry out activities designed to protect or promote the general health, safety, or welfare of the population. It is the public that bands together to achieve social goods that could not be secured without collective action. And it is the public, or electorate, that legitimizes or authorizes government to act for the common welfare. However, the political commitment to public health is not absolute. What constitutes ‘enough’ public health? How much? What kinds of services? How will they be paid for and distributed? These remain political questions. Democratic governments will never devote unlimited resources to public health; core public health functions compete for scarce resources with other demands for services, and resources are allocated through a prescribed political process. There must be a vigorous and expanded democratic discussion about the population’s health. Public health measures must be based on clearly defined criteria. When policies are enacted, it must be clear what harms they are intended to ameliorate or prevent, what means will be employed to do so, and what circumstances will trigger implementation (Daniels, 2000). The first requirement facilitates democratic prioritization of issues. Governments should be responsive to the concerns of the public and address those issues that most affect it. The second requirement allows the populace to weigh public health ends against means and ensure that restrictions are not pyrrhic in the eye of those whom the government is to serve. The third requirement helps protect proportionality. Even when there is broad agreement that particular harms, if present, justify restrictive interventions, disagreement about when those harms actually exist in sufficient magnitude to trigger a response will exist. These requirements for accountability are particularly important when public health policies are adopted to address future or extraordinary concerns. When policy is made to address risks that have not yet come into fruition, it is important that the goals and methods of intervention be set out clearly in advance so that the public can state a preference for how government should behave during the exercise of emergency powers. Consider the risk of pandemic influenza. Policy created during the stress of such an emergency would have little accountability. Thus, determinations should be made beforehand about what level of priority disease prevention should be given when it is in tension with economic stability or other important public goods. The extent to which coercive measures will be exercised should be debated at the national, state, and local levels, and government should make clear at what point it will implement various interventions and when they will be lifted. Transparency is essential to create and maintain public trust and accountability. Openness and accountability are important to public health governance because of their intrinsic value and capacity to improve decision making. Citizens gain a sense of satisfaction by participating in policymaking and having their voices heard. Even if government decides that personal interests must yield to common needs, the individual feels acknowledged if he or she is listened to and his or her values are taken into account. Transparency also has instrumental value because it provides a feedback mechanism – a way of informing public policy and arriving at more considered judgments. Open forms of governance engender and sustain public trust, which benefits the public health enterprise more generally. Without public

support, and the voluntary cooperation of those at risk, coercive public health interventions would be difficult to achieve. The populace must be able to trust that its government is acting in its best interests.

Public Health Law Reform The laws relating to public health are scattered across countless statutes and regulations at multiple levels of government. Problems of antiquity, inconsistency, redundancy, and ambiguity often render these laws ineffective, or even counterproductive, in advancing the population’s health (Gostin, 2001). In particular, health codes frequently are outdated, built up in layers over different periods of time, and highly fragmented among subnational political units. Some regions have made efforts to modernize their public health laws, but many are still plagued by these problems. Public health law reform will present unique difficulties to individual nations. In order for public health laws to be effective, they need to be tailored to a country’s capacities and needs. Each country must consider state-specific factors such as national political structures and principles, educational and cultural environment, prevalence patterns of disease, available resources, and the strengths and weaknesses of the healthcare system. However, improving global public health should not be seen as a purely intranational endeavor. Internationally, developed countries are increasingly concerning themselves with global health issues and have an emerging responsibility to assist developing countries in improving the health of their populations (Gostin, 2007a).

Problem of Antiquity The most striking characteristic of state public health law, and the one that underlies many of its defects, is its overall antiquity. Certainly, some statutes are relatively recent in origin, such as those relating to health threats that became salient in the latter part of the twentieth century (e.g., environmental law). However, a great deal of public health law was framed in the late nineteenth and early to mid-twentieth century and contains elements that are 40–100 years old, such as infectious disease law. Old laws are not necessarily bad laws. A wellwritten statute may remain useful, effective, and constitutional for many decades. Nevertheless, old public health statutes that have not been substantially altered since their enactment are often outmoded in ways that directly reduce both their effectiveness and their conformity with modern standards. These laws often do not reflect contemporary scientific understandings of injury and disease (e.g., surveillance, prevention, and response) or legal norms for protection of individual rights. Rather, public health laws utilize scientific and legal standards that prevailed at the time they were enacted. Society faces different sorts of risks today and deploys different methods of assessment and intervention. When many of these statutes were written, public health (e.g., epidemiology and biostatistics) and behavioral (e.g., client-centered counseling) sciences were in their infancy. Modern prevention and treatment methods did not exist.

Foundations in Public Health Law At the same time, many public health laws predate the vast changes in constitutional (e.g., tighter scrutiny and procedural safeguards) and statutory (e.g., disability discrimination) law that have transformed social and legal conceptions of individual rights. Failure to reform these laws may leave public health authorities vulnerable to legal challenge on grounds that they are unconstitutional or that they are preempted by modern statutes. Even if state public health law is not challenged in court, public health authorities may feel unsure about applying old legal remedies to new health problems within a very different social milieu.

Problem of Multiple Layers of Law Related to the problem of antiquity is the problem of multiple layers of law. The law usually consists of successive layers of statutes and amendments, built up in some cases over 100 years or more in response to existing or perceived health threats. This is particularly troublesome in the area of infectious diseases, which forms a substantial part of state health codes. Because communicable disease laws have been passed piecemeal in response to specific epidemics, they tell the story of the history of disease control (e.g., smallpox, yellow fever, cholera, tuberculosis, venereal diseases, polio, and AIDS). Through a process of accretion, some governments have come to have several classes of communicable disease law, each with different powers and protections of individual rights: those aimed at traditional STDs (or venereal diseases), including gonorrhea, syphilis, chlamydia, and herpes; those targeted at specific currently or historically pressing diseases, such as tuberculosis and HIV; and those applicable to ‘communicable’ or ‘contagious’ diseases, a residual class of conditions ranging from measles to malaria whose control does not usually seem to raise problematic political or social issues. There are, of course, legitimate reasons to treat some diseases separately. Nevertheless, affording health officials substantially different powers, under different criteria and procedures for different diseases, is more an accident of history than a rational approach to prevention and control. The disparate legal structure of public health laws can significantly undermine their effectiveness. Laws enacted piecemeal over time are inconsistent, redundant, and ambiguous. Even the most astute lawyers in public health agencies or offices of the attorney general have difficulty understanding these arcane laws and applying them to contemporary health threats.

Problem of Inconsistency among Political Subunits Public health laws remain fragmented not only within specific jurisdictions, but among them as well. Health codes in various regions have evolved independently, leading to profound variation in the structure, substance, and procedures for detecting, controlling, and preventing injury and disease. In fact, statutes and regulations can vary so significantly in definition, method, age, and scope that they defy orderly categorization. Ordinarily a different approach is not a problem and is often perceived as a virtue; independent areas can become laboratories for innovative solutions to challenging health

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problems. Nevertheless, there may be good reason for greater uniformity in matters of public health. Health threats are rarely confined to single jurisdictions but pose risks within whole regions or the nation itself. For example, geographic boundaries are largely irrelevant to issues of air or water pollution, disposal of toxic waste, or the spread of infectious diseases. Similarly, a bioterrorism event threatens the nation and is not confined to a single location. Public health law, therefore, should be reformed so that it conforms with modern scientific and legal standards, is more consistent within and among states, and is more uniform in its approach to different health threats. Rather than making artificial distinctions among diseases, public health interventions should be based primarily on the degree of risk, the cost and efficacy of the response, and the burdens on human rights. A single set of standards and procedures would add needed clarity and coherence to legal regulation, and would reduce the opportunity for politically motivated disputes about how to classify newly emergent health threats.

Conclusion These are the challenges of public health law: Does it act modestly or boldly? Does it choose scientific neutrality or political engagement? Does it leave people alone or change them for their own good? Does it intervene for the common welfare or respect civil liberties? Does it aggressively tax and regulate or nurture free enterprise? The field of public health law presents complex tradeoffs and poses enticing intellectual challenges, both theoretical and essential, to the body politic.

See also: Codes of Ethics in Public Health; Health Inequalities; Health Technology Assessment: Ethical, Legal and Social Issues; Legal Issues in Public Health; Resource Allocation: Justice and Resource Allocation in Public Health.

References Centers for Disease Control and Prevention, 2002. Public Health’s Infrastructure: A Status Report. CDC, Atlanta, GA. Childress, J.F., Faden, R.R., Gaare, R.D., et al., 2002. Public health ethics: mapping the terrain. J. Law Med. Ethics 30, 170–178. Daniels, N., 2000. Accountability for reasonableness. Br. Med. J. 321, 1300–1301. Gostin, L.O., 2001. Public health law reform. Am. J. Public Health 91, 1365–1368. Gostin, L.O., 2004. The AIDS Pandemic: Complacency, Injustice, and Unfulfilled Expectations. University of North Carolina Press, Chapel Hill, NC. Gostin, L.O., 2007a. Global Health Law. Harvard University Press, Cambridge, MA. Gostin, L.O., 2007b. Public Health Law: Power, Duty, Restraint, second ed., Milbank Memorial Fund and University of California Press, New York and Berkeley. Institute of Medicine, 2002. The Future of the Public’s Health in the 21st Century. National Academies Press, Washington, DC. Lynch, J., Smith, G.D., Harper, S., et al., 2004. Is income inequality a determinant of population health? Part 1. A systematic review. Milbank Q. 82, 5–99. Lytton, T. (Ed.), 2005. Suing the Gun Industry: A Battle at the Crossroads of Gun Control and Mass Torts. University of Michigan Press, Ann Arbor. Perdue, W.C., Stone, L.A., Gostin, L.O., 2003. The built environment and its relationship to the public’s health: the legal framework. Am. J. Public Health 93, 1390–1394. Rogot, E., Sorlie, P., Johnson, N., et al. (Eds.), 1992. A Mortality Study of 1.3 Million Persons by Demographic, Social and Economic Factors: 1979–1985 Follow-Up. National Institutes of Health, Bethesda, MD.

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Further Reading Fidler, D.P., 2000. International Law and Public Health. Transnational Publishers, Ardsley, New York. Garrett, L., 2000. Betrayal of Trust: The Collapse of Global Public Health. Hyperion, New York. Goodman, R.A., Rothstein, M.A., Hoffman, R.E., et al., 2007. Law in Public Health Practice, second ed., Oxford University Press, New York. Gostin, L.O., 2008. Meeting basic survival needs of the worlds, least healthy people toward a framework convention on global health. Georget. Law J. 96, 989–1008.

Gostin, L.O., 1986. The future of public health law. Am. J. Law Med. 12, 461–490. Grad, F.P., 2005. The Public Health Law Manual, third ed., American Public Health Association, Washington, DC. Martin, R., Johnson, L. (Eds.), 2001. Law and the Public Dimension of Health. Cavendish Publishing Ltd, London. Reynolds, C., Howse, G., 2004. Public Health: Law and Regulation. Federation Press, Sydney, Australia. Taylor, A.L., 2004. Governing the globalization of public health. J. Law Med. Ethics 32, 500–502.

Functions and Deficiencies of B-Vitamins (and Their Prevention) Wolfgang Herrmann and Rima Obeid, University of Saarland, Homburg, Germany Ó 2017 Elsevier Inc. All rights reserved.

cell-toxic compound Hcy and for delivering sufficient methionine for S-adenosyl methionine (SAM) synthesis.

Folate (Vitamin B9) Natural Sources, Forms and Bioavailability Folates occur in a wide variety of foods of animal and plant origin. Liver, mushrooms, and green leafy vegetables are rich sources of folate. Folates occur in foods as polyglutamyl derivatives of tetrahydrofolic acid (FH4). 5-methyl-FH4 is the most important derivative. Food folate is mostly present as polyglutamate derivatives that must be hydrolyzed before they can be absorbed. After absorption, cells accumulate folate in a polyglutamate form. Folates in food are unstable and can be oxidized (by heat, light, and/or metal ions). Therefore, the bioavailability of naturally occurring folate can be reduced when foods are cooked. Pteroylmonoglutamate (folic acid) is a stable synthetic analog that is used in multivitamin preparations and is considered more bioavailable than naturally occurring folates.

Functions of Folate The novel biological role of folate is to transfer one-carbon units (C1 units) for the de novo synthesis of purines and pyrimidines required for DNA synthesis (Figure 1). Therefore, all living cells have strict requirements for folate to maintain their biological activities. This is especially important for cells with a higher division rate such as blood cells and for cells with a limited regeneration capacity such as cells of the nervous system. The other important role of folate is in the catabolism of the sulfur-containing amino acid homocysteine (Hcy). Folate donates a methyl group for Hcy that is converted into methionine. This metabolic pathway is important for eliminating the

Folate Deficiency The recommended dietary intake (RDI) of folate for adults is 400 mg day
1 (Institute of Medicine, 2000). Folate stores in the body are relatively low (5–10 mg); thus, the effect of a low folate ingestion or absorption may appear within a short time. The hepatic stores of folate might be sufficient to supply the daily requirements of the body for approximately 6 months. Clinical manifestations related to folate deprivation may become clear only after about 2–3 months. Folate deficiency is relatively common and the most important acquired causes of this deficiency are presented in Table 1. The pathological effect of folate deficiency is related to impairment of DNA and RNA synthesis and the methylation reactions. Folate deficiency exerts its effect on all rapidly dividing cells, like blood-forming cells and the enterocytes. Hence, cell division is slowed and red blood cells develop a megaloblastic form. Table 1

Acquired causes of folate deficiency

Increased requirements Reduced ingestion Increased destruction Secondary folate deficiency

Pregnancy, lactation, elderly Malabsorption, malnutrition, poverty, one-sided diet Heavy smokers, alcoholism, folate antagonists In vitamin B12–deficient subjects

Figure 1 Folate metabolism. DHF, dihydrofolate; Hcy, homocysteine; Met, methionine; MTHFR, methylen tetrahydrofolate reductase; THF, tetrahydrofolate; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionin.

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Diseases Described in Relation to Folate Deficiency Neural Tube Defects

Neural tube defects (NTDs) are one of the most common birth defects that have been related to folate deficiency during the prenatal period. Numerous studies have supplied evidence for the protective effect of a high folate intake in women of childbearing age (Steegers-Theunissen et al., 1991). Folate fortification programs in the United States, Canada, and Chile caused higher folate status in young women and reduced the incidence of NTDs by 15–50%. The mechanism by which folate deficiency can cause NTDs is not yet elucidated. Experimental models support the concept that low folate levels result in a lower DNA synthesis rate and reduced concentrations of SAM (S-adenosylmethionine), which is crucial for DNA methylation in the rapidly dividing cells of the embryo.

Cancer

Folate deficiency has been reported to increase the risk of cancer, owing to a disturbed DNA synthesis and mechanisms of DNA methylation and repair. DNA hypomethylation is accompanied by higher rates of gene transcription. Enough folate is crucial for uracil methylation to cytosine; otherwise uracil will be misincorporated into the newly synthesized DNA. These genetic manifestations will cause chromosomal instability and increase the risk of uncontrolled gene expression.

Neuropsychiatric Disorders

Folate deficiency is very common in patients with depressive disorders. Current evidence suggests that disturbed methylation in folate-deficient subjects may underlie mood disorders (Reynolds et al., 1984). Folic acid and SAM are frequently used as a complementary treatment in depression (Godfrey et al., 1990). Folate deficiency can also be a result of poor diet in patients with mood disorders. Therefore, folate deficiency can be primary or secondary in depression. Folate administration has been shown to enhance recovery of the mental state (Godfrey et al., 1990). Folate deficiency may cause elevated plasma concentrations of total homocysteine (tHcy), which is a risk factor for dementia. Furthermore, folate deficiency is common in patients receiving L-dopa and those receiving antiepileptics. Recent studies indicated that this metabolic dysfunction may be associated with a worse progression of the disease.

Folate Deficiency, Hyperhomocysteinemia, and Human Diseases

Folate deficiency is the most common cause of hyperhomocysteinemia. Elevated plasma concentrations of tHcy have been related to the risk of coronary diseases, stroke, and osteoporosis. Folate supplementation can improve the endothelial function. These effects might be mediated by the role of folate as an antioxidant or its important role in generating the methyl donor SAM.

Recommendations As a preventive measure, all healthy subjects should maintain a sufficient intake of folate. The mean folate intake in adults is around 300 mg day
1 in European countries. For pregnant women and women planning for pregnancy, an intake above

400 mg day
1 is recommended and is considered protective against neural tube defects. The US Food and Drug Administration mandated in 1998 that all grain products be fortified with folic acid (140 mg per 100 g grain). This policy is proposed to provide a daily intake of at least 400 mg day
1 folic acid in women of reproductive age. Folate status has been improved in women of childbearing age after the fortification. This strategy succeeded also in reducing NTDs. Folate supplementation is recommended for patients with depression, dementia, previous NTD child, or food malabsorption. Moreover, patients with moderate hyperhomocysteinemia (>12 mmol l
1) who are at risk for coronary or cerebral diseases may benefit from folate supplementation (i.e., 1 mg day
1). A preventative folate supplementation between 200 and 800 mg is advised for elderly people. Care should be taken to supplement folate together with vitamin B12, because folate deficiency can mask cobalamin deficiency and allow the neurological damage to progress.

Vitamin B12 (Cobalamin) Sources of Vitamin B12 in Human Diet Bacterial synthesis is the only source of vitamin B12. Plants, animals, and humans are unable to make this novel vitamin. Animals get the vitamin from the B12-synthesizing bacteria in their gastrointestinal tract. Humans can get vitamin B12 only from foods and foodstuffs of animal origins. Bacteria that grow in the human colon can synthesize the vitamin; however, no absorption can take place in this distant part of the intestine (Herbert, 1988). Cobalamin is sensitive to light and heat (Herbert, 1988). Cyanocobalamin is a synthetic stable derivative, which is supplied in most pharmaceutical preparations. Cyanocobalamin should be hydrolyzed in vivo into hydroxycobalamin before being biologically active. There are several vitamin B12-like molecules, also known as corrinoids, that have no biological significance for humans, or they may even play as vitamin B12 analogs.

Vitamin B12 Absorption and Transport Vitamin B12 in human foods occurs usually as complexes with food proteins. The release of the vitamin from food protein is a rate-limiting step for the absorption. Cobalamin release from food proteins may be initiated in presence of a cobalamin binder (R binder or haptocorrin) and some enzymes in saliva. In the acidic milieu of the stomach, R binder and intrinsic factor (IF, a glycoprotein secreted by the gastric parietal cells) compete for binding cobalamin. However, cobalamin binds favorably to IF in the jejunum, where the pH is more neutral and the pancreatic enzymes help to release cobalamin from the R binder (Seetharam, 1999). In the proximal ileum, IF-bound cobalamin can be absorbed via a specific receptor for intrinsic factor. Transcobalamin (TC), another B12 binder, is produced within the enterocytes. TC captures vitamin B12 and transfers it into the blood. TC binds 6–20% of total vitamin B12 in blood and facilitates delivering the vitamin into all DNA-synthesizing cells. This part is known as holotranscobalamin (holoTC). HoloTC enters the cells via a specific receptor for TC,

Functions and Deficiencies of B-Vitamins (and Their Prevention)

Figure 2

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The metabolic pathways enhanced by cobalamin.

TC-receptor. Approximately 80% of the total serum vitamin B12 circulates bound to haptocorrin, and this part has no known biological role. Restricted intake or reduced absorption of vitamin B12 causes a sharp decrease in holoTC owing to the short half-life of this complex (6 min), whereas total serum cobalamin (80% bound to haptocorrin) is less affected by a short-term low intake of vitamin B12.

Functions of Vitamin B12 There are only two vitamin B12-dependent pathways in humans. First, the cytosolic enzyme methionine synthase, which converts Hcy into methionine, utilizes methylcobalamin as a cofactor. Second, 50 -deoxyadenosyl-cobalamin is a cofactor for the mitochondrial enzyme methylmalonyl-CoA mutase (Figure 2). Cobalamin is required for the generation of the active form of folate (tetrahydrofolate, or THF) from 5-MTHF via methionine synthase. Moreover, cobalamin is important for the generation of the methyl donor SAM. Cobalamin has a role in synthesizing DNA and RNA and maintaining DNA methylation.

Estimation of Vitamin B12 Status Total vitamin B12 is not reliable in detecting vitamin B12 deficiency because of its low diagnostic sensitivity and specificity (Herrmann et al., 2005). Total B12 consists of two main fractions: the metabolically inert major part, holohaptocorrin (80% of total B12), and the metabolically active minor part, holoTC (20% of total B12). HoloTC has a higher diagnostic sensitivity and specificity compared with total B12. Functional B12 deficiency is indicated by measuring serum concentrations of sensitive metabolic markers like methylmalonic acid (MMA) and tHcy. While concentrations of tHcy will increase in folate, B12, and vitamin B6 deficiency, MMA increment is sensitive to B12 deficiency. Serum concentration of MMA is, however, not fully specific for vitamin B12 deficiency because MMA elevation can be related to renal insufficiency. At present, the combination of holoTC and MMA is recommended for evaluating vitamin B12 status.

Vitamin B12 Deficiency Causes of vitamin B12 deficiency are summarized in Table 2. Chronic vitamin B12 deficiency may cause megaloblastic anemia and neurological dysfunction. Because folate deficiency is more common than cobalamin deficiency and because the clinical and hematological manifestations are similar, many vitamin B12-deficient patients are mistakenly treated with folate. This will lead to development of neurological disorders. In general, both folate and vitamin B12 should be administered to patients who have either of these deficiencies.

Cobalamin Deficiency Related to a Low Intake of the Vitamin

Chronic low intake of cobalamin can cause deficiency. Because of the large body stores of the vitamin, the deficiency takes years to develop. Subjects who adhere to a lifelong strict vegetarian diet develop cobalamin deficiency. The severity of cobalamin deficiency is related to the degree of animal food restriction and to the duration of the vegetarian lifestyle. Metabolic markers indicating cobalamin deficiency were more common in lacto- and lacto-ovo vegetarians compared with omnivorous subjects (Herrmann et al., 2003). Vegan subjects who ingest no animal foods have usually the worst cobalamin status (Herrmann et al., 2003). Metabolic and clinical signs of cobalamin deficiency have been reported in Table 2

Acquired causes of cobalamin deficiency

Restricted intake Reduced absorption Increased demands Medications that alter gastrointestinal pH Gastrointestinal morbidities

Vegetarians, children of vegetarian mothers, poverty, malnutrition, anorexia nervosa Pancreatic insufficiency, pernicious anemia Bleeding, pregnancy, lactation Proton pump inhibitors, antihistamine H2 (cimitidine) Crohn disease, celiac disease, total gastrectomy, atrophic gastritis, chronic pancreatitis, intestinal parasites, intestinal bacterial overgrowth

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Functions and Deficiencies of B-Vitamins (and Their Prevention)

newborn babies from strict vegetarian mothers or in breastfed infants from deficient mothers.

Vitamin B12 Deficiency in Higher Age

Vitamin B12 deficiency is a major public health problem in elderly populations (Obeid et al., 2004). The incidence rate ranges between 10% and 60% depending on the marker used to rule out the deficiency and the age groups investigated (Herrmann et al., 2005). Malabsorption is the main cause of vitamin B12 deficiency in elderly people. Atrophic gastritis, achlorhydria, infection with Helicobacter pylori, and pernicious anemia are common in elderly people and may substantially inhibit the absorption of vitamin B12.

Renal Insufficiency

Chronic hemodialysis patients are at risk for cobalamin deficiency. Therapeutic doses of vitamin B12 induce significant improvements in serum concentrations of MMA and tHcy in renal patients. Because concentrations of MMA and tHcy increase even in mild degrees of renal insufficiency, it is difficult to determine how much of MMA and tHcy elevation is attributable to B12 deficiency. Impaired kidney function limits the use of MMA as a functional marker of vitamin B12 status in renal patients. A significant reduction of MMA after B12 administration may indicate a pretreatment B12 deficiency.

Recommendations

The RDI of vitamin B12 is 2.4 mg day
1 for adults. A typical Western diet provides an average intake of 2–6 mg day
1 of B12. Because a low intake of vitamin B12 and malabsorption of the vitamin are common especially in vegetarians and in elderly people, respectively, an additional source of the vitamin is highly recommended. A study on postmenopausal women has shown that a total daily intake of 6 mg day
1 of B12 is sufficient to maintain normal vitamin B12 marker in blood. The use of vitamin B12 supplements (1–50 mg) was associated with a better vitamin status in elderly people. Moreover, most elderly people who have already developed metabolic signs indicating vitamin B12 deficiency (i.e., elevated MMA) require more than 100 mg of oral B12 to normalize serum MMA, which is a larger dose than is available in most standard multivitamins and vitamin B12 supplements. No adverse effects for vitamin B12 have been reported.

Transport and Metabolism B6 absorption in the gut involves phosphatase-mediated hydrolysis followed by transport of the nonphosphorylated forms into mucosa cells. The absorption takes place by a nonsaturable passive diffusion mechanism. Most of the absorbed vitamin B6 goes to the liver and is transformed there to PNP, PLP, and PMP by PL kinase. PMP is also generated from PLP via aminotransferase reactions. PLP is bound to various proteins in tissues. Excess of free PLP is hydrolyzed and released by liver and other tissues in nonphosphorylated forms. PLP is the major B6 form in blood plasma, and albumin is the major binding protein for this compound.

Functions of Vitamin B6 The active form of vitamin B6 is PL, which is coenzyme in more than 60 enzymatic reactions involved in amino acid metabolism. Furthermore, it catalyzes the d-aminolevulinate synthase reaction that is part of heme synthesis. Tryptophan metabolism is dependent on B6 status because kynureninase requires PLP, and this enzyme is very sensitive to B6 deficiency. The tryptophan load test is used to establish B6 status. Determination of excretion of kynurenic and xanthurenic acids indicates B6 nutritional status. PLP is also involved in metabolism of sulfur-containing amino acids like Hcy, methionine, taurine, and cysteine. Consequently, vitamin B6 deficiency influences the glutathione metabolism in the liver and in that way the redox status. Homocystinuria and cystathioninuria are rare inborn errors of metabolism involving the B6-dependent enzymes cystathionine b-synthase and g-cystathionase. Both diseases have a wide range of clinical features and mental retardation and can be treated by large dosages of PN.

Tolerable Upper Intake Level The critical adverse effect from high intake of B6 is sensory neuropathy. The evidence of neurotoxicity due to administration of B6 is mostly related to case reports of patients with severe effects, which are associated with extremely high B6 intakes. Severe toxicity can be produced at doses of 500 mg day
1 or more after prolonged periods of treatment. Minor neurological symptoms may be apparent at dosages of 100 mg day
1 or more when administered chronically (>several months). The tolerable upper intake level of 25 mg per day has not been associated with adverse effects.

Vitamin B6 (Pyridoxine) Forms and Sources of Vitamin B6

Vitamin B6 Deficiency

Vitamin B6 comprises a group of six related compounds: pyridoxal (PL), pyridoxine (PN), pyridoxamine (PM), and their respective 50 -phosphates (PLP, PNP, and PMP). The major forms of B6 in animal tissue are PLP and PMP. Plant-derived foods primarily contain PN and PNP. Vitamin B6 is widespread in nature. It is synthesized by microbes but also by higher-developed plants. Meat and vegetables are rich sources of vitamin B6. The loss of vitamin B6 during food preparation (on average 30–40%) depends on the vitamin B6 form present in the food source, because PN is less heat-sensitive than PL or PM.

PN deficiency has a significant effect on neuronal development (Morre et al., 1978). The classic symptoms of B6 deficiency are seborrheic dermatitis, microcytic anemia, epileptic convulsions, depression, Parkinson’s disease, and impaired cognitive function. Microcytic anemia reflects decreased hemoglobin synthesis. The role as cofactor of decarboxylases may explain the onset of convulsions in B6 deficiency. In B6-depleted animals, low levels of neurotransmitters such as dopamine, serotonin, and g-aminobutyrate have been demonstrated. Conversely, higher dietary intake of B6 is associated with a decreased risk for Parkinson’s disease. PLP is essential for transformation of tryptophan

Functions and Deficiencies of B-Vitamins (and Their Prevention) Table 3 Diseases and conditions related to abnormal vitamin B6 metabolism Older age Malnutrition Atherosclerosis and cerebrovascular diseases Neurodegenerative diseases Renal insufficiency, dialysis patients Gastrointestinal diseases Hyperhomocysteinemia Alcoholism Niacin deficiency

to niacin. Diseases where impaired tryptophan metabolism was demonstrated and B6 was supplemented are asthma, diabetes, some tumors, pellagra, and rheumatoid arthritis. B6 deficiency diminishes the humoral and cellular immune response (Talbott et al., 1987). Table 3 summarizes diseases and conditions in which vitamin B6 has been described to play a role.

Recommendations The mean daily PN intake in the United States and several European countries ranges between 1.7 and 3.6 mg. The daily requirement of vitamin B6 is related to protein intake. An intake of 15 mg g
1 dietary protein is recommended for adults, which is equivalent to 2–3 mg of B6 per day. Individuals taking high-estrogen contraception may have a higher requirement of B6. However, there is no evidence that combined oral contraceptives (estrogen plus progestagen) increase the need of PN. There is a high frequency of vitamin B6 deficiency in elderly people that increases significantly with age and ranges from 23% (65–75 years) to 44% (>80 years) (Herrmann et al., 1999). There is also a very high prevalence of lowered B6 levels in renal patients (Herrmann et al., 2001). Doses of 5–25 mg B6 per day can be safely used. Higher doses of B6 have been used for treatment of homocystinuria, premenstrual syndrome, depression, Down Syndrome, hyperkinesis, autism, neurosis, Hodgkin disease, and Parkinson’s disease.

See also: Aging: Nutrition and the Older Adults.

References Godfrey, P.S., Toone, B.K., Carney, M.W., et al., 1990. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336, 392–395. Herbert, V., 1988. Vitamin B-12: plant sources, requirements, and assay. Am. J. Clin. Nutr. 48, 852–858.

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Herrmann, W., Obeid, R., Schorr, H., Geisel, J., 2005. The usefulness of holotranscobalamin in predicting vitamin B12 status in different clinical settings. Curr. Drug Metab. 6, 47–53. Herrmann, W., Quast, S., Ullrich, M., Schultze, H., Bodis, M., Geisel, J., 1999. Hyperhomocysteinemia in high-aged subjects: relation of B-vitamins, folic acid, renal function and the methylenetetrahydrofolate reductase mutation. Atherosclerosis 144, 91–101. Herrmann, W., Schorr, H., Geisel, J., Riegel, W., 2001. Homocysteine, cystathionine, methylmalonic acid and B-vitamins in patients with renal disease. Clin. Chem. Lab. Med. 39, 739–746. Herrmann, W., Schorr, H., Obeid, R., Geisel, J., 2003. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am. J. Clin. Nutr. 78, 131–136. Institute of Medicine, 2000. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. National Academy Press, Washington, DC, pp. 150–195. Morre, D.M., Kirksey, A., Das, G.D., 1978. Effects of vitamin B-6 deficiency on the developing central nervous system of the rat: myelination. J. Nutr. 108, 1260–1265. Obeid, R., Schorr, H., Eckert, R., Herrmann, W., 2004. Vitamin B12 status in the elderly as judged by available biochemical markers. Clin. Chem. 50, 238–241. Reynolds, E.H., Carney, M.W., Toone, B.K., 1984. Methylation and mood. Lancet 2, 196–198. Seetharam, B., 1999. Receptor-mediated endocytosis of cobalamin (vitamin B12). Annu. Rev. Nutr. 19, 173–195. Steegers-Theunissen, R.P., Boers, G.H., Trijbels, F.J., Eskes, T.K., 1991. Neural-tube defects and derangement of homocysteine metabolism. N. Engl. J. Med. 324, 199–200. Talbott, M.C., Miller, L.T., Kerkvliet, N.I., 1987. Pyridoxine supplementation: effect on lymphocyte responses in elderly persons. Am. J. Clin. Nutr. 46, 659–664.

Further Reading Clarke, R., Grimley, E.J., Schneede, J., et al., 2004. Vitamin B12 and folate deficiency in later life. Age Ageing 33, 34–41. Clarke, R., Sherliker, P., Hin, H., et al., 2007. Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, holotranscobalamin. Clin. Chem. 53, 963–970. Coppen, A., Bolander-Gouaille, C., 2005. Treatment of depression: time to consider folic acid and vitamin B12. J. Psychopharmacol. 19, 59–65. Hvas, A.M., Juul, S., Bech, P., Nexø, E., 2004. Vitamin B6 level is associated with symptoms of depression. Psychother. Psychosom. 73, 340–343. Monsen, A.L., Refsum, H., Markestad, T., Ueland, P.M., 2003. Cobalamin status and its biochemical markers methylmalonic acid and homocysteine in different age groups from 4 days to 19 years. Clin. Chem. 49, 2067–2075. Obeid, R., Munz, W., Jager, M., Schmidt, W., Herrmann, W., 2005. Biochemical indexes of the B vitamins in cord serum are predicted by maternal B vitamin status. Am. J. Clin. Nutr. 82, 133–139. Reynolds, E., 2006. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 5, 949–960. Spence, J.D., Bang, H., Chambless, L.E., Stampfer, M.J., 2005. Vitamin intervention for stroke prevention trial: an efficacy analysis. Stroke 36, 2404–2409. Zaina, S., Lindholm, M.W., Lund, G., 2005. Nutrition and aberrant DNA methylation patterns in atherosclerosis: more than just hyperhomocysteinemia? J. Nutr. 135, 5–8.

Future Organization of Cancer Care Karol Sikora, Medical School, University of Buckingham, Buckingham, UK Ó 2017 Elsevier Inc. All rights reserved.

Introduction In the field of cancer medicine, great strides have been made in understanding the fundamental biology of cancers and impressive treatments have emerged, resulting in markedly prolonged survival for many patients. These advances mean that cancer could well become a chronic disease within the next 20 years, but that promise depends on sustained investment in innovation, both in diagnostics and therapies, as well as on society’s willingness to pay for continued increasing innovation. The three great challenges facing cancer medicine in the future will be an understanding of the biology of the very wide range of cancers affecting different organs, the increased prevalence of the disease that can be expected in an aging population, and the optimal way to deliver care across a wide range of economic environments. How will biomedical science and health-care systems rise to these challenges? An understanding of the way in which advances have been applied in personalizing treatments in the past points a way ahead to address future challenges. Our cancer future will emerge from the interaction of four factors: the success of new technology, society’s willingness to pay, future health-care delivery systems, and the financial mechanisms that underpin them. The only way to reduce the costs of cancer care is to ensure that the right patient gets the right treatment. Investing in sophisticated diagnostics is a clear imperative in making personalized medicine for cancer a reality and delivering it as close to patients’ homes as possible. The age of the world’s population is rising dramatically. This will increase the total burden of cancer, with many patients living with considerable comorbidity. At the same time, new technology in many areas of medicine is bringing improvements to the quality and length of life. Major innovations in the following six areas are likely to have the greatest impact on cancer: l l

l l l l

molecularly targeted drugs with associated sophisticated diagnostic systems to personalize care; biosensors to detect, monitor, and correct abnormal physiology and to provide surrogate measurements of cancer risk; our ability to modify the human genome through new, systemically administered targeted vectors; the continued miniaturization of surgical intervention through robotics, nanotechnology, and precise imaging; computer-driven interactive devices to help with everyday living; and the use of virtual reality systems, which, together with novel mood-control drugs, will create an illusion of wellness.

Developments in all these areas will need to be anticipated in designing the future configuration of cancer services. Global providers will arise to deliver optimal care tailored to the local economic environment. The future landscape of cancer service delivery will be very different from now: fast-paced,

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competitive, consumer-focused, and Internet-driven, with far more real patient empowerment through educated choice. New organizations with associated franchises are likely to emerge to drive optimal cancer care in a world where national borders and cultures will be no barrier to excellence in service delivery. The same service changes that have occurred in mobile phones, airline travel, and insurance will take place in health care. The consumer will be the king. This is difficult to imagine when we see how cancer services are still provided today, even in some wealthy countries, especially Britain. Over the last 20 years, a huge amount of fine detail of the basic biological processes that become disturbed in cancer has been amassed. We now know the key elements of growth factor binding, signal transduction, gene transcription control, cell cycle checkpoints, apoptosis, and angiogenesis. These have become fertile areas to hunt for rationally based anticancer drugs. This approach has already led to a record number of novel compounds currently in trials. Indeed expensive targeted drugs such as rituximab, Herceptin, imatinib, gefitinib, Avastin, and Erbitux are now all in routine clinical use. Over the next decade, there will be a marked shift in the types of agents used in the systemic treatment of cancer. Because we know the precise targets of these new agents, there will be a revolution in how we prescribe cancer therapy. Instead of defining drugs for use empirically and relatively ineffectively for different types of cancer, we will identify a series of molecular lesions in each tumor biopsy. Future patients will receive drugs that target these lesions directly. The Human Genome Project provides a vast repository of comparative information about normal and malignant cells. The new therapies will be more selective and less toxic and will be given for prolonged periods of time, in some cases for the rest of the patient’s life. Many will be given as tablets, requiring less frequent clinic visits but still with close monitoring. This will lead to a radical overhaul of how we provide cancer care. Investment in more sophisticated diagnostics is going to be essential to target treatment to those in whom it will have the biggest impact. Holistic systems such as genomics, proteomics, metabolomics, and methylomics provide fascinating clues to understanding disturbed cell growth. By developing simple, reproducible, and cheap assays for specific biomarkers, a battery of companion diagnostics will emerge. It is likely that for the next decade, these will be firmly rooted in tissue pathology, making today’s histopathologist essential to move this exciting field forward. Ultimately, the fusion of tissue analysis with imaging technologies may make virtual biopsies possible for any part of the body – normal and diseased. The radiologists of the future will be the new pathologists in a world without needles. Individual cancer risk assessment by DNA analysis will lead to tailored prevention messages and a specific screening program to pick up early cancer. This will have far-reaching public health consequences. Cancer-preventive drugs will be developed to reduce the risk of further genetic deterioration.

International Encyclopedia of Public Health, 2nd edition, Volume 3

http://dx.doi.org/10.1016/B978-0-12-803678-5.00046-1

Future Organization of Cancer Care The use of gene arrays to monitor serum for fragments of DNA containing defined mutations could ultimately develop into an implanted gene chip. When a significant mutation is detected, the chip would signal the holder’s home computer and set in train a series of investigations based on the most likely type and site of the primary tumor. There will be an increase in the total prevalence of cancer as a result of improved survival, as well as a shift in the distribution of cancer types toward those with longer survival, such as prostate cancer. This will create new challenges for assessing the risks of recurrence, designing care pathways, use of information technology, and improving access to services. There will be new opportunities for further targeting and development of existing therapies as experience grows with risk factors over the longer term. Careful monitoring of patient experiences could help in improving results. Cancer could soon become a long-term management issue for many patients, where they enjoy a high quality of life even with a degree of chronic illness. The funding of cancer care will become a significant problem. Already we are seeing inequity in access to the taxanes for breast and ovarian cancers, and gemcitabine for lung and pancreatic cancers. These drugs are only palliative, adding just a few months to life. The emerging compounds are likely to be far more successful, and their long-term administration will be considerably more expensive. Increased consumerism in medicine will lead to increasingly informed and assertive patients seeking out novel therapies and bypassing traditional referral pathways through global information networks. It is likely that integrated molecular solutions for cancer will develop, leading to even greater inequity than at present. Cost-effectiveness analyses will be used to scrutinize novel diagnostic technology as well as therapies.

Delivering Value Future cancer services will be rigorously reviewed for their value. Two simple value equations pertain. The first relates value to access and quality of services. VALUE ¼

ðaccess þ qualityÞ cost

Providing better access and increasing quality can obviously add costs to the service. Better value will be obtained from providers who can use new technology, recruit more productive staff, create incentives for greater efficiency, and deliver economies of scale. These improvements are unlikely to come from the public sector acting alone. The second equation expresses the value of a specific treatment intervention. Sophisticated new diagnostics are likely to increase the value of treatments by guiding the right treatment to the right patient – heralding an era of personalized medicine. A revolution in diagnostics will lead to increased effectiveness of new therapies, because they will increasingly be given only to those patients who will benefit from them, thus increasing their value. Quantifying the top line of this equation is difficult, as can be seen in many recent health technology assessments. While increase in overall survival is easy to measure, the toxicity and lifestyle impact is much

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more difficult to quantify because of huge variability between patients. VALUE ¼

ðbenefit  toxicity  lifestyle changeÞ cost

However imperfect they may be, these two equations will relentlessly drive the economic future of cancer in all healthcare systems.

The Future Within 20 years, cancer will be considered a chronic disease, joining conditions such as diabetes, heart disease, and asthma. These conditions impact on the way people live, but do not inexorably lead to death. The model of prostate cancer, where many men die with it rather than from it, will become more usual. Progress will be made in preventing cancers. Even greater progress will be made in understanding the myriad causes of cancer. Our concepts will be different to those of today, and the new ways in which cancer will be detected, diagnosed, and treated will be crucial to understanding the future. When a cancer does develop, refinements of current technologies and techniques – in imaging, radiotherapy, and surgery – together with the availability of targeted drugs, will make it controllable. Cure will still be sought, but it will not be the only satisfactory outcome. Patients will be closely monitored after treatment, but fear that cancer will definitely kill, still prevalent in the early years of the twenty-first century, will be replaced by an acceptance that many forms of cancer are a consequence of old age. Looking into the future is fraught with difficulties. Medicine will be overtaken by unexpected step changes in innovation. For this reason, economic analysis of the impact of developments in cancer care is difficult. The greatest benefit will be achieved simply by ensuring that the best care possible is on offer to the most patients. This would be irrespective of their socioeconomic circumstances and of any scientific developments. But this is unrealistic. Technologies are developing fast, particularly in imaging and the exploitation of the human genome. Well-informed patients, with adequate funds, will ensure that they have rapid access to the newest and the best, wherever it is in the world. More patients will benefit from better diagnosis and newer treatments, with greater emphasis on quality of life. Innovation will bring more inequality to health. The outcome of the same quality of care differs today between socioeconomic groups, and it will continue to do so. Clinicians in Europe will continue to be dependent on technologies primarily designed for the major health market in the world, the United States, which currently consumes nearly 55% of cancer medication but contains less than 5% of the population. European legislation covering clinical trials has threatened to bring research in the United Kingdom to a grinding halt, while ethicists – zealously overinterpreting privacy legislation – could force the imposition of restrictions on the use of tissue. Targeted niche drugs will be less appealing to industry, because the costs of bringing each new generation of drugs to market will not be matched by the returns from the most economically successful drugs

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Future Organization of Cancer Care

Table 1 l l l l l l l

The challenges of cancer care

Increasing the focus on prevention. Improving screening and diagnosis and the impact of this on treatment. New targeted treatments – how effective and affordable will they be? How the expectation of patients and their carers will translate into care delivery? Reconfiguration of health services to deliver optimal care. The impact of reconfiguration on professional territories. Will society accept the financial burden of these opportunities?

that are currently on the market. The delivery of innovation will be underpinned by patient expectation. The wellinformed will be equal partners in deciding the health care they will receive. Much of it will take place close to their homes, using mechanisms devised by innovative service providers. These developments will have huge implications for the training of health professionals and for the demarcations between specialties. Emerging technologies will drive the change. Intraprofessional boundaries will blur; doctors from traditionally quite distinct specialties may find themselves doing the same job. Some clinical responsibilities will be taken up by health professionals who will not be medically qualified. All professionals are likely to find challenges to their territory hard to accept. Table 1 shows the challenges that need to be addressed in order to deliver most health benefit.

Prevention and Screening At the beginning of the twenty-first century, 10 million people in the world developed cancer each year. The cause of these cancers is known in roughly 75% of cases: 3 million are tobacco-related; 3 million are a result of diet; and 1.5 million are caused by infection. In the United Kingdom, 130 000 people died from cancer each year, even though many of those cancers were preventable, with one-third related to smoking. But cancer prevention absorbs only 2% of the total funding of cancer care and research. Antismoking initiatives are considered to be successful, although it has taken 50 years from the time the association between smoking and cancer was first identified. In the 1960s, 80% of the population smoked; by 2006, the average was under 30%. This masks real health inequality, the percentage of smokers in the higher socioeconomic classes is well under 10%, while the percentage in the deprived is still about 50% in some parts of the country. Despite the known risks, if friends and family smoke and there is no social pressure to stop, there is no incentive to stop. Banning smoking in public places will lead to a further drop of approximately 4%. Increases in tax have been a powerful disincentive to smoke, but the price of a packet of cigarettes is so high that smokers turn to the black market: As many as one in five cigarettes smoked is smuggled into the country. Lung cancer is now a rare disease in higher socioeconomic groups; it is a disease of poverty.

Lessons from antismoking initiatives will be instructive for prevention in the future. Although the link between poor diet, obesity, and lack of exercise and cancer has not been confirmed, there is sufficient circumstantial evidence to suggest that strong associations will be found. There will be bans on advertising for potato chips, candy, and soft drinks on television; the introduction of a health tax on these products; and a ban on sponsorship of any public event by manufacturers of these products. By 2020, obesity among the middle classes will be socially unacceptable, but it will remain common among the economically disadvantaged. Creating meaningful, imaginative incentives for people to adopt healthy lifestyles will be a major challenge. The future prevention picture will be colored by postgenomic research. It is now accepted that about 100 genes are associated with the development of a whole range of cancers. The detection of polymorphisms in low-penetrance cancerrelated genes – or a combination of changed genes – will identify people who are at increased risk. Within 20 years, most people will be genetically mapped. The information – gained from a simple blood test or buccal smear – will be easily stored on a smart card. Legislation will be required to prevent this information being used to determine an individual’s future health status for mortgage, insurance, and employment purposes. However, the process of mapping will reveal that every person who has been screened will carry a predisposition to certain diseases. People will learn to live with risk. Today, the average age at diagnosis of cancer is 68. Improvements in screening, detection, and diagnosis may reduce this for some cancers, but increased longevity could well increase this figure. A predisposition for some cancers that currently manifests in the seventh or eighth decade will in the future be detected in young adult life and corrected successfully while the patients are still in their 30s. Increasing age will remain the strongest risk predictor. Little of what has been described is not happening already in some form, but the computing power of the future will bring accurate calculation of risk, and risk predictions will take place on a currently unimaginable scale. Screening programs will be developed on a national basis if they are simple, robust, and cheap. Patients will expect that screening will take place at a convenient venue for them, such as shopping malls, and that it will not be painful or overly time-consuming. Health professionals will demand that any program be accurate and not give misleading results, and governments will demand that its costs lead to more effective use of other resources. Novel commercial providers of risk assessment services are likely to emerge (Table 2). Table 2 l l l l l l

Balancing cancer risk

Great health inequity exists in smoking-related diseases. Novel prevention strategies are likely to lead to similar inequity. Creating meaningful incentives to reduce risk will be essential. Individually tailored messages will have greater power to change lifestyles. Biomarkers of risk will enhance the validation of cancer-preventive drugs. Novel providers of risk assessment and correction will emerge.

Future Organization of Cancer Care

Detecting Cancer Cancers are fundamentally somatic genetic diseases that result from several causes: physical, viral, radiation, and chemical damage. Other processes are also implicated, e.g., chronic inflammatory change, immunosurveillance, and failure of programmed cell death (apoptosis). In the future, cancer will no longer be understood as a single entity – it will be considered to be a cellular process that changes over time. Many diseases labeled as cancer today will be renamed, as their development will not reflect the new paradigm. Patients will accept that cancer is not a single disease and increasingly understand it as a cellular process. Many more old people will have increased risk or a precancer. This has huge implications for cancer services. Today, most diagnoses of cancer depend on human interpretation of changes in cell structures seen down a microscope. Microscopes will be superseded by a new generation of scanners to detect molecular changes. These scanners will build up a picture of change over time, imaging cellular activity rather than just a single snapshot. We will have the ability to probe molecular events that are markers for early malignant change. This dynamic imaging will lead to more sensitive screening and treatments; imaging agents that accumulate in cells will exhibit telltale signs of precancer activity and will be used to introduce treatment agents directly. Imaging and diagnosis will be minimally invasive and will enable the selection of the best and most effective targeted treatment (Table 3). Even better imaging will be able to pick up early disease phases and deal with them at a stage long before they are currently detectable. These techniques will also be crucial in successful follow-up. A patient who has a predisposition to a certain cancer process will be monitored regularly and offered treatment when necessary. Not all cancers will be diagnosed in these earliest of stages – some patients will inevitably fall through the screening net. Nevertheless, there will be opportunities to offer less-invasive treatment than at present. Surgery and radiotherapy will continue, but in greatly modified form as a result of developments in imaging. Most significantly, surgery will become part of integrated care. Removal of tumors or even whole organs will remain necessary on occasion. However, the surgeon will be supported by 3D imaging, by radiolabeling techniques to guide incisions, and by robotic instruments. And although many of the new treatments made possible by improved imaging will be biologically driven, there will still be a role for radiotherapy – the most

Table 3 l l l l l l

Innovation in diagnostics

Radiology and pathology will merge into cancer imaging and classification. Dynamic imaging will create a changing image of biochemical abnormalities. Cancer changes will be detected prior to disease spread from primary site. Greater precision in surgery and radiotherapy will be used for precancer. Molecular signatures will determine treatment choice. Cost control will be essential for health-care payers to avoid inefficient diagnostics.

207

potent DNA-damaging agent – to treat cancer with great geographical accuracy. The targeting of radiotherapy will be greatly enhanced, enabling treatment to be more precise. In addition to the reconfiguration and merging of the skills of clinicians, the delivery of care will also change. Minimally invasive treatments will reduce the need for long stays in hospital. As more patients are diagnosed with cancer, the need to provide the care close to where patients live will be both desirable and possible, and it will be expected by the patients. The prospect of highly sophisticated scanning equipment and mobile surgical units being transported to where they are required is not unrealistic. Technicians, surgical assistants, and nurses would provide the hands-on care, while technical support will be provided by the new breed of clinician – a disease-specific imaging specialist working from a remote site. Cost control will be an essential component of the diagnostic phase. Health-care payers will create sophisticated systems to evaluate the economic benefits of innovative imaging and tissue analysis technology.

New Treatment Approaches Future cancer care will be driven by the least invasive therapy that is consistent with long-term survival. Eradication, although still desirable, will no longer be the primary aim of treatment. Cancers will be identified earlier, and the disease process will be regulated in a similar way to chronic diseases such as diabetes. Surgery and radiotherapy will still have a role, but how much will depend on the type of cancer a patient has and the stage at which the disease is identified. It will also depend on how well the drugs being developed today perform in the future. Cancer treatment will be shaped by a new generation of drugs (Figure 1). The profile of this new generation of drugs will depend critically on the relative success of agents currently in development. Over the next 3–5 years, we will understand more fully the benefits that compounds such as kinase inhibitors are likely to provide. It is estimated that there are about 500 drugs currently being tested in clinical trials. Of these, around 300 inhibit specific molecular targets. But this number is set to rise dramatically: 3000 compounds will be available to enter clinical trials by 2020, and 5000 by 2025. Many of these drug candidates will be directed at the same molecular targets. The pharmaceutical industry is racing to screen those most likely to succeed in the development process. Tremendous commercial pressures have arisen from the loss of patent protection for the majority of older high-cost chemotherapy drugs in 2014. Unless new premium-priced innovative drugs are available, cancer drug provision will come from global generic manufacturers currently gearing up for this change. So what will these drug candidates look like? Small molecules are the main focus of current research, most of which are designed to target specific gene products that control the biological processes associated with cancer, such as signal transduction, growth of new blood vessels (angiogenesis), cell cycle control, apoptosis, inflammation, invasion, and differentiation. Treatment strategies involving monoclonal antibodies, cancer vaccines, and gene therapy are also being

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Future Organization of Cancer Care

Figure 1 Predicted new drug application dates for molecular therapies in the United States. The years 2005–10 saw an explosion of novel therapies coming into clinical use outside the research setting.

explored. Although we do not know exactly what these targeted agents will look like, there is growing confidence that they will work. More uncertain is their overall efficacy at prolonging survival. Many could just be expensive palliatives. In future, advances will be driven by a better biological understanding of the disease process (Figure 2). Already we are seeing the emergence of drugs targeted at a molecular level: Herceptin, directed at the HER2 protein; Glivec, which targets the Bcr-Abl tyrosine kinase; and Iressa and Tarceva, directed at EGFR tyrosine kinase. These therapies will be used across a range of cancers. What will be important in future is whether a person’s cancer has particular biological or genetic characteristics. Traditional categories will continue to be broken down, and genetic profiling will enable treatment to be targeted at the right patients. Patients will understand that treatment options are dependent on their genetic profile. The

risks and benefits of treatment will be much more predictable than today. Therapies will emerge from our knowledge of the human genome and the use of sophisticated bioinformatics. Targeted imaging agents will be used to deliver therapy at the time of screening or diagnosis. Monitoring cancer patients will also change as further developments in technology allow the disease process to be tracked much more closely. Treatment strategies will reflect this, and drug resistance will become much more predictable. Biomarkers will allow specialists treating cancer patients to measure if a drug is working on its target. If it is not, an alternative treatment strategy will be sought. Tumor regression will become less important as clinicians look for molecular patterns of disease and its response. There will be greater focus on therapies designed to prevent cancer. A tangible risk indicator and risk-reducing therapy,

Figure 2 The future of cancer drug development. Drugs will enter patients for the first time accompanied by effective biomarkers. These in turn will be used to identify surrogate markers of response, thus selecting patients early in pivotal studies to either continue or stop a specific trial. In addition, continued laboratory research will be used to create diagnostic kits to identify signatures of response. CRO, contract research organization; MED, minimally effective dose; PD, pharmacodynamic.

Future Organization of Cancer Care Table 4

Cancer diagnostics – future

Baseline 2025

Upside 2025

Risk prediction in small subsets

l

Examples of early cancer detection Used for dose determination for some mechanistically based drugs Accepted by regulators in some diseases

Population risk banding for cancer l Identify people for chemoprevention l Massive expansion in patients with early cancer l Universal use

l

Short-term surrogates used to register and obtain sNDAs

sNDA, supplementary new drug application.

along the lines of cholesterol and statins, would allow people to monitor their risk and to intervene. Delivering treatment early in the disease process will also be possible, because subtle changes in cellular activity will be detectable. This will lead to less-aggressive treatment. The role of industry in the development of new therapies will continue to change. Smaller, more specialized companies, linked to universities, will increasingly deliver drug candidates and innovative diagnostics for the major pharmaceutical companies to market (Table 4). People will be used to living with risk and will have much more knowledge about their propensity for disease. Programs will enable people to determine their own predisposition to cancer. This in turn will encourage health-changing behavior and will lead people to seek out information about the treatment options available to them. Patients will become more involved in decision-making as medicine becomes more personalized. Indeed, doctors may find themselves being directed by well-informed patients. This, and an environment in which patients are able to demonstrate choice, will help drive innovation toward those who will benefit. However, inequity based on education, wealth, and access will continue.

Barriers to Innovation Innovation in cancer treatment is inevitable. However, there are certain prerequisites for the introduction of new therapies (Table 5). First, innovation has to be translated into usable therapies. These therapies must be deliverable, to the right biological target and to the right patient, in a way that is acceptable by patient, health-care professional, and society. Late-stage attrition – failure of a drug at a late stage in the development Table 5 l l

l l l l

The uncertainty of novel drugs for cancer

Will the new generation of small-molecule kinase inhibitors really make a difference or will they just provide expensive palliation? How will the major pharmaceutical companies cope when most of the current high-value cytotoxics lose patent protection in 2008 (when they can be supplied as cheaper generic drugs)? Can expensive late-stage attrition really be avoided in cancer drug development? How will sophisticated molecular diagnostic services be provided? Will effective surrogates for cancer-preventive agents emerge? Will patient choice involve cost considerations in guiding therapy?

209

pipeline, with the loss of substantial research investment – must be minimized. Innovation must also be marketed successfully so that professionals, patients, and those picking up the cost understand the potential benefits. Those making the investment in research will inevitably create a market for innovation even if the benefits achieved are minimal. As one oncology marketing director said, “I enjoy my job for the challenges it brings. Selling drugs that work is no fun but oncology is about selling hope.” The explosion of new therapies in cancer care will continue, and the prices of these drugs will remain high. The cost of cancer drugs in 2005 is estimated to be $24 billion globally, of which $15 billion is spent in the United States. If effective drugs emerge from the research and development pipeline, the cancer drug market could reach $300 billion globally by 2025, with this cost spreading more widely around the world (Table 6). But parallel to this explosion in therapies and the increase in costs, a number of confounding factors will make markets smaller. The technology will be there to reveal which patients will not respond to therapy. Blockbuster drugs that bring huge commercial rewards to the developer will become rare. Doctors will know the precise stage of the disease process at which treatment is necessary. And as cancer becomes transformed into a chronic disease, people will have more comorbidity, which will bring associated drug–drug interactions and an increase in care requirements. How do we balance this equation? The pharmaceutical companies will not necessarily want to do the studies to fragment their market. Research leading to rational rationing will need to be driven by the payers of health care. There is a risk that pharmaceutical companies will stop developing drugs for cancer and focus instead on therapeutic areas where there is less individual variation and therefore more scope for profit. Furthermore, development costs are rising. Ten years ago, the average cost of developing a new cancer drug was around $400 million. Now it is $1.2 billion. At this rate of growth, the cost of developing a new drug could soon reach $2 billion, an amount unsustainable in a shrinking market. With this in mind, the process of developing drugs needs to be made faster. However, instead of research being made simpler, changes in legislation concerned with privacy and prior consent are making it more difficult. The EU Clinical Trials Directive will make quick, hypothesis-testing trials impossible. Other challenges exist, such as obtaining consent for new uses of

Table 6 Marketed targeted therapies showing their high cost per year Drug

Generic

Manufacturer

Yearly cost

Herceptin Mabthera Glivec Erbitux Avastin Tarceva Iressa Sutent Nexavar Tykerb

Trastuzumab Rituximab Imatinib Cetuximab Bevacizumab Erlotinib Gefitinib Sunitinib Sorafenib Lapatinib

Roche Roche Novartis BMS Genentech Roche AZ Pfizer Bayer GSK

$80K $50K $80K $80K $90K $75K $60K $80K $70K $60K

210 Table 7 l l l l l l

Future Organization of Cancer Care Barriers to innovation

The drug industry will continue to compete for investment in a competitive, capitalist environment. Blockbuster drugs drive profit; niche products are unattractive in today’s market. Personalized therapies are difficult for today’s industry machine. Surrogate endpoints will be essential to register new drugs. Novel providers will emerge, providing both diagnostic and therapy services. Payers will seek robust justification for the use of high-cost agents.

existing, stored human tissue, following political anxiety when consent for removing and storing tissues had not been obtained in the early years of the twenty-first century. However, surveys have shown that patients who give consent for tissue to be used for one research purpose are happy for it to be used for another. They do not wish to be reminded of their cancer years later. To overcome these constraints, regulators will have to start accepting surrogate markers when approving therapies, rather than insisting on clinical outcomes. Outcome studies may well move to postregistration surveillance of the efficacy of a drug, similar to the position for cholesterol-lowering agents today. The rise of personalized medicine will mean the temptation to overtreat will disappear. Doctors and patients will know whether a particular treatment is justified. The evidence will be there to support the decisions. As a consequence of this, treatment failure – with all its associated costs – will be less common (Table 7).

The Cancer Patient’s Experience Two separate developments will determine the patient’s experience of cancer care in future. Increasing expectations of patients as consumers will lead health services to become much more responsive to the individual, in the way that other service industries have already become. Targeted approaches to diagnosis and treatment will individualize care. People will have higher personal expectations, be less deferential to professionals and more willing to seek alternative care providers if dissatisfied. As a result, patients will be more involved in their care. They will take more responsibility for decisions, rather than accepting a paternalistic doctor knows best approach. This will partly be fueled by the Internet and competitive provider systems. By 2025, the overwhelming majority of people in their 70s and 80s will be familiar with using the Internet to access information through the massive computing power that they will carry personally. Patients will need someone to interpret the huge volumes of accessible health information, to help them assess the risks and benefits, as well as to determine what is relevant to them. These patient brokers will be compassionate but independent advocates who will act as patients’ champions, guiding them through the system. They will be helped by intelligent algorithms to ensure patients understand screening and the implications of early diagnosis. They will spell out what genetic susceptibility means and guide patients through the treatment options. Patients and health professionals will have confidence

in computer-aided decision-making because they will have evidence that the programs work. The extent to which the service will be designed around patients’ needs and expectations will be determined by the improved treatments available and their individualization (Figure 3). Care in the early stages will be provided near to where the patients live. Even the most sophisticated diagnostic machinery or robotic surgeon will be mobile; so much of this intervention will be carried out by technicians and nurses, with the most highly trained professionals in audiovisual contact from a distant base. When cancer centers developed in the mid-twentieth century, these diseases were relatively rare, and survival was low. Although distressing for patients when they were referred to a center, their existence concentrated expertise. Cancers will become commonly accepted chronic conditions, and even when inpatient care is required, patients will be able to choose many places in the world where they will receive care at a cancer hotel. But for many patients, even that option will not be necessary (Figure 4). Most new drugs will be given orally, so patients will be treated in their communities. However, this approach to cancer and other chronic conditions will place a huge burden on social services and families. Systems will be put in place to manage the ongoing control of these diseases and conditions, psychologically as well as physically. The relief of pain and the control of other symptoms associated with cancer treatment will be much improved. Figure 5 shows the integration required to reconfigure the entire cancer service around the patient at its center. Today, 70% of the cancer budget is spent on care associated with the last 6 months of people’s lives. Although many recognize that such treatment has more to do with the management of fear than the management of cancer, medical professionals have relatively few treatment options available and there is limited awareness of which patients would benefit. There is also an institutional reluctance to destroy patients’ hopes that leads to confusion between the limits of conventional medicines and reluctance to face the inevitable – by patients, their families, and their doctors. There is a widespread perception that if terminally ill patients continue to be offered anticancer treatment, there is the possibility that their health might be restored. With better treatments, consumers of services will be able to focus on quality of life. Much of the fear now associated with cancer will be mitigated. Demand for treatments with few side effects or lower toxicity will be high, even if there are only quite modest survival gains. The transition between active and palliative care is often sudden, but in future, because patients will be in much greater control of their situation, the change in gear will not be as apparent (Table 8).

Professional Reconfiguration One of the greatest challenges to providing the best cancer care in future will be having the right people in the right jobs. It will be essential not to continue to train people for jobs that will no longer exist. Policy makers have begun to grasp some of the workforce difficulties that lie ahead. There are moves to ensure that health-care professionals

Future Organization of Cancer Care

Figure 3

The integration of cancer services within the health-care system. DH, Department of Health; GPs, general practitioners.

Figure 4

Extending the services to become closer to patients using distributive care models.

have responsibilities that are commensurate with their level of education and professional skills. Nurses and pharmacists are being encouraged to take over some responsibilities that have been firmly held by doctors, such as prescribing, while some of their traditional roles are handed on to technicians and other support staff.

211

The appropriate skill mix will become even more critical. Barriers between health-care professions will have to be broken down so that new approaches to the care of patients with cancer and many other diseases can be delivered. Intraprofessional barriers will disappear. The work of pathologists and radiologists will become one as their traditional skills are

212

Figure 5

Table 8

Future Organization of Cancer Care

Creating an integrated cancer network around a patient. CT, chemotherapy; FT, Foundation Trust; RT, radiotherapy.

Experiencing cancer in future

Patient brokers will guide people with cancer through the system. Choice will be real and will involve cost decisions. l Patients will make a contribution to the costs of their care. l Complementary therapies will be widely available and well regulated. l Themed death chosen by patients will be possible. l l

augmented by the new generation of diagnostic and treatment devices. Oncologists will find that many forms of chemotherapy will be delivered with the aid of the new technology, and surgeons will be using robots to enable them to operate. Fewer of the most highly trained specialists will be required, since much of their responsibility will be delegated to specialist technicians and nurses working to protocols. In addition, the most highly trained individuals will be able to work at a number of sites on the same day, since the technology will be mobile and their skills can be deployed remotely. The balance between skills will be driven by a number of factors: the size of the medical workforce and the capacity of the system to provide care, as well as the availability of trained support staff (Table 9).

Table 9

The right person for the right job: key challenges

Manpower planning for new technology Doctors and other health-care specialists l Prescribing cancer drugs by nurses, pharmacists, and others l Training carers for elderly people with substantial comorbidity l Making patients equal partners in decision-making l l

Conclusion Cancer will become incidental to day-to-day living. A cancer will not necessarily be eradicated by treatment, but that will not cause patients the anxiety that it does today. People will have far greater control over their medical destinies. Patients in all socioeconomic groups will be better informed. In addition, surgery and chemotherapy will no longer be rationed on grounds of age, since all interventions will be less damaging, psychologically as well as physically. The accuracy of this image of the future depends on whether the technological innovations do actually emerge and the extent to which they become widely available. For example, will people really live in smart houses where their televisions play a critical role in monitoring their health and well-being? It is also dependent on health-care professionals working alongside each other, valuing the input of carers who, even more than today, will provide voluntary support, because of the number of people in older age groups compared with those of working age. The reality for cancer care may be rather different. The ideal will exist for a minority of patients, but the majority may not have access to the full range of services. Old people, having been relatively poor all their lives, may suffer from cancer and a huge range of comorbidities that will limit their quality of life. Looking after them all – rich and poor – will place great strains on younger people: Will there be enough of them to provide the care? As with all health issues, the question of access will be determined by cost and political will. In 2006, a cancer patient consumes about £25 000 ($50 000) of direct medical care costs, 70% of which is spent in the last 6 months of life. Conservatively, with

Future Organization of Cancer Care

Figure 6

213

The four building blocks of cancer’s future: innovation, society, delivery, and finances.

patients living with cancer, rather than dying from it, and with access to new technologies, this could reach £100 000 per patient per year by 2026. In theory, cancer care could absorb an ever-increasing proportion of the health-care budget. Would this be a reflection of what patients want? Probably yes. Surveys reveal that three-quarters of the population believe cancer care should be the main priority of the health-care system, with no other disease even a close second. But to achieve that expenditure – and assuming that part of the health service will be funded from taxation – the tax rate might have to rise to 60%. Inevitably, there will be conflicting demands on resources: The choice may be drugs or care costs. And how are the costs computed? Although the technology will be expensive, it will be used more judiciously, since it will be better targeted. Another argument suggests that when patients are empowered they use fewer and less-expensive medicines, in effect lowering the overall costs. An extension of this argument is that although costs will increase for treating each individual patient, the overall costs will decrease, because more care will be delivered at home. But because people will live longer, the life-time costs of cancer care will rise along with comorbidity costs. Politicians will be faced with a real dilemma: If the prevalence of cancer increases, the cost of delivering innovative care could be massive. Will cancer care need to be rationed in a draconian way? One dilemma for the future will be the political power of old people. More will be living longer, and their chronic problems will not necessarily incapacitate them physically or mentally. This educated elderly population will have high expectations, sharpened through the first two decades of the twenty-first century, and they will not tolerate the standards of care now offered to many old people. They will wield considerable influence. Will a tax-based health system be able to fund their expectations? Politicians will have to consider the alignment between patients’ requirements, and taxpayers’ and voters’ wishes. Fewer than 50% of voters now pay tax, and

the percentage of tax-paying voters is set to fall as the population ages. Will the younger taxpayers of the future tolerate the expensive wishes of nontaxpayers? The interests of voters may be very different from the interests of taxpayers. It seems likely, therefore, that the days of an exclusively tax-funded health service are numbered. Co-payments and deductibles will be an inevitable part of the new financial vocabulary. Figure 6 shows the four components of cancer’s future: innovation, delivery, finances, and society, and Figure 7 looks at the four alternative scenarios. Whatever system is put in place, there is the prospect of a major socioeconomic division in cancer care. A small percentage of the elderly population will have made suitable provision for their retirement, both in terms of health and welfare, but the vast majority will not be properly prepared. Policy makers need to start planning now. The most productive way forward is to start involving cancer patients and health

• • • •

Paent power New technology Compeve intensity Increasing numbers

• Technological success • Society willing to pay

• Technological success • Society not willing to pay

• Longevity • Compressed morbidity

• Increased inequity

• Technological failure • Society not willing to pay

• Technological failure • Society willing to pay

• Priorizaon essenal

• Quality of life • Social care

Figure 7

Alternative cancer futures.

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Future Organization of Cancer Care

advocacy groups in the debate, to ensure that difficult decisions are reached by consensus. Societal change will create new challenges in the provision of care. A decline in hierarchical religious structures, a reduction in family integrity through increasing divorce, greater international mobility, and the increased selfishness of a consumer-driven culture will leave many lonely and with no psychological crutch to lean on at the onset of serious illness. There will be a global shortage of carers – the unskilled, low-paid but essential component of any health-care delivery system. The richer parts of the world are now obtaining this resource from the poorer parts of the world, but the supply of this precious human capital will eventually dwindle. New financial structures will emerge with novel consortia from the pharmaceutical, financial, and health-care sectors, enabling people to buy into the level of care they wish to pay for. Cancer, cardiovascular disease, and dementia will be controlled and will join today’s list of chronic diseases such as diabetes, asthma, and hypertension. Hospitals will become attractive health hotels, run by competing private-sector providers. Global franchises will provide specialty therapies through these structures, similar to the internationally branded shops in today’s malls. Governments will have long ceased to deliver care. Britain’s NHS, one of the last centralized systems to disappear, will convert to UK Health, a regulator and safety-net insurer early in the twenty-first century. The ability of technology to improve cancer care is assured. But this will come at a price: the direct costs of providing it and the costs of looking after the increasingly elderly population

that it will produce. We will eventually simply run out of things to die from. New ethical and moral dilemmas will arise as we seek the holy grail of compressed morbidity. Living long and dying fast will become the mantra of twenty-first-century medicine. Our cancer future will emerge from the interaction of four factors: the success of new technology, society’s willingness to pay, future health-care delivery systems, and the financial mechanisms that underpin them.

See also: Breast Cancer; Cancer Economics; Cancer and Senescence; Cancer Epidemiology; Cancer: Global Burden, Trends, and Projections; Cancer Mortality; Cancer Screening: Theory and Applications; Cancer Survival; Carcinogens, Environmental.

Further Reading Bosanquet, N., Sikora, K., 2006. The Economics of Cancer Care. Cambridge University Press, Cambridge, UK. Masters, G.A., et al., 2015. Clinical cancer advances 2015: annual report on progress against cancer from the American Society of Clinical Oncology. J. Clin. Oncol. 33, 217. Price, P., Sikora, K., 2015. Treatment of Cancer. CRC Press, Oxford.

G Gastric Cancer Suminori Kono, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 3, pp. 1–8, Ó 2008, Elsevier Inc.

Introduction Gastric cancer remains one of the most common cancers in the world, although it has declined substantially in many countries. It remains the fourth most common cancer in the number of new cases, and the second most common cause of death from cancer. According to global estimates (Parkin et al., 2005), 934 000 new cases of gastric cancer occurred in 2002, accounting for 8.6% of all new cases of cancer. The number of deaths from gastric cancer was estimated to be 700 000 (10.4% of all cancer deaths). It can be roughly inferred from the mortality-to-incidence ratio (0.75) that the prognosis of gastric cancer is generally poor. Five-year survival is little more than 30% in developed areas and 20% in developing areas. Most gastric cancers are adenocarcinomas arising from the gastric epithelium. Adenocarcinomas can be classified into two histological types: The intestinal type is more frequent in men and in older persons, while the diffuse type is more frequent at younger ages and shows little difference in frequency by sex. It has been hypothesized that variation in the intestinal type of adenocarcinoma is the main component of international and temporal variation in the incidence of gastric cancer, but the hypothesis is controversial. It is of interest to know whether etiological factors are different for the intestinal and diffuse types, but epidemiological studies, though limited, have not supported a differential etiology for the two histological types of gastric cancer. The stomach is classified anatomically into cardia (near the esophagus), fundus, corpus, and antrum (near to the duodenum). Cancers of the cardia seem to differ from cancer in other parts of the stomach with respect to etiological factors. There is evidence that the incidence of adenocarcinoma of the gastric cardia has increased in recent decades in Europe and North America. Chronic atrophic gastritis is a well-established precursor lesion. The prevalence of chronic atrophic gastritis is higher in popuations with higher rates of gastric cancer, and the risk of gastric cancer is substantially increased in individuals with chronic atrophic gastritis. It is hypothesized that atrophic gastritis advances to intestinal metaplasia, dysplasia, and finally the intestinal type of gastric cancer.

Descriptive Features

Time Trend

Geographic Variation Wide international variation in both incidence and mortality of gastric cancer has long been recognized. The incidence rates are

International Encyclopedia of Public Health, 2nd edition, Volume 3

highest in registries in Japan, Korea, and northeast China, with annual age-standardized rates of 70–80 per 100 000 in men and 35 in women (Figure 1). Relatively high rates of incidence are recorded in South America and Eastern Europe. The rates are lower in populations in Western Europe and Scandinavian countries, and lowest in North America, Oceania, and South Asia. It is well known that Portugal has the highest rate in Western Europe. Mortality statistics indicate an international variation similar to that noted from the incidence data (Figure 2). Cancer mortality statistics in Russia and Korea have become available very recently, while high rates of mortality from gastric cancer in Chile and Portugal have been well recognized. Both incidence and mortality data demonstrate that rates in males are 1.5–2.5 times higher than those of females in all populations and countries. Apart from China, regional variation within countries is much less than international variation between countries. For example, in Japan, the difference between the highest mortality rates in the northern part along the Sea of Japan and the lowest rates in southern Kyushu is approximately threefold. In England and Wales, there is a twofold difference between North and South. In China, by contrast, there is an eightfold difference between provinces with the highest and lowest mortality rates. Multiethnic registries in the United States provide incidence rates by ethnicity within the same geographic region. Koreans and Japanese living in Los Angeles have much lower incidence than Koreans and Japanese living in their home countries, but still have higher incidence than African and Caucasian Americans in Los Angeles. This type of information alone strongly indicates that environmental factors are important in the etiology of gastric cancer. Migrant studies provide more definite information regarding the role of genetic and environmental factors and also the time of exposure. As early as 1969, Haenszel and Kurihara reported a historical finding that the firstgeneration migrants (born in Japan) tended to maintain the high risk of gastric cancer as experienced by Japanese in Japan, but the second generation (born in the United States) had a risk of gastric cancer closer to that of Caucasians in the United States. Similar findings have been observed in other migrant studies in Colombia, Australia, and Brazil. Exposure to environmental factors in early life is considered to be crucial in the development of gastric cancer.

The decline in gastric cancer incidence and mortality is a global phenomenon, although the starting point and the rate of decline differ somewhat in different countries and

http://dx.doi.org/10.1016/B978-0-12-803678-5.00167-3

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0

20

Males 40

60

80

0

20

Females 40 60

80

China, Cixian Japan, Miyagi Korea, Seoul USA, LA: Korean Portugal Colombia, Cali Italy, Parma USA, LA: Japanese Slovakia Poland, Warsaw Germany, Saarland USA, LA: Chinese USA, SEER: Black UK, England France, Bas-Rhin Finland Norway Australia, Victoria Canada Sweden Denmark Uganda, Kyadondo USA, SEER: White India, Mumbai

China, Cixian Japan, Miyagi Korea, Seoul USA, LA: Korean Portugal Colombia, Cali Italy, Parma USA, LA: Japanese Slovakia Poland, Warsaw Germany, Saarland USA, LA: Chinese USA, SEER: Black UK, England France, Bas-Rhin Finland Norway Australia, Victoria Canada Sweden Denmark Uganda, Kyadondo USA, SEER: White India, Mumbai

Figure 1 Age-standardized incidence rates (per 100 000/year) for gastric cancer in selected populations, 1993–97. NB: Age standardized to the world standard population. Data for Portugal are from the registry of Vila Nova de Gaia. LA, Los Angeles; SEER, Surveillance, Epidemiology and End Results Program. From International Agency for Research on Cancer, 2005. CANCER Mondial Statistics Information System. IARC, Lyon. http://wwwdep.iarc.fr (accessed November 2007).

0 Republic of Korea Chile Russian Federation Japan Colombia Portugal Romania Poland Slovak Republic Italy Spain Iceland Germany Ireland The Netherlands Finland England and Wales Norway France Sweden Canada Australia Denmark USA

20

Males 40 60

80

0

20

Females 40 60

80

Republic of Korea Chile Russian Federation Japan Colombia Portugal Romania Poland Slovak Republic Italy Spain Iceland Germany Ireland The Netherlands Finland England and Wales Norway France Sweden Canada Australia Denmark USA

Figure 2 Age-standardized mortality rates (per 100 000/year) of gastric cancer in selected countries, 2000. NB: Age standardized to the world standard population. Years for Chile and Colombia are both 1994. From International Agency for Research on Cancer, 2005. CANCER Mondial Statistics Information System, IARC, Lyon. http://www-dep.iarc.fr (accessed November 2007).

Gastric Cancer populations. This phenomenon was aptly described in 1986 as an unplanned triumph by Howson et al. (1986) who suggested that the decline was due to widespread use of refrigerators; the advent of refrigerators resulted in decreased consumption of salted, preserved foods and increased consumption of fresh vegetables and fruits (see section Diet). The most extensive analysis of time trends in gastric cancer as well as other sites of cancer was conducted by Coleman et al. (1993), based on incidence and mortality data up to the late 1980s. The decline in mortality from gastric cancer started much later in Japan than in countries in Europe and North America (Figure 3). It is notable that mortality rates in Japan and Finland were at the same level in the 1950s. In Japan, the incidence of gastric cancer has not declined as rapidly as the trend in mortality (Figure 4). The increasing divergence between incidence and mortality in Japan can probably be ascribed to nationwide screening for gastric cancer. The greater decline in mortality than in incidence may be attributable to earlier detection and more effective treatment. Alternatively, gastric cancers that are pathologically malignant but clinically more benign may have been detected more frequently because of screening. The incidence has declined more in females than in males (Figure 4) and it is less likely that the so-called overdiagnosis is more frequent in men than in females.

Sex, Age, and Social Class Men have gastric cancer incidence and mortality rates approximately twice as high as women in most countries and populations, mainly at ages 40 and older: There is no difference at younger ages (Figure 5). With few exceptions, this

phenomenon is seen worldwide, although divergence in the rates between men and women begins at slightly different ages in different populations. The lack of sex difference at younger ages is compatible with the observation that the diffuse type of gastric cancer is more common at younger ages, with no clear sex difference. Lower socioeconomic status is consistently associated with an increased risk of gastric cancer in different countries. The most likely explanation is that factors etiologically linked to gastric cancer are more prevalent in individuals ranked at lower socioeconomic status.

Etiology Helicobacter pylori H. pylori infection has emerged as an important etiological factor in the past 20 years. There is no doubt that H. pylori infection is a cause of gastric cancer, as concluded by the expert panel of the International Agency for Research on Cancer in 1994. Evidence for the causal link with H. pylori infection is primarily based on findings from prospective studies. In the year 1991, three prospective studies all reported an increased risk of gastric cancer in individuals who were seropositive for H. pylori infection. The subjects in these pioneering studies were subscribers to the Kaiser Permanente Medical Care Program in the United States, Japanese participants in the Honolulu Heart Program, and participants in the British United Provident Association (BUPA) and the Caerphilly collaborative heart disease (CCHD) studies. Serum IgG antibody to H. pylori was measured using frozen stored blood samples in cases of gastric cancer and matched controls within each cohort. These initial findings have been corroborated by subsequent

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Figure 3 Age-standardized mortality rates (per 100 000/year) of gastric cancer in Japan (circles), Finland (diamonds), and US Whites (triangles), 1950–2004. NB: Age standardized to the world standard population. From International Agency for Research on Cancer, 2005. CANCER Mondial Statistics Information System, IARC, Lyon. http://www-dep.iarc.fr (accessed November 2007).

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Figure 4 Age-standardized incidence rates (per 100 000/year) of gastric cancer in Miyagi and Osaka, Japan, Finland, and Connecticut, United States, 1959–97. NB: Age standardized to the world standard population. The years of reporting incidence rates differ by registry, and each plot represents the mid-point of the period. Markers indicating registries are as follows: Miyagi (black circles), Osaka (gray circles), Finland (diamonds), and Connecticut (triangles). From International Agency for Research on Cancer, 2005. CANCER Mondial Statistics Information System, IARC, Lyon. http://www-dep.iarc.fr (accessed November 2007).

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Figure 5 Age-specific incidence rates for gastric cancer in males (black circles) and females (gray circles) in Osaka, Japan (left), and England (right), 1993–97. From International Agency for Research on Cancer, 2005. CANCER Mondial Statistics Information System, IARC, Lyon. http://wwwdep.iarc.fr (accessed November 2007).

prospective studies. A pooled odds ratio of 2.36 (95% confidence interval, 1.98–2.81) was reported for the association between H. pylori infection and gastric cancer in a combined analysis of 12 case–control studies nested in prospective cohorts (Helicobacter and Cancer Collaborative Group, 2001). Importantly, H. pylori infection was exclusively associated with non-cardia cancer, with an odds ratio of 3.0 (95%

CI, 2.3–3.8), while the odds ratio for cancer of the gastric cardia was 1.0 (95% CI, 0.7–1.4). It was also observed that the increased risk of non-cardia cancer associated with H. pylori infection was attenuated when H. pylori infection was assessed closer to the time of cancer diagnosis. H. pylori infection is probably lost in the development of gastric atrophy, which precedes the occurrence of carcinoma in many patients. It is

Gastric Cancer thus not surprising that the results from case–control studies are rather inconsistent. There is no difference between the two histological types (intestinal and diffuse) in the magnitude of the increased risk associated with H. pylori infection. Despite established causality, H. pylori infection alone cannot sufficiently explain the descriptive features of gastric cancer. As illustrated in the EUROGAST study, which showed a positive geographical correlation at international level between H. pylori infection and gastric cancer risk, there is no difference in the prevalence of H. pylori infection between men and women in many populations, whereas incidence and mortality rates of gastric cancer are 1.5–2.5 times higher in males than in females across populations. There is also a notable variation in gastric cancer rates among populations with similar rates of H. pylori infection. This phenomenon is referred to as the African or Asian enigma: H. pylori infection is fairly high, but gastric cancer rates are generally low in African and southeast Asian countries. Furthermore, only a very small proportion of individuals infected with H. pylori develop gastric cancer. Host and environmental factors, as well as the virulence of the bacterium, have recently become of interest as determinants of the outcome of H. pylori infection. The virulence of H. pylori differs with the presence of cytotoxin-associated gene A (CagA). Strains that are positive for CagA induce more severe inflammation and are associated with a higher risk of gastric cancer. Interleukin (IL)1b, a pro-inflammatory cytokine and a potent inhibitor of gastric acid secretion, is upregulated during H. pylori infection. Specific genotypes thought to enhance IL-1b production are associated with an increased risk of hypochlorhydria and of gastric cancer in response to H. pylori infection. Among the dietary factors, it is suggested from a mechanistic viewpoint that vitamin C may be protective and that salt intake may synergistically enhance the risk of gastric cancer.

Diet In 1997, the World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) issued an expert report on diet and cancer based on a comprehensive literature review. The summary for diet and gastric cancer is presented in Table 1. The main conclusion is that high consumption of vegetables and fruit convincingly confers a lower risk of gastric cancer and that high intake of salt or salted foods probably increases the risk. Refrigeration of food is indirectly protective by reducing salt intake. The importance of these two dietary factors is also acknowledged in the joint report of the World Health Organization (WHO) and the Food and Agriculture Organization (FAO) issued in 2003, although the evidence for a protective effect of vegetables and fruit is regarded as less convincing. The reduced risk of gastric cancer associated with high consumption of vegetables and fruit has been observed in a large number of case–control studies in different populations, but supportive findings from prospective studies are limited. Decreased risk has been more consistently observed with the consumption of fresh vegetables and citrus fruits. Garlic and other allium vegetables are of particular interest, because of the abundant experimental evidence on the anticarcinogenic effects of allium compounds (e.g., allyl sulfides). High consumption of garlic and other allium vegetables was shown

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Table 1 Summary table of diet and gastric cancer risk in the 1997 WCRF/AICR report Evidence

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Salt and salting Starch, grilled/ barbecued meat and fish Cured meats, Nnitrosamines

a

Shifted to the category of ‘probable’ in the 2003 WHO/FAO report and the 2007 WCRF/AICR report. World Health Organization, 2003. Diet, Nutrition and the Prevention of Chronic Diseases. Report of a joint WHO/FAO expert consultation. World Health Organization, Geneva.

to be related to a decreased risk of gastric cancer in China and Italy, where allium vegetables are commonly consumed. Vegetables and fruit are rich in vitamin C and carotenoids. Vegetables are also a major source of vitamin E and selenium. These micronutrients exert antioxidative effects through different mechanisms and have aroused much interest in the prevention not only of gastric cancer but also of other cancers. Vitamins C and E inhibit the formation of N-nitroso compounds, potential carcinogens for the human stomach (Kono and Hirohata, 1996). Among these micronutrients of anticarcinogenic potential, vitamin C seems to have gained considerable evidence regarding its protective association with gastric cancer. Observational studies have suggested a decreased risk associated with high intake of carotenoids, but supplementation with b-carotene did not decrease the risk of gastric cancer in Finland. On the other hand, combination supplements of b-carotene, vitamin E, and selenium resulted in a 16% reduction in incidence and a 21% reduction in mortality from gastric cancer in Linxian, China, where the inhabitants were marginally deficient in micronutrients. Folate is abundant in leafy vegetables, and it plays an important role in DNA methylation and DNA synthesis. High folate intake is related to a decreased risk of colorectal cancer, so the relation of folate to gastric cancer risk is naturally of interest. Results from nine case–control studies and two cohort studies are inconsistent, with a pooled relative risk of 0.9 (95% CI, 0.7–1.1) for the highest versus lowest intake (Larsson et al., 2006). However, genetic polymorphism of a key enzyme in folate metabolism, MTHFR C677T, is related to gastric cancer risk, suggesting that folate metabolism is involved in gastric carcinogenesis as well. Salt itself has no carcinogenic effect, but it is well documented that high salt intake enhances chemical carcinogenesis in the rat stomach. Increased risk associated with high intake of salt and salted foods has mainly been observed in case–control studies, but it has recently been substantiated in prospective studies in Japan. Salt intake in Korea and Japan is the highest

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in the world, and in parallel with the highest rates of gastric cancer in those countries. Nitrite reacts with amines, amides, and other proteins to form N-nitrosocompounds. Nitrate is not a nitrosating agent in its own right, but it is reduced to nitrite by bacteria in the mouth and in the achlorhydric stomach. Nitrosation is an acid-catalyzed chemical reaction in the normoacidic condition, and the reaction is also catalyzed by bacteria in the achlorhydric stomach. Vegetables are the major source of nitrate intake, and nitrite intake largely derives from preserved meats. In most circumstances, daily intake of nitrate is 100-fold greater than that of nitrite. Thus epidemiological studies have not adequately addressed the role of nitrate, nitrite, or Nnitrosocompounds in gastric carcinogenesis in humans (Kono and Hirohata, 1996). A possible anticarcinogenic effect of green tea has been a topic in cancer prevention. Green tea extract and epigallocathechin, a major constituent of green tea polyphenol, have been shown to inhibit chemical carcinogenesis in the glandular stomach in rats. High consumption of green tea has been shown to be associated with a reduced risk of gastric cancer in case–control and cohort studies in Japan and China, though such a protective association has not always been replicated in other cohort studies in Japan. Capsaicin, the pungent component of chilli peppers, is known to be both mutagenic and carcinogenic. High consumption of chilli pepper has been reported to be associated with increased risk of gastric cancer in Mexico, India, and Korea.

Alcohol Consumption A few case–control studies have reported an increased risk of gastric cancer in relation to vodka drinking before breakfast in Poland, and heavy consumption of red wine in Portugal and France. An increased risk of gastric cancer associated with high alcohol consumption has also been reported from small prospective studies in Japan and in the United States. However, a high number of much larger case–control and cohort studies have found no association between alcohol use and gastric cancer risk. The increased risk associated with alcohol use in the more limited studies is probably due to confounding or chance, but the possibility that alcohol intake may increase the risk of cardiac cancer cannot be excluded.

Smoking Many case–control and cohort studies have fairly consistently showed increased risk of gastric cancer among smokers, but a dose–response relation has not always been observed. The International Agency for Research on Cancer has concluded that smoking is causally related to gastric cancer. Several studies reported that smoking was associated with increased risk of cardia cancer, rather than of non-cardia cancer, but the evidence is not consistent.

Obesity A high body mass index is related to an increased risk of adenocarcinoma of the gastric cardia, although the increased risk associated with obesity is much greater for adenocarcinoma of the esophagus. In Sweden, for instance, a high body mass

index was associated with a 7.6-fold increased risk of esophageal adenocarcinoma and 2.3-fold increased risk of cardia adenocarcinoma. Gastroesophageal reflux associated with obesity is a possible explanation.

Treatment and Survival Partial or total gastrectomy (removal of the stomach) is a conventional approach to treatment for surgical cases. Endoscopic mucosal resection has recently been developed for treatment of early cancer (i.e., mucosal or submucosal cancer). Survival depends strongly on the stage of disease at diagnosis and it varies substantially between countries. In Europe, the 5-year agestandardized relative survival for male adults diagnosed in 1990–94 ranged from 9.0% in Poland to 28.9% in Iceland, and the corresponding range for females was from 6.8% in Malta to 37.4% in Austria. The overall 5-year relative survival for men and women combined in 22 European countries was 23% (Sant et al., 2003). In the SEER Program of the United States, the 5-year survival of patients diagnosed during 1988–2003 was 24.1%. In Osaka, Japan, the 5-year relative survival for gastric cancer patients registered during 1993–95 was 48.9%. In the SEER Program and Osaka Cancer Registry, survival rates were reported by stage. The 5-year relative survival for gastric cancer at the localized stage in Osaka is higher than that in the SEER Program areas, but there is little difference in survival between the regional and distant stages (Figure 6). The proportion of the localized stage was far greater in Osaka than in the SEER Program areas (59% vs. 23%), suggesting early stages of gastric cancer are detected because of the mass screening in Japan. The 5-year relative survival of patients with early gastric cancer is greater than 95%. Cancer survival is generally poorer in patients of low socioeconomic status than for those of higher status, as well as in Blacks as compared with Whites in the United States. No such difference is evident for gastric cancer survival, however (Coleman et al., 2004).

Prevention Strategies Screening Gastric cancer screening by means of X-ray photofluorography has been practiced in Japan since the 1960s. The sensitivity and specificity of the double-contrast barium X-ray technique currently used for mass screening in Japan are reportedly 57– 90% and 77–91%, respectively. As described above, it is not clear that mass screening is effective in reducing mortality from gastric cancer, although a limited number of case– control and prospective studies have suggested decreased mortality from gastric cancer in individuals with recorded participation in the screening (Watanabe and Fukao, 2001). Nonetheless, 5–6 million persons receive the screening examination annually in Japan. In the year 2003, a total of 5 976 000 persons received X-ray screening in the community or at the workplace, and 5970 cases of gastric cancer were detected among the screenees, resulting in an overall detection rate of 1 per 1000 screenees (Okuda et al., 2006). A new method of screening using serum pepsinogen I and II has recently been introduced in Japan. Pepsinogen I is secreted

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Figure 6 Five-year relative survival (%), by stage at diagnosis: Osaka, Japan, and SEER, the United States. From Ajiki, W., Tsukuma, H., Oshima, A., 2004. Trends in cancer incidence and survival in Osaka. In: Tajima, K., Kuroishi, T., Oshima, A. (Eds.), Cancer Mortality and Morbidity Statistics Japan and the World – 2004. Gann Monograph on Cancer Research No. 51, pp. 137–163; Basel: Karger; National Cancer Institute, 2007. Suveillance, Epidemiology, and End Results. http://www.seer.cancer.gov/ (accessed November 2007).

by the chief cells and mucus neck cells in the fundus of the stomach, and pepsinogen II throughout the stomach and proximal duodenum. A decrease in serum levels of pepsinogen I and in the I/II ratio has been shown to be a good measure of gastric atrophy. The combination of cutoff points of pepsinogen I below 70 mg L 1 and pepsinogen I/II ratio below 3.0 is currently used as a diagnostic criterion for gastric cancer in screening. The sensitivity and specificity of this criterion are estimated to be 60–96% and 55–84%, respectively. While effectiveness of screening by serum pepsinogen has not been addressed, the use of serum pepsinogen has been incorporated in the screening in Japan as an alternative method or in combination with the X-ray method.

Eradication of H. pylori Infection Strong evidence that H. pylori infection confers an increased risk of gastric cancer naturally leads to the idea that H. pylori eradication treatment would necessarily prevent the occurrence of gastric cancer. However, there is no evidence in favor of screening for (and eradication of) H. pylori infection in the prevention of gastric cancer. In a randomized trial in Colombia, the pharmacological eradication of H. pylori resulted in a higher rate of regression of premalignant lesions such as atrophic gastritis, intestinal metaplasia, and dysplasia. On the other hand, there was no clear reduction in the risk of gastric cancer associated with H. pylori eradication treatment in a randomized trial lasting 7.5 years in China. Currently, eradication of H. pylori infection is selectively recommended in high-risk groups, for example, patients who already have atrophic gastritis, a premalignant condition, and in first-degree relatives of patients with gastric cancer.

Dietary Recommendation It is estimated in the WCRF/AICR report that gastric cancer risk can be reduced by two-thirds or three-quarters by modification of the diet, that is, increased consumption of vegetables and fruit and decreased salt intake. More specifically, it is advised to eat 400–800 g (or five or more portions) of a variety of vegetables and fruit daily and to reduce salt intake to less than 6 g per day. The use of refrigeration is also advised to preserve perishable food.

See also: Aging: Nutrition and the Older Adults; Alcohol Consumption: An Overview of International Trends; Burden of Disease and Injury Caused by Alcohol; Helicobacter pylori; Smoking Cessation; Smoking, The Burden of Mortality of.

References Coleman, M.P., Rachet, B., Woods, L.M., et al., 2004. Trends and socioeconomic inequalities in cancer survival in England and Wales up to 2001. Br. J. Cancer 90, 1367–1373. Helicobacter and Cancer Collaborative Group, 2001. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case–control studies nested within prospective cohorts. Gut 49, 347–353. Howson, C.P., Hiyama, T., Wynder, E.L., 1986. The decline in gastric cancer: Epidemiology of an unplanned triumph. Epidemiol. Rev. 8, 1–27. Kono, S., Hirohata, T., 1996. Nutrition and stomach cancer. Cancer Causes Control 7, 41–55. Larsson, S., Giovannucci, E., Wolk, A., 2006. Folate intake MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis. Gastroenterology 131, 1271–1283. Okuda, J., Ida, K., Sakai, H., Yokomizo, C., Kojima, T., Kato, T., 2006. Secondary prevention of gastric cancer: present and future. Clin. Gastroenterol. 21, 683–688.

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Parkin, D.M., Bray, F., Ferlay, J., Pisani, P., 2005. Global cancer statistics, 2002. CA Cancer J. Clin. 55, 74–108. Sant, M., Aareleid, T., Berrino, F., et al., 2003. EUROCARE-3: survival of cancer patients diagnosed 1990–94 – results and commentary. Ann. Oncol. 14 (Suppl. 5), v61–v118. Watanabe, Y., Fukao, A., 2001. Stomach cancer screening. In: Hisamichi, S. (Ed.), Report on the Evaluation of the Efficacy of New Cancer Screening Methods. Japanese Public Health Association, Tokyo, pp. 81–120.

World Cancer Research Fund/American Institute for Cancer Research, 1997. Food, nutrition and the prevention of Cancer: a global perspective. Washington D.C. Am. Inst. Cancer Res. Yamaguchi, N., Kakizoe, T., 2001. Synergistic interaction between Helicobacter pylori gastritis and diet in gastric cancer. Lancet Oncl. 2, 84–94.

Further Reading

http://www-dep.iarc.fr – CANCER Mondial Statistics Information System, IARC (last accessed on 10.04.16.). http://www.seer.cancer.gov/ – Surveillance, Epidemiology, and End Results Program, National Cancer Institute, USA (last accessed on 10.04.16.).

Shibata, A., Parsonnet, J., 2006. Stomach cancer. In: Schottenfeld, D., Fraumeni Jr., J.F. (Eds.), Cancer Epidemiology and Prevention. Oxford University Press, Oxford, UK, pp. 707–720.

Relevant Websites

Gastrointestinal Disorders: Overview Amanda J MacFarlane and Patrick J Stover, Cornell University, Ithaca, NY, USA Ó 2017 Elsevier Inc. All rights reserved.

Glossary Apoptosis Programmed cell death activated by an intracellular death program; prevents the release of harmful substances into the surrounding tissue. Cytokine Proteins made by cells that drive the behavior of other cells, act via specific receptors on the susceptible cells, for example, interleukin (IL)-12, interferon (IFN)-g. Epigenetic Inheritable information that is encoded by modifications of the genome and chromatin, which can affect gene expression without changes to the nucleotide sequence of DNA. Human leukocyte antigen (HLA) Human major histocompatibility complex; individual loci are designated by uppercase letters and alleles are designated by numbers; they are found on all tissues and allow the immune system to distinguish ‘self’ antigens and cells from ‘nonself’ antigens and cells; for example, HLA-DQ2 is associated with celiac disease. Immunoglobulin Antibody proteins.

Form Follows Function in the Gastrointestinal Tract Structure of the Intestinal Epithelium The mucosa of the gastrointestinal (GI) tract is the largest organ in the body, covering approximately 300–400 m2 (Figure 1). The intestinal tract, including the stomach, small intestine, and colon, is lined with a single layer of absorptive epithelial cells; the esophagus contains a squamous epithelial cell lining. In the small intestine, the epithelium forms finger-like projections, termed villi, which protrude into the lumen. The apical membrane of each epithelial cell is shaped into microvilli, which compose the brush border. The villi and microvilli, as well as the folds in the colon, maximize surface area and therefore absorptive capacity of the intestine. The crypts of Lieberkühn reside at the base of the villi, and each villus is surrounded by 5–10 crypts. The crypts contain pluripotent stem cells that continuously divide and generate daughter cells that migrate upward along the crypt–villus axis prior to becoming fully differentiated absorptive enterocytes at the villus tip (Figure 2(a)). Other differentiated cells of the intestine include mucus-secreting goblet cells, hormone-secreting enteroendocrine cells, and Paneth cells that are involved in host innate immunity. The majority of the cells residing in the villus tip are mature enterocytes. As the enterocytes reach the tip, they undergo apoptosis and shed into the lumen. The entire process of differentiation, from stem cell to enterocyte apoptosis and shedding, occurs continuously; the entire intestinal epithelium undergoes complete renewal within 1 week. Cell renewal processes in the colon and stomach are similar to those in the intestine; however, their cytoarchitecture varies somewhat (Figure 2(b)). Villi are not present in the stomach and colon,

International Encyclopedia of Public Health, 2nd edition, Volume 3

Lamina propria Area of loose connective tissue found below the epithelium, submucosa. Major histocompatibility complex (MHC) Membrane glycoproteins that are involved in antigen presentation to T cells; they present cytosolic-derived peptides (class I) or exogenously derived peptides (class II) to CD8þ and CD4þ T cells, respectively. Malabsorption Impaired intestinal absorption of nutrients and other substances. Mucosa Epithelial lining of the gastrointestinal tract. Polygenic Trait or condition associated with more than one gene. Single nucleotide polymorphisms (SNPs) A common genetic difference among humans in which only a single nucleotide in the genetic code is different. There are estimated to be 10 million SNPs in the human genome.

but stem cells present at the base of crypts divide and the progeny migrate upward, enter cell cycle arrest, and differentiate

Figure 1 General anatomy of the gastrointestinal (GI) tract. The GI tract includes the mouth, esophagus, stomach, small intestine, large intestine, rectum, and anus. The small intestine comprises, from proximal to distal, the duodenum, jejunum, and ileum. The large intestine comprises, from proximal to distal, the ascending colon, transverse, descending, and sigmoid colon. Reproduced with permission from Mayo Clinic Health Information.

http://dx.doi.org/10.1016/B978-0-12-803678-5.00168-5

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Figure 2 Anatomy of the small intestine (a) and colon (b). (a) In the small intestine, stem cells in the crypts continually divide and daughter cells move upward, differentiating into epithelial cells at the villus border, and continuing upward to the tip of the villus, where they undergo apoptosis and are shed into the lumen of the small intestine. (b) A similar process takes place in the colon, except differentiation takes place when cells reach the surface layer of the epithelium. Reproduced with permission from Sancho, E., Batlle, E., Clevers, H., 2004. Signaling pathways in intestinal development and cancer. Annu. Rev. Cell Dev. Biol. 20, 695–723.

before finally reaching the luminal surface, where they undergo apoptosis and shed into the lumen.

Digestion and Absorption of Nutrients Proper digestion and absorption of nutrients involves a number of sequential processes, including mechanical mixing, enzymatic digestion, and nutrient uptake by enterocytes. Digestion processes are initiated by the sight, smell, and taste of food, which induce the secretion of digestive juices into the mouth, stomach, and intestine. Amylase, for example, is an enzyme that hydrolyzes carbohydrates and is secreted into saliva. The mixing of saliva with food during chewing results in the physical and enzymatic breakdown of food and lubricates the mixture for easy swallowing. Food entering the GI tract stimulates the secretion of a number of regulatory peptides that promote the digestion and subsequent uptake of nutrients; the food’s composition determines which regulatory peptides are induced. Gastrin, in response to food, stimulates gastric acid secretion in the stomach, which in turn facilitates protein digestion and nutrient absorption. Gastric acid activates the

proteolytic enzyme pepsin and also induces the release of pancreatic proteases into the duodenum. Secretin produced by the duodenum stimulates secretion of fluid and bicarbonate from the pancreas and inhibits gastric acid secretion from the stomach. Gastric inhibitory peptide also inhibits gastric acid secretion and stimulates insulin release from the pancreas. Motilin stimulates upper GI tract motility. Stomach motility continues mixing the food with acidic gastric juices that contain digestive enzymes. Gastric emptying of the liquefied food, called chyme, into the upper small intestine via the pyloric sphincter occurs over several hours. The chyme is further mixed in the duodenum with pancreatic enzymes and bile salts, exposed to digestive enzymes at the surface of the mucosa, and moved along the intestine by peristaltic motility. Different classes of macronutrients, including carbohydrates, protein, and fat, require different sets of digestive enzymes to complete their breakdown for subsequent uptake by absorptive epithelial cells. Digestible carbohydrates such as starch, sucrose, lactose, and maltose are hydrolyzed to less complex sugars, such as glucose or fructose, before they are taken up by the intestine by specific transporters. Glucose

Gastrointestinal Disorders: Overview absorption stimulates the release of insulin from the b cells of the pancreas, which promotes glucose and amino acid uptake from circulation. Insulin promotes glycolysis and the synthesis of glycogen, protein, and fatty acids in target tissues, including the liver. Because insulin responds to glucose uptake by the intestine, factors such as nondigestible carbohydrates that alter the rate of carbohydrate digestion will in turn alter the whole-body insulin response. Nondigestible carbohydrates, mostly nonstarch polysaccharides, are the primary component of dietary fiber and can slow gastric emptying, increase viscosity, and promote commensal microflora growth in the large intestine. Proteins are hydrolyzed by a variety of proteases and peptidases secreted by the stomach or pancreas or bound to the brush border membrane of enterocytes. Protein hydrolysis generates free amino acids, as well as a large number of short- and medium-length peptides. Free amino acids and di/tripeptides are taken up by enterocytes via amino acid and oligopeptide transporters. Although most proteins and oligopeptides are rapidly degraded, some peptide sequences are variably resistant to hydrolysis and this resistance may have implications in disease pathogenesis (see following discussion under Autoimmunity: Celiac Disease). Fat, known chemically as triacylglycerol, is a heterogeneous substance that contains glycerol esterified with fatty acids that differ by chain length, degrees of saturation, and isomeric form. Enzymatic digestion is initiated by lingual and gastric lipases that liberate free fatty acids. Pancreatic lipases are released into the duodenum in response to the peptide hormone cholecystokinin. Pancreatic lipase binds to fat droplets and hydrolyzes the triacylglycerols to monoacylglycerols and to free fatty acids or glycerol. In the duodenum, monoacylglycerols and free fatty acids are emulsified into micelles by bile acids, from which enterocytes take up monoacylglycerols and free fatty acids at the brush-border membrane. Fatty acids and monoacylglycerols passively cross enterocyte plasma membranes. While fatty acid transporters have been identified, they do not contribute quantitatively to fatty acid absorption, but rather have been proposed to play a regulatory role in their uptake and metabolism. Once in the cell, fatty acids are bound by fatty acid–binding proteins for further processing. Cholesterol and other sterols uptake by enterocytes is mediated by the NPC1L1 receptor, which when bound undergoes clathrin-coated vesicle internalization.

Intestinal Flora: The Living Organ within Us A wide range of nonpathogenic commensal microflora resides within our intestinal tract. This resident community is essential for life and can be considered a virtual and functional organ. The proximal regions of the GI tract, namely the stomach and duodenum, contain low numbers of microorganisms with fewer than 103 bacterial cells per gram of contents, as these environments are not bacteria ‘friendly.’ The presence of acid, bile, and pancreatic secretions kills most microbes. The rapid transit times, which result from intrinsic phasic propulsive motor activity, also prevent colonization of these tissues. However, the environment becomes more hospitable further distal along the small intestine, which correlates with a progressive increase in the number of bacteria from 104 per gram

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contents in the jejunum to 107 in the ileum. The colon contains dramatically higher numbers of bacteria with some 1010 to 1012 bacteria per gram of luminal contents. Transit time is slow in the colon, allowing microorganisms to proliferate by fermenting diet-derived substrates. The species of bacteria also varies depending on location along the GI tract. The small intestine supports mostly gram-negative aerobes and some obligate anaerobes, whereas the colon supports mostly anaerobic bacteria. Overall, it is estimated that 400 –500 species of bacteria reside in the GI tract, but the majority comprises 30–40 species. The presence of commensal microflora provides a number of benefits for the host (Figure 3). Germ-free animals exhibit compromised structural and functional integrity of the GI tract. Other studies indicate that the microflora is essential for intestinal motility, secretion, absorption, cell differentiation and mitotic activity, villous length, and crypt depth. The microflora also influences other organ systems by affecting organ weight, cardiac output, and lymph node and immune system development. The microflora perform a variety of metabolic functions on behalf of the host. The commensal bacteria break down nondigestible dietary substrates, such as carbohydrates, that can then be readily absorbed by the host. The microflora also produce a number of essential nutrients, including vitamin K, B12, biotin, folic acid, and pantothenate, as well as amino acids.

Form Can Lead to Vulnerability: Countermaneuvers of the GI Tract Protection from the Environment Physical Barrier

The first line of defense against toxins and opportunistic pathogens is the physical yet selective barrier provided by the epithelial cells between the underlying lamina propria and the external environment. Macromolecules can cross the epithelium in two ways: (1) through the epithelial cells in a transcellular manner or (2) between the epithelial cells in a paracellular manner. The epithelial cells are impermeable to hydrophilic solutes and thereby allow transcellular passage only through specific transporters. Paracellular passage of macromolecules is highly regulated by tight junction protein complexes that are localized intercellularly at the apical margin of the lateral membrane. Tight junctions, which join the membranes of two adjacent cells, create an impermeable barrier and control the passage of solutes according to size and charge while limiting the passage of luminal content. The rate at which passage occurs can be modulated in response to physiological, pharmacological, and pathophysiological stimuli. For example, increased intestinal epithelial tight junction permeability can be initiated by sodium-coupled nutrient absorption. Epithelial cells also provide barrier protection by secreting mucus into the lumen. The mucus consists of high-molecularweight glycoproteins called mucins that form polymers creating a sticky gel that coats and protects the epithelium. The mucus acts as a barrier against the colonization of pathogenic microorganisms and prevents their adherence to epithelial cells. Epithelial cells also secrete antimicrobial peptides

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Health-promoting effects

Harmful pathogenic effects 1011 cfu/g Bacteroides Eubacteria Potential for: • Translocation

Bifidobacteria Peptostreptococci and ruminococci

• Putrefaction

Potential for: • Lower gas production • Short-chain fatty acids

Clostridia

• Production of toxins

• Immunostimulation Lactobacilli

• Production of carcinogens

• Antitumor activity

Enterobacteria Sulfate reducers and fusobacteria Veillonellae Staphylococci 104 cfu/g Figure 3 Scheme of the predominant groups of colonic bacteria, indicating how each genera may exhibit potentially beneficial and harmful functions. Reproduced with permission from Salminen, et al., 1998. Functional food science and gastrointestinal physiology and function. Br. J. Nutr. 80 (Suppl. 1), S147–S171.

and immunoglobulin A (IgA) antibodies into the lumen. IgA antibodies interact directly with undesirable foreign antigens and prevent their passage across the epithelium.

Bacterial Barrier

The epithelial cells provide an environment which supports the growth of ‘good’ commensal bacteria and thereby protect the host from invasion by opportunistic microorganisms. Commensal bacteria restrict the growth of pathogens by providing competition for nutrients and by their physical habitation in and attachment to the gut. Certain members of the commensal microflora also secrete antimicrobial substances to inhibit the growth of unwanted pathogens.

submucosa through specialized M cells residing in the epithelial cell layer of Peyer’s patches, or be captured by professional antigen-presenting cells, called dendritic cells, that reside in the lamina propria and among the surface epithelial cells. If the bacteria are deemed pathogenic, active immunity is stimulated. Immune activation can also occur if bacteria cross the epithelial cell layer by active invasion, through regions of tissue damage, or by minor leakage across the epithelium. Regardless of the mechanism that leads to immune activation, exposure of the gut to activating stimuli initiates an adaptive immune response. Presentation of microbial/dietary antigens by dendritic cells to T cells occurs either in lymphoid structures within the intestine such as the Peyer’s patches or after migration to the mesenteric lymph nodes in the GI submucosa.

Gut-Associated Lymphoid Tissues

The gut possesses a unique and selective immune response to avoid being in a continuous inflammatory state due to chronic exposure to foreign antigens. This allows the GI tract to tolerate the presence of innocuous bacteria and dietary antigens, while maintaining the ability to mount a selective defensive response against invading pathogenic organisms. Both innate and adaptive immune response systems exist in the GI tract. Differentiated epithelial cells residing at the base of villi in the small intestine, called Paneth cells, contribute to the innate immune defense response by releasing antimicrobial agents belonging to the alpha-defensin family. Gut-associated lymphoid tissues (GALT) are found in regions of the submucosa (Peyer’s patches, lymphoid follicles, the lamina propria), as well as integrated within the surface epithelium (intraepithelial lymphocytes), and play a role in innate immunity but also provide an environment for the initiation and maintenance of an adaptive immune response. The GALT can interact with environmental antigens in a number of ways. For example, bacteria are actively sampled by the immune system of the host. Bacteria can enter the

Oral Immune Tolerance

Under normal circumstances, immunological processes occurring in the gut will promote and maintain a state of immunotolerance in the presence of innocuous dietary or microbial stimuli. Immunotolerance, a state of immune unresponsiveness, is established by the coordinated release of specific anti-inflammatory cytokines and other mediators following exposure of dendritic cells to benign antigens found on commensal bacteria or innocuous dietary components (Figure 4(a)). Prostaglandins (PGE2) and transforming growth factor-beta (TGF-b), produced by epithelial cells, macrophages, and mesenchymal cells, promote the maturation of tolerogenic dendritic cells, which in turn produce interleukin (IL)-10 and TGF-b. Presentation of antigen by dendritic cells to naïve T cells in the Peyer’s patches and mesenteric lymph nodes in this tolerogenic cytokine milieu activates T-regulatory (Treg) and T-helper-3 (Th3) cells. While Treg cells secrete IL-10 and interferon (IFN)-g to induce local and systemic tolerance, Th3 cells produce TGF-b, which promotes B cell isotope switching to IgA.

Gastrointestinal Disorders: Overview

(a)

Gut lumen

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Commensal bacteria

Epithelium

LPS, other products

Local lgA Local/systemic tolerance

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IFN-γ IL-10

TGF-β

TGF-β

PGE2 PGE2

CD4 TReg

CD80/ CD86 IL-10

TH3

DC

CD28/ CTLA4

CD40

Naive CD4+

OCR6 Food antigen commensal antigen

CD40L

Peyer’s patch or MLN

α4β7

CCR7

Peyer’s patch or lamina propria (b)

CCR9

Costimulation +/− Invasive organisms LPS, other PAMPs

Local lgA Local/systemic immunity IL-1 IL-6 IL-8 CCL5

IL-1 IL-6 IL-8

IFN-γ

TGF-β IL-4, IL-5

TH1

IL-12 TH2

TLR DC

CCR6 Pathogen antigen

CD28 Naive CD4+

OCR9 α4β7

Costimulation +++ Figure 4 Mucosal tolerance occurs in response to innocuous, environmental stimuli, whereas immune sensitization is stimulated by exposure to environmental pathogens. The activation of a tolerogenic or sensitized response depends on the specific assortment of proinflammatory cytokines that are released upon exposure to these stimuli. (a) In a tolerogenic response mesenchymal cells and macrophages produce prostaglandins (PGE2) and transforming growth factor-beta (TGF-b), leading to release of interleukin (IL)-10 by dendritic cells upon interaction with naïve T cells. The naïve T cells then mature into T-regulatory (Treg) and T-helper-3 (Th3) cells, which produce their own immune mediators to induce immunoglobulin A (Continued)

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A completely different picture emerges when immune sensitization is invoked by a pathogenic activating stimulus (Figure 4(b)). In this case, the immune system can be activated by recognition of pathogens by Toll-like receptors of the dendritic cell, which leads to internalization of antigen. Otherwise, dendritic cells may become activated after directly taking up pathogens through phagocytosis. Activated dendritic cells express the corresponding antigenic peptide fragments in the context of major histocompatibility complex (MHC) class II molecules on their surface for presentation to naïve T cells. The dendritic cells can secrete the cytokines IL-12 and IL-23 and upregulate costimulatory molecules creating a proinflammatory environment. T cells primed under these conditions can mature into gut-homing Th1 and Th17 cells, resulting in a cellular immune response and the production of IFN-g. In addition, naïve T cells can differentiate into Th2 cells, producing TGF-b, IL-4, and IL-6, which invoke a humoral immune response.

vitamin B12, and iron. In tropical or subtropical regions, humans are susceptible to tropical sprue, a syndrome associated with bacterial infection that typically presents with diarrhea, weight loss, and nutrient malabsorption. Finally, most inflammatory diseases of the intestine, such as celiac disease and inflammatory bowel disease, often result in malabsorption of nutrients due to damage to the intestinal epithelium as described in sections below (see Celiac Disease; Inflammatory Bowel Disease).

Loss of Oral Tolerance: Immune-Mediated Diseases Immune-mediated diseases of the GI tract are complex and multifactorial, usually requiring the interaction of both genetic and environmental factors. Loss of oral immune tolerance to normally benign dietary or microbial antigens results in irritation and inflammation of the GI tract, and subsequent damage of the epithelium, which can ultimately lead to pathology. Often, the timing and degree of exposure to environmental antigens determine the disease outcome.

Diseases of the GI Tract Malabsorption Nutrient malabsorption disorders are common and can result from genetics, age-related changes in physiology, bacterial overgrowth, inflammation (see following discussion under Autoimmunity: Celiac Disease), and other causes that impair gut function. Lactose intolerance is a classical example of a genetic condition that affects nutrient digestion and absorption. Human adult populations differ in their ability to metabolize the sugar lactose, which cannot be absorbed directly. Lactose must be hydrolyzed in the duodenum to glucose and galactose by the enzyme lactase-phlorizin hydrolase, encoded by the LCT gene. In most humans and other mammals, LCT expression declines after weaning, resulting in primary lactose intolerance. In some human populations, including those of Northwest European descent and nomads of the Afro-Arabian desert region, LCT expression persists into adulthood and confers the ability to effectively digest dairy products and utilize lactose. The inability to break down lactose in the small intestine results in its fermentation in the large intestine leading to abdominal discomfort, flatulence, and diarrhea. Age can also affect the absorption of specific nutrients. Vitamin B12 deficiency can result from atrophic gastritis, which is the loss of gastric glandular cells in the stomach and impaired ability to acidify the stomach. This condition is common in the elderly and can result from chronic inflammation. Without sufficient acid content in the stomach, vitamin B12 cannot be liberated from food proteins and therefore is not available for intestinal absorption. Overgrowth of pathogenic bacteria can also cause damage and disappearance of villi and specific malabsorption of folate,

Allergic Responses to Food Antigens

It is estimated that the cumulative prevalence of food allergy is 3–6% in Western populations. Of these, about half develop GI symptoms. Common food allergens are found in cow’s milk, eggs, nuts, fish, and shellfish. Many factors influence the development of food allergies. Intrinsic factors may include the state of maturation of the mucosal immune system, impaired enteric nervous system, genetic susceptibility for increased mucosal permeability or impaired immune responses, IgA deficiency, or Th2-biased mucosal immunity. Other factors include the timing of food introduction to the diet, the amount of antigen on initial exposure, concomitant GI tract infections, and resistance of dietary proteins to digestion. Type I hypersensitivity is an IgE antibody-mediated immune response to food allergens. In sensitized individuals, ingested allergens cross the gut epithelium into the submucosa, where they cross-link with antigen-specific IgE antibodies bound by corresponding high-affinity IgE receptors on the surface of mucosal mast cells. This activates the mast cells to release soluble preformed mediators such as histamine, serotonin, or tryptase, resulting in increased vascular permeability and contraction of smooth muscle. The released soluble mediators induce intestinal smooth muscle contractions and outflow of fluid across the epithelium, resulting in vomiting and diarrhea, respectively. If the food allergens enter the bloodstream, urticaria (hives) on the skin can occur. Anaphylaxis may develop in certain individuals following exposure to peanuts, tree nuts, and shellfish, which can lead to cardiovascular collapse, acute asthmatic symptoms, and, if left untreated, death.

=Figure 4 (cont’d) d (IgA) production and local and systemic tolerance. (b) In comparison, immune sensitization after exposure to invading

microorganisms is invoked after the release of a number of different cytokines by cells of the subepithelium, including IL-1, IL-6, and IL-8. These cytokines act on dendritic cells, leading to the production of IL-12 and the upregulation of costimulatory molecules. This allows for an immunostimulatory interaction to occur between the dendritic cells and naïve T cells, resulting in their maturation into T-helper-1 (Th1) and T-helper2 (Th2) cells, which then produce proinflammatory and immune mediators that lead to IgA production and local and systemic immunity. Reproduced with permission from Macmillan Publishers Ltd: from Mowat, A.M., 2003. Anatomical basis of tolerance and immunity to intestinal antigens. Nat. Rev. Immunol. 3 (4), 331–341.

Gastrointestinal Disorders: Overview Celiac Disease

Celiac disease (CD) is a food-induced autoimmune disease caused by the exposure to gluten proteins from wheat, barley, and rye in genetically susceptible individuals. Exposure to the culpable cereal proteins activates a T cell–mediated inflammatory, IFN-g-dependent immune response that results in intestinal damage. CD is relatively common with an incidence of 1 in 100 to 600 people. However, it is estimated that over 90–95% of cases go undiagnosed due to subclinical symptoms. The etiology of CD is well understood compared to other autoimmune diseases. A repertoire of offending dietary cereal proteins/peptides that initiate the inflammatory response can be found in wheat gluten, a mixture of gliadin and glutenin proteins, and their counterparts in barley and rye. These proteins have a high proline and glutamine content which makes them resistant to complete proteolytic digestion in the GI tract. CD is strongly associated with two MHC class II alleles found at the HLA-DQ locus. Approximately 90–95% of patients with CD express human leukocyte antigen (HLA)-DQ2 and the remaining 5–10% express HLA-DQ8. Gut-associated antigenpresenting cells expressing either HLA-DQ2 or HLA-DQ8 present hydrolysis-resistant immunodominant gliadin peptides to T cells in the lamina propria of the small intestine. The CD autoantigen, tissue transglutaminase, also plays a unique role in disease pathogenesis. This intestinal enzyme deamidates specific neutral glutamine residues found in gluten peptides and converts them to negatively charged glutamic acid. The amino acid change results in peptides with increased binding affinity for the disease-relevant HLA-DQ2 and HLA-DQ8 molecules. The activation of an IFN-g, inflammation-mediated response causes the mucosa of the small intestine to undergo numerous alterations (Figure 5). The number of intraepithelial lymphocytes and plasma cells in the lamina propria increases dramatically. Villous atrophy is accompanied by crypt hypertrophy and increased crypt mitoses. In severe cases of CD, the

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inflammatory process results in a complete loss or flattening of the villi of the small intestine. Patients with CD may demonstrate symptoms of malabsorption of nutrients such as iron, calcium, or folic acid due to the underlying damage to the epithelium, although severe cases of malabsorption are rare. Symptoms of malabsorption in these cases are diarrhea, weight loss, and potentially mild abdominal symptoms. CD is often associated with dermatitis herpetiformis, an itching and blistering skin disease, which, like CD, can be alleviated by a gluten-free diet. Other diseases associated with chronic CD are enteropathy-associated T cell lymphoma and osteoporosis. CD patients are also at increased risk for other autoimmune diseases, including insulin-dependent diabetes and autoimmune thyroiditis, likely due to shared genetic risk factors among the diseases.

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis (UC), has a complex pathogenesis involving the interaction of various susceptibility genes, altered mucosal immunity, compromised mucosal barrier, and mucosal interactions with microflora. The incidence of IBD varies greatly from region to region, with developed countries demonstrating a higher prevalence. The incidence of UC is estimated to be between 0.5 and 31.5 per 100 000 people, and Crohn’s disease is estimated to be between 0.1 and 20.2 per 100 000 individuals worldwide. Of note, the prevalence of IBD appears to have plateaued in Western nations, but is on the rise in traditionally low-incidence regions such as Asia, South America, and Southern and Eastern Europe. IBD is polygenic with over 150 genetic loci that have been associated with disease. However, like most other polygenic diseases, the contribution of any single genetic loci to disease risk is low and dependent on gene–gene or gene–nutrient interactions. Most identified genes/loci modify the risk for Crohn’s disease, such as in the gene nucleotide oligomerization domain 2 NOD2/CARD15, which is normally expressed by macrophages.

Figure 5 A comparison of biopsies from normal and celiac disease (CD) small intestinal mucosa. (a and b) Small-intestinal mucosal biopsy viewed through a dissecting microscope. The normal biopsy (a) shows numerous surface villi, whereas a biopsy from an individual with CD and total villous atrophy shows, in place of the villi, numerous surface openings to underlying crypts and surface ridges (b). (c) H&E-stained section of a normal small-intestinal mucosal biopsy. Original magnification, 400. (d) H&E-stained section of a small-intestinal mucosal biopsy from an individual with CD and total villous atrophy. Original magnification, 400. The original figure was published in Gastroenterology 128 (Suppl. 1), Kagnoff, M.F., 2005. Overview and Pathogenesis of Celiac Disease, pp. S10–S18. Copyright of the American Gastroenterological Association, Published by Elsevier Inc. Reprinted with permission.

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Other genes associated with IBD include autophagy-related 16like 1 (ATG16L1), immunity-related GTPase family M protein (IRGM), NACHT, IL-23R, IL-10, IL-27, and fucosyltransferase 2 (FUT2). Some genes have been specifically associated with UC, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, death-associated protein (DAP), PR domain-containing 1 (PRDM1), janus kinase-2 (JAK2), interferon regulatory factor 5 (IRF5), guanine nucleotide binding protein (G protein) D12 (GNA12), and lymphocyte-specific protein 1 (LSP1). Together the data indicate that a loss of immune homeostasis that may result in inflammation or aberrant responses to the microbiome likely plays a significant role in the pathogenesis of IBD. It has been proposed that exposure to normally innocuous gut microflora in genetically susceptible individuals, especially when the epithelial barrier is disrupted, can trigger a chronic inflammatory response due to dysregulation of the mucosal immune system and loss of immune tolerance. Changes in gut microflora composition may also occur, resulting in an increased load of bacterial pathogens or toxins, which act as initiating factors. Whether disease progression relies on one or a combination of these scenarios, the result is a robust and chronic inflammation of the gut. UC and Crohn’s disease, though similar, are not identical. Crohn’s disease is associated with excess expression of proinflammatory cytokines, including IL-12/IL-23 and IFN-g/IL-17. Patients present with discontinuous ulceration and fullthickness bowel wall inflammation, often including granulomas in both the small and large intestines. Symptoms of Crohn’s disease include abdominal pain, diarrhea, and rectal bleeding, as well as weight loss, fever, and fatigue. In severe cases, patients develop obstructing strictures of the bowel and inflammatory connections (fistulae) between segments of bowel or between the bowel and skin and other organs. In contrast, UC is associated with excess IL-13 production, primarily affecting the colon, with a continuous inflammation of the mucosa nearly always involving the rectum and extending proximally. The symptoms are similar to Crohn’s disease, although fistula development does not occur. Usually both conditions are chronic and relapsing, although UC can be cured by surgical removal of the colon. Medical therapy relies on anti-inflammatory and immunosuppressant drugs. A serious consequence of IBD is a fivefold increased risk of colon cancer, due in part to chronic inflammation (see Inflammation in Intestinal Carcinogenesis). As many as 1.4 million people in the United States are affected by IBD. The relative risk of colorectal cancer in UC patients is 2% after 10 years, 8% after 20 years, and 18% after 30 years, making early detection critical.

Cancers of the GI Tract Gastrointestinal cancers account for 20% of all cancer incidences and are the leading cause of cancer deaths in many countries around the world. GI cancers are extremely difficult to treat; detection is challenging and often occurs late in disease progression.

Colorectal Cancer

In the US, colorectal cancer (CRC) represents the third most common cancer and is the third leading cause of

cancer-related mortality. GI cancers can be difficult to treat often due to late detection. The most prevalent precancerous lesion in colorectal cancer is the adenoma and it occurs on average 15 years before CRC develops. The majority of colorectal cancers occur spontaneously, in the absence of genetic susceptibility. In sporadic cancer, the progression from adenoma to carcinoma is apparent, with the dysplastic precursor generally localized to a discrete focus. Molecular alterations that contribute to the development of sporadic colon cancer include DNA damage (single point mutations, the loss of chromosomal material (e.g., loss of heterozygosity), and microsatellite instability) and DNA methylation. Specifically, implicated in the development of cancer is the somatic loss of function of the tumor suppressor genes adenomatous polyposis coli (APC) and p53, as well as epigenetic alterations, such as methylation of DNA that acts to silence tumor suppressor genes. DNA damage can result from dietary deficiency of critical nutrients or from chronic inflammation. The generation of oxidative stress during inflammation increases rates of DNA damage and thereby has the potential to induce genetic mutations and instability that is responsible for the initiation and progression of carcinogenesis. Deficiencies in nutritional factors such as folate, selenium, and vitamin D are also implicated in cancer initiation and progression. Folate is a B vitamin that is required for DNA synthesis and repair and for the generation of S-adenosylmethionine, a cofactor required for DNA and histone methylation. Disruptions in folate metabolism lead to alterations in genome methylation patterns, which affect the expression of tumor suppressor genes, and genome instability resulting from uracil accumulation in DNA. Several lines of evidence support the association of folate intake with colon cancer risk. Epidemiological evidence suggests that individuals with low folate concentrations are at increased risk of colon cancer. Furthermore, there also appears to be an interaction between folate status and single nucleotide polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, which encodes an enzyme that is critical for folate metabolism and influences genomic DNA methylation. Individuals with a common MTHFR polymorphism (C677T) have dramatically decreased risk of developing colorectal cancer compared with carriers of the ‘wild-type’ gene. Heritable forms of CRC are less common and often result in intestinal polyposis syndromes with high risk for cancer development and early onset. The genetic underpinnings of these forms of CRC include mutations in the APC gene, such as in familial adenomatous polyposis (FAP), genes involved in DNA repair mechanisms such as MUT, among others. Nonpolyposis CRC also occurs and mechanisms include the loss of function of DNA mismatch repair.

Inflammation in Intestinal Carcinogenesis

Avoidance of long-term chronic inflammation is a key to cancer prevention in the gut. Simplistically, inflammation-driven carcinogenesis results from an environmental trigger that acts on the epithelium and invokes an inflammatory response. The activation of inflammatory cells is believed to induce oxidative stress and generation of harmful chemical radicals. These radicals damage the epithelium. Although mechanisms in the cell are available for repair and regeneration, the presence of

Gastrointestinal Disorders: Overview

APC

Normal mucosa

MSI Aneuploidy k-ras methylation COX-2

Early adenoma

DCC/DPC4

Intermediate adenoma

Aneuploidy/CIN MSI methylation COX-2 p53 p53 mut. LOH DCC/DPC4

Colitis; no dysplasia

Indefinite dysplasia

Low-grade dysplasia

p53

Late adenoma

k-ras

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Carcinoma

APC

High-grade dysplasia

Carcinoma

Figure 6 Molecular pathogenesis of sporadic colon cancer (top) and colitis-associated colon cancer (bottom). COX-2, cyclooxygenase-2; CIN, chromosomal instability; MSI, microsatellite instability; mut, mutation; LOH, loss of heterozygosity; DCC, deleted in colon cancer; DPC, deleted in pancreatic cancer; APC, adenomatous polyposis coli. Reproduced with permission from Itzkowitz, S.H., Yio, X., 2004. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am. J. Physiol. Gastroint. Liver Physiol. 287 (1), G7–G17.

continued inflammation may lead to DNA damage or epigenetic alterations or both. At early stages, these effects on the genome may result in cellular dysplasia, but over the longer term, the accrual of genetic alterations may lead to carcinogenesis. The proinflammatory cytokine, tumor necrosis factor (TNF), which is released mainly by macrophages, T cells, and natural killer cells, has earned the reputation of playing a key role in tumor promotion. Chronic and low-level exposure to TNF activates a complex system of intracellular messengers and proinflammatory mediators that can lead to carcinogenesis in specific cell types, such as epithelial cells. TNF can convey both survival and cell proliferative, as well as proapoptotic signals; it is when the balance favors cell survival that TNF contributes to the development of a malignant phenotype. The binding of TNF to the TNF receptor 1 leads to a cascade of intracellular events that promotes the activation of transcription factors, including nuclear factor kappa B (NF-kB) and cfos/cjun. Their activation in epithelial cells induces expression of antiapoptotic, immunomodulatory, and inflammatory genes which sustain the inflammatory response and promote cell proliferation, growth, invasiveness, and metastasis. Similarly, exposure of cells to other proinflammatory cytokines, including IL-1b and IL-6, may act through the NF-kB pathway to promote the survival of activated T cells, promoting chronic inflammation and thereby leading to tumor formation. Two widely cited examples of gut-related chronic inflammatory conditions that may lead to carcinogenesis over time are IBD and infection by Helicobacter pylori. These conditions invoke a number of common processes implicated in the progression to GI cancer, including the loss of immune tolerance, increased expression of inflammatory cytokines, induction of cyclooxygenase-2 (COX-2), and ultimately, genetic and epigenetic modifications that promote tumorigenesis.

Inflammation-Mediated Colon Cancer

Risk factors for colon cancer include nutritional factors, genetics, and inflammatory state, all of which interact and contribute to the initiation and progression of inflammation-mediated carcinogenesis. In both sporadic and IBD-associated colon cancer, carcinogenesis is associated with genetic instability arising from both chromosomal instability and microsatellite instability. However, the clinical features of these two types of colon cancer differ (Figure 6). Unlike sporadic colorectal cancer, IBD-associated carcinogenesis results when the epithelium in areas of inflammation progresses to dysplasia and then to carcinoma, with dysplastic lesions generally appearing as multifocal and diffuse. In addition, the timing and frequencies of molecular alterations in sporadic and IBD-associated colon cancer differ (Figure 6). In IBD-associated colorectal cancer, molecular mechanisms such as DNA damage and DNA methylation changes occur, and many of the same genes are involved, but these events generally occur simultaneously and early in progression to carcinogenesis.

Gastric Cancer

Infection by H. pylori is common, occurring in over half of all individuals around the world. The prevalence of infection can be as high as 75% in many regions including Latin America, Latvia, and Morocco. An inflammatory response is invoked by infection, and its persistence leads to cellular transformation and gastric cancer in 0.5% of infected individuals. Following H. pylori infection, chronic superficial gastritis develops from normal mucosa, followed by atrophic gastritis and then intestinal metaplasia. If the inflammatory response subsides at this stage, progression to cancer may not occur. However, if cellular transformation proceeds to high-grade dysplasia, carcinoma will invariably result. Individuals infected with H. pylori

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run a 2- to 20-fold increased risk of developing gastric cancer with 5-year survival being only 50%. A number of disease-modifying factors have been proposed to influence the likelihood of progression to carcinogenesis in those infected with H. pylori. These include characteristics intrinsic to the host (e.g., genetics, age), as well as to the infecting bacteria, and environmental factors. A number of immune response factors have also been associated with progression to cancer after H. pylori infection. These include the types of cytokines activated following infection (e.g., IL-1b, IL-8, TNF, IL10), the induction of reactive oxygen and nitrogen radical species, and activation of the transcription factor cfos, which is involved in cell cycle regulation. The expression of COX-2 has also been implicated in progression to cancer, owing to its role in disrupting the balance between cell proliferation and cell death. The carcinogenic effects of COX-2 in H. pylori infection may be related to the function of this enzyme in prostaglandin production and proangiogenesis. Surprisingly, although NSAIDs inhibit COX enzymes and prevent cancer in some studies, there is some evidence suggesting these agents may in fact increase susceptibility to gastric ulcers and carcinogenesis in some individuals infected with H. pylori. Although the reasons for this are unclear, they may relate to the association between NSAIDs and other GI disorders such as ulcers, bleeding, and perforations. Other factors associated with the development of H. pylori-mediated gastric cancer include genetic (e.g., single nucleotide polymorphisms or SNPs) and

epigenetic (e.g., methylation of tumor suppressor genes) alterations.

See also: Aging: Nutrition and the Older Adults; Colorectal Cancer; Gastric Cancer; Helicobacter pylori.

Further Reading Baumgart, D.C., Sandborn, W.J., 2007. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 12, 1641–1657. Jang, H., Mason, J.B., Choi, S.W., 2005. Genetic and epigenetic interactions between folate and aging in carcinogenesis. J. Nutr. 135, 2967S–2971S. Morteau, O. (Ed.), 2004. Oral Tolerance: The Response of the Intestinal Mucosa to Dietary Antigens. Kluwer Academic/Plenum Publishers, Landes Bioscience, Georgetown: TX; New York. O’Hara, A.M., Shanahan, F., 2006. The gut flora as a forgotten organ. EMBO Rep. 7, 688–693. Oral tolerance: new insights and prospects for clinical application. In: Weiner, H.L., Mayer, L., Strober, W. (Eds.), 2004. Annals of the New York Academy of Sciences, vol. 1029. Strober, W., Fuss, I., Mannon, P., 2007. The fundamental basis of inflammatory bowel disease. J. Clin. Invest. 117, 514–521. Vollset, S.E., Clarke, R., Lewington, S., Ebbing, M., Halsey, J., Lonn, E., Armitage, J., Manson, J.E., Hankey, G.J., Spence, J.D., Galan, P., Bønaa, K.H., Jamison, R., Gaziano, J.M., Guarino, P., Baron, J.A., Logan, R.F., Giovannucci, E.L., den Heijer, M., Ueland, P.M., Bennett, D., Collins, R., Peto, R., B-Vitamin Treatment Trialists’ Collaboration, March 23, 2013. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals. Lancet 381 (9871), 1029–1036.

Gender Aspects of Sexual and Reproductive Health Jane C Cottingham, Independent Consultant, Geneva, Switzerland Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Jane C. Cottingham, T.K. Sundari Ravindran, volume 3, pp. 19–25, Ó 2008, Elsevier Inc.

Definitions Sexual and reproductive health was first defined at the International Conference on Population and Development (ICPD), held in Cairo in 1994. The term ‘reproductive health’ reflected a sharp departure from previous approaches to the question of how, and to what extent, humans reproduce. In reaction to the often aggressive population control programs launched in the 1960s and 1970s in Africa, Asia, and Latin America, the international women’s movement and others called for programs that would both respect women’s human rights and provide them with services for a range of issues beyond just birth control – going through childbirth safely, having a healthy, wanted child, and being free from sexually transmitted infections (STIs). The definition of reproductive health also pointed to the central importance of human sexual relationships, and the fact that they often represent an unequal exchange between people, and particularly between women and men. This inequality, rooted in societies’ views of gender, plays a critical role in sexual and reproductive health. The concept ‘gender’ is defined as encompassing the different roles, rights, expectations, and obligations that culture and society attach to individuals on the basis of their sex. Sex refers to the anatomy of an individual’s reproductive system and secondary sex characteristics, often categorized as male or female, but it is important to note that sex is not a binary category. Gender, on the other hand, concerns categories of masculinity and femininity that are learned through socialization and that are subject to change over time. (Some public health literature uses the terms ‘sex’ and ‘gender’ interchangeably. The authors would like to emphasize that, while sex and gender are closely linked, for the purposes of analysis it is important to separate out gendered norms, experiences, and expectations from purely biological dimensions. See Snow (2007).) Gender thus encompasses the changeable roles and socially determined meanings attached to expressions of masculinity and femininity as displayed by men, women, and transgender people, and the value judgments that go along with these. In most societies, there are differences and inequalities between women and men in responsibilities assigned, activities undertaken, access to and control over resources, as well as decision-making opportunities, all of which have an impact on, and are affected by, sexual and reproductive health (WHO, 2015a; UN Women, 2015).

Dimensions of Gender Considerations The past three decades have seen an explosion of studies and interventions on the way in which gender differences have an impact on all dimensions of development. In the area of health – including sexual and reproductive health – it is

International Encyclopedia of Public Health, 2nd edition, Volume 3

generally accepted that the different dimensions of gender play a role in women’s, men’s, and transgender persons’ vulnerability to exposure to disease and the outcome of that exposure, and in their health-seeking behavior, their ability to access health information and services, their experience of health services, and the social and economic consequences of a health problem (Klugman and Theobald, 2006; Snow, 2007). Gender dimensions include (1) the sociocultural norms and values attached to what women and men, girls and boys, do, that is, gender roles, (2) the differential access to control (including making decisions) over resources such as money, information, and education, (3) the influence that social institutions such as family, school, religious institutions, workplaces, and health services have in reinforcing gender norms, and (4) the impact of laws and policies, which often have gender-based inequalities written into them. For the purposes of this article, these categories are used to highlight some of the major gender aspects of sexual and reproductive health. However, examination of gender dimensions in any area of inquiry must start with sex-disaggregated data.

The Burden of Sexual and Reproductive Ill Health, by Sex Estimates of the global burden of disease, which assesses the burden to the world’s population from premature mortality and disability by using a combined measure, the disabilityadjusted life year (DALY), indicate that sexual and reproductive ill health contributes to 20% for women and 14% for men (see Figure 1). The elements included in the calculation are maternal and perinatal mortality and morbidity, reproductive cancers, HIV/AIDS, and STIs. Since only women get pregnant and give birth, the burden from maternal causes is unique to women, making the overall burden higher for them than for men. In addition, there are biological differences in, for instance, susceptibility to STIs. Biologically, women, and particularly young women, are at greater risk of infection through heterosexual sex (Zierler and Krieger, 1997). This is partly because of prolonged exposure to organisms when infected ejaculate is retained in the vagina, particularly for pathogens that produce discharge or are present in genital secretions, such as gonococci, chlamydia, trichomonads, and HIV (Howson et al., 1996; Ramanathan and Woodrow, 2015). It is also known the sex hormones influence infectious disease transmission and there are grounds for suggesting that estrogen enhances the pathogenicity of many urogenital microorganisms (Sonnex, 1998; Kaushic et al., 2011). In the case of HIV, biological and genetic differences have been identified that lead to differential disease courses and outcomes in men and women, with progression to AIDS being fast in women for the same level

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Gender Aspects of Sexual and Reproductive Health

8 7 5.7

6.2

5.8

Males 19.4

20

4.7

5

13.4

15

4 10

3

% of total DALYs

% of total DALYs

6

25

Females 6.9

1.8

2

5

1

1

0.5

0.2 0

0 HIV/AIDS

STIs

Maternal

Cancer

Perinatal

Total

Figure 1 Global burden of sexual and reproductive ill-health conditions. STIs, sexually transmitted infections; DALYs, disability-adjusted life years. Source: World Health Report, 2004. World Health Organization, Geneva, Switzerland.

of viremia (Addo and Altfeld, 2014). Reproductive cancers are more numerous in women, such as cancers of the cervix, corpus of the uterus, breast, and ovaries, than in men (prostate and testicular cancer). This situation already puts women at a disadvantage from a sexual and reproductive health point of view. In reality, the situation is probably even more unbalanced since the global burden estimates are limited in their definition of sexual and reproductive health. They do not include conditions such as obstetric fistula, urinary incontinence, uterine prolapse, menstrual disorders, non-sexually transmitted reproductive tract infections, female genital mutilation (FGM), stillbirth, infertility, and the reproductive health consequences of sexual abuse. Nor do the estimates capture the social and psychological effects of sexual and reproductive ill health, some of which – like those associated with obstetric fistulae – may be significant (AbouZahr and Vaughan, 2000). Therefore, it seems likely that, if and when estimates are made to include these additional elements, the burden for women would be considerably higher.

Norms and Values Norms and values in any given society or community are a powerful influence in the shaping of gender roles and responsibilities. They define, from an early age, what is appropriate behavior, including sexual behavior, for men and women. In many parts of the world, masculinity is associated with early sexual activity, having many sexual partners and experiences, virility, and pleasure. Femininity, on the other hand, is frequently associated with passivity, virginity, chastity, and fidelity. The need for men to ensure that their progenies are really theirs has given rise, over the centuries, to the devising of myriad methods of maintaining women’s chastity, from chastity belts to seclusion to partial or total covering of the body in public, with sometimes severe penalties for transgressors. In some parts of the world, this pattern has changed or is changing to a more affirmative vision of female sexuality and softer notions of masculine sexuality, with an accompanying affirmation that sexuality includes homosexuality as well as heterosexuality.

These norms and values attached to gender roles and sexuality have a considerable impact on sexual and reproductive health. For instance, in sub-Saharan Africa, although HIV prevalence among young women and men aged 15–24 years fell by 42% from 2001 to 2012, HIV prevalence among young women remained more than twice as high as that among young men (UNAIDS, 2013). The major factors that contribute to this difference have been identified as the culture of silence around sexuality, limited access to economic opportunities and autonomy leading to exploitative transactional and intergenerational sex, and violence against women in relationships (UNICEF, 2015). In countries as different as Côte d’Ivoire (Painter et al., 2007), India (Schensul et al., 2006), and Mexico (Hirsch et al., 2007), marriage – implying sexual exclusivity – may not afford protection for women from HIV or other STIs because of men’s extramarital sexual behavior. At the same time, poverty may often push young – especially urban – women into early, premarital sexual relations, incurring a higher risk of contracting HIV (Hattori and Dodoo, 2007; UNICEF, 2015), but this does not increase men’s vulnerability to HIV in marriage (Glynn et al., 2003). Masculine sexuality often incorporates elements of selfdestructive risk, conquest, and even violence. This genderbased difference has an enormous impact on girls’ and women’s (and, to a lesser extent, boys’ and men’s) sexual and reproductive health. WHO estimates suggest that one in three women globally have experienced either physical or sexual violence from a partner, or sexual violence by a nonpartner at some point in their lives (WHO, 2013). Women exposed to intimate partner violence, in comparison with those who are not, are twice as likely to experience depression, almost twice as likely to have alcohol use disorders, 16% more likely to have a low birth-weight baby, and one-and-a-half times more likely to acquire HIV and contract syphilis infection, chlamydia, or gonorrhea (WHO, 2013). A related phenomenon is forced sexual initiation or coerced sex during adolescence, which have been reported in many studies of young women and men (WHO, 2002; Jejeebhoy and Bott, 2005). Findings from a multicountry study show that the prevalence of coerced sex before the age of 15 years varied from 1 to 21%, and an adult male family member was usually the

Gender Aspects of Sexual and Reproductive Health perpetrator. Overall, more than 5% of women reported their first sexual experience as forced, with the prevalence ranging from 1% in Japan to 17% in Ethiopia, 14–17% in Tanzania, 24% in Peru, and 24–30% in Bangladesh (Garcia-Moreno et al., 2006). While many more studies have been conducted on forced and/or coerced sex as it concerns girls and women rather than boys and men, studies that have included both females and males in the sample show that boys too report such coercion (see Figure 2). A case study of young persons (aged 16–17 and 19–30) in Lima, Peru, found that, of the young men reporting a heterosexual experience, 11% reported a nonconsensual experience at first sex; among those reporting a homosexual experience, as many as 45% report nonconsensual initiation (Cáceres, 2005). Sex workers – the majority of whom are women, sometimes very young and trafficked into prostitution – are particularly vulnerable to forced sex and its attendant sexual and reproductive ill-health consequences, because sex work is often illegal and sex workers considered legitimate targets of violence. Surveys in different continents show that up to 70% of sex workers report being raped (WHO, 2006) or coerced into providing sex, often to police in exchange for freedom from detainment, arrest, and fines (Gould and Fick, 2008; Rhodes et al., 2008; OSI, 2006). Irrespective of the setting, gender power imbalances tend to underlie the persistence of forced sex – both marital and extramarital – among young women (Jejeebhoy and Bott, 2003), and to some extent among boys or men where the perpetrators are usually older men. The sexual and reproductive health outcomes of such coercive and/or violent relationships include unwanted pregnancy and an associated risk of unsafe abortion (especially in countries where abortion is legally restricted), chronic pelvic pain,

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STIs including HIV, and painful intercourse. Having suffered sexual abuse, particularly in childhood, is also associated with increased risk-taking such as alcohol and drug abuse, multiple sex partners, low self-esteem, and depression. Interventions to change gender-related inequalities, especially with regard to sexual behavior, may be one of the most important contributions to the improvement of sexual and reproductive health in the world. Gender norms and values also contribute to early marriages and early childbearing, lack of knowledge about one’s body, embarrassment around discussing contraception with partners, and silence around sexual and reproductive health problems and conditions, all of which can lead to delays in health-care seeking or unwillingness to disclose or discuss one’s problem with a health-care provider (Roudi-Fahimi, 2006). Although early marriages have declined in many parts of the world, at least one-third of women aged 20–24 years in more than 40 countries in developing regions were married or in union before their eighteenth birthday. About 12% of them were married or in union before age 15 (UNFPA, 2012). Among men, however, marriage during the teenage years is quite rare, and marriage in the early 20s has also declined in most places over the past decades. Early marriage for women leads to early childbearing, which carries well-documented increased risks of death in pregnancy or childbirth, premature labor, complications during delivery, low birth weight, and a higher chance that the newborn will not survive (UNFPA, 2012). FGM – also called female circumcision or excision – is closely related to perceptions of femininity and female sexuality. It is often performed on young girls as a rite of passage into adulthood (although in some parts of the world it is practiced on girls soon after they are born, and sometimes

45 Latin America Africa Asia

40 35 30

Girls

Boys

%

25 20 15 10 5

Caceres et al. 1997

Slap et al. 2003

Ajuwon et al. 2001a

Silva et al. 1997

Patel and Andrew 2001

Handwerker 1993

McFarlane et al. 1999

Kgosidintsi 1997

Ajuwon et al. 2001a

Slap et al. 2003

Ajuwon et al. 2001a

Jewkes et al. 2001

Caceres et al. 1997

Worku and Addisie 2002

Patel and Andrew 2001

Mulugeta et al. 1998

Kim 1998

Jewkes et al. 2002

Stewart et al. 1996

0

Figure 2 Percentage of young women and men (aged 10–24 years) reporting a coercive sexual relationship. Reproduced with permission from Jejeebhoy, S., Bott, S., 2003. Non-consensual Sexual Experiences of Young People: A Review of the Evidence from Developing Countries. Population Council, New Delhi, India.

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on adult women). The most reliable estimates indicate that more than 125 million girls and women alive today have undergone some form of FGM, and that 3 million are at risk of undergoing FGM each year (UNICEF, 2013). It is practiced in 29 countries across northern and central Africa, the Middle East, and some countries in Asia, although trend data show that the practice of FGM is becoming less common in slightly more than half of those countries. It is also practiced by members of communities from these regions who have emigrated to Europe and North America. FGM is considered a violation of human rights, and a marker for serious genderbased inequalities. The health consequences of FGM – particularly the more extreme types of mutilation – include hemorrhage, infection, chronic pelvic pain, infertility, painful urination, difficulties with menstruation and sexual intercourse, problems during childbirth, and death (WHO, 2008). A multicountry study found that the death rate among babies during and immediately after birth was between 15% and 55% higher (depending on the severity of the FGM) in mothers with FGM than those without. It also found an increased risk of postpartum hemorrhage and cesarean section for the mothers with FGM (WHO Study Group on Female Genital Mutilation and Obstetric Outcome, 2006).

Access to Resources Gender roles have an impact on how and whether men and women have access to essential resources such as education, information, disposable income, and health services. All of these resources in their turn have an impact on sexual and reproductive health. The gender gap in education has been closing (dramatically in some places) over the past two decades, with girls’ enrollments increasing faster than those of boys at all levels of education. However, while boys usually drop out of school at higher rates than girls (with wide variations across countries), girls continue to face discrimination in access to primary education in some countries (UNESCO, 2012). The link between education and (sexual and reproductive) health has been well established, with a multitude of studies having documented a direct association between education and reduced fertility, implying greater use of contraception (see Table 1), as well as greater use of antenatal care services and skilled attendance at childbirth, the use being greater the higher the levels of women’s education. Women now generally outperform men in education, yet they still face significant shortfalls and discrimination in the labor market and often find themselves in jobs where their skills are not well used (UNESCO, 2012). On the other hand, men, like women, have needs for information and services that may not be easy for them to fulfill. For instance, they use health services less than women and so may be less exposed to health-specific information. Especially in the domain of sexuality, social norms may dictate that men ‘know’ what should be done, and they do not want to appear ignorant or foolish. Yet studies in countries as varied as India, Iran, and Kenya reveal that men often have misguided beliefs, little or no knowledge of contraception and STIs, and that this poses a threat to both their own and their partners’ sexual and

Table 1 Total fertility rates for selected countries, by level of education of mothers Country

Survey date

No education

Primary

Secondary or higher

Overall

Bangladesh Bolivia Guatemala Nepal Nicaragua Pakistan Senegal Zambia

2007 2008 2008 2006 2006 2006–07 2008–09 2007

3.0 6.1 5.2 3.9 4.4 4.8 5.6 8.2

2.9 5.2 3.8 2.8 3.1 4.0 4.5 7.1

2.5 3.7 2.3 2.2 2.0 2.8 3.1 3.9

2.7 5.7 3.6 3.1 2.7 4.1 4.9 6.2

Source: Lutz, W., Samir, K.C., 2013. Demography and human development: education and population projections. United Nations Development Programme, Human Development Report Office, New York.

reproductive health (Joshi et al., 2009; Mohammadi et al., 2006; Wambui, 2012). Sexual relationships have an economic basis that determines the terms on which sex takes place. In marriages, women who are financially and socially dependent on men may not feel able to refuse sex or particular kinds of sex. While boys and men also go into prostitution, the vast majority of sex workers in the world are women, nearly always for economic reasons. If women have no control of financial resources, they may turn to prostitution as a seemingly easy way to earn money. Thus, the very act of attempting to gain access to economic resources can put women at risk of sexual ill health. Because sex work is privately condoned but publicly condemned, women all over the world move in and out of situations where they are condemned for immorality while earning money, frequently to support their children. The power implicit in economic relationships also can lead young boys into exploitative situations with older men. Economic dependency has an impact on whether or not women have access to food and health services they need during pregnancy, childbirth, and the postpartum period. A large proportion of women who become pregnant in developing countries are poorly nourished and frequently anemic. Anemia compromises immunity to infections and healing capacity, making childbirth much more risky than for wellnourished women. In addition, where women’s status is low – as it is in many societies and families – family resources are unlikely to be mobilized to cover costs of emergency care and transportation that could save women from dying or becoming severely ill from pregnancy or birth-related causes. Where family resources are almost nonexistent, women’s needs in childbirth are therefore likely not to be met. Compounded, as is often the case, by a weak health system that cannot provide essential health services such as pregnancy, delivery, and postpartum care free to poor women, this situation is a stark example of how gender and poverty work together to the detriment of women, with sometimes fatal consequences.

Gender Biases in Health Services While it is difficult to generalize from a global point of view, there is evidence that many health service providers make

Gender Aspects of Sexual and Reproductive Health different assumptions about their male and female patients. Health-care providers also have gender norms and values instilled. Their lack of understanding of the ways in which gender roles affect women’s ability to access health services can lead to ‘victim blaming,’ for instance, when women do not seek timely antenatal care or emergency obstetric care. In societies where sexual relations outside marriage are condemned, pregnant unmarried women may be treated with disrespect, while unmarried men who have a STI would not be treated in the same way. Typically, sexual and reproductive health-care providers have little or no training in talking about sexuality and sexual relationships, nor are they prepared to listen to, and treat, people who fall outside of gender and related sexual norms such as men who have sex with men, lesbians, transgender people, or even sex workers. For health-care providers – be they men or women – being aware of gender norms and values and the impact these have on women’s and men’s health (as described above) is an essential tool for improving the quality of care of sexual and reproductive health services. Numerous studies also show that the sex of the health-care provider plays a key role in a patient’s satisfaction and whether or not he or she will continue to use a health service; generally speaking, both women and men prefer same-sex providers. Health services may also be organized in gender-insensitive ways. For example, user fees may be introduced for routine sexual and reproductive health commodities that women need, such as contraceptives, in situations where other essential medicines are provided free of charge. Men, if they use sexual and reproductive health services at all, may not receive adequate, comprehensive, or integrated levels of care (Kalmuss and Tatum, 2007). At the health policy level, the central part played by gender inequalities in sexual and reproductive (ill) health makes it imperative to give priority to services that only women need – such as emergency and other obstetric care, antenatal and postnatal care, abortion services, and repair of pregnancy-related problems such as fistulas and urinary incontinence. Examples from both developed and developing countries show that, where such services have been given high priority, the health of women (and of their infants) has improved enormously (Van Lerberghe and De Brouwere, 2001).

Laws and Policies Gender inequalities are often captured and reinforced in laws and policies, some of which have a direct effect on sexual and reproductive health. Marriage law is one example. In many countries, both the legal minimum age and actual age of marriage, particularly for girls, are still very low, leading to early or very early childbearing with its attendant risks, as discussed above. The enactment of laws that prohibit early marriage, while not sufficient to halt the practice initially, has been shown to contribute to positive change and an increased protection of girls and women (UNICEF, 2001). There is a growing trend for countries to align their age-at-marriage laws with international human rights standards (i.e., 18 years of age), but child marriage governed by customary law is still

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widespread in some parts of the world and will require intensive community education to shift. The nonrecognition in law of rape within marriage is a serious gap from which women suffer. Since the Declaration on Violence Against Women in 1993, the Fourth World Conference on Women in Beijing in 1995, and the human rights standards elaborated by the Committee on the Elimination of Discrimination Against Women (CEDAW, 1992), many countries have enacted laws to criminalize the various forms of domestic violence against women, including marital rape, and to protect women’s rights and safety. Creating such a legal environment contributes to changing the societal perception of women, so that violence becomes unacceptable behavior. Despite many years of international attention to promoting women’s autonomous decision-making as central to their human rights, many countries still have in place laws or policies that require a husband’s approval for a woman to use contraception, to have professional assistance during childbirth, or to have access to her own medical records. Other laws may allow only married women to obtain access to health services (WHO, 2015b). These regulations and rules represent a barrier to women obtaining access to services that they need in order to remain healthy, which are either not required for men or are irrelevant since men do not use the services. Perhaps the most serious example of gender inequalities reinforced by law is the restriction on access to safe abortion services. Unintended/unwanted pregnancies occur because of women’s and men’s lack of access to, or lack of use of, appropriate contraceptive methods, method failure, sexual coercion or rape, and changing economic circumstances. Women will therefore always have need for safe abortion services, something that men will never need. WHO estimates, based on 2008 data, that there are approximately 22 million unsafe abortions annually, resulting in 47 000 deaths and 5 million complications resulting in hospital admission (WHO, 2015c). Nearly all unsafe abortions (98%) occurred in lowand middle-income countries. Restriction in access to safe abortion services – which are often unavailable even where abortion is allowed by law – results in both unsafe abortions and unwanted births, with all their attendant ill-health consequences. Where laws severely restrict abortion services to cases where a woman’s life is threatened, it has been clearly demonstrated that deaths and injury from the complications of unsafe abortion are much higher than in countries that provide legal access to abortion on broad grounds including on request (Berer, 2004; WHO, 2015c). Providing safe abortion services is a cost-efficient way of contributing substantially to the reduction of maternal mortality and morbidity around the world, and to redressing gender inequalities.

Conclusion The social norms and values that govern what women and men do and how they behave have an extensive impact on sexual and reproductive health. Biologically, women and men are differently susceptible to certain conditions such as STIs, but gender dimensions can significantly magnify such

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vulnerability through specific behaviors that are socially acceptable (or not acceptable), through access (or lack of it) to essential resources, through the ways in which institutions perceive and treat men and women, and through laws that may uphold gender inequalities or not protect one sex or the other against injustices. For these reasons, sexual and reproductive health services must include more than medical interventions. Gender-sensitive sexual and reproductive health services call for a mind-set that takes into account not only the user’s medical history but also the many ways in which gender affects his or her sexual and reproductive behavior. In serving men, services can help counteract negative aspects of masculinity contributing to risky behaviors; they can respect every woman’s right to self-determination in matters related to sexuality and reproduction, and promote her dignity, and the exercise of her rights. For the past two decades, interventions to counteract these gender inequalities have ranged from the passing of laws to support an end to gender discrimination, often as part of the implementation of the Convention on the Elimination of All Forms of Discrimination Against Women, to the training of health workers and policy makers in gender analysis and approaches. They have included programs to empower women through becoming financially independent and, more recently, programs specifically targeted to men on sexual and reproductive health and encouraging zero tolerance for violence. While some advances have been made, particularly in the widespread recognition of gender inequalities, such interventions constitute only some of the necessary elements on a long path toward lasting change in gender roles and relations.

See also: Populations at Special Health Risk: Women; Violence against Women; Women’s Mental Health.

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Relevant Websites http://www.unwomen.org/en – UN Women (last accessed 22.05.16.). http://www.unfpa.org/ – UNFPA (last accessed 22.05.16.). http://www.unicef.org/ – UNICEF (last accessed 22.05.16.). http://www.who.int/reproductivehealth/topics/en/ – World Health Organization (last accessed 22.05.16.).

Gender in Health and Illness Carol Vlassoff, University of Ottawa, Ottawa, ON, Canada Ó 2017 Elsevier Inc. All rights reserved.

Glossary Gender “[R]efers to the socially constructed characteristics of women and men – such as norms, roles and relationships of and between groups of women and men. While most people are born either male or female, they are taught appropriate norms and behaviours – including how they should interact with others of the same or opposite sex within households, communities and work places. When individuals or groups do not ‘fit’ established gender norms they often face stigma, discriminatory practices or social exclusion – all of which adversely affect health. It is important to be sensitive to different identities that do not necessarily fit into binary male or female sex categories” (WHO, 2015). Gender analysis “The identification and description of inequalities that arise from the different roles of men and women, and the unequal power relationships between

Relevance of Gender to Health and Illness Until the twentieth century in the United States and globally, differences between men and women, in relation to health and illness, received very little attention. Moreover, research on those with different sexual orientations, including lesbian, gay, bisexual, and transgender (LGBT), remained, until very recently, almost absent from the health literature. (In this article ‘LGBT’ is used to encompass all nonheterosexual orientations, recognizing that the expressions, LGBTQ and LGBTI, are sometimes used to include queer and those with indefinite sexual orientations, i.e., those who do not fit into any defined category). Into the late 1900s women were widely assumed to be physiologically the same as men, except for their reproductive functions, and middle-aged white male patients were taken as the norm. At the beginning of the twentieth century, early feminists, including Emma Goldman and Margaret Sanger in the United States and Marie Stopes in England, began to draw attention to the need for women to have control over pregnancy and childbearing. In 1916 the first birth control clinic was founded by Margaret Sanger, and in 1921 Stopes opened a birth control clinic in London. Although illegal, these and other private clinics, founded and staffed by socially progressive women, began to take root. Sanger and Stopes were greatly concerned with racial purity and the fact that the poor classes continued to multiply while the upper and middle classes were controlling their fertility. Nonetheless, these women promoted an important message that women should be free to enjoy sex without worrying about pregnancy. They also pointed out the link between fewer births and improved health for both women and children. For the first time women’s health and right to sexual well-being were publicly pronounced and promoted.

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them, as well as the consequences of these inequalities on their lives, health and well-being” (WHO, 1998). Gender equality in health “Men and women, across the life-course and in all their diversity, have the same conditions and opportunities to realize their full rights and potential to be healthy, contribute to health development and benefit from the results. Achieving gender equality in health often requires specific measures to mitigate barriers” (WHO, 2015). Gender equity in health “Fairness and justice in the distribution of benefits and responsibilities between men and women” (WHO, 1998). Gender sensitivity Being aware of the need for equality between men and women in the design and implementation of policies and programs.

During World War II, with the exodus of men from traditional male occupations, including medicine, women began to fill professional posts, to earn money, and to make decisions for themselves and their families. The growth of the feminist movement played an important role in promoting women’s control over their sexuality and reproductive health, but it was only in the mid-1980s that attention to other aspects of women’s health, such as heart disease and cancer, began to emerge in the United States. Until then, protocols for the diagnosis and treatment of heart disease, the number one cause of all deaths in the United States, were based upon findings from middle-aged white male patients. As a result, women were diagnosed later with more advanced disease, and consequently were harder to treat successfully. In 1986 the National Institutes of Health established a policy requiring the inclusion of female subjects in clinical investigations, when appropriate. The establishment of the Office of Research on Women’s Health in 1990 was an important landmark in the recognition that women’s health is not limited to reproduction and childbearing. In 1993 the Office published ‘Guidelines for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs,’ recommending that women be appropriately represented in clinical studies and that their findings be analyzed from a gender perspective. These guidelines ended the policy of the routine exclusion of females from drug studies in the United States. Given the long period during which women’s health was largely equated with that of men, it is hardly surprising that, until 1990, little attention was devoted to gender issues in general health. In the social sciences the concept of gender was already accepted as a valid tool for understanding human behavior and for providing greater clarity and precision in scientific and lay language. However, the term ‘gender’ was

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Gender in Health and Illness not widely accepted among health professionals. It was not until the late 1990s that the World Health Organization (WHO) adopted gender, as distinct from sex, as a valid concept. This failure to address gender issues was also indicative of the relatively minor role the social sciences played in influencing medical science, research, and practice. From the last years of the twentieth century it has been well established that health, including the prevention and control of disease, is affected not only by biological factors but also by social, economic, cultural, environmental, and political conditions, now known as the social determinants of health. Understanding health therefore requires a holistic perspective in which people’s perceptions, needs, priorities, and the environment in which they live, including the characteristics and behavior of people around them, are taken into account. As a result of this growing understanding of the broader context of health, social scientists have become increasingly involved in public health research and programs, both in developing and industrialized countries. A body of research in the area of gender and health has now emerged, recognizing that the distinct categories of sex and gender are key to understanding the many and complex determinants of health and illness. Krieger (2003), for example, provides examples of differential effects of gender relations and sex-linked biology on health outcomes. Nonetheless, there is still a need for a unifying theoretical framework bringing together the different issues and perspectives that should to be considered to fully capture and analyze the interrelationships between gender, health, and illness.

Gender and Health Policy, Planning, and Programming Gender and Initiatives in Global Health In the twenty-first century, international organizations have increasingly acknowledged that gender needs to be considered if development programs and policies are to be successful. However, there is still insufficient evidence of the impact of globalization on gender equality. Cross-country analyses in developing regions weakly indicate that globalization has helped to reduce gender inequality (Aguayo-Tellez, 2012) and that countries that have implemented public policies to strengthen gender equality are also more likely to realize greater gender equality with respect to globalization processes (World Bank, 2012). For sector-wide programs, such as health sector reform (HSR), research has found that women are adversely affected by user fees and inadequate access to private insurance schemes introduced as new forms of cost recovery. A critical review of research on the consequences of illness and health care use for households in low- and middle-income countries (LMICs) (McIntyre et al., 2006) found that the out-of-pocket payments required by health-care financing strategies had serious economic consequences for families. Such households were ‘pushed into poverty’ by the combination of medical expenses and the loss of income due to ill health. Poor rural women have been especially impacted (Johnson et al., 2012). On the other hand, a number of authors have argued that HSR approaches could benefit women’s health by focusing

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on common goals of quality, universal access, and nondiscrimination. They point out that the criteria of efficiency and cost-effectiveness are compatible with gender equity in health. High-quality services consistent with efforts to reform health systems can stimulate greater demand among women for these services and improve their impact. This is particularly true for poorer countries, where the main objective of HSR is to direct more resources into essential reproductive health services. Similarly, providing improved, decentralized services to women and the poor is a key component of most HSR policies. Inconsistencies in expected and actual outcomes for women’s health seem to be due more to the application of policies and the implementation of programs than in the concept of HSR as such. As with other initiatives, the lack of participation of the users of health services, a large proportion of whom are women, in setting priorities and designing programs, as well as an absence of public accountability for their impact, has been a major impediment to the success of HSR. Financing mechanisms are also more likely to have the desired effects if they take into account women’s unequal access to and control over resources, and the need for supporting core areas of women’s health through means other than user fees. In early global initiatives in health, such as the eradication of smallpox and polio, ‘The Stop TB Partnership,’ and global malaria eradication campaigns, gender issues were taken into consideration more as an afterthought than as a central component from the beginning. However, more recent global initiatives, including the President’s Emergency Plan for AIDS Relief (PEPFAR), the Global Fund to fight AIDS, Tuberculosis and Malaria (Global Fund), the World Bank’s Multi-country AIDS Programme (MAP), and Roll Back Malaria, have attempted to make gender equality a key component of their programs. While inroads to remove gender inequities were made, as, for example, in access to services and treatments, their vertical nature (focusing on a single or selected diseases) sometimes led to inequities elsewhere as programs and human resources were diverted from mainline health services benefiting women, such as sexual and reproductive health. Moreover, none of these programs addressed the underlying social and economic causes of gender inequities. The United Nations Millennium Declaration, popularly known as ‘Millennium Development Goals’ (MDGs), was ratified in September 2000 with a deadline of 2015. It set measurable goals, targets, and indicators to combat poverty, hunger, disease, illiteracy, environmental degradation, and discrimination against women. Gender was recognized as an important determinant of development, and MDG 3 called for male– female parity in education, political participation, and economic empowerment by 2015. In its evaluation report on MDG achievements the most progress was found in primary education, where about two-thirds of the countries achieved parity. Labor force participation of women also increased but still only 50% of women worldwide were working, compared to 77% of men, and political participation was still far lower for women. While the MDGs were intended as an important vehicle for removing inequities, including in gender, an important group, the LGBT population, was not included as a particularly vulnerable group. Efforts of the LGBT community and many United Nations and national development agencies to highlight this omission were nullified by a majority of

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countries which still consider nonheterosexual identities illegal or immoral. The MDGs are now being followed up with new sustainable development goals (SDGs) which aim to complete the unfinished MDG agenda and to address the root causes of poverty and inequality, including gender. While global goals and pronouncements are said to galvanize the international community around concrete development objectives, a major drawback is the lack of accountability of the various stakeholders in achieving them. The tendency has been for international and national actors to simply move on to another set of targets without acknowledging and accounting for failures and shortcomings, learning from them and working together to overcome them. At the international level, attention to gender sensitivity in health sector policy, planning, and programming has focused mostly on women and the need for their greater involvement. There has been little attention to the role of men, beyond a recognition of their key position in decision making. The needs and perspectives of the LGBT population are also largely missing from the SDG agenda, although the community and its advocates are becoming more vocal than was the case previously with the MDGs, thanks largely to the attention paid to their issues by industrialized country policies and programs. However, to be truly gender-sensitive and effective, policies need to be revisited and analyzed from a broader perspective that takes into account men, women, and the LGBT population, within the context of their cultures, constraints, and potentialities. This context itself must be open to challenge, and efforts are needed to redress inequalities and harmful practices such as gender-based violence and rape, forced sex, female trafficking, genital cutting, and stigma and discrimination against nonheterosexual people. The design of gender-sensitive health policies and programs requires a change in philosophy at all levels of the health sector, refocusing on the reduction of inequities between men and women in society, including health inequities. It requires policies and programs that are grounded in evidence and based on sex-disaggregated data and other indicators of gender differences. It requires leaving behind the male paradigm in health and illness and opening up a new gender paradigm, moving toward the goal of health as a human right for all, whether male, female, or LGBT.

Gender and National Health Policies, Planning, and Programming Gender-sensitive health policies, plans, and programs include making the health of all members of society of equal priority, fostering decentralized decision making, and encouraging community participation with the involvement of all. Health systems in most countries, both industrialized and developing, model the gender-based power structures in other parts of society, and human resource planning in developing countries is only beginning to consider gender issues. For example, women make up the majority of health workers at the primary level, yet policies often fail to consider their specific needs or strengths. Moreover, planners rarely include stakeholders in the design of training and career development programs.

Decision makers within the medical hierarchy in developing countries are predominantly males, and other community members are seldom consulted when new initiatives are conceived. Consultation with communities is a growing part of rolling out national health programs, but their true participation in developing and prioritizing programs and in assigning budgets and resources is still far from the norm. Rather than promoting a robust and politically conscious public health constituency, communities tend to be placed in a purely reactive mode. Changing the unequal gender hierarchy requires a transformation in training and socialization of health staff at all levels and the creation of opportunities for women and people of diverse sexual orientation to advance to the highest positions in the health sector. A positive development in this regard is the introduction of ‘gender medicine’ training and research in some institutions in industrialized countries, although this still tends to emphasize male–female differences. As such, it incorporates an understanding of women and men’s health, including how disease processes differ in men and women, and their impact on prevention, diagnosis, and treatment. Such programs are meant to facilitate the incorporation of women’s perspectives into health policies, planning, and program development, but the integration of LGBT perspectives is not yet well developed. Conceptualizing health policies and programs from a gender perspective also requires fundamental changes in working environments, including the use of gender-sensitive language and flexible working and opening hours that are responsive to the needs of women and other family members. For example, when facilities are open only during the morning and early afternoon, it is difficult for working mothers and fathers to visit them. Purely because of structural impediments, it becomes impossible for most men to visit the services for their own problems or to take their children for attention, thus hampering their participation in the provision of health care for their families. Mechanisms to monitor and evaluate gender approaches to policy setting and programming, though becoming more prominent in the agendas of development agencies, are still not widely available or utilized in developing countries. While the raw data to permit male–female comparisons are increasingly collected, they are frequently difficult to access because they are not stored appropriately, either physically or electronically. Where the information is required by health authorities or other organizations, it is usually provided by lower-level services but rarely analyzed or used by these services themselves. Where the data are not required for any special purpose, they tend to be left unanalyzed and unused. Similarly, information on other determinants beyond sex, which would make a gender analysis possible, is virtually nonexistent. For example, in most countries of Latin America and the Caribbean, where data tend to be of relatively high quality compared to other developing regions, sex- and age-disaggregated data by health indicators are not readily available. A further problem is that the data collected are not often used to inform local programs that could most benefit from this information. It is increasingly apparent that an understanding of the epidemiology of disease and other health problems requires an understanding of gender issues. In HIV/AIDS, for instance,

Gender in Health and Illness discerning the nature of the epidemic and the interventions needed to combat it requires the tracking of emerging trends in vulnerable groups and in the general population. The control strategy selected should be based upon such information. For example, where the epidemic is concentrated in vulnerable populations, such as gay and bisexual men, programs and budgets should be targeted to those populations, as well as to prevention for the larger population. When the epidemic is generalized to the whole population, a more balanced approach between prevention and treatment is needed. Yet data on the epidemic, in terms of characteristics of populations affected, particularly with respect to vulnerable groups, are often too limited to allow for evidence-based decisions and appropriate strategies and programs for them. The profound changes in work and management cultures required to integrate gender issues into national health systems need commitment from senior program managers and the assignment of sufficient resources to these programs. Only with adequate funding can the building blocks of new gender-sensitive programs, including the revision of personnel and work policies and practices, operational research, data analysis, and relevant training, be effectively planned and implemented.

Gender and Health Services The integration of gender into the design of health policies and programs is an essential first step in increasing the gender sensitivity of health services. However, as is frequently noted in the literature on quality of health care, its translation into strategies and guidelines for implementation within health-care settings remains a challenge. The reasons cited for the gap between programming and implementation include the inexperience of the health sector in the practical implications of incorporating gender into programs and their failure to take into account traditional differences in gender norms. Many studies have demonstrated that the hierarchy in the health system, where men are viewed as doctors and decision makers and women as subordinates, reproduces itself at all levels of the services. Hence, nurses may treat lower-level staff in a condescending manner, and this pattern is perpetuated in the way health workers behave with their clients, especially poor women. Marks (1994) provided a detailed review of these relationships, citing examples of domination and subordination linked to class, race, and gender inequalities in the nursing field from England, the United States, South Africa, and India. In all countries, female health providers replicated the male model of dominant behavior, particularly with female clients of lower social classes. Gender inequalities in the health services influence the quality of data they generate, and hence the reporting of epidemiological data and trends. In the absence of vital registration data in many developing countries, hospital statistics are used for surveillance purposes. However, inferences from hospital data may be faulty because they are based on a selective sample. For example, where men tend to utilize hospital services more for terminal illness, statistics on the prevalence of certain diseases may be disproportionately skewed toward men. Several studies from East Africa have found that women are

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underrepresented in hospital data because of their greater economic and social constraints in seeking medical care. Research on gender and quality of health services has focused mainly on reproductive health, where services are necessarily different for men and women. In the area of reproductive health, gender plays an important role in determining women’s ability to seek treatment or make decisions about their health. For example, women may be more constrained than men by traditional beliefs and family pressures. Young girls and boys generally lack access to youth-friendly services to guide them through important life changes that significantly impact their health. Less information is available concerning women’s needs beyond the reproductive period. While many special programs exist, there has been very little analysis of the health-care needs and adequacy of services for those outside the reproductive years, such as youth, older women and men, and people of different sexual orientations. Evidence on gender differences in nonreproductive health conditions indicates that males and females are viewed and treated differently by health services, including the specific treatment diagnosed and the way they are counseled by health staff. Studies in industrialized countries have found that technologies selected for the treatment of the same disease often differ according to the sex of the client. For instance, women with heart disease are less likely to receive coronary bypass surgery or organ transplants, and women more often die from their first heart attack. Gender stereotypes may affect providers’ perceptions of health needs and how their advice to clients is framed. Women are more likely than men to be treated with psychotropic drugs because of stereotyping of women as depressive. Male providers tend to be more authoritative and give less time to patients than female providers. They are also less likely to engage in two-way communication with clients. Interestingly, studies have found that female patients report receiving good care when the provider engages in a dialogue with them, independently of the objective quality of attention received. Health workers, especially in poor developing countries, are often unequipped to counsel clients about health problems in a gender-sensitive way. The economic, social, and psychological factors affecting health are not part of the curricula of health providers in most LMICs, and they are therefore not prepared to counsel clients on sensitive issues such as domestic abuse, unwanted pregnancies, psychological problems, and HIV/AIDS. Similarly, many health professionals find it difficult to speak frankly about sexual issues or to counsel people with nonconventional sexual orientations, especially in settings where LGBT populations are stigmatized and excluded from equitable services. Such weaknesses in the health service inadvertently contribute to the spread of infections such as sexually transmitted infections (STIs) because people at high risk, such as men who have sex with men, may fail to seek assistance from facilities that are unresponsive to their needs. In several studies, providers admitted that they covered up for their lack of ability to respond to clients’ needs by closing off communication or blaming clients for causing their own problems. A growing number of methodologies to incorporate gender into various aspects of health services exist, but they are rarely utilized in developing countries. For example, a systematic review of 146 gender-integrated health programs

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in LMICs found that they were conducted mainly by NGOs, with little governmental uptake, although they had positive impacts on health status, behavior, and knowledge where they were implemented (Muralidharan et al., 2014). Similarly, a review of 25 interventions by the Interagency Gender Working Group and the World Health Organization (Feldman-Jacobs et al., 2005) reported that incorporating a gender perspective resulted in improvements in women’s mobility and literacy, self-confidence and self-esteem, and greater partner communication. However, considerable work still remains to be done to improve the availability of data to measure such outcomes, to promote the use of scientifically based evaluation methodologies, and increase their inclusiveness of gender diverse populations.

Gender and Health Status Just as gender plays an important role in health policies, programs, and services, it also affects health status and the experience of health and illness at the individual level. In other words, gender is both a determinant of health, resulting in improved or worsening health status, and a consequence, in terms of how individuals experience health and illness. In this section, gender is addressed from the perspective of the determinants of individual health status and in the following section, from the perspective of consequences for health status. Universally, women live longer than men, but the gender gap is greatest in industrialized societies where women outlive men by about 6 years, on average. As they age, men and women suffer from similar types of illnesses. However, men tend to suffer from acute illnesses for relatively short periods before they die, whereas women live longer lives, marked by chronic non-life-threatening disabilities that can greatly affect their quality of life. For example, osteoporosis, due to a natural decline in bone density after menopause, affects mainly women. Gender differences in the biological determinants of health and illness include factors influencing genetic vulnerability to certain infections and conditions, hormonal and reproductive characteristics, and physiological changes over the life cycle. Gender affects how health problems are viewed, how priorities are established, and why it is necessary to question and challenge traditional biological explanations. For example, although women’s biological vulnerability to HIV is greater than men’s, gender norms also place men at considerable risk. Bisexual and homosexual men tend to have high rates of partner change, increasing their vulnerability. Sex between men frequently involves anal intercourse, which puts both partners (and especially the receptive partner) at high risk. Studies of gender differences in health status in later life have been conducted mainly in industrialized countries. For example, a study of 14 000 men and women aged 60 and above living in their homes in Britain examined self-assessed health to test the validity of the common assumption that women overreport morbidity. There was little gender difference in self-assessed morbidity once class, income, age, and level of functional disability were taken into account. In fact, multivariate analysis indicated that, when the greater

functional disability of older women was included, older women reported less poor health than older men (Arber and Cooper, 1999). Gender differences were also found in living arrangements for those living with severe disabilities. Half of the older women lived alone, compared to one-quarter of older men. Most men with severe or moderate disability lived with their spouses and received care from them, whereas most women had to rely on help from outsiders. Recent evidence from India mirrors the earlier findings in Britain concerning gender differences in the health of the elderly. Indian women outlive men by 3 years, but they are more likely to suffer from disability and chronic health conditions at older ages. A study of self-assessed health differences between older men and women, based on national survey data, found that women were significantly more disadvantaged and that this difference was mainly accounted for by differences in socioeconomic factors such as education, occupation, and income (Pandey and Ladusingh, 2015). Older women were also less likely to receive support from family members than older men. These findings, from both industrialized and developing countries, illustrate the importance of reexamining common gender-based assumptions and of ensuring that comparisons between men and women are based on similar socioeconomic and demographic groups. Moreover, gender relations and their impact on biological factors are changing as women increasingly assume positions traditionally occupied by men and vice versa. Gender research has focused on the near-universal subordination of women by men, such as the sharp distinction between women’s and men’s roles and their separate assignment to domestic and public spheres. In most cultures productive and reproductive activities are valued differently. Generally, earning an income brings greater autonomy, decision-making power, and respect in society. Men’s greater involvement in the paid labor force and their higher earnings mean that they enjoy more autonomy and higher social status. The positive relationship between mothers’ education and the survival of their children is well documented. Gender inequality from infancy can lead to a whole life cycle of disadvantage and malnutrition for women and girls, and intergenerational transmission of ill health and poverty through the undernourishment and overwork of pregnant or lactating women. Health status is also affected by household power relations. Several studies have found that female decision-making power is strongly associated with improved health and nutritional status of both women and their children, and therefore nutritional education and information about food preparation is directed mainly toward women. Yet in most developing countries, men make decisions about the production, sale, and purchase of food and may opt to sell food for beer or luxuries. Research in the area of gender and nutrition has demonstrated that changing the focus of nutritional interventions to include both men and women can positively affect the family’s food consumption patterns, and hence nutrition. The ability to take health-protective actions depends on gender roles in many ways. For example, women who are dependent on husbands or others may be exploited sexually and may feel that they have little recourse to help of any

Gender in Health and Illness kind. Studies of the prevalence of forced sex in both developing and industrialized countries have found that poor women and those who are economically dependent upon their partners report a history of sexual coercion more frequently than others, putting them at greater risk of STI and HIV. For example, in a study of women in rural Haiti who accessed services at a clinic in the Central Plateau, 54% reported being subject to forced sex (Smith Fawzi et al., 2005). Those who said they had to have sex to provide for their children were 3.5 times more likely to have experienced forced sex. These women were also more likely to have an unplanned pregnancy and a history of STI. The authors concluded that gender inequality, combined with acute poverty, severely limited women’s ability to take preventive actions and placed them at significant risk of STI and HIV. Gender influences health-seeking behavior and health actions at household and community levels. Many studies, especially in South Asia, have found significant differences in how parents care for male and female children when they are ill. Boys are more likely to be seen by a modern health provider, whereas girls are more often treated at home or by traditional healers. Boys tend to be taken to health facilities earlier in the illness, and parents are more willing to pay for the care of sons. Many practices, such as female genital cutting, deemed a necessary rite of passage for girls in some countries in Africa, the Middle East, and parts of East Asia, are extremely harmful to women’s health. Ironically, this practice is strongly upheld by older women in communities where it is prevalent. On the other hand, traditional norms can be protective for females. Far fewer women than men take up smoking in Southeast Asia, for example, because smoking is widely seen as inappropriate for them; and some tropical diseases affect men more than women because their work in the forest or fields exposes them to vectors such as mosquitoes and sand flies. Gender plays an important role in determining healthy or unhealthy lifestyles. For instance, males are more likely than women to suffer from accidents and injuries, including self-directed violence and suicide; on average, there are three times as many male suicides annually than female suicides worldwide. Males are more prone to risk taking, such as dangerous driving leading to road accidents. Gender differences in socialization perpetuate the association between masculinity and risk taking. For example, risky behavior among adolescent motorcyclists has been linked to the need to assert gender identity and to cope with psychological stress. Gender differences in risk taking seem to have some basis in biological differences. Highly assertive, dangerous behavior among men, including aggressiveness, anger, and physical violence, are exacerbated in Western cultures by gender-role socialization portraying men as risk takers and thrill seekers, and as protectors and defenders of women and children. Women’s nurturing and supporting roles are equally reinforced by social norms. Biological differences can also be suppressed by social factors. For example, boys can be socialized in childhood to suppress violent or angry behavior and to adopt supportive and nurturing roles. Women’s vulnerability to lifestyle-related illnesses, such as stress, is growing as they increasingly enter high-pressure jobs.

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Gender Differences in the Experience of Health and Illness Evidence concerning gender differences in the experience of health and illness is far from conclusive, due partly to the lack of definition of what constitutes this experience. However, a considerable amount of information is available on differences in the support received from others when men and women are ill, the roles of family members, recovery time, responses to stigmatizing diseases, health-seeking behavior, and how men and women are treated by health services. Several studies have found gender disparities in the social support received by family members during illness. The support of family members or close friends can give patients the confidence to seek and adhere to the full course of treatment. It is a key element of many successful treatment programs, including for HIV and tuberculosis. However, families may also have a negative influence, such as encouraging patients to try alternate remedies or to seek help from traditional healers rather than from health services. The roles of men and women can affect their experience of health and illness. Women’s role, as the major caregivers in the household, can be detrimental to their ability to fully recover from an illness. According to a limited number of studies on recovery times of men and women, poor women in developing countries tend to take longer time than men to convalesce because they return to work before they have completely recuperated. When men are ill, others encourage them to seek medical help, as a result of which they are more likely to be appropriately diagnosed and treated. They also receive greater care from wives and others and are not expected to go back to work until they are better. Women often substitute for their husbands in agricultural work when men are ill, but husbands rarely substitute for their wives, and only essential duties are assumed by other family members. Women owning small businesses lose income necessary for daily survival, and many have to use their scarce resources for medicines and other health-related costs. When women recover, they are faced with many pending chores in addition to their normal work. Women’s lower social status influences how society responds when they are affected by stigmatizing illnesses such as HIV/AIDS, leprosy, tuberculosis, and mental illness. Reports from Africa and Asia have noted that men, at the time of diagnosis of HIV, are less ready than women to acknowledge that they are infected and less likely to support one another and look for help from family or friends. However, when men become ill they typically receive more care and support from their families than women. The fact that illness prevents women from continuing to perform their caregiving roles adds to their marginalization and the feelings of rejection. Studies of gender and diseases such as leprosy, tuberculosis, or onchocercal skin disease have found that both men and women are concerned about physical symptoms such as disfiguration, but women are more anxious about the way they will be treated by society. As a result, they wait longer than men before telling others or seeking care. There have been many studies of gender differences in the use of health services, especially in industrialized countries, where it seems clear that women consult services more than men. Some researchers have argued that this difference can

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be explained by differences in socialization, knowledge, sensitivity to symptoms, and health status. For example, women may have more chronic conditions than men due to their longer life span, often requiring prolonged, constant care. Others have argued that women’s caregiving roles within the family make them more interested in health and more sensitive to symptoms, and that their recall of symptoms is more accurate than men’s. Data from a longitudinal household study of the same individuals in the United States over a 22-year period were analyzed by Green and Pope (1999) and revealed that female sex and age were consistent predictors of higher health-care use over the study period and that baseline self-reported health status and symptoms, as well as reported health-related concerns and behavior, were the only other significant predictors of utilization. Health knowledge and interest were not significant predictors of use. The authors conclude that interventions targeted at attitudes and behavior would be more likely to affect health-seeking behavior than interventions aimed at increasing people’s technical knowledge about health and illness. They also note that research is needed on how gender affects the appropriateness of health-care choices, in order to better target the use of preventive and cost-effective services. Studies on gender and health-seeking behavior in developing countries generally agree that women are less likely than men to visit health facilities for their own problems and that they prefer to go to traditional healers or community shops. Nonetheless, women are more frequent users of rural health clinics for their children. The reasons that women often go to traditional healers for their own health problems may stem from the fact that they are less able than men to pay for services and that traditional healers are more likely to accept payment in kind. Other reasons may include the easier accessibility of traditional healers and the fact that the explanations they give are more in keeping with women’s daily experiences (Allotey and Gyapong, 2005). Unfortunately, traditional healers can prescribe treatment that is ineffective or even harmful, and as a result women often seek medical care late, after their illness has become more severe. As previously noted, studies on how clients are counseled at health services in developing countries have found that women are often treated in an inferior way and sometimes blamed for reporting late or for not taking their children for regular immunizations or checkups. This exacerbates women’s reluctance to access health care, even when other access barriers are removed. Insensitive treatment by health personnel is also a problem in industrialized countries, but in these countries women have more options for restitution. A gender perspective in the development of medications and technologies is also important for women’s and men’s experience of health and illness. For example, the needs of men with nontraditional sexual orientations, such as those who are bisexual or gay, have not been adequately taken into account in the design of condoms. Male condoms are designed for traditional male–female relationships and are not appropriate for the receiving partner in men who have sex with men. Some male couples rely on the female condom but its efficacy for HIV and sexually transmitted infection prevention is not yet known. Given that men who have sex with men, including bisexuals, constitute an at-risk group for STI and

HIV, new technologies are urgently needed to protect such men and their partners. The traditional exclusion of women from clinical trials, while now less frequent in more developed countries, is still the norm in LMICs. The resultant lack of knowledge about gender differences in treatment appropriateness can have negative consequences for women’s experience of illness and can mean that they are improperly diagnosed and treated. Moreover, the interactions between women’s reproductive cycles, contraception, and the use of other medicines such as antimalarial medicines have received very little attention.

Conclusion Gender affects how health problems are viewed, how priorities are established, and why it is necessary to challenge traditional biological explanations. In this article, it has been argued that a gender perspective is essential to understanding the various dimensions of health, including health policies and planning, health services, health status, and the experience of health and illness. In the conceptualization of most global health initiatives gender has been generally omitted, and though, in most cases, it has received some acknowledgment at a later stage, it has never been central to these programs. National health policies, plans, and programs, especially in developing countries, have been even less gender-sensitive. Incorporating a gender perspective from the planning of new initiatives could contribute significantly to their success. In the area of health services, most of the evidence has focused on the quality of reproductive health care for women. Considering the need for comprehensive services for men and women of all ages, this article identified important gaps in quality in both developing and industrialized countries, and the need for greater application of gender-sensitive policies, more flexibility in the way services are delivered, greater creativity in the design of practical training curricula, improvements in health information systems, and ongoing monitoring and evaluation of services. Health status and the experience of health is, to some extent, a result of the public health environment. For the most part, health policies, plans, and programs determine the nature and quality of health services, and these in turn at least partially determine the health status of the population served. The hierarchical and rigid nature of health services negatively affects people’s care-seeking behavior and constrains these services from delivering the quality of care that could be offered. On the positive side, several studies report affirmative gains in health status where gender-sensitive services are provided, including with the participation of men. The experience of health and illness is also affected by gender in terms of family support, length of illness and recovery, the stigma associated with certain illnesses, use of health services, and how illness is diagnosed and treated. The caregiving role of women is often taken for granted, and women are expected to cope better with illness than men. Men’s income-earning role is more valued by society, with the result that men are better cared for when they are sick and, consequently, recover more quickly. Nonetheless, women generally live longer and suffer longer from chronic illnesses

Gender in Health and Illness than men, who tend to die earlier from acute illnesses. Hence, interventions to empower both women and men in understanding the basic principles of health and nutrition, and the actions they can take to prevent and treat illness, are key to positive health outcomes. Clearly, integrating gender into the study of health and illness at various levels can greatly enhance understanding of important risk factors and responses, as well as sensitivity to a wider range of possible interactions. It can also contribute to the prevention of illness and the mitigation of negative health outcomes. However, although research in this area is rapidly expanding, the literature in this field lacks a comprehensive conceptual framework into which individual studies can be integrated. Hence, there is a growing body of evidence that gender has an important impact on various dimensions of health and illness, as indicated in this article, but it is time to move beyond a compilation of findings that repeat the same observations for different diseases or conditions. For example, similar results are obtained in the experience of stigma for diseases such as leprosy, tuberculosis, mental illness, and HIV/AIDS. Additionally, there has been very little systematic research in either industrialized or developing countries on gender differences in health and illness within different ethnic, social, and economic groups. An authentic gender analysis requires an exhaustive investigation of these interactions that go well beyond sex differences. Further examination of existing research and gaps in current knowledge is required in order to continue to make real progress in this field, especially with regard to how a gender perspective can enhance existing health promotion approaches and contribute meaningfully to improved health outcomes and quality of life.

See also: Health Inequalities; Populations at Special Health Risk: Men; Populations at Special Health Risk: Women; Resource Allocation: Justice and Resource Allocation in Public Health.

References Aguayo-Tellez,, E., 2012. The impact of trade liberalization policies and fdi on gender inequalities: a literature review. Background paper for World Development Report. http://www.siteresources.worldbank.org/INTWDR2012/Resources/ 7778105-1299699968583/7786210-1322671773271/aguayo-trade-and-genderliterature-april15-2011.pdf (accessed 27.05.14.). Allotey, P., Gyapong, M., 2005. Social, Economic and Behavioural Research Special Topics No. 4: The Gender Agenda in the Control of Tropical Diseases; A Review of the Evidence. World Health Organization, Geneva, Switzerland. Arber, S., Cooper, H., 1999. Gender differences in health in later life: the new paradox? Soc. Sci. Med. 48, 61–76. Feldman-Jacobs, C., Olukoya, P., Avni, M., 2005. A Summary of the “So What?” Report: A Look at Whether Integrating a Gender Focus into Programmes Makes a Difference to Outcomes. Report for the Interagency Gender Working Group (IGWG) and WHO, Geneva, Switzerland. Green, C.A., Pope, C.R., 1999. Gender, psychosocial factors and use of medical services: a longitudinal analysis. Soc. Sci. Med. 48, 1363–1372. Johnson, A., Goss, A., Beckerman, J., Castro, A., 2012. Hidden costs: the direct and indirect impact of user fees on access to malaria treatment and primary care in Mali. Soc. Sci. Med. 75 (10), 1786–1792.

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Krieger, N., 2003. Genders, sexes, and health: what are the connections – and why does it matter? Int. J. Epidemiol. 32, 652–657. Marks, S., 1994. Divided Sisterhood: Race, Class, and Gender in the South African Nursing Profession. St. Martins Press, New York. McIntyre, D., Thiede, M., Dahlgren, C., Whitehead, M., 2006. What are the economic consequences for households of illness and of paying for health care in low- and middle-income country contexts? Soc. Sci. Med. 62, 858–865. Muralidharan, A., Fehringer, J., Pappa, S., Rottach, E., Das, M., Mandal, M., 2014. Transforming Gender Norms, Roles, and Power Dynamics for Better Health. Evidence from a Systematic Review of Gender-Integrated Health Programs in Lowand Middle Income Countries. Futures Group, Health Policy Project, Washington, DC. http://www.healthpolicyproject.com/pubs/381_GPMIndiaSummaryReport.pdf. Pandey, A., Ladusingh, L., 2015. Socioeconomic correlates of gender differential in poor health status among older adults in India. J. Appl. Gerontol. 34 (7), 879–905. Smith Fawzi, M.C., Lambert, W., Singler, J.M., et al., 2005. Factors associated with forced sex among women accessing health services in rural Haiti: implications for the prevention of HIV infection and other sexually transmitted diseases. Soc. Sci. Med. 60, 679–689. WHO, 1998. Gender and Health. Technical Paper. Women’s Health and Development, Family and Reproductive Services. WHO, Geneva, Switzerland. WHO, 2015. Gender, Equity and Human Rights. http://www.who.int/gender-equityrights/understanding/gender-definition/en/ (accessed 30.09.15.). World Bank, 2012. World Development Report 2012: Gender Equality and Development. World Bank, Washington, DC.

Further Reading Bird, C.E., Rieker, P.P., 1999. Gender matters: an integrated model for understanding men’s and women’s health. Soc. Sci. Med. 48, 745–755. Chege, J., 2005. Interventions linking gender relations and violence with reproductive health and HIV: rationale, effectiveness and gaps. Agenda Spec. Focus Gend. Cult. Rights 114–123 (special issue). Doyal, L., 1995. What Makes Women Sick: Gender and the Political Economy of Health. Rutgers University Press, New Brunswick, NJ. Doyal, L., 2001. Sex, gender, and health: the need for a new approach. Br. Med. J. 323, 1061–1063. Eckman, A., Huntley, B., Bhuyan, A., 2004. How to Integrate Gender into HIV/ AIDS Programs: Using Lessons Learned from USAID and Partner Organizations. Report of the Interagency Gender Working Group Task Force (IGWG), Washington, DC. Farmer, P., Conners, M., Simmons, J. (Eds.), 1996. Women, Poverty and AIDS: Sex, Drugs and Structural Violence. KIT, Amsterdam, the Netherlands. Hartigan, P., 2001. The importance of gender in defining and improving quality of care: some conceptual issues. Health Policy Plan. 16, 7–12. Kublinsky, M., Timyan, J., Gay, S. (Eds.), 1993. The Health of Women: A Global Perspective. Westview Press, Boulder, CO. Liverpool School of Tropical Medicine, Department for International Development (DFID), 1999. Guidelines for the Analysis of Gender and Health. Liverpool School of Tropical Medicine, Liverpool, UK. National Institutes of Health, 1999. Agenda for Research on Women’s Health for the 21st Century. Office of Research on Women’s Health, Washington, DC. Shen, C., Williamson, J.B., 1999. Maternal mortality, women’s status, and economic dependency in less developed countries: a cross-national analysis. Soc. Sci. Med. 49, 197–214. Standing, H., 1999. Frameworks for Understanding Gender Inequalities and Health Sector Reform: An Analysis and Review of Policy Issues, Harvard Center for Population and Development Studies. Working Paper Series No. 99.06, Boston, MA. UNAIDS, 2000. Men and AIDS: A Gendered Approach. Report of the 2000 World AIDS Campaign. Joint United Nations Programme on HIV/AIDS, Geneva, Switzerland. Vlassoff, C., Garcia Moreno, C., 2002. Placing gender at the centre of health programming: challenges and limitations. Soc. Sci. Med. 54, 1713–1723. World Bank, 1995. An Overview of Women’s Health and Nutrition. World Bank, Washington, DC.

Genetic Epidemiology Harry Campbell and Niall Anderson, University of Edinburgh Medical School, Edinburgh, UK Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 3, pp. 39–43, Ó 2008, Elsevier Inc.

Introduction

Research Strategies

It is clear that genetic factors are an important determinant of most if not all human diseases and thus investigation of these factors should be an essential element of any epidemiological study of disease causation or variations in disease frequency. Familiarity with research strategies in genetic epidemiology should therefore be a requirement in the training of all epidemiologists and clinical scientists studying disease mechanisms. Although the ability to study specific genetic factors directly is relatively recent, the advances in the Human Genome Project and related genetic laboratory methods now mean that it is possible to measure these factors with considerably greater precision and validity and less expense than for most environmental exposures. By understanding the basic mechanisms of physiological pathways and pathological processes implicated in disease etiology through the identification of genetic factors underlying these processes, it is hoped that new treatments and disease prevention strategies will be developed. A secondary aim is to identify increased genetic susceptibility within individuals where this risk has been shown to be reversible through genetic manipulation or amenable to reduction by some other intervention. Khoury et al. (1993) have suggested a hierarchy of research hypotheses in genetic epidemiology, addressing questions such as:

Currently little is known about the genetic architecture underlying complex diseases. This makes it difficult to be certain which approach is likely to be the most successful in identifying genetic factors. Important issues include:

Does the disease cluster in families? Is the clustering due to genetic or environmental factors? l Do environmental factors modify the expression of the genetic factor? l l

In the following sections, we consider how we may attempt to provide answers to these questions. For those readers unfamiliar with basic genetics, Figure 1 provides a schematic of a pair of chromosomes in order to define some key genetic concepts and Table 1 provides a glossary of some other commonly used terms.

If there is evidence for a genetic factor, can a specific mode of inheritance be identified? l Can the genetic risk factor be identified? l Can the risk of disease associated with the genetic risk factor be quantified? l

Table 1

Glossary of some genetics terminology

Term

Definition

Complex disease

A condition thought to result from a mixture of genetic and environmental risk factors, rather than a mutation in a single gene (a Mendelian disorder) A sequence of DNA responsible for coding protein structures An organism’s complete sequence of DNA, contained within one full chromosomal set The set of alleles present on a single chromosome at two or more loci that are physically close (linked) to each other Association between the alleles of two different loci at a population level that results from the loci being physically close (allowing the same genetic material to be inherited intact in successive generations) A sequence of DNA (that may or may not be a gene) that is identifiable by molecular biological techniques and thus has a known position within the genome Cell divisions within germ cells that result in offspring with random assortments of parental DNA A collection of genetically related individuals, most often an extended family group An observable manifestation (such as a physical measurement or a disease state) of the action of one or more genes. Sometimes referred to as a trait A form of confounding: varying rates of disease and allele frequencies within subgroups of the population induce a disease–marker association at the level of the whole population A locus at which the DNA sequence between individuals will differ by only one base pair but may still function as a marker

Gene Genome Haplotype Linkage disequilibrium

Marker

Meioses Pedigree

A and B are the alleles (variant sequences of DNA) found at locus (location) M The genotype (set of alleles) at locus M is AB (described as heterozygous − different alleles on each chromosome) M A

B

Phenotype

Population stratification

AA and BB (described as homozygous) genotypes would also be possible Single nucleotide polymorphism (SNP)

Figure 1 Schematic of a pair of chromosomes, with an explanation of some fundamental concepts.

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http://dx.doi.org/10.1016/B978-0-12-803678-5.00172-7

Genetic Epidemiology Frequency of variants: Most variation in the human genome is considered to be due to common alleles (present at a minor allele frequency of >1%). Less frequent variants include the primary causes of the rare, Mendelian genetic diseases. Common variants may contribute significantly to genetic risk for common diseases (common variant– common disease hypothesis). The alternative, common disease–rare variant hypothesis holds that late-onset diseases are due to large numbers of rare variants at many loci with the contribution of most individual variants being very small (perhaps too small to further our understanding of disease). l Heterogeneity in gene expression and due to interactions: Other levels of complexity include heterogeneity in expression patterns of different alleles in the same gene and the presence of gene–gene and gene–environment interaction effects. These issues are important since most current statistical methods are based on an oligogenic model of complex disease, with a single risk allele in each gene. l

Some consideration of these issues is important in selecting the most appropriate study design. For example, substantial allelic heterogeneity considerably reduces the power of association methods and favors family-based association or linkage approaches. Since the genetic architecture of complex diseases is largely unknown, it is important that the selected analytic methods are robust and perform well under a variety of models. A further important consideration is the choice of study population in order to minimize the effects of environmental or lifestyle and cultural factors, so as to maximize genetic effects and the relationship between the genetic markers and disease phenotypes under study. Number of loci involved: Animal models suggest that the genetic basis of many complex diseases and traits is polygenic (many genes with small effects) rather than oligogenic (a small number of genes with large effects). l Genetic diversity: Experience from published studies of Mendelian disorders and monogenic forms of complex disease suggests that extreme locus and allelic heterogeneity is the rule. There are few data on locus and allelic complexity in common disorders, although most published examples show substantial heterogeneity. l

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familial aggregation. However, two specific measurements are useful: Lambda sib (ls) describes the increase in risk of disease in a sibling of an affected individual compared to the general population risk. It provides a summary of evidence for genetic factors in complex disease and is an important determinant of power. Note, however, that its value could also be due in part to shared environmental exposure, that ls relates to the total genetic effect and not of individual factors, and that results are specific to a given population with a particular pattern of environmental exposure. l Heritability is defined as the proportion of disease variation directly attributable to genetic differences among individuals relative to the total variation in the population (genetic and nongenetic). As above, the estimate is always population specific. l

More definitive evidence can be found in twin and adoption studies. Studies of disease or trait value concordance rates in twins provide an alternative estimate of the size of the genetic component that is less confounded by environment. Evidence in favor of the importance of genetic variants is given by: high level of monozygotic twin concordance; monozygotic twin greater than same sex dizygotic twin concordance (both affected or unaffected by disease); l monozygotic twin concordance same when twins reared apart. l l

Evidence from these studies is, however, limited by ascertainment bias: Concordant monozygotic twins are more likely to self-refer or to be referred by a doctor and monozygotic twins are likely to experience more similar environmental factors than dizygotic twins. Adoption studies are able to estimate separately genetic and environmental contributions to disease risk by comparing disease rates in true parents of affected and nonaffected adopted children (who share genetics, but not environment) or disease rates in the adopted children of affected and nonaffected true parents (who share environment but not genetics), which allows an estimate of heritability to be made. However, there are limited opportunities to conduct these studies and the utility of the results is limited by small numbers, selection biases, and problems in determining true parental status.

First Step: Detecting the Influence of Genes

Second Step: Gene Discovery

Genetic epidemiology requires a substantial commitment of time and resources, so that it is important first to show a clear influence of genetic factors on variation in a complex trait or on disease frequency. Subsequently, these data can be used to estimate the size of the genetic contribution to disease susceptibility. Evidence suggestive of a genetic influence can be found in the presence of genetic syndromes, for example, familial polyposis coli leading to colon cancer, or from animal models of disease shown to have a clear genetic basis. More quantitative estimates of genetic contribution are typically obtained from family studies by analysis of pedigrees. Family history information is of limited utility for estimating

Most gene discovery studies utilize DNA-based methods and statistical genetic mapping techniques that use recombination events to determine genetic distance between two loci. Two major approaches, linkage and association, can be used: linkage studies use information from observed meioses and association studies use information from the unobserved meioses that connect pedigrees historically.

Linkage Analysis Linkage studies test whether a disease and a genetic variant are inherited together in a pedigree by identifying coinheritance of

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chromosomal regions. It assesses whether genetic variants (markers) segregate with the disease according to Mendelian patterns of inheritance in large pedigrees with multiple affected individuals. This approach has proven to be very effective for rare Mendelian single-gene disorders and Mendelian forms of common complex disease. Thus it is the main strategy for identification of genetic variants of large effect. However, the same large genetic effect results in selection against these genes and so by definition they cause rare diseases or rare forms of common diseases. It has much less power to detect genetic variants with small effects and so may be much less effective for common complex diseases. Most common disorders show a complex segregation pattern in which the type of inheritance is not clear, so simpler pedigrees are studied. The most common unit of study consists of two affected siblings and their parents, with increased sharing of markers providing evidence that the marker is genetically linked to a nearby gene that affects susceptibility to the disease. However, this approach is relatively inefficient and to provide strong evidence large numbers of such families must be studied and hence international collaboration is usually required. This approach is robust to the genetic heterogeneity that is typically found in different affected sib pairs and can provide information on the approximate localization of genetic variants. This approach can also be used to identify loci underlying quantitative traits (usually abbreviated to QTL – quantitative trait locus or loci) by correlating the degree of phenotypic similarity between affected relatives with the number of alleles shared at a locus that causes disease.

Association Studies Association studies measure differences in the frequency of genetic variants between unrelated affected individuals (cases) and controls (unaffected individuals who are unrelated to any cases or controls in the sample). They thus study recombination and transmission of genes in populations over large timescales and are affected by the relatedness of populations, the effect of mutation and genetic drift on allele frequencies, migration, and gene–gene and gene–environment interaction. Association studies are premised on the hypothesis that common genetic variants underlie susceptibility to common diseases and take one of two main forms: Direct or indirect.

Direct Association

In direct association studies, genetic variants in selected genes that are believed to cause disease are studied. This, however, requires the genetic variant of interest to be known and markers in or close to the gene to have been identified. Studies of these so-called candidate genes have been successful in identifying genetic variants affecting disease susceptibility. These studies are most meaningful when applied to functionally significant variants with a clear biological relation to disease mechanisms or the trait under study.

Indirect Association

Indirect association studies investigate the association between a disease and neutral variants located near disease

susceptibility variants. The association is therefore a result of allelic association (linkage disequilibrium or LD) between the marker and risk allele. This approach can also be considered as the identification of segments of the genome that are shared by people because they are inherited from a common ancestor. Among individuals affected by the disease, these segments may harbor susceptibility genes. The average size of shared segments is set by the number of generations separating two individuals from their common ancestor and this governs the number of markers needed to discover them. A few hundred markers are sufficient when the common ancestor is recent (as in siblings), but hundreds of thousands of markers are required to discover very ancient gene variants. The markers of choice are single nucleotide polymorphisms (SNPs) because of their high frequency, low mutation rates, and amenability to automation. A very comprehensive SNP database and massive genotyping capacity are thus required for these genome-wide association studies. Association studies should follow the principles of good study design established in traditional epidemiological case– control studies as a means of improving the validity of study findings by reducing the opportunities for chance, bias, or confounding to account for study results. Technological advances such as the availability of SNP databases and affordable, very high-throughput genotyping are set to extend the potential and improve the efficiency of association approaches. However, the very large number of genetic variants in the human genome and the lack of detailed knowledge about the molecular and biochemical processes involved in the etiology of complex diseases suggest that it is very likely that many spurious associations will be found and reported. The great majority of reported associations have not led to new insights into complex disease or drug response mechanisms and are now considered to be false-positive results. These positive associations could be due to: l l

l

l l

artifacts such as differences in handling, storage, or genotyping between cases and controls; chance, with multiple association studies performed with publication of only those that show positive results (multiple testing with publication bias); chance, with multiple testing of markers, each with low prior probability of causing disease (inappropriate significance levels chosen); bias in the estimate of association due to poor study design, particularly in the choice of controls; confounding due to population stratification or other (unrecorded) differences between cases and controls.

Association studies can be population-based (case– control) or family-based, in which transmission of alleles from parents to affected and unaffected offspring is studied (see Figure 2). Family-based association studies offer some advantages in the ability to assign haplotypes and the ability to look at parent-of-origin effects, as well as protecting against confounding via population stratification. A number of alternative genomic control approaches have been described which utilize data from unlinked DNA markers to measure and adjust for population substructure effects in population-based association studies.

Genetic Epidemiology

AB

Allele not transmitted A B

AB A Allele transmitted B AA

0

2

0

0

Analyzed by McNemar⬘s test

Figure 2 Example of a family-based association analysis – the transmission/disequilibrium test (TDT). Shown for a single family trio (out of the larger trio collection actually needed) of two heterozygous parents (father, square; mother, circle) and one child (diamond, either sex; shaded, affected by disease), with each individual genotyped for a single marker with two possible alleles. The A allele is transmitted twice, once by each parent, and AA (the child’s genotype) forms a pseudo-case. The two B alleles are never transmitted, so BB is a pseudo-control. Data are analyzed by the 2  2 table shown.

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disease. During gamete formation and conception, a random assortment of genes is passed from parents to offspring. In those offspring, if a genetic variant directly influences the level of an intermediate trait, which in turn alters disease risk, then the relationship between the variant and disease risk should be consistent with the associations between the variant and the intermediate trait and that trait and disease. If the trait level is directly influenced by an environmental exposure, this Mendelian randomization approach will provide data on the relationship between the environmental exposure and disease, but may reduce or avoid the confounding that is inherent in observational epidemiology studies. It may thus improve the ability to determine the causal nature of some environmental exposures, because the association between a disease and a genetic variant that mimics the biological link between a proposed environmental exposure and disease is not susceptible to reverse causation or confounding.

Future Perspectives Third Step: Gene Characterization Key questions to be addressed after the identification of a genetic variant’s role in a disease process or variation in a trait associated with health or disease are: What is the prevalence of gene variants in different populations? l What is the risk (relative and attributable) of disease associated with these variants? l What is the contribution of gene variants to the occurrence of disease in different populations (population-attributable risk)? l What is the risk of disease associated with gene–gene and gene–environment interactions? l

The prevalence of gene variants (allele frequencies) can be estimated from large unselected cohorts or large randomly sampled control series in different populations. Absolute risks can be measured in population-based cohort studies and relative risks in cohort or genetic association studies (which measure an odds ratio). The attributable risk expresses the size of excess risk to an individual due to the presence of a particular genetic variant. The population-attributable risk estimates the overall contribution of the genetic factor to a disease in a specific population, but depends not only on the relative risk (or odds ratio) but the allele frequency of the variant. In environmental epidemiology, population-attributable risk can be used to express the reduction in incidence of disease that would be achieved if exposure to the factor in the population were eliminated. This has less meaning with respect to genetic variants and disease. However, it may be useful when considering pharmacogenetics and the potential for the reduction in side effects that may be achieved if genetic testing could identify all those genetically predisposed to a certain drug adverse effect and prescriptions were avoided in those found to carry that variant.

There is likely to be a move from the focus on gene discovery to include the need to understand function, biochemistry, and physiology before causal pathways can be understood and eventual public health benefits can be realized. The explosion of genomic technological capability and information is therefore the start and not the end of the path leading to the development of new drugs or other interventions. In the short term, this will involve studies that integrate data on genetic variants, expression microarrays and pathophysiological phenotypes in order to define variants that influence mRNA expression levels and QTL so that casual pathways can be studied. Increasingly, the phenotypes will include protein intermediates measured by proteomic technologies. This systems biology approach will involve huge complexity and great computing power and new analytic approaches (such as clustering algorithms to classify genes into hierarchical sets, genes with similar expression patterns grouped together) will be required to analyze and interpret these data. This will require greater collaboration between research groups in order to share data for meta-analysis and to increase power. Increasing partnership between governments, the pharmaceutical industry, medical research charities, and universities will become the norm for future genetic epidemiological research.

See also: New Technologies: Ethics of Genomics.

Reference Khoury, M.J., Beaty, T.H., Cohen, B., 1993. Fundamentals of Genetic Epidemiology. Oxford University Press, Oxford, UK.

Further Reading Mendelian Randomization Genetic epidemiology has the potential to improve the understanding of environmental as well as genetic determinants of

Balding, D.J., 2006. A tutorial on statistical methods for population association studies. Nat. Rev. Genet. 7, 781–791. Burton, P.R., Tobin, M.D., Hopper, J.L., 2005. Key concepts in genetic epidemiology. Lancet 366, 941–951.

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Campbell, H., Rudan, I., 2002. Interpretation of genetic association studies in complex disease. Pharmacogenomics J. 2, 349–360. Campbell, H., Rudan, I., 2007. Study design in mapping complex disease traits. In: Hastie, N., Wright, A.F. (Eds.), Genetics and Common Disease. Churchill Livingstone, Edinburgh, UK, pp. 92–112. Davey Smith, G., Ebrahim, S., 2005. What can mendelian randomisation tell us about modifiable behavioural and environmental exposures? Br. Med. J. 330, 1076–1079. Hattersley, A.T., McCarthy, M.I., 2005. What makes a good genetic association study? Lancet 366, 1315–1323. Hirschorn, J.N., Daly, M.J., 2005. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95–108. Hopper, J.L., Bishop, D.T., Easton, D.F., 2005. Population-based family studies in genetic epidemiology. Lancet 366, 1397–1406. Nitsch, D., Molokhia, M., Smeeth, L., DeStavola, B.L., Whittaker, J.C., Leon, D.A., 2006. Limits to causal inference based on mendelian randomization: a comparison with randomized controlled trials. Am. J. Epidemiol. 163, 397–403. Ott, J., 1991. Analysis of Human Genetic Linkage. Johns Hopkins University Press, Baltimore, MD. Palmer, L.J., Cardon, L.R., 2005. Shaking the tree: mapping complex disease genes with linkage disequilibrium. Lancet 366, 1223–1234. Risch, N.J., 2000. Searching for genetic determinants in the new millennium. Nature 405, 847–856. Thomas, D.C., 2004. Statistical Methods in Genetic Epidemiology. Oxford University Press, Oxford, UK.

Wang, W.Y.S., Barratt, B.J., Clayton, D.G., Todd, J.A., 2005. Genome-wide association studies: theoretical and practical concerns. Nat. Rev. Genet. 6, 109–118. Wright, A., Charlesworth, B., Rudan, I., Carothers, A., Campbell, H., 2003. A polygenic basis for late-onset disease. Trends Genet. 19, 97–106.

Relevant Websites http://www.linkage.rockefeller.edu/ – Genetic Analysis Resources at Rockefeller University (accessed on 09.04.16.). http://www.cdc.gov/genomics/hugenet – Human Genetic Epidemiology Network (accessed on 09.04.16.). http://www.massgeneral.org/psychiatry/research/pngu_home.aspx – University of Harvard, Psychiatric & Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital. http://www.kumc.edu/gec/geneinfo.html – University of Kansas Medical Center, Information for Genetic Professionals (accessed on 09.04.16.). http://www.csg.sph.umich.edu/ – University of Michigan Centre for Statistical Genetics (accessed on 09.04.16.). http://www.watson.hgen.pitt.edu/ – University of Pittsburgh Department of Human Genetics (accessed on 09.04.16.). http://www.well.ox.ac.uk – Wellcome Trust Centre for Human Genetics.

Geographic Information Systems (GIS) in Public Health Corinna Keeler and Michael Emch, University of North Carolina, Chapel Hill, NC, USA Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by L. Montana, volume 3, pp. 56–59, Ó 2008, Elsevier Inc.

Introduction A geographic information system (GIS) is a computer-based system that is capable of displaying, processing, or storing spatial data. Its core functions are data creation, data management, and data analysis and visualization. This article details each of these three core functions of a GIS, and discusses important considerations when using spatial data and some key public health applications of GIS. During the past 20 years, there has been exponential growth in the use of spatial information in public health studies and an increased attention understanding how place and spatial context are important for many health issues. Due to technological advances, incorporating a spatial component into public health research has become easier because of the availability of new data and methods.

Data Creation Spatial data have traditionally been generated through mapping data in the field, but recent technological developments have widened the possible avenues for creating data for use in GIS. The most common method of collecting spatial data is the use of global positioning system (GPS) receivers. GPS data collection can be done with a dedicated GPS unit, which communicates with a constellation of satellites to measure the position of the GPS unit on the earth’s surface. Beyond the recreational- and scientific-grade GPS units made by companies such as Garmin and Trimble, GPS data collection can also be conducted with many smartphones, tablets, and other mobile devices, which contain a GPS receiver that allows them to use the same satellite network to calculate location. While GPS data collection offers ways to generate spatial information in the field, much spatial data are generated without ever stepping away from the computer. Geocoding is a key method in generating spatial information for public health data. Geocoding refers to the process of converting addresses into geographic coordinates, which can then be stored in a GIS database and mapped. Many GIS software programs contain reference databases of street addresses that allow for in situ geocoding, but there are also online tools which can convert batches of addresses to spatial x- and ycoordinates. In some cases, geocoding is conducted at a smaller geographic scale, mapping health observations at the level of the city, zip/postal code, or state/province. Geocoding allows researchers to add spatial locational information to observations in a health database using existing fields (such as county or postal code) that have already been collected. Another computer-based approach to creating spatial data is image interpretation. This could refer to the use of satellite images taken from space, or aerial photography taken from aircraft. Remotely sensed data taken by satellites can be used

International Encyclopedia of Public Health, 2nd edition, Volume 3

for a variety of spatial data applications. For example, satellite images of the earth’s surface from the Landsat program can be classified into land use and land cover categories, which can then be integrated into a GIS analysis. Similarly, data from the Tropical Rainfall Measuring Mission satellite contain information about surface moisture, which can be processed to give spatial estimates of rainfall and precipitation. Aerial photographs usually contain fewer spectral bands than satellite images, so they cannot be processed into as many different data products; however, these photographs are often available at a higher resolution and can allow researchers to identify specific known locations, buildings, or areas of interest. Therefore, aerial photography is particularly useful in the process of heads-up digitizing, which refers to creating spatial data layers by marking the locations of interest (e.g., health centers) on a map or photo within a GIS environment. Eventually, the underlying map or photo, called a basemap, can be removed and the spatial database containing the locations of interest can be integrated with other data. The availability of free, Internet-based high-resolution aerial images from Google and Bing mapping services has made heads-up digitizing an indispensable method in spatial data creation. Participatory mapping is a community-based research method that allows local inhabitants or study participants to indicate important patterns, locations, or phenomena on a map (Dunn, 2007). This approach draws on local knowledge in order to generate spatial locations for discrete factors such as the location of a water source, or more subjective variables like unsafe walking locations. Participatory mapping also can be employed in conjunction with some of the aforementioned spatial technologies such as GPS data collection and Internetbased imagery interpretation to identify key locations or spatial patterns within a health study.

Data Management Spatial data can be stored in two main formats: raster or vector. The raster format is most appropriate for continuous data such as elevation or temperature, and is defined by its extent and its pixel size, with each pixel having an associated value for the variable of interest. The vector format, on the other hand, is most appropriate for discrete locations, geographic features, or regions. Vector data can be stored as either as point, line, or polygon features. A point feature on a small-scale map could be a city or study site, while a point on a large-scale map could be a health center or household. Line features often include rivers, roads, and other transportation networks. Polygon features include administrative units such as provinces, counties, or census areas, or other areas of interest such as parks or catchment areas. A GIS data file consists of both the spatial location associated with a set of features, and the tabular or numerical data

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associated with those features, referenced together. For example, a GIS database may contain the spatial locations of a set of water pumps, as well as attribute data about who manages each pump, the level of various environmental contaminants measured at each pump, and the year each pump was installed. The coordinate system used to measure the locations within a spatial database depends on how the data were generated and the geographic extent of the GIS data layer. There are two standard coordinate systems used internationally, and most GIS software can convert between them. First, the latitude and longitude system measures locations worldwide using the degree as a unit. This coordinate system is commonly used because it allows one set of coordinates to span the entire earth, but it can introduce spatial error at locations closer to the north and south poles. On the other hand, the UTM (Universal Transverse Mercator) coordinate system uses different sets of coordinates based on the region and is measured in meters, so the UTM coordinate system causes much less distortion when working with national-level data or when measuring distance is a primary goal of the GIS analysis. When working with multiple GIS data layers, it is important that their coordinate systems match. Map projections are closely associated with the concept of coordinate systems. A projection refers to how the threedimensional (3D) nature of spatial data is ‘flattened’ onto a two-dimensional map on paper or on a computer screen. Different projections can maintain area, shape, or distance, but no projection can accurately represent all three of these qualities of the 3D earth (Monmonier, 1996). Therefore, choosing a projection that is appropriate for the type of data being shown on the map is essential. While latitude and longitude, the UTM coordinate system, and many other coordinate systems can each be used with almost all projections, both projections and coordinate systems require the user to think abstractly about how the true spatial location of the data is measured, described through coordinates, and then represented on the map.

Data Analysis and Visualization The spatial dimension of the data in a GIS opens up different visualization possibilities than traditional graphing and different analytical capabilities than traditional statistics. Exploratory mapping, the process of visualizing one or more variables on a map, is a valuable analytical process in and of itself. Displaying the spatial location of observations in one or more data sets can indicate patterns in sampling, response rates, or other study characteristics. Additionally, using the attribute data associated with a set of locations, exploratory mapping can use color, symbol size, or symbol shape to show the spatial trends or relationships between or within data layers. In addition to providing opportunities for inspection and visual analysis of data, one or more vector layers can be queried against each other in a GIS. These queries include operations such as determining the distance from a set of points to another geographic feature, such as the distance from sampling sites to a point-source contaminant, or from households in a study to a health center. Additionally, the

underlying attribute data in a GIS data layer can be integrated into a spatial query. To use the previous household and health center example, if all of the health centers in the region had an associated attribute indicating the number of doctors on staff at that health center, the distance query could calculate the distance from each household in a study to the nearest health center with more than five doctors on staff. Similarly, using GIS, researchers can determine the proportion of observations in one data layer that lie within a buffer, intersection, or union of other layers of interest. An important analytical approach in GIS is the use of spatial statistics. Just as traditional statistics that compare a distribution of observations against a distribution of observations that might occur by chance, spatial statistics compare a spatial arrangement of values against what could be expected to occur by chance to determine if clustering or spatial patterns in data are statistically significant. While there are a large variety of spatial statistical tests that are based on wide range of statistical assumptions and underlying distributions, several key spatial statistics are employed frequently as a first line of analysis before building more advanced spatial statistical models. The Moran’s I statistic is a global measure of spatial autocorrelation across an entire data set, giving one value ranging from 1 (significantly dispersed) to 1 (significantly clustered). Moran’s I indicates whether like values are significantly close to other like values, significantly far from other like values, or randomly distributed. In contrast, the LISA statistic (Local Indicator of Spatial Autocorrelation) gives a statistic for each spatial location or observation in the data set, rather than one global statistic, indicating whether each unique spatial observation has significantly higher or lower value than those around it, or is not significantly different. Therefore, the LISA statistic can be mapped across space. Finally, the process of spatial interpolation uses input data observations, usually in vector point format, to create estimates of a continuous surface between the data points. Spatial interpolation is a form of spatial statistical analysis which allows GIS users to impute a value for a variable of interest a given location, based on the measured values at data points nearby. Two primary approaches for performing spatial interpolation are inverse distance weighting and Kriging (Cromley and McLafferty, 2012).

Important Considerations There are several key considerations for maintaining data privacy and reducing data error when working with spatial error. First, the ecological fallacy can occur when making inferences using spatial data. The ecological fallacy occurs when analyses of group data are applied to conclusions at the individual level. Because spatial data often lend itself to aggregation (i.e., combining all observations for a given city or county into one group when using a geocoding approach to data creation), it is quite possible to unintentionally introduce an ecological fallacy because these aggregations may combine highly heterogeneous data into one group. Similarly, the modifiable areal unit problem (MAUP) is a related aggregation fallacy present only in geographic data. The MAUP occurs when different ways of drawing a geographic boundary

Geographic Information Systems (GIS) in Public Health result in vastly different patterns in data measured at that boundary level. For example, if a certain research group analyzed car exhaust exposure by grouping populations according to urban and rural areas then calculating exposure rates, they might obtain very different results than a rival research group who measured exposure rates using a population grouping by county that combined the urban county seat with surrounding rural areas. Therefore, the way that the geographic boundaries are imposed in grouping the population could introduce bias in the results. The small numbers problem from traditional statistics is doubly at play in analyzing spatial data. In addition to introducing error due to the high variance of areas or spatial units with small numbers of observations or small denominators, the small numbers problem in spatial data also presents a privacy concern. For example, suppose that a study investigating rates of a rare type of cancer across health districts finds that there are only two cases of the cancer in Health District A with one fatality. This gives a fatality rate of 50% in that District A due to the small numbers problem, which could create a needless public health alarm or faulty inferences in that area. But furthermore, because the spatial nature of the data inherently provides more information, the two people who had that rare cancer in Health District A may be at risk of other people inferring personal medical knowledge, or their privacy might be otherwise compromised by publishing data with such a small number of cases. In general, one of the most important considerations when working with spatial data is privacy. As the example above shows, the inclusion of spatial information or coordinates often renders data, especially health data, more sensitive since the spatial coordinates could undermine

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the anonymity of the data. Therefore, it is especially important to be aware of how spatial data are secured and where these data are stored. For example, as discussed above with regard to data creation, replacing scientific GPS units with GPS receiver–enabled mobile devices may make spatial data collection more affordable and accessible for a certain project. However, this could also create a situation where the cellular phone company or the cloud-based storage provider for the GPS application has access to sensitive data.

See also: Biostatistics; Measurement and Modeling: Infectious Disease Modeling; Social Epidemiology.

References Cromley, E.K., McLafferty, S.L., 2012. GIS and Public Health, second ed. Guilford Press, New York, New York. Dunn, C.E., 2007. Participatory GIS – a people’s GIS? Prog. Hum. Geogr. 31 (5), 616–637. Monmonier, M., 1996. How to Lie with Maps, second ed. University of Chicago Press, Chicago, Illinois.

Further Reading Health and Place, Volumes 1–41. Science Direct: Elsevier B.V., 1995–2016. International Journal of Health Geographics, Volumes 1–15. BioMed Central: Springer Science and Business Media, 2002–2016. Meade, M.S., Emch, M., 2010. Medical Geography, second ed. Guilford Press, New York, NY. Social Science and Medicine, Volumes 34–163. Science Direct: Elsevier B.V., 1992–2016.

Global Burden of Disease Colin Mathers, World Health Organization, Geneva, Switzerland Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 3, pp. 59–71, Ó 2008, Elsevier Inc.

Introduction

Global Burden of Disease Studies

A common approach for describing and quantifying the health of populations is to aggregate individual-level data to generate estimates of quantities such as the proportion of the population (or of a particular age-sex group) suffering from a particular health problem or dying from a specific cause in a defined time period. When we are interested in assessing all important causes of loss of health, the numbers of statistics that must be compared rapidly become large, and we also face difficulties in comparing indicators relating to different health states, mortality risks, or disease events. Such statistics also suffer from several other limitations that reduce their practical value for policy makers: first, they are partial and fragmented. Basic information on causes of death is not available for all important causes in many countries, and mortality statistics fail to capture the impact of nonfatal conditions, such as mental disorders, musculoskeletal disorders, or blindness or deafness. Second, analyses of incidence, prevalence, or mortality for single causes often result in under- or overestimates when not constrained to fit within demographically plausible limits or to be internally consistent. Governments and international agencies are faced with setting priorities for health research and investment in health systems and health interventions in a context of increasing health-care costs, increasing availability of effective interventions, and numerous and diverse priorities and interest groups. One of the key inputs to such decision making should be detailed and comprehensive assessments of the causes of loss of health in populations, that incorporates both causes of death, as well as the main causes of nonfatal illness and their long-term sequelae. Broad evaluation of the effectiveness of health systems and major health programs and policies also requires assessments of the causes of loss of health that are comparable not only across populations, but also over time. The World Bank’s (1993) World Development Report, Investing in Health, recommended cost-effective intervention packages for countries at different levels of development. Underpinning these analyses was the first Global Burden of Disease (GBD) study, carried out by Chris Murray at Harvard University and Alan Lopez at the World Health Organization (WHO), in collaboration with a global network of over 100 scientists. As well as generating a comprehensive and consistent set of estimates of mortality and morbidity by age, sex, and region for the world, the GBD study introduced a new metric – the disabilityadjusted life year (DALY) – to simultaneously quantify the burden of disease from premature mortality and the nonfatal consequences of over 100 diseases and injuries (Murray and Lopez, 1996a).

The initial GBD study was commissioned by the World Bank to provide a comprehensive assessment of disease burden in 1990 from more than 100 diseases and injuries, and from 10 selected risk factors (Murray and Lopez, 1996a,b; World Bank, 1993). Earlier attempts by Lopez and others to quantify global cause-of-death patterns had been largely restricted to broad cause-of-death groups and did not address nonfatal health outcomes. The results of the original GBD study were surprising to many health policy makers, more familiar with the pattern of causes represented in mortality statistics. Neuropsychiatric disorders and injuries were major causes of lost years of healthy life as measured by DALYs, and were greatly undervalued when measured by mortality alone. More broadly, noncommunicable diseases, including neuropsychiatric disorders, were estimated to have caused 41% of the global burden of disease in 1990, only slightly less than communicable, maternal, perinatal, and nutritional conditions combined (44%), with 15% due to injuries. The GBD study stimulated a number of similar studies at national and subnational level, and also contributed to the setting of global health research priorities (World Health Organization, 1996). Between 1998 and 2004, WHO undertook a new assessment of the global burden of disease for the years 1999–2002, under the leadership of Chris Murray, with annual assessments published in annex tables to the World Health reports. These were based on an extensive analysis of mortality data for all regions of the world together with systematic reviews of epidemiological studies and population health surveys, as well as incorporating a range of methodological improvements. Additionally, a major and expanded research program, the Comparative Risk Assessment (CRA) project, was undertaken to quantify the global and regional attributable mortality and burden for 26 major risk factors. The WHO GBD analysis for the year 2001 was used as the framework for cost effectiveness and priority setting analyses carried out for the Disease Control Priorities Project, a joint project of the World Bank, WHO, and the National Institutes of Health, funded by the Gates Foundation. The GBD results were documented in detail, with information on data sources and methods as well as uncertainty and sensitivity analyses, in a book published as part of the Disease Control Priorities Project (Lopez et al., 2006). The basic units of analysis for the first GBD study were the eight World Bank regions defined for the 1993 World Development Report. The heterogeneity of these large regions limited their value for comparative epidemiological assessments. For the recent GBD assessments by WHO, a more refined approach was followed. Mortality estimates by disease and injury cause, age, and sex were first developed for each of the 192 WHO member states using different methods for countries with

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90 YLL(0,0) – males YLL(0,0) – females YLL(3,1) – males YLL(3,1) – females

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different sources of information on mortality. Epidemiological estimates for incidence, prevalence, and years lost due to disability (YLD) were first developed for 17 groupings of countries, and then imputed to country populations using available country-level information and methods to ensure consistency with the country-specific mortality estimates. The resulting country-level estimates were made available by WHO at a summarized level, and also facilitated the production of regional estimates for any desired regional groupings of countries.

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Analytic Methods The DALY – Construction and Concepts The DALY extends the concept of potential years of life lost due to premature death (PYLL) to include equivalent years of ‘healthy’ life lost from living in states of poor health or disability. One lost DALY can be thought of as one lost year of ‘healthy’ life (either through death or illness/disability), and total DALYs (the burden of disease) as a measurement of the gap between the current health of a population and an ideal situation in which everyone in the population lives into old age in full health. DALYs for a specific disease or injury cause are calculated as the sum of the years of life lost due to premature mortality (YLL) from that cause and the YLD for incident cases of the disease or injury. The YLL are calculated from the number of deaths, dx, at each age x multiplied by a global standard life expectancy, Lx, which is a function of age x: X YLLx ¼ dx  Lx x

The GBD 1990 study chose not to use an arbitrary age cutoff such as 70 years in the calculation of YLL, but rather specified the loss function Lx in terms of the life expectancies at various ages in standard life tables with life expectancy at birth fixed at 82.5 years for females and 80.0 years for males (Figure 1). The loss function was specified to be the same for all deaths of a given age and sex, in all regions of the world, irrespective of other characteristics such as socioeconomic status or relevant current local life expectancies. Because YLL measure the incident stream of lost years of life due to deaths, an incidence perspective is also taken for the calculation of YLD. The YLD for a particular cause in a particular time period are calculated by multiplying the number of incident cases ix, at each age x in that period, by the average duration of the disease for each age of incidence, lx, and a weight factor dwx, that reflects the severity of the disease on a scale from 0 (full health) to 1 (dead): X YLDx ¼ ix  lx  dwx x

YLD are generally calculated either for the average incident case of the disease, or for one or more disabling sequelae of the disease. For example, YLD for diabetes are calculated by adding the YLD for uncomplicated cases and the YLD for sequelae such as diabetic neuropathy, retinopathy, and amputation. Murray and Lopez chose to apply a 3% time discount rate to the years of life lost in the future to estimate the net present

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Figure 1 Years of life lost (YLL) for a death at various ages. The upper curves show the undiscounted, nonage-weighted YLL used in the calculation of DALYs based on the life expectancy at each age in standard life tables (Coale and Demeny West Model Level 26) with life expectancy at birth fixed at 82.5 years for females and 80.0 years for males. The lower curves show the effects of age-weighting and discounting on the YLL lost per death at various ages for males and females. YLL(r,K) denotes YLL calculated with discount rate r (%) and standard age-weighting (K ¼ 1) or uniform age-weighting (K ¼ 0). Reproduced from Mathers, C.D., Salomon, J.A., Ezzati, M., Begg, S., Lopez, A.D., 2006. Sensitivity and uncertainty analyses for burden of disease and risk factor estimates. In: Lopez, A.D., et al. (Eds.), Global Burden of Disease and Risk Factors. Oxford University Press, New York, pp. 399–426.

value of years of life lost in calculating DALYs. Based on a number of studies that suggest the existence of a broad social preference to value a year lived by a young adult more highly than a year lived by a young child or an older person, Murray also incorporated nonuniform age weights. When discounting and age weighting are both applied, a death in infancy corresponds to 33 DALYs, while deaths at ages 5 to 20 equate to around 36 DALYs (Figure 2). Discounting and age weighting essentially modify the loss function Lx in the calculation of YLL and the average duration, lx, in the calculation of YLD. A more complete account of the DALY, calculation formulae, and the philosophy underlying parameter choices, is given by Murray and Lopez (1996a). The ‘valuation’ of time lived in nonfatal health states formalizes and quantifies social preferences for different states of health as disability weights (dwx). Depending on how these weights are derived, they are variously referred to as disability weights, quality-adjusted life year (QALY) weights, health state valuations, or health state preferences. Because the DALY is measuring loss of health (unlike the QALY that measures equivalent healthy years lived), the disability weights for DALYs are inverted, running from 0 (ideal health) to 1 (state comparable to death). The original GBD study used two forms of the person tradeoff method to value health states and asked participants in weighting exercises to make a composite judgment about the severity distribution of the condition and the preference for time spent in each severity level. This was largely necessitated

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Figure 2 The relationship between health gaps and health expectancies in a stationary population. The health gap is area C þ f(B) where f(B) is a function of B in the range 0 to area B representing the lost equivalent years of full health lived in states B. The health expectancy is the area A þ g(B), where G(B) ¼ B  f(B) represents the equivalent years of full health lived in states B. DALYs are the best known example of a health gap indicator; examples of health expectancies include disability-free life expectancy (DFLE) and health-adjusted life expectancy (HALE). Reproduced from Murray, C.J.L., Salomon, J.A., Mathers, C.D., Lopez, A.D., 2002. Summary Measures of Population Health: Concepts, Ethics, Measurement and Applications. WHO, Geneva, Switzerland.

by the lack of population information on the severity distribution of most conditions at the global and regional levels. A Dutch disability weight study attempted to address this problem by defining the distribution of health states associated with each sequela using the EuroQol health profile to describe the health states (Stouthard et al., 1997). Using similar methodology to the original GBD study with three panels of public health physicians and one lay panel, this study concluded that it makes little difference whether the valuation panels comprise medical experts or lay people, as long as accurate functional health state profiles are provided.

Relationship to Other Summary Measures of Population Health (SMPH) The DALY is one example of a time-based summary measure of population health that combines mortality and morbidity into a single indicator (Murray et al., 2002). Two classes of SMPH have been developed: health expectancies (e.g., disability-free life expectancy, active life expectancy, healthy life expectancy) and health gaps (e.g., disability-adjusted life years, healthy life years, etc.). Health expectancies extend the concept of life expectancy to refer to expectations of various states of health, or of the overall expectation of years of equivalent full health, not just of life per se (see Figure 2). Health gaps are a complementary class of indicators that measure lost years of full health against some normative ideal (see Figure 2). Measures of potential YLL have been used for many years to measure the mortality burden of various causes of death. The DALY is one of several examples of a health gap indicator which extends the notion of mortality gaps to include time lived in states with other than excellent health. A health gap measure was chosen for the GBD studies because it allows the use of categorical attribution to attribute the fatal and nonfatal burden of diseases and injuries to an

exhaustive and mutually exclusive set of disease and injury categories. The lost years of health (or DALYs) on one hand are additive across such a set of disease or injury categories. However, health expectancy measures, on the other, do not naturally lend themselves to disaggregation by categorically defined causes. Instead, counterfactual methods, such as ‘disease elimination,’ are required to quantify the contribution of disease causes to overall health expectancy measure, as well as for dealing with risk factors. Health gap measures also generally require counterfactual analysis to attribute the burden of disease to health determinants and risk factors.

Dealing with Incomplete and Partial Data The GBD study developed methods and approaches to make estimates for causes of burden for which there were limited data and considerable uncertainty, to ensure that causes with limited information were not implicitly considered to have zero burden and hence ignored by health policy makers (Murray et al., 2003). The basic philosophy guiding the GBD approach is that there is likely to be useful information content in many sources of health data, provided they are carefully screened for plausibility and completeness, and that internally consistent estimates of the global descriptive epidemiology of major conditions are possible with appropriate tools, investigator commitment, and expert opinion. This philosophy has remained central to the WHO updates of the GBD, which incorporated a range of new data sources both for mortality (YLL) and YLD calculations (Lopez et al., 2006). Despite this, there remains very considerable uncertainty in cause-specific mortality estimates for Africa and many other developing countries, and also for YLD for many diseases in both developed and developing countries (Mathers et al., 2006). To address criticisms about lack of transparency in the GBD enterprise, substantial effort was also put into documenting cause-specific analyses and the overall analytical approach (Mathers et al., 2006).

Estimation of Mortality Levels and Causes of Death For the most recent GBD estimates at WHO, life tables specifying mortality rates by age and sex for 192 WHO member states were developed for 2002 from available death registration data (112 member states), sample registration systems (India, China), and data on child and adult mortality from censuses and surveys such as the Demographic and Health Surveys (DHS) and UNICEF’s Multiple Indicator Cluster Surveys (MICS). Death registration data containing useable information on cause-of-death distributions were available for 107 countries, the majority of these in the high-income group, Latin America and the Caribbean, and Europe and Central Asia. Populationbased epidemiological studies, disease registers, and notifications systems (in excess of 2700 data sets) also contributed to the estimation of mortality due to 21 specific communicable causes of death, including HIV/AIDS, malaria, tuberculosis, childhood immunizable diseases, schistosomiasis, trypanosomiasis, and Chagas’ disease. Almost one-third of these data sets related to sub-Saharan Africa.

Global Burden of Disease To address information gaps relating to other causes of death for populations without useable death registration data, models for estimating broad cause-of-death patterns based on GDP and overall mortality levels were used. The approach to cause-of-death modeling used for the GBD 1990 study was substantially revised and enhanced for the 2000–02 study to estimate deaths by broad cause group in regions with limited information on mortality (Salomon and Murray, 2002).

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Around 8700 data sets were used to quantify the YLD estimates for GBD 2000–02, of which more than 7000 related to Group I causes. One-quarter of the datasets relate to populations in sub-Saharan Africa, and around one-fifth to populations in high-income countries. Together with the more than 1370 additional data sets used for the estimation of YLL, the 2000–02 GBD study incorporated information from over 10 000 data sets relating to population health and mortality. This almost certainly represents the largest synthesis of global information on population health ever carried out.

Data and Methods for Estimation of YLD Estimating YLD requires systematic assessments of the available evidence on incidence, prevalence, duration, and severity of a wide range of conditions, often based on inconsistent, fragmented, and partial data available from different studies. Data sources included disease registers, epidemiological studies, health surveys, and health facility data (where relevant). Two key tools in dealing with limited or missing data were to carefully screen sources of health data for plausibility and completeness, drawing on expert opinion and on crosspopulation comparisons, and to explicitly ensure the internal consistency of estimates of incidence, prevalence, case fatality, and mortality for each specific disease cause. A software tool called DisMod was developed for the GBD study to help model the incidence and duration parameters needed for YLD calculations from available data, to incorporate expert knowledge, and to check the consistency of different epidemiological estimates and ensure that the estimates used were internally consistent. Figure 3 shows the underlying model used by DisMod (Barendregt et al., 2003).

Population without disease Incidence rate i

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Figure 3 The basic disease model underlying DISMOD. For a given population with specified all cause mortality rates, the three transition rates for incidence (i), remission (r) and cause-specific mortality (f) completely determine the prevalence of cases of the disease, and the average duration of cases. As well as calculating solutions when the three hazard rates (for incidence, remission, and mortality) are provided as inputs, DISMOD allows other combinations of inputs such as prevalence, remission, and case fatality. In these cases, DISMOD uses a goal-seeking algorithm to fit hazards such that the model reproduces the available input variables. DISMOD may thus be used either to estimate parameters needed for YLD calculations (incidence and average duration) from other available epidemiological information, or to check the internal consistency of the various parameter estimates from available studies. Reproduced from Mathers, C.D., Lopez, A.D., Murray, C.J.L., 2006. The burden of disease and mortality by condition: data, methods and results for 2001. In: Lopez, A.D., et al. (Eds.), Global Burden of Disease and Risk Factors. Oxford University Press, New York, pp. 45–240.

Latest Results This section gives a brief overview of results for the year 2002 grouped in World Bank regions, with high-income countries grouped together separately. Diseases and injuries are classified in the GBD using a tree structure based on the International Classification of Diseases. The highest level of aggregation consists of three broad cause groups: Group I (communicable, maternal, perinatal, and nutritional conditions), Group II (noncommunicable diseases), and Group III (injuries). Group I causes are those conditions that typically decline at a faster pace than all-cause mortality during the epidemiological transition, and occur largely in poor populations. Figure 4 compares the distribution of deaths and DALYs across the three groups in 2002 for high-income countries and low- and middle-income countries.

Global and Regional Mortality in 2002 Slightly over 57 million people died in 2002, 10.4 million (or nearly 20%) of whom were children younger than 5 years of age. Of these child deaths, 99% occurred in low- and middle-income countries. Worldwide, one death in every three is from a Group I cause. This proportion remains almost unchanged from 1990, with one major difference. Whereas HIV/AIDS accounted for only 2% of Group I deaths in 1990, it accounted for 16% in 2002. The risk of a child dying before age 5 ranged from 17% in sub-Saharan Africa to 0.7% in high-income countries in 2002. Low and middle-income countries accounted for 99% of global deaths among children under the age of 5 years and 85% of these were in the low-income countries. Just five preventable conditions – pneumonia, diarrheal diseases, malaria, measles, and perinatal causes are responsible for 70% of all child deaths (Figure 5). In developing countries, Group II causes (noncommunicable diseases) were responsible for more than 50% of deaths in adults aged 15–59 in all regions except South Asia and sub-Saharan Africa, where Group I causes including HIV/ AIDS remained responsible for one-third and two-thirds of deaths, respectively (Figure 6). In other words, the epidemiologic transition is already well established in most developing countries. Table 1 summarizes estimated numbers of deaths and DALYs in 2002 for diseases and injuries causing more than 1% of global deaths or DALYs. Ischemic heart disease (IHD) and cerebrovascular disease (stroke) were the leading causes of death in both high-income countries and low and

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Low- and middle-income countries 49.2 million deaths in 2002

High-income countries 7.8 million deaths in 2002 6%

10%

7%

36%

54% 87% Group I

Group II

Low- and middle-income countries 1368 million DALYs in 2002

Group III High-income countries 118 million DALYs in 2002 6%

9%

12%

44%

44%

85% Figure 4 Distribution of deaths and DALYs by broad cause group, for low to middle-income countries and high-income countries, 2002. Group I conditions include communicable diseases, and maternal, perinatal, and nutritional conditions, Group II conditions include noncommunicable diseases, and Group III includes unintentional and intentional injuries. Source: World Health Organization.

High income

Malaria Diarrheal diseases Respiratory infections

Europe and Central Asia

Other infectious and parasitic Perinatal causes Latin America and Caribbean

Nutritional deficiencies Noncommunicable Injuries

Middle East and North Africa

East Asia and Pacific

South Asia

Sub-Saharan Africa 0.0

5.0

10.0 15.0 20.0 25.0 30.0 35.0 Death rate per 1000 children aged 0–4

40.0

45.0

Figure 5 Death rates by disease group and region for children aged 0–4 years, 2002. For all the World Bank geographical regions, high-income countries have been excluded and are shown as a single group at the top of the graph. Source: World Health Organization.

Global Burden of Disease

High income

261

HIV/AIDS Other infectious and parasitica Maternal and nutritional

Europe and Central Asia

Cardiovascular diseases Cancers Other noncommunicable

Latin America and Caribbean

Unintentional injuries Intentional injuries

Middle East and North Africa

East Asia and Pacific

South Asia

Sub-Saharan Africa 0

2

4 6 8 Death rate per 1000 adults aged 15–59

10

12

Figure 6 Death rates by disease group and region for adults aged 15–59 years, 2002. For all the World Bank geographical regions, high-income countries have been excluded and are shown as a single group at the top of the graph. a The category ‘Other infectious and parasitic diseases’ includes acute respiratory infections such as influenza and pneumonia. Source: World Health Organization.

middle-income countries in 2002, together responsible for more than 20% of all deaths worldwide (Table 2). Four of the top ten causes of death in the world are related to smoking (ischemic heart disease, stroke, chronic obstructive pulmonary disease, and lung cancer). In low- and middle-income countries, 5 of the leading 10 causes of death remain infectious diseases, including lower respiratory infections, HIV/AIDS, diarrheal diseases, tuberculosis, and malaria.

Leading Causes of Disability The overall burden of nonfatal disabling conditions is dominated by a relatively short list of causes. In all regions, neuropsychiatric conditions are the most important causes of disability, accounting for over 37% of YLDs among adults aged 15 years and over. While depression is the leading cause of disability for both males and females, the burden of depression is 50% higher for females than males, and females also have higher burden from anxiety disorders, migraine, and senile dementias. In contrast, the male burden for alcohol and drug use disorders is nearly six times higher than that for females, and accounts for one-quarter of the male neuropsychiatric burden. Vision disorders, hearing loss, and musculoskeletal disorders are also important causes of YLD, in both developed and developing countries (Figure 7).

The Burden of Diseases and Injuries HIV/AIDS is now the third-leading cause of burden of disease globally, and the leading cause in sub-Saharan Africa,

followed by malaria. Five other Group I causes also appear in the top ten causes for low and middle income countries (Table 3). Group I conditions accounted for 73% of the burden of disease in sub-Saharan Africa, and 47% of the burden in South Asia (Figure 8). In other low and middleincome regions, Group I conditions account for a little under one-quarter of the disease burden. Total disease burden in Europe and Central Asian countries increased by nearly 40% over the period since 1990 and was higher in 2002 than for other developing regions of the world apart from South Asia and sub-Saharan Africa. The epidemiological transition in low and middle income countries has resulted in a 20% reduction since 1990 in the per capita disease burden due to Group I causes (communicable, maternal, perinatal, and nutritional conditions). Without the HIV/AIDS epidemic and the associated lack of decline in tuberculosis burden, this reduction would have been substantially greater, closer to 30% over the period. The burden of noncommunicable diseases accounted for nearly half of the global burden of disease in 2002, a 10% increase from estimated levels in 1990. Indeed, almost 50% of the adult disease burden in low and middle-income countries of the world is now attributable to noncommunicable disease. The burden of disease in Europe and Central Asia was dominated by ischemic heart disease and stroke, which together accounted for more than one-quarter of total disease burden. In contrast, in Latin America and Caribbean countries, these diseases accounted for 8% of disease burden. However, there were very high levels of diabetes and endocrine disorders in this region, compared to others.

262 Table 1

Global Burden of Disease Estimated deaths and burden of disease by cause – low- and middle-income, high-income countries, and World, 2002a High-incomeb

Low- and middle-income All causes

Deaths

DALYs

Total number (thousands) 49 164 1 368 156 Rate per 1000 population 9.3 259.0 Age-standardized rate per 1000c 11.4 261.5 Selected cause groups: Number (thousands) I. Communicable, maternal, perinatal, and nutritional conditions Group I total 17 840 (36.3) 601 885 (44.0) Perinatal conditions 2428 (4.9) 96 798 (7.1) Lower respiratory infections 3603 (7.3) 92 186 (6.7) HIV/AIDS 2833 (5.8) 81 771 (6.0) Diarrheal diseases 1863 (3.8) 64 445 (4.7) Malaria 911 (1.9) 34 758 (2.5) Tuberculosis 1550 (3.2) 34 454 (2.5) Maternal conditions 509 (1.0) 32 957 (2.4) Measles 607 (1.2) 20 953 (1.5) Protein-energy malnutrition 251 (0.5) 16 740 (1.2) II. Noncommunicable diseases Group II total 26 630 (54.2) 596 788 (43.6) Unipolar depressive disorders 11 (0.0) 56 474 (4.1) Ischemic heart disease 5856 (11.9) 51 646 (3.8) Cerebrovascular disease 4736 (9.6) 43 748 (3.2) Chronic obstructive pulmonary disease 2442 (5.0) 24 176 (1.8) Hearing loss, adult onset 0 (0.0) 21 978 (1.6) Cataracts 0 (0.0) 24 780 (1.8) Alcohol-use disorders 67 (0.1) 14 767 (1.1) Diabetes mellitus 775 (1.6) 13 044 (1.0) Schizophrenia 21 (0.0) 14 631 (1.1) Asthma 212 (0.4) 13 333 (1.0) Osteoarthritis 2 (0.0) 12 163 (0.9) Congenital heart anomalies 249 (0.5) 14 508 (1.1) Vision disorders, age-related 0 (0.0) 12 975 (0.9) Bipolar disorder 0 (0.0) 12 437 (0.9) Cirrhosis of the liver 668 (1.4) 12 233 (0.9) Trachea, bronchus, lung cancers 786 (1.6) 7751 (0.6) Nephritis and nephrosis 561 (1.1) 7802 (0.6) Stomach cancer 707 (1.4) 7061 (0.5) Hypertensive heart disease 783 (1.6) 6995 (0.5) Liver cancer 514 (1.0) 6275 (0.5) Colon and rectum cancer 365 (0.7) 3759 (0.3) III. Injuries Group III total 4694 (9.5) 169 483 (12.4) Road traffic accidents 1071 (2.2) 35 158 (2.6) Violence 536 (1.1) 20 373 (1.5) Self-inflicted injuries 750 (1.5) 18 149 (1.3) Falls 320 (0.7) 14 876 (1.1)

World

Deaths

DALYs

Deaths

DALYs

7847 8.4 4.9

118 093 126.7 111.5

57 011 9.2 10.0

1 486 249 239.2 239.6

539 (6.9) 30 (0.4) 336 (4.3) 20 (0.3) 6 (0.1) 0 (0.0) 15 (0.2) 1 (0.0) 0 (0.0) 9 (0.1)

7162 (6.1) 1438 (1.2) 1303 (1.1) 609 (0.5) 315 (0.3) 2 (0.0) 149 (0.1) 479 (0.4) 3 (0.0) 98 (0.1)

18 378 (32.2) 2459 (4.3) 3939 (6.9) 2853 (5.0) 1868 (3.3) 911 (1.6) 1565 (2.7) 510 (0.9) 607 (1.1) 260 (0.5)

609 047 (41.0) 98 236 (6.6) 93 489 (6.3) 82 380 (5.5) 64 759 (4.4) 34 760 (2.3) 34 602 (2.3) 33 436 (2.2) 20 955 (1.4) 16 838 (1.1)

6843 (87.2) 3 (0.0) 1340 (17.1) 766 (9.8) 304 (3.9) 0 (0.0) 0 (0.0) 23 (0.3) 208 (2.7) 2 (0.0) 28 (0.4) 3 (0.0) 12 (0.2) 0 (0.0) 0 (0.0) 117 (1.5) 456 (5.8) 115 (1.5) 142 (1.8) 126 (1.6) 104 (1.3) 256 (3.3)

100 291 (84.9) 10 588 (9.0) 7502 (6.4) 5708 (4.8) 3873 (3.3) 3974 (3.4) 376 (0.3) 5471 (4.6) 3121 (2.6) 1458 (1.2) 1908 (1.6) 2648 (2.2) 802 (0.7) 1127 (1.0) 1467 (1.2) 1685 (1.4) 3497 (3.0) 585 (0.5) 1028 (0.9) 693 (0.6) 813 (0.7) 2051 (1.7)

33 473 (58.7) 13 (0.0) 7195 (12.6) 5502 (9.7) 2746 (4.8) 0 (0.0) 0 (0.0) 90 (0.2) 983 (1.7) 23 (0.0) 240 (0.4) 5 (0.0) 262 (0.5) 0 (0.0) 1 (0.0) 785 (1.4) 1242 (2.2) 676 (1.2) 850 (1.5) 908 (1.6) 617 (1.1) 621 (1.1)

697 079 (46.9) 11 (0.0) 5856 (11.9) 4736 (9.6) 2442 (5.0) 0 (0.0) 0 (0.0) 67 (0.1) 775 (1.6) 21 (0.0) 212 (0.4) 2 (0.0) 249 (0.5) 0 (0.0) 0 (0.0) 668 (1.4) 786 (1.6) 561 (1.1) 707 (1.4) 783 (1.6) 514 (1.0) 365 (0.7)

465 (5.9) 118 (1.5) 22 (0.3) 123 (1.6) 71 (0.9)

10 640 (9.0) 3085 (2.6) 780 (0.7) 2327 (2.0) 1240 (1.1)

5159 (9.0) 1189 (2.1) 558 (1.0) 873 (1.5) 391 (0.7)

180 123 (12.1) 38 244 (2.6) 21 153 (1.4) 20 475 (1.4) 16 116 (1.1)

Note: Numbers in parentheses indicate % of column total. a Within each major group, disease and injury causes resulting in greater than 1% of total deaths or DALYs are shown, ranked within each group by global DALYs. b High-income countries are those countries with gross national income per capita of $9206 or more in 2001, according to the World Bank’s 2003 World Development Report. This group includes the countries of Western Europe, North America, Australia, New Zealand, Japan, the Republic of Korea, Singapore, and four of the Gulf States. c Age-standardized using the WHO World Standard Population. Source: World Health Organization.

Road traffic accidents are among the top 10 causes of DALYs for both high-income and low and middle-income countries. Violence is also the fourth leading cause of burden in Latin America and Caribbean countries. In these countries, as well as the Europe and Central Asian region, and the Middle East and North Africa, more than 30% of the entire disease and injury burden among male adults aged 15–44 is attributable to injuries, including road traffic accidents, violence, and selfinflicted injuries. Additionally, injury deaths are noticeably

higher for women in some parts of Asia and the Middle East and North Africa, in part due to high levels of suicide and violence.

Applications of Burden of Disease Analysis The GBD studies have provided a base or starting point for a number of analytic exercises to provide inputs to

Global Burden of Disease Table 2

All causes 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

international and national health policy and priority setting. Apart from the application to health research priority setting mentioned earlier, the GBD has also provided a population base for the calculation of the potential health gains through cost-effective interventions, and for the analysis of priorities for health interventions and investments in low and middleincome countries (Jamison et al., 2006; Tan-Torres Edejer et al., 2003). Perhaps the major methodological advance has been in the quantification of the attributable burden for 26 global risk factors. During the years 2000–03, WHO reported on the average levels of population health for its 192 member countries using a health expectancy measure, healthy life expectancy (HALE). The HALE calculations were based substantially on imputed national-level data from the GBD study as difficulties in comparing self-reported health data across populations severely limited the information input from populationrepresentative surveys (Mathers et al., 2004). HALE was also used as one of the key outcome measures in WHO analysis of the overall performance, or efficiency, of national health systems (Murray and Evans, 2003).

Fifteen leading causes of death, world, 2002

Ischemic heart disease Cerebrovascular disease Lower respiratory infections HIV/AIDS Chronic obstructive pulmonary disease Perinatal conditionsa Diarrheal diseases Tuberculosis Trachea, bronchus, lung cancers Road traffic accidents Diabetes mellitusb Malaria Hypertensive heart disease Suicide Stomach cancer

Total deaths (millions) 57.01

% of total deaths 100.0

7.20 5.50 3.94 2.85 2.75

12.6 9.7 6.9 5.0 4.8

2.46 1.87 1.56 1.24

4.3 3.3 2.7 2.2

1.19 0.98 0.91 0.91 0.87 0.85

2.1 1.7 1.6 1.6 1.5 1.5

263

a

Includes ‘causes arising in the perinatal period’ as defined in the International Classification of Diseases, and does not include all causes of deaths occurring in the perinatal period. b Does not include renal failure deaths attributable to diabetic nephropathy or cardiovascular disease deaths attributable to diabetes mellitus as a risk factor. Taking these attributable deaths into account, a total of approximately 3 million deaths are attributable to diabetes mellitus. Source: World Health Organization.

Projections The original GBD study included projections of mortality and burden of disease by cause, age, and sex for the eight GBD regions for the years 2000, 2010, and 2020. These projections

HIV/AIDS, TB, and malaria Other infectious and parasitic diseases Respiratory infections Maternal conditions Perinatal conditions Nutritional deficiencies Malignant neoplasms Neuropsychiatric conditions Sense organ diseases Cardiovascular diseases and diabetes Respiratory diseases Digestive diseases Musculoskeletal diseases Congenital anomalies Other group II conditions

YLL

Unintentional injuries

YLD

Intentional injuries 0

50

100

150

200

250

DALYs (millions)

Figure 7 Global YLD, YLL, and DALYs for major disease groups, 2002. DALYs are the sum of years of life lost due to premature mortality (YLL) and years lived with disability (YLD). Source: World Health Organization.

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Global Burden of Disease

Table 3

The 10 leading causes of burden of disease, DALYs by broad income group, 2002 Low and middle-income countries

1 2 3 4 5 6 7 8 9 10

High-income countries

Cause

DALYs (million) % of total DALYs

Perinatal conditions Lower respiratory infections HIV/AIDS Diarrheal diseases Unipolar depressive disorders Ischemic heart disease Cerebrovascular disease Road traffic accidents Malaria Tuberculosis

96.8 92.2 81.8 64.4 56.5 51.6 43.7 35.2 34.8 34.5

7.1 6.7 6.0 4.7 4.1 3.8 3.2 2.6 2.5 2.5

1 2 3 4 5 6 7 8 9 10

Cause

DALYs (millions) % of total DALYs

Unipolar depressive disorders Ischemic heart disease Cerebrovascular disease Alcohol use disorders Alzheimer and other dementias Hearing loss, adult onset Chronic obstructive pulmonary disease Trachea, bronchus, lung cancers Diabetes mellitus Road traffic accidents

10.6 7.5 5.7 5.5 4.1 4.0 3.9 3.5 3.1 3.1

9.0 6.4 4.8 4.6 3.5 3.4 3.3 3.0 2.6 2.6

HIV/AIDS

High income

Other infectious and parasitica Maternal, perinatal and nutritional

Europe and Central Asia

Cardiovascular diseases Cancers

Latin America and Caribbean

Neuropsychiatric Other noncommunicable

Middle East and North Africa

Unintentional injuries Intentional injuries

East Asia and Pacific

South Asia

Sub-Saharan Africa 0

50

100 150 200 250 300 350 400 450 500 550 600 DALYs per 1000

Figure 8 DALYs per 1000 population, by region and cause group, all ages, 2002. For all the World Bank geographical regions, high-income countries have been excluded and are shown as a single group at the top of the graph. aThe category ‘Other infectious and parasitic diseases’ includes acute respiratory infections such as influenza and pneumonia. Source: World Health Organization.

have been widely used and quoted, and due to ongoing demand, WHO prepared updated projections to the year 2030 using similar but updated methods (Mathers and Loncar, 2006). According to these projections, overall (age-standardized) mortality rates worldwide are expected to decline by 0.6– 1.0% per year over the next 30 years, but at two to three times this rate for most major communicable diseases, the exception being HIV/AIDS. Indeed, by 2030, global HIV/AIDS mortality is expected to double from the 2005 annual toll of just under 3 million deaths. Table 4 shows the projected 10 leading causes of death globally in 2030. Total tobaccoattributable deaths will rise from 5.4 million in 2005 to 8.3 million in 2030, 11% of all deaths globally. The three leading causes of burden of disease in 2030 are projected to

be HIV/AIDS, unipolar depressive disorders, and ischemic heart disease.

National Burden of Disease Studies The methods and findings of the original GBD study stimulated quite a number of national disease burden studies of varying scope and methodological rigor during the 1990s. The earliest comprehensive studies were for Mexico and Mauritius, followed by studies in the late 1990s in the Netherlands and Australia. In the last few years, comprehensive national burden of disease studies have also been carried out in countries such as Brazil, Malaysia, Turkey, South Africa, Zimbabwe, Thailand, and the United States, and studies are under way in Canada and several other countries. (A reasonably up-to-date list of

Global Burden of Disease Table 4

Projected leading causes of death, by income group, 2030 Both sexes

Rank

265

Disease or injury

World 1 Ischemic heart disease 2 Cerebrovascular disease 3 HIV/AIDS 4 COPD 5 Lower respiratory infections 6 Trachea, bronchus, lung cancers 7 Diabetes mellitusb 8 Road traffic accidents 9 Perinatal conditionsa 10 Stomach cancer High-income countries 1 Ischemic heart disease 2 Cerebrovascular disease 3 Trachea, bronchus, lung cancers 4 Diabetes mellitusb 5 COPD 6 Lower respiratory infections 7 Alzheimer and other dementias 8 Colon and rectum cancers 9 Stomach cancer 10 Prostate cancer

Both sexes % total deaths 13.4 10.6 8.9 7.8 3.5 3.1 3.0 2.9 2.2 1.9 15.8 9.0 5.1 4.8 4.1 3.6 3.6 3.3 1.9 1.8

Rank

Disease or injury

Middle-income countries 1 Cerebrovascular disease 2 Ischemic heart disease 3 COPD 4 HIV/AIDS 5 Trachea, bronchus, lung cancers 6 Diabetes mellitusb 7 Stomach cancer 8 Hypertensive heart disease 9 Road traffic accidents 10 Liver cancer Low-income countries 1 Ischemic heart disease 2 HIV/AIDS 3 Cerebrovascular disease 4 COPD 5 Lower respiratory infections 6 Perinatal conditionsa 7 Road traffic accidents 8 Diarrheal diseases 9 Diabetes mellitusb 10 Malaria

% total deaths 14.4 12.7 12.0 6.2 4.3 3.7 3.4 2.7 2.5 2.2 13.4 13.2 8.2 5.5 5.1 3.9 3.7 2.3 2.1 1.8

a Includes ‘causes arising in the perinatal period’ as defined in the International Classification of Diseases, and does not include all causes of deaths occurring in the perinatal period. b Does not include renal failure deaths attributable to diabetic nephropathy or cardiovascular disease deaths attributable to diabetes mellitus as a risk factor. Reproduced from Mathers, C.D., Loncar, D., 2006. Projections of global mortality and burden of disease from 2002 to 2030. Public Libr. Sci. Med. 3 (11), e442.

references and links may be found on the WHO website; see section Relevant Websites later in this article.)

Criticisms and Controversies The burden of disease methodology and the DALY have been controversial in the international and national health policy arenas, in the health economics and epidemiological research communities, and among disability interest groups (FoxRushby, 2002). Criticisms of the GBD approach fall into three main groups: (1) those concerned with the extrapolation of population health estimates in which data are limited, uncertain, or missing; (2) those concerned about a number of issues in how the DALY summarizes fatal and nonfatal health outcomes; and (3) some well known health economists who have argued that burden of disease analysis is irrelevant or potentially misleading for setting health priorities. The GBD analyses have been criticized for making estimates of mortality and burden of disease for regions with limited, incomplete, and uncertain data, and have even been characterized by some critics as having at best only tenuous links to empirical evidence (Cooper et al., 1998). Murray and colleagues have argued that health planning based on uncertain assessments of the available evidence – which attempt to synthesize it while ensuring consistency and adjustment for known biases – will almost always be more informed than planning based on ideology; there will be practically no cases in which we are totally ignorant about an issue to the point

where there is no alternative to ideology (Murray et al., 2003). The GBD analytic approach has been strongly influenced by demographic and economic traditions of making the best possible estimates of quantities of interest for populations from the available data, using a range of techniques depending on the type and quality of evidence. The second group of criticisms has largely focused on the disability weights, social value choices such as age weights, and on concepts of health incorporated in the DALY (Anand and Hanson, 1997; Williams, 1999). The DALYs have received a great deal of criticism from disability advocates and some health analysts, who have seen the inclusion of disability in the DALY as implying that people with disability are less valued than people in full health. Some of this criticism relates to claims that cost-effectiveness analysis imposes an implicit utilitarianism on policy choices, but a more fundamental criticism is that the conceptualization of disability found in the DALY confounds the ideas of ‘health’ and ‘disability,’ whereas in fact people with disabilities may be no less healthy than anyone else. In response to these critics, the conceptual basis for the measurement of health and the valuation of health states in the DALY has been further developed and clarified (Salomon et al., 2003). As used in the DALY, the term disability is essentially a synonym for health states of less than full health. The DALY is actually attempting to quantify loss of health, and the disability weights should thus reflect social preferences for health states, not broader valuations of ‘quality of life,’ ‘well-being,’ or ‘utility.’ Thus disability weights should reflect judgments about the ‘healthfulness’ of defined states, not any

266

Global Burden of Disease

judgments of quality of life or the worth of persons. A high disability weight for a health state then implies that people place a high social value on preventing such health states or on provision of treatment interventions that replace them by states closer to full health. The valuation methods used in the original GBD have also been criticized on the grounds that the groups used to elicit weights were not representative of the general global population, and that the person trade-off method used in the GBD is unethical, in that it involves hypothetical scenarios trading off saving the lives of people in full health versus saving the lives of people with specified health conditions (Arnesen and Nord, 1999). Subsequent GBD work on eliciting health state valuations has moved away from reliance on the person trade-off method, and has also made use of large representative population surveys, although a full revision of the weights used in the GBD has not yet been carried out. Finally, some economists have expressed concern that burden of disease analysis might result in priority setting solely on the basis of the magnitude of disease burden and that burden of disease studies are irrelevant for priority setting (Mooney et al., 1997). Although this view has little credibility among policy makers, who are generally very interested to understand the patterns of causes of loss of health in populations, and the changes in these over time, it is a misrepresentation of the purpose of burden of disease analysis. Both the original GBD study, and the later round of GBD work at WHO, have been accompanied by substantial efforts in costeffectiveness analysis and an explicit recognition that health priority setting requires not only information on the size and causes of health problems, but also on the cost-effectiveness of interventions and on other information relating to equity and social values (Jamison et al., 2006; Tan-Torres Edejer et al., 2003; World Bank, 1993).

Future Priorities and Developments While methodological and data developments over the past decade have improved the empirical base for disease burden assessment, there are still very substantial data gaps and uncertainties, particularly for causes of death and levels of adult mortality in Africa and parts of Asia. Improving the population-level information on causes of death, and on the incidence, prevalence, and health states associated with major disease and injury causes, remains a major priority for national and international health and statistical agencies. The Bill and Melinda Gates Foundation has provided funding for a new GBD 2005 study, to be carried out over 3 years, commencing in 2007. The study will be led by the new Institute for Health Metrics and Evaluation at the University of Washington, headed by Chris Murray, with key collaborating institutions including Harvard University, the World Health Organization, Johns Hopkins University, and the University of Queensland. The GBD 2005 study will include a comprehensive revision of disability weights, and assess trends from 1990 to 2005, and will be completed in 2010. As international programs and policies to improve health worldwide become more widespread, so too will the need for

more comprehensive, credible, and critical assessments to periodically monitor population health and the success, or not, of these policies and programs. Repeated one-off assessments of global burden of disease do not provide comparability over time due to improvements in data and methods. There is a need to move beyond these, toward truly consistent and comparable monitoring of the world population’s health over time.

See also: Burden of Disease and Injury Caused by Alcohol; Cancer: Global Burden, Trends, and Projections; Comparative Risk Assessment; Measurement and Modeling of HealthRelated Quality of Life; Measurement and Valuation of Health for Economic Evaluation; Public Health Approaches to Dying, Death, and Loss; Smoking, The Burden of Mortality of.

References Anand, S., Hanson, K., 1997. Disability-adjusted life years: a critical review. J. Health Econ. 16 (6), 685–702. Arnesen, T., Nord, E., 1999. The value of DALY life: problems with ethics and validity of disability adjusted life years. Br. Med. J. 319 (7222), 1423–1425. Barendregt, J., van Oortmarssen, G.J., Vos, T., Murray, C.J.L., 2003. A generic model for the assessment of disease epidemiology: the computational basis of DisMod II. Popul. Health Metr. 1, 4. Cooper, R.S., Osotimehin, B., Kaufman, J.S., Forrester, T., 1998. Disease burden in sub-Saharan Africa: what should we conclude in the absence of data? Lancet 351 (9097), 208–210. Fox-Rushby, J.A., 2002. Disability Adjusted Life Years (DALYS) for Decision-Making? An Overview of the Literature. Office of Health Economics, London. Jamison, D.T., Breman, J.G., Measham, A.R., et al., 2006. Disease Control Priorities in Developing Countries, second ed. Oxford University Press, Oxford, UK. Lopez, A.D., Mathers, C.D., Ezzati, M., Murray, C.J.L., Jamison, D.T., 2006. Global Burden of Disease and Risk Factors. Oxford University Press, New York. Mathers, C.D., Iburg, K., Salomon, J., et al., 2004. Global patterns of healthy life expectancy in the year 2002. BioMed Cent. Public Health 4 (1), 66. Mathers, C.D., Loncar, D., 2006. Projections of global mortality and burden of disease from 2002 to 2030. Public Libr. Sci. Med. 3 (11), e442. Mathers, C.D., Lopez, A.D., Murray, C.J.L., 2006a. The burden of disease and mortality by condition: data, methods and results for 2001. In: Lopez, A.D., et al. (Eds.), Global Burden of Disease and Risk Factors. Oxford University Press, New York, pp. 45–240. Mathers, C.D., Salomon, J.A., Ezzati, M., Begg, S., Lopez, A.D., 2006b. Sensitivity and uncertainty analyses for burden of disease and risk factor estimates. In: Lopez, A.D., et al. (Eds.), Global Burden of Disease and Risk Factors. Oxford University Press, New York, pp. 399–426. Mooney, G., Irwig, L., Leeder, S., 1997. Priority setting in healthcare unburdening from the burden of disease. Aust. N.Z. J. Public Health 21, 680–681. Murray, C.J.L., Evans, D.A., 2003. Health Systems Performance Assessment: Debates, Methods and Empiricism. World Health Organization, Geneva, Switzerland. Murray, C.J.L., Lopez, A.D., 1996a. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries and Risk Factors in 1990 and Projected to 2020. Harvard University Press, Cambridge, MA. Murray, C.J.L., Lopez, A.D., 1996b. Global Health Statistics. Harvard University Press, Cambridge, MA. Murray, C.J.L., Salomon, J.A., Mathers, C.D., Lopez, A.D., 2002. Summary Measures of Population Health: Concepts, Ethics, Measurement and Applications. WHO, Geneva, Switzerland. Murray, C.J.L., Mathers, C.D., Salomon, J.A., 2003. Towards evidence based public health. In: Murray, C.J.L., Evans, D. (Eds.), Health Systems. Performance Assessment: Debates, Methods and Empiricism. World Health Organization, Geneva, Switzerland, pp. 715–726.

Global Burden of Disease Salomon, J., Mathers, C.D., Chatterji, S., Sadana, R., Ustun, T.B., Murray, C.J.L., 2003. Quantifying individual levels of health: definitions, concepts and measurement issues. In: Murray, C.J.L., Evans, D. (Eds.), Health Systems Performance Assessment: Debates, Methods and Empiricism. World Health Organization, Geneva, Switzerland, pp. 301–318. Salomon, J.A., Murray, C.J.L., 2002. The epidemiologic transition revisited: compositional models for causes of death by age and sex. Popul. Dev. Rev. 28 (2), 205–228. Stouthard, M., Essink-Bot, M., Bonsel, G., Barendregt, J., Kramers, P., 1997. Disability Weights for Diseases in the Netherlands. Department of Public Health, Erasmus University, Rotterdam, the Netherlands. Tan-Torres Edejer, T., Baltussen, R., Adam, T., et al., 2003. WHO Guide to CostEffectiveness Analysis. WHO, Geneva, Switzerland. Williams, A., 1999. Calculating the global burden of disease: time for a strategic reappraisal. Health Econ. 8, 1–8. World Bank, 1993. World Development Report 1993. Investing in Health. Oxford University Press for the World Bank, New York. World Health Organization, 1996. Investing in Health Research and Development. Report of the Ad Hoc Committee on Health Research Relating to Future Intervention Options. WHO, Geneva, Switzerland.

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Further Reading Murray, C.J.L., 2007. Towards good practice for health statistics: lessons from the Millennium Development Goal health indicators. Lancet 369, 862–873.

Relevant Websites https://www.hsph.harvard.edu/ – Burden of Disease Unit, Center for Population and Development Studies at the Harvard School of Public Health. http://www.dcp2.org/pubs/GBD – Disease Control Priorities Project, Global Burden of Disease and Risk Factors (last accessed on 21.04.16.). http://www.globalhealth.harvard.edu – Harvard Initiative for Global Health (last accessed on 21.04.16.). http://www.who.int/evidence/bod – World Health Organization, Burden of Disease Statistics (last accessed on 21.04.16.).

Global Health Law: International Law and Public Health Policy Allyn L Taylor, University of Washington School of Law, Seattle, WA, USA Ó 2017 Elsevier Inc. All rights reserved.

Introduction The growth and elaboration of the field of global health law over the last two decades has been a notable development in global health policy. Traditionally, public health was viewed as a realm of almost exclusive national jurisdiction, and multilateral cooperation in this realm was restricted to discrete areas. Public health law today remains predominantly domestic and national, but the field of global health law is extant and growing. Through the codification of binding global health law standards that regulate interstate behavior and national conduct as well as the creation of other global norms that influence state actions, global health law has expanding significance in national public health law and policy. The domain of global health law now encompasses increasingly diverse concerns, including aspects of biomedical science and human reproduction/cloning; organ transplantation and xenotransplantation; infectious and noncommunicable diseases; the control of the safety of health services; food and pharmaceuticals in international trade; access to medicines; and the control of addictive and harmful substances such as tobacco and narcotics. Global health law is also increasingly linked to other traditional areas of international legal concern. Environmental law and the control of toxic pollutants, arms control and the banning of weapons of mass destruction, human rights law, nuclear safety and radiation protection, international drug control, customs law, and occupational health and safety are increasingly recognized as inextricably connected to public health. Table 1 hereto provides a variety of examples of the wide domain of international law related to public health, including international agreements that have positive as well as negative implications for public health. This article provides an overview of the field of global health law. It examines the historical origins of the field and the factors contributing to its contemporary evolution. In addition, the article briefly reviews the nature and the significance of international law and the contribution of international organizations to the codification of global health law. Finally, the role of two international organizations, the World Health Organization (WHO) and the World Trade Organization (WTO), in the contemporary development of international law is considered in connection with examples of lawmaking with important public health and public health policy implications.

The Evolution of Global Health Law Although public health is one of the earliest fields of international cooperation and one of the first domains in which an intergovernmental organization was created, the scope of international legal cooperation in public health was, until recently, highly limited. Disease has been the unwelcome traveling companion of international commerce throughout history and international

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public health cooperation from the beginning was as concerned with facilitating trade as with protecting public health. The functions of the early international health organizations of the nineteenth and twentieth centuries centered on combating infectious and communicable diseases and preventing their spread across international boundaries (Pannenborg, 1979). For example, the Conseil superieur de santé (Superior Council of Health) of Constantinople, composed of delegates of the Ottoman Empire and the chief maritime states, was established in 1838 to supervise sanitary regulation of the Turkish ports to prevent the spread of cholera. As a further example, the international legal activities of the first permanent international health organization, L’Office International d’Hygiene Publique, were restricted to the administration of international sanitary conventions, including the international exchange of epidemiological information. International communicable disease control remained the predominant area of international legal cooperation throughout the midnineteenth century and most of the twentieth century. With a focus limited to international communicable disease control, public health law remained a relatively neglected field of international legal concern throughout most of the twentieth century. In particular, the WHO, established in 1948 as the specialized agency of the United Nations in the field of health, stood out as unique among such UN agencies in that the Organization traditionally neglected the use of international legislative strategies to promote its global public policies (Taylor, 1992). WHO Member States also paid little attention to the potential contribution of international law in advancing global health during most of the last century. Although public health remained a narrow realm of multilateral cooperation for over 150 years, the long-standing historical connection between international law and communicable disease control pointed to the larger role that international law could serve in future international health diplomacy. Global health law has been defined as a “field that encompasses the legal norms, processes, and institutions needed to create the conditions for people throughout the world to attain the highest possible level of physical and mental health” (Gostin and Taylor, 2008). In the last couple of decades, the field of global health law has expanded significantly. The breadth and depth of contemporary international health law can be traced to a number of recent and interconnected developments, including (1) the impact of globalization on public health diplomacy; (2) the growth of global concern with economic and social rights, including the right to health; and (3) expanding appreciation of the nexus between global health law and other realms of international legal concern.

Globalization and the Expanding Domain of International Health Law It is widely recognized that contemporary globalization is contributing to the expansion of the field of global health

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Examples of international legal instruments and public health

Category of public health concern Disability Communicable disease control Global tobacco control Human rights

Arms control

Environmental health

Date

International agreement

2006 2005 2011 2003 2012 1966 1966 1979 1980 1984

Convention on the Rights of Persons with Disabilities International Health Regulations (revised) Pandemic Influenza Preparedness Framework WHO Framework Convention on Tobacco Control Protocol to Eliminate Illicit Trade in Tobacco Products International Covenant on Economic, Social and Cultural Rights International Covenant on Civil and Political Rights Convention on the Elimination of All Forms of Discrimination Against Women Convention on Certain Conventional Weapons Convention Against Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment Convention on the Rights of the Child Treaty on the Non-Proliferation of Nuclear Weapons Biological Weapons Convention Chemical Weapons Convention UN Convention on the Law of the Sea Comprehensive Test Ban Treaty Vienna Convention for the Protection of the Ozone Layer Montreal Protocol to the 1985 Vienna Convention for the Protection of the Ozone Layer UN Convention on Climate Change Convention to Combat Desertification Convention on the Transboundary Effect of Industrial Accidents Kyoto Protocol to 1992 UN Convention on Climate Change Convention on Prior Informed Consent for Certain Hazardous Chemicals and Pesticides in International Trade Stockholm Convention on Persistent Organic Pollutants Minamata Convention on Mercury WHO Global Code of Practice on the International Recruitment of Health Personnel Single Convention on Narcotic Drugs Convention on Psychotropic Substances UN Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances White Lead (Painting) Convention Protection Against Accidents (Dockers) Convention Radiation Protection Convention Occupational Cancer Convention Occupational Safety and Health Convention Convention Concerning the Promotional Framework for Occupational Safety and Health General Agreement on Tariffs and Trade (GATT 1994) General Agreement on Trade in Services (GATS) Agreement on the Application of Sanitary and Phytosanitary Measures Agreement on Trade-Related Aspects of Intellectual Property Rights Agreement on Technical Barriers to Trade

1989 1968 1972 1993 1982 1996 1985 1987 1992 1994 1992 1997 1998

Health worker migration International narcotic drug control

Occupational health and safety

International trade law

2001 2013 2010 1961 1971 1988 1921 1932 1960 1974 1981 2006 1994 1994 1994 1994 1994

law. Although increasing global integration is not an entirely new phenomenon, contemporary globalization has had an unprecedented impact on global public health and is creating new and increasingly difficult governance needs and health policy-making challenges. Globalization has contributed to the rapid decline in the practical capacity of sovereign states to address public health challenges through unilateral national action alone and expanded the need for health governance structures that transcend traditional and increasingly inadequate national approaches. Treaty law, often referred to as conventional international law, has received new prominence as a mechanism or a tool that can be used by states to facilitate multilateral

cooperation in this era of globalization, as states increasingly recognize the need for international cooperation to attain national public health objectives for which domestic law and other policy responses are increasingly inadequate (Taylor, 2004). For example, rapid worldwide dissemination of recent advances in scientific knowledge and technology has encouraged international cooperation in a wide range of treaties, including those concerning the safety of chemicals, pesticides, and food, and the disposal of hazardous wastes. Globalization has increased the need for new, formalized frameworks for international cooperation, including international law, to address emerging global health threats. For

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example, the dynamics of globalization have created fertile global breeding conditions for the cross-border spread of emerging threats to health, such as weapons of mass destruction, including bioterrorism; emerging and reemerging infectious diseases; and the vectors of noncommunicable diseases including tobacco, alcohol, and obesity. In addition, globalization has expanded global interest in codifying new international commitments to protect the health status of populations in low-income and emerging market states that have not benefited from globalization – the so-called losers of globalization. For example, the need to promote more equitable innovation and universal access in health-care products, including medicines, pharmaceuticals, diagnostics, and medical devices, is generating ongoing debate about the efficacy of codifying a new international instrument on medical research and design. Because of the momentum of globalization, states must increasingly turn to international cooperation in order to protect and promote domestic health. Consequently, we are likely to see wider use of international legal instruments in this century to control the risks and threats to health associated with globalization and, perhaps, to take advantage of the opportunities to improve world health that have been afforded by global change. For example, the WHO International Health Regulations (IHRs), the sole international legal instrument designed to provide a framework for multilateral efforts to combat infectious diseases, were revised in 2005 to address the increasing threat posed by the transnationalization of infectious diseases and to incorporate newly developed mechanisms for international coordination and response. As a further example, in 2010 WHO Member States adopted the first international legal instrument to address the challenges increasingly raised by health worker migration in the WHO Global Code of Practice on the International Recruitment of Health Personnel. In addition, in 2011, the Member States of WHO adopted the Pandemic Influenza Preparedness (PIP) Framework to facilitate the sharing of influenza viruses and increase access to vaccines and antiviral medications in low- and middle-income countries.

Health and Human Rights The evolution of global health law in the last two decades is very much tied to the protection and promotion of human rights related to physical and mental integrity. Although global health law is largely utilized as a mechanism to protect and expand state interests in an era of global interdependence, it is also conceived of and employed as a framework or tool for protecting the rights of individuals and, perhaps, creating a more just and equitable world (Meier, 2011). The preamble to the WHO Constitution, the first international expression of the right to health, declares that “[t]he enjoyment of the right of the highest attainable standard of health is one of the fundamental rights of every human being without distinction or race, religion, political belief, economic or social condition.” The principal international legal basis for the right to health is found in the core instruments of international human rights law promulgated under the auspices of the United Nations: the International Bill of Rights, which consists

of the Universal Declaration of Human Rights (1948), the International Covenant on Economic, Social and Cultural Rights (1966) (ICESCR), and the International Covenant on Civil and Political Rights (1966). Read in conjunction with Article 2, Article 12 of the ICESCR, the most significant binding legal expression of the right to health, provides, among other things, that each state ‘undertakes to take steps,’ to the maximum extent of its available resources and with a view toward progressive achievement, toward “the highest attainable standards of physical and mental health of all individuals, without discrimination.” Beyond this broad formulation, however, Article 12 is replete with ambiguity. The Covenant neither defines ‘health’ nor the particular obligations of states necessary to realize the right to health. No subsequent binding international legal instrument has provided an authoritative interpretation of the Covenant. In 2000 the Committee on Economic, Social and Cultural Rights to the ICESCR adopted General Comment 14, a detailed explanatory commentary on the right to health under Article 12 of the Covenant. Among other things, the broadly formulated General Comment 14 sets forth that the right to health is not simply a right to be healthy, but rather a robust human right extending not only to access to health-care services but also to the underlying determinants of health, including an access to safe water and adequate sanitation, occupational health and environmental conditions, and access to healthrelated education and information. Although highly influential, the legal significance of General Comment 14 remains controversial. The General Comment is not binding international law. In addition, some observers, including the United States, have directly questioned the legal authority of the Committee on Economic, Social and Cultural Rights, a committee established by a decision of ECOSOC and not pursuant to the Covenant, to issue authoritative interpretations of the ICESCR. An important concern with the formulation of the right to health is whether it is an individual or a collective standard reflecting the health-related interests of communities. As a human right, the conventional interpretation of the right to health pertains to individual and not collective claims. However, in public health practice, the right to health is often used to refer to public or community health. There can also be tension between the idea of the collective right to health and the exercise of other human rights, including liberty, physical integrity, and privacy. Despite the long historical linkage, the strong connection between health and human rights has only recently received significant attention. A number of emerging global concerns, including HIV/AIDS and women’s health issues, including rape and other forms of violence against women, brought the intrinsic connection between health and human rights to the forefront of international policy concern beginning in the late 1980s and early 1990s. Of particular importance was a pioneering human rights approach to the global HIV/AIDS pandemic adopted by WHO in the late 1980s. It is widely recognized that this novel emphasis on the linkage between public health and human rights law had a groundbreaking impact in that it compelled governments to be publicly accountable on an international stage for their actions against persons living

Global Health Law: International Law and Public Health Policy with HIV/AIDS. (Ultimately, this innovative global political approach to public health issues publicly highlighted for the very first time the underlying legal responsibility of governments to protect and promote the health of their populations and has served as a forerunner for increasingly widespread links between human rights and other public health issues (Mann and Tarantola, 1998).) The domain of health and human rights has expanded significantly under the auspices of agencies and organs of the United Nations and other international organizations. Specific international legal instruments addressing the rights of particular populations, such as persons with HIV/AIDS, women, children, migrant workers, and refugees, have been adopted. For example, on 13 December 2006 the United Nations General Assembly adopted the Convention on the Rights of Persons with Disabilities. Other contemporary developments are contributing to the further elaboration of international legal instruments in the realm of health and human rights, including, in particular, globalization. For example, widespread recognition of growing inequalities in health status and differential access to medical advances in rich and poor states has expanded interest in the relationship between social and economic rights and health. Of particular concern is the impact of international intellectual property protection under the WTO Trade-Related Aspects of Intellectual Property (TRIPS) Agreement, discussed in the section titled ‘The World Trade Organization, International Law and Global Health,’ in restricting access to essential medicines, particularly HIV/AIDS antiretrovirals, in low-income countries. The unprecedented human catastrophe posed by HIV/AIDS led the international community to adopt a number of nonbinding resolutions at the United Nations General Assembly, the former United Nations Commission on Human Rights and the WHO specifying the relationship between HIV/ AIDS, human rights, and access to medicines. In June 2006, the United Nations General Assembly adopted a Political Declaration on AIDS (UN Res. 60/262) reaffirming that access to medicines in the context of pandemics, including HIV/AIDS, is one of the fundamental elements to achieving full realization for everyone of the international right to health. In May 2013 the UN Special Rapporteur on the right to health issued a report analyzing existing international challenges toward realizing access to medicines within a right to health framework and called upon the international community to shift from the ‘dominant market-oriented paradigm’ to promote access to medicine (A/HRC/23/42). Following the release of the report in June 2013, the UN Human Rights Council adopted a resolution on access to medicines (A/HRC/RES/23/14) broadly recognizing that access to medicines is one of the fundamental elements in achieving progressively the full realization of the right to everyone to the enjoyment of the highest attainable standard of physical and mental health. Globalization is also furthering the elaboration of international instruments in this realm because increasing global integration is compounding the impact of other contemporary global developments associated with health status and human rights. An interesting recent development in this realm is the negotiation and adoption of the 2010 WHO Global Code of Practice on the International Recruitment of Health Personnel discussed in the section ‘The World Health Organization.’

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As a further example, the links between scientific progress, global diffusion of new technologies and human rights is also receiving increased attention in the elaboration of international legal instruments. For instance, the implications of advances in biotechnology for the protection of human rights and human dignity have been a topic of interest by international and regional organizations, including consideration of bans on novel technologies. In 1997 the United Nations Educational, Scientific and Cultural Organization (UNESCO) adopted a nonbinding instrument, the Universal Declaration on the Human Genome and Human Rights, and in 2003 it adopted the International Declaration on Genetic Data. In addition, in the wake of failed treaty negotiations, in 2005 the United Nations General Assembly adopted a declaration urging Member States to prohibit reproductive cloning as incompatible with human rights. At the regional level, the Council of Europe adopted a Convention on the Protection of Human Rights and Human Dignity with regard to the Application of Biology and Medicine: the Convention on Human Rights and Biomedicine in 1997. Four protocols to the Convention – separate agreements – on human cloning, biomedical research, transplantation of organs and tissues, and genetic testing for health purposes have also been adopted by the Council of Europe between 1998 and 2008. Biomedical research is emerging as important topic in global and regional nonbinding and binding international legal instruments. For example, the European Union adopted a directive on clinical practice in the conduct of clinical trials on medicinal products for human use in 2001 and investigational medicinal products in 2005. The biotechnology revolution is putting continuing pressure on the international community to develop international law, including human rights law, to effectively govern this realm, and we are likely to see further developments in the future. Notably, the elaboration of international law on biotechnology is exemplary of how the international community develops regulatory responses. Rather than codifying a comprehensive instrument in this realm, existing international agreements on biotechnology have been adopted in a piecemeal and, at times, incoherent fashion and today consist of different instruments, including guidelines, code of conduct, resolutions, and treaties adopted under the auspices different international organizations.

Linkage and the Scope of Global Health Law The expanding domain of global health law can be understood, in part, as a product of enhanced appreciation of the interconnectedness of contemporary global concerns and, concomitantly, the linkage of health to other legal issues. International legal scholars traditionally compartmentalized and treated substantive subject matters such as human rights, environmental protection, arms control, and public health as discrete self-contained areas with limited connections. Rapid global integration propelled by contemporary globalization has contributed to the recognition of the nexus among different realms of international law. As a consequence of issue linkage, international law and global health is increasingly understood to be a central component of other international legal regimes, including labor law, human rights, arms control, and international trade. The recent

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connection between health and human rights in contemporary international law and practice discussed in the preceding section is an important example of the linkage of two traditionally distinct realms of international law. The evolution of the concept of human security provides another interesting example of this development. The traditional understanding of human security has come under increasing pressure in recent years, with growing support for a comprehensive approach to human security that addresses the wide-ranging factors that impact upon the vulnerability of people. In 2003, the UN Commission on Human Security released a report proposing a new security framework and recognizing the linkage between health and human security (United Nations Commission on Human Security, 2003). WHO’s 2005 IHRs described further herein have been at the center of discussion of the linkage between global health and security. The IHRs are designed to facilitate countries and the WHO working together to identify contain and control health risks. For example, at the time of the drafting of the revised IHRs expanding global concern with weapons of mass destruction and terrorism underscored the strong interconnection between public health and security and legal commitments established under the Regulations are clearly designed to apply to releases of biological, chemical, and radiological events, accidental and deliberate. Recent disease outbreaks, epidemics, natural disasters, and other health emergencies have reinforced the linkage between global health and security. For example, the recent Ebola outbreak discussed further herein has revitalized discussions of global health security, including a range of proposals for reframing the global health governance to strengthen the global health security regime (Kickbush, 2016). The linkage between health, security, and other traditionally defined legal realms is also exemplified in the contemporary global threat of counterfeit medicines. Expanding international community concern with the global challenge of international trafficking in counterfeit medicines, including substandard, defective or adulterated medicines has underscored the interconnections among global health law, international customs law, international criminal law, and international trade law and led to expanding support for the adoption of an international legal instrument in this realm (Attaran, 2012). The nexus between global health law and other traditionally distinct realms of international law is further exemplified by the rapidly evolving field of biotechnology described in the preceding section. Biotechnology closely interlinks many quarters of the law including, global health, human rights, intellectual property, trade regulation, and environmental law. For example, advances in biotechnology have prompted debate and development of the field of international environmental law with the main area of environmental concern being the potential effect of intentional or unintentional releases of genetically modified organisms (GMOs) for health and the environment. International instruments of relevance in this field include the Convention on Biological Diversity and its 2010 Cartagena Biosafety Protocol, the International Plant Protection Convention, and the WHO/FAO Codex Alimentarius. International trade law, particularly the General Agreement on Tariffs and Trade, the Agreement on the Application of Sanitary and Phytosanitary Measures (SPS Agreement), and the Technical Barriers to Trade Agreement (TBT Agreement),

functions to discipline or restrict the authority of member states of the WTO to take food, safety, health, environmental and food security considerations into account in making regulatory decisions on the import and use of GMOs. Among regional instruments, the European Union regulatory framework in this realm is one of the most extensive, covering issues including import, cultivation, monitoring, and labeling of GMOs and GMO-derived material. The main piece of European legislation regarding GMO food is EU Directive 2001/18/EC, which was amended in 2008 by Directive 2008/ 27/EC and again in 2015 by Directive (EU) 2015/412. These directives govern ‘the deliberate release of GMOs in the environment’ and consequently cover both cultivation and imports of GMO crops. In addition, EU regulations set forth detailed rules regarding the authorization, labeling, and placing on the market of GMOs meant for food and feed.

An Introduction to Public International Law The Nature and Sources of International Law Understanding the implications of recent developments in global health law, including those for domestic public health policy, requires some appreciation of the nature of international law and the international political system. Since the end of the Thirty Years War in 1648, the global political system has principally involved the interactions of sovereign states. Consequently, the elaboration of international law has focused on the establishment of consensual rules concerning the status of states and their fundamental rights and obligations as well as commitments. International law, therefore, is primarily focused on the interactions of sovereign states and can broadly be defined as the rules that govern the conduct and relations of states. International law is traditionally understood as consisting of two core realms: public international law and private international law. While public international law is primarily concerned with the relations of states, private international law focuses on the law of private transactions of individuals and corporations. The traditional distinction between public and private international law persists even though it is not fully accurate. For example, much of private international law concerns the transactions of public entities. In addition, while states are the primary subjects of public international law, they are not the only subjects. International organizations and, through the development of international human rights law, individuals, are also considered subjects of public international law. In international law, the sources of legal rules are very different than in most domestic legal systems because the global political system of sovereign states differs fundamentally from domestic political systems. While there are important differences in the sources of law among countries, domestic law generally comes from national constitutions, municipal statutes, parliamentary or executive regulations, and decisions of municipal courts. In contrast to domestic political systems, there is generally no supranational authority within the global system to develop and enforce law against sovereign states. In the absence of a supranational authority, states establish the rules of international law. Article 38(1) of the Statute of the

Global Health Law: International Law and Public Health Policy International Court of Justice is generally regarded as an authoritative list of the sources of international law (Table 2). Although there is a wide and complex array of binding international legal sources, most international law today, including global health law, can be found in treaties. The word treaty is a generic term that encompasses all written instruments concluded between states by which states establish obligations by and among themselves. Treaties function essentially as contracts between states whereby states make binding written rules to govern their own conduct and the conduct of their individual and corporate nationals. When states become parties to treaties, they explicitly agree to limit their sovereign freedom of action in some respect to achieve mutually agreed-upon goals. Generally, treaties are only binding upon states that give their express written consent. Treaties are also subject to a significant corpus of international law: the 1969 Vienna Convention on the Law of Treaties (the Vienna Convention). The Vienna Convention, the socalled law of treaties, provides general rules of treaty implementation and interpretation. The Vienna Convention confirms the generic use of the term treaty by defining a treaty as ”an international agreement concluded between States in written form and governed by international law, whether embodied in a single instrument or in two or more related instruments and whatever its particular designation.” The terms treaty, convention, protocol, and pact are largely used interchangeably in international legal parlance. Article 19 of the Vienna Convention sets forth the basic legal principle concerning the observance of treaties, pacta sunt servanda: “Every treaty in force is binding upon the parties to it and must be performed in good faith.” A second important source of international law is customary international law. Analogous to domestic legal concepts such as usage of the trade and course of dealing, the idea behind customary international law is that widespread international practice undertaken out of a sense of legal duty creates reasonable expectations of future observance and constitutes implicit consent to the creation of legal rules. The determination of whether or not a particular practice constitutes customary international law is a complex analysis that is more like an art than a science. But, generally, the determination requires near-uniform-state practice undertaken because of a sense of legal obligation. With some important exceptions, once a rule is recognized as part of customary international law, it is generally considered binding upon all states. For example, the Vienna Convention is accepted as declaratory of

Table 2

Statute of the International Court of Justice

The Court, whose function it is to decide in accordance with international law such disputes as are submitted to it, shall apply: a. international conventions, whether general or particular, establishing rules expressly recognized by the contesting states; b. international custom, as evidence of a general practice accepted as law; c. the general principles of law recognized by civilized nations; d. subject to the provisions of Article 59, judicial decisions and the teachings of the most highly qualified publicists of the various nations, as subsidiary means for the determination of rules of law.

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customary international law and binding for all states, including those that have not formally ratified it. Like treaty law, customary international law is said to emanate from the consent of states. States party to a treaty explicitly consent to be bound by codified rules, whereas with customary international law states implicitly agree to be bound to particular rules through consistent state practice. In addition to binding international law, states produce a wide variety of nonbinding international legal instruments that can have an important impact on state behavior. Such instruments include resolutions, declarations, codes of conduct, guidelines, or standards. However named, general declaratory resolutions are, for the most part, intended to be nonbinding instruments expressing the common interest of many states in specific areas of international cooperation. Significantly, these nonbinding international legal instruments are not comparable to voluntary instruments adopted at the national level or by industry. To begin with, nothing in such nonbinding intergovernmental resolutions prohibits states from incorporating the terms of the instruments into national law. Although generally nonbinding, such instruments are not without legal or political significance. Like treaties, these nonbinding instruments can be mechanisms for advancing international consensus on rules and for promoting consistent state action. There are prominent examples of nonbinding instruments in public health with important policy impacts developed under the auspices of different international organization. For example, the WTO Doha Declaration on Trade and Public Health, discussed below, is widely considered to have advanced global understanding and, perhaps, action on trade and health matters, particularly in relation to access to essential medicines, even though the legal significance of the declaratory instrument is unclear. Another well-known example of a nonbinding international code with a significant public health impact is the 1981 WHO Code of Marketing Breastmilk Substitutes that was designed to protect and promote breastfeeding through the provision of adequate information on appropriate infant feeding and the regulation of the marketing of breastmilk substitutes, bottles, and teats. Additional Health Assembly resolutions adopted over the years since the adoption of the Breastmilk Code have further defined and strengthened the instrument and, according to UNICEF, as of 2016 over 84 countries have adopted legislation implementing all or part of the Code. Another example of a nonbinding legal regime that has had an impact on state practice is the legal framework established by 2001 United Nations General Assembly Special Session (UNGASS) Declaration of Commitment on HIV/AIDS and the monitoring mechanism mandated under its auspices and under two other subsequent UN General Assembly resolutions. At times, nonbinding intergovernmental resolutions have been highly persuasive, and the conduct of states has tended to follow the principles embodied in these resolutions. The effectiveness of some nonbinding intergovernmental resolutions in promoting international cooperation has led some commentators to refer to them as soft-law, although the term is highly controversial. Such instruments are often carefully negotiated and, at times, drafted with the intention to influence state practice. Nonbinding legal instruments, at times, have

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also paved the way for the evolution of treaty law by generating an ongoing diplomatic forum. Not all resolutions lead to the development of formalized treaty obligations or are a significant factor in state practice. However, intergovernmental resolutions, particularly resolutions of the UN General Assembly that are supported by influential states often, have a political significance that can stimulate national behavior and lead to the eventual development of binding international law.

The Limitations of Global Health Lawmaking in International Health Policy It is important to recognize that international law is an inherently imperfect mechanism for international cooperation. The innate weakness of international law stems in large part from the core principle of state sovereignty. The law that is made and the law that is implemented depend upon the will of states. In the treaty-making process, states are explicitly agreeing to make rules to govern and, thereby, limit their own conduct and that of their nationals through the development and implementation of legislation and other policies, depending upon the terms of the treaty, which are consistent with their international commitments. The concept of sovereignty looms large in the international system, and states are generally loath to sacrifice their freedom of action through the development of binding international obligations. A related weakness stemming from the principle of sovereignty is the general lack of formal enforcement mechanisms in most contemporary economic and social agreements. In contrast to the dispute resolution mechanism established under the WTO, described below in the section on the ‘World Trade Organization,’ in most social and economic treaties and other instruments states do not include machinery to compel parties to comply with their international legal commitments. The fact that many treaties tend to be well respected in practice largely reflects the fact that they are generally seen as mutually beneficial for states’ parties. In addition, there is increasing awareness that the failure of states at times to implement international commitments may reflect more a lack of capacity than political will. Many states, particularly developing countries, face acute problems of limitations of resources and capacity in implementing contemporary treaties. Recent advances in the international legislative process have expanded mechanisms to address these problems of domestic capacity through international technical and financial assistance programs incorporated in the texts of relevant conventions. International law and the international legislative process suffer from other important difficulties. Notably, the international legislative process itself is characterized by numerous challenges and limitations – including challenges to timely national commitment by states through timely treaty ratification and implementation – although considerable advances have been made in the last few decades. An emerging challenge in international health lawmaking is the limited scope of entities that are subjects of international law and thereby entitled to participate in international agreements and hold rights and duties thereunder. As described above in the ‘Nature and Sources of International Law’ section, states have traditionally been the sole subjects of international

law. The scope of international law was only expanded in the twentieth century to include individuals and international organizations. However, the nature of global health and the major actors in health policy are changing in such a way that challenges this restricted approach to international legal cooperation. To begin with, in an era of globalization, the exclusive focus on territorial statehood is irrelevant to global health policy. Nonstates ranging from Taiwan to Palestine are excluded from a range of international agreements because of lack of statehood. In addition, the major actors in global health policy today, including foundations, most notably the Bill and Melinda Gates Foundation, and a wide range of significant public–private partnerships, such as the Global Alliance for Vaccines and Immunizations and the Global Fund for AIDS, Tuberculosis and Malaria, or civil society organizations, such as Medicines sans Frontiers, are also excluded from the international lawmaking process. A major challenge for this century is to establish mechanisms to promote more effective cooperation between states and the other major health actors under international law. Recognition of the limitations of treaty making is contributing to growing interest in nonbinding legal mechanisms for global governance in health and other realms of international concern. Despite the conspicuous limitations of the formal international lawmaking process and the inherent challenges of using treaties to promote collective action, treaties can be useful for raising global awareness and stimulating international commitment and national action. As an increasing number of health threats are global in scope or have the potential to become so, international legal agreements, including treaties, are likely to become of increasing importance and an essential component of global health governance. Consequently, international legal agreements, both binding and nonbinding, are likely to become an increasingly important factor underpinning and guiding national policy and action on health.

The International Lawmaking Process and the Role of International Organizations The process of international lawmaking, such as the identification of international legal rules, is very different than it is in most domestic legal systems. The unique character of the international lawmaking process, such as the international legal rules themselves, can be understood as a consequence of the core principle of state sovereignty. In the international political system, there generally exists no supranational authority to make binding international rules. International health law is largely treaty-based, and most international treaty making today is typically conducted under the auspices of international organizations. The vast majority of international legislative projects tend to be undertaken at public international organizations because such institutions function as formal mechanisms for multilateral negotiation and cooperation for their member states. International organizations can anchor and facilitate treaty-making efforts because their organizational structures and administrative arrangements enable them to serve as stable and ongoing negotiating forums.

Global Health Law: International Law and Public Health Policy In recent years, there has been considerable development in the field of international organization with a significant increase in the number of international organizations active in the domain of health. Within the United Nations system, for example, organizations with significant involvement in the health sector include WHO, UNICEF, FAO, UNEP, UNDP, UNFPA, and The World Bank. Overall, an increasing number of international organizations have served as platforms for the codification of international health law, while others have had a significant influence on the development of international law in this field. It is important to recognize that not all international organizations have lawmaking authority or the legal mandate to serve as a platform for international health negotiations. The World Bank, for example, is an organization that is highly influential in the field of health but has no actual legal authority to serve as a framework for treaty negotiations. In the international legal system, lawmaking authority is always expressed and never implied. The existence and scope of lawmaking authority can generally be identified by carefully examining an organization’s constituent instrument, typically its constitution. Today there is considerable jurisdictional overlap in the field of international health lawmaking. Unlike most domestic systems where lawmaking efforts are largely coordinated into an integrated legal system, in the international legal system lawmaking efforts among different international organizations are notoriously uncoordinated. In the absence of an umbrella organization to manage lawmaking efforts, the proliferation of international organizations with overlapping legal authority and ambitions is creating the risk of institutional overload and inconsistent standard setting (Taylor, 2004). For example, during the early stages of the WHO Framework Convention on Tobacco Control (FCTC) negotiation process, other international organizations initiated novel efforts to negotiate binding instruments on global tobacco control. In 1998, for example, the Pan American Health Organization, a regional office of WHO with separate constitutional status, initiated efforts to develop a regional treaty on tobacco control under the auspices of the Organization of American States. As a further example, in 2000 the Secretary General of the World Customs Organization (WCO), an international organization outside of the United Nations framework, advanced efforts to develop a WCO treaty on global tobacco control. While both of these overlapping treatymaking efforts ultimately failed, problems of jurisdictional overlap and inconsistent standard setting are occurring in other realms. Forum shopping is also a widely used policy tool in international standard setting generally and of increasing importance in the domain of global health. A host of factors that may influence the outcome of negotiations may shape the choice of negotiating forum, including differences in composition, jurisdiction, decision-making procedures, working methods, and other characteristics of international organizations. Rising institutional density is contributing to expanded use of forum shopping in global health and other realms of international legal concern. In some cases forum shopping is aimed at gaining a single favorable agreement. In other contexts, however, forum shopping is part of an iterative long-term strategy aimed at

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“broadening the policy spaces within which relevant decisions are made.” International relation scholars have sought to distinguish this broader strategy of forum shopping by defining it as ‘regime shifting’ (Helfer, 2004). An important example of potential ‘regime shifting’ in global health revolves around intellectual property and access to medicines, a topic of fierce political and legal battles in the international community. The WTO TRIPS, discussed in the section entitled ‘The World Trade Organization,’ ushered in a new era of powerful international intellectual property law that has had a critical impact on access to medicines, particularly in low-income countries. TRIPS is also at the core of a wave of international legal instruments and processes seeking to redefine the law of international intellectual property. Dissatisfaction with TRIPS and shifting power bases at the WTO has led those who support stronger and weaker intellectual property protections in search of alternative and more favorable venues to promulgate treaties and other legal instruments. For example, some countries, along with nongovernmental organizations, have undertaken efforts since 2005 to initiate the development of a proposed treaty on medical research and development under the auspices of the WHO. While public health efforts to shift debate and codification to WHO have thus far stalled, other global health actors have undertaken steps to establish more robust intellectual property than provided by TRIPS in a number of forums. Most well-known are the so-called ‘TRIPS-plus’ bilateral and multilateral agreements that establish intellectual property rights and obligations that are more stringent than required under TRIPS. A significant recent example of a TRIPS-plus agreement is the Trans-Pacific Partnership Agreement among 12 Pacific Rim countries that was adopted in October 2015 and, at the time of this writing, has not yet entered into force. Less well-known than TRIPS-plus agreements are a range of global standard-setting initiatives that act below the level of formal international law through global networks of international regulators. Although not formally international law, such standard-setting initiatives, can at times have a powerful impact in harmonizing state practice. In the field of intellectual property, the most important are best practice standards for custom authorities established by the WCO. The WCO also cooperates with Interpol and the Universal Postal Union to strengthen the enforcement of intellectual property law.

The Process of International Lawmaking International law allows considerable flexibility in the process by which multilateral agreements are developed. The primary source of international law governing the creation of treaties, the Vienna Convention, provides a limited number of ground rules for the conclusion of treaties, concerning the capacity of states to enter into agreements, adoption, and authentication of a treaty by a valid representative, and expressions of consent to be bound by a treaty. Beyond these few basic requirements, the Vienna Convention does not mandate any particular methods of negotiation or ratification. In the absence of binding international rules, international organizations have adopted a wide variety of strategies to initiate, negotiate, and conclude international agreements.

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Despite the differences in legal processes, the treaty-making process generally consists of four stages: initiation, negotiation, adoption, and entry into force (Szasz, 1997). Negotiations are the most difficult and generally the longest substage of the treaty process. In practice, all recent public health negotiations have been open to participation by all states or all states’ members of the international organization sponsoring the negotiations.

Examples of International Organizations and International Lawmaking The World Health Organization The WHO, the largest international health agency and one of the largest specialized agencies of the United Nations system, has wide-ranging responsibilities to address global public health concerns based upon responsibilities assigned by its constitution and by its affiliation with the United Nations. The structure of the relationship between WHO and the United Nations, a separate international organization, is grounded in the United Nations Charter and, in particular, those sections that describe the objectives of the United Nations. Article 55 of the Charter describes the goals that the United Nations has pledged to promote among its members, including solutions to international economic, social, health, and related problems. As the United Nations specialized agency with the constitutional directive to act as ‘directing and coordinating authority’ on international health work, WHO has the cardinal responsibility to fulfill the aims of the Charter with respect to health. WHO’s broad authority to serve as a platform for international health lawmaking is expressly established by the terms of its Constitution. Article 19 of the WHO Constitution specifies that the World Health Assembly, WHO’s legislative body composed of all of its Member States, “shall have the authority to adopt conventions or agreements with respect to any matter within the competence of the Organization.” Article 1 of the Constitution defines the objective of WHO as “shall be the attainment by all peoples of the highest possible level of health.” The broad scope of WHO’s mandate under Article 1 vests the Organization with the legal authority to serve as a platform for conventions and agreements that potentially address all aspects of national and global public health, as long as advancing human health is the primary objective of such instruments. Although vested with broad legal authority to protect global health and serve as a platform for global health lawmaking, the WHO has undergone severe financial and political challenges and has been in the process of instituting a reform agenda since 2011. The splintering of WHO’s political and financial capacity is contributing to the process of forum shopping in global health governance. Elsewhere I have argued that expanded use of WHO’s extensive normative authority could help solidify an integral position for the Organization in the increasingly crowded and complex global health institutional landscape of global health (Taylor, 2004).

Framework Convention on Tobacco Control

Despite WHO’s wide authority in the field of international health lawmaking, it has only recently used its constitutional

authority to develop conventions by serving as a platform for the negotiation of the 2003 WHO FCTC. Initiated in the early 1990s by Taylor and Roemer, the WHO FCTC was envisioned as a mechanism to promote national public health interventions and multilateral cooperation on aspects of tobacco control that transcend national boundaries. Formally negotiated between 1999 and 2003 in six negotiation rounds open to all WHO Member States, the text of the treaty was adopted by the World Health Assembly in May 2003 and entered into force in February 2005. The final text of the Convention cuts across a wide range of tobacco control topics, including advertising, production, smuggling and counterfeit cigarettes, warning labels, clean indoor air policies, and health education (Roemer et al., 2005). In 2012 the State Parties to the FCTC adopted the first protocol to the treaty – the Protocol to Eliminate Illicit Trade in Tobacco Products. As of October 2015, 180 countries have ratified the FCTC making it one of the most widely subscribed to treaties in the history of the United Nations. One of the important lessons from WHO’s first treaty negotiation is the significance of the international lawmaking process itself in promoting national action and international cooperation during negotiations before the treaty is adopted and after it has formally entered into force. I have described this phenomenon elsewhere as the ‘power of the process.’ It is widely recognized that WHO’s efforts to achieve global public support for an international regulatory framework for tobacco control, stimulated national policy change in a number of countries and thus made an important, albeit limited, contribution to curtailing the epidemic well before global consensus on binding tobacco control norms was secured. The FCTC negotiations were also the raison d’être for the establishment of the first global alliance of tobacco control activists, the Framework Convention Alliance – a coalition of over 300 nongovernmental organizations worldwide – and thus further influenced the strengthening and deepening of tobacco control legislation in many states around the world. Despite the significance of the treaty in mobilizing national and international action, the record of implementation has been mixed. The treaty has some key weaknesses that limit its effectiveness. As a consequence of the lack of consensus during the formal negotiation process, broadly drafted with significant wiggle room for interpretation. In addition, the instrument does not include a robust monitoring mechanism to supervise and encourage national action. Finally, the tobacco industry and state interests that support it have pushed back against strong tobacco control measures in national and international fora, including disputes brought to the WTO and pursuant to investment treaties against Australia and Uruguay for their use of plain packaging of tobacco products. At the time of this writing, these disputes have not been settled. As discussed further below, the conflict between international trade and public health is increasingly an important theme in the realm of global health law.

International Health Regulations

In another recent lawmaking initiative, on 23 May 2005 the World Health Assembly adopted the new IHRs. As described above in the ‘Evolution of International Public Health Law’ section, virulent infectious diseases have a long history in civilization, and international disease control was one of the

Global Health Law: International Law and Public Health Policy earliest areas of international cooperation. WHO, upon its founding, inherited the responsibility for the management of the international legal regime for the control of the international spread of diseases. The IHRs, first adopted by the Health Assembly in 1951 and last modified in 1981, were designed to provide an effective framework for addressing the international spread of disease while ensuring minimum interference with world traffic. However, the IHRs were ineffective in ensuring national action and global cooperation to stop the spread of disease. The IHRs only applied to a highly narrow subset of infectious diseases and were routinely ignored by states. The magnitude of the global impact of catastrophic appearances of new infectious diseases and the virulent reemergence of old contagions during the 1980s and 1990s underscored the irrelevancy of the old IHRs in global health initiatives and initiated global interest in securing more effective international cooperation to control infectious diseases. Although the IHR revision process had been underway since 1995, the negotiations were galvanized by the well-publicized global threats of severe acute respiratory syndrome (SARS) in late 2002 and 2003 and outbreaks of both human (H3N2) and avian (H5N1) influenza less than a year later. The SARS epidemic spread rapidly from its origins in Southern China until it had reached more than 25 countries within a matter of months. The magnified public attention to these recent epidemics jolted global awareness of the global vulnerability spurred by the rapid spread of disease in this era of globalization as well as the necessity of international cooperation in halting the spread of deadly agents. As such, the SARS epidemic provided a mobilizing vision for coordinated health action. Consequently, the IHR revision process provides an important lesson in the significant role played by a galvanizing event, and associated global public and media attention, in bringing states to the table in contemporary international law negotiations. The new IHRs are also an important example of the linkage of traditionally distinct subject matters for the protection of global public health. The new Regulations bring together under one treaty intertwined concerns of public health, security, international trade, and human rights. The complex regulations include 66 articles divided into 10 parts as well as 9 annexes. The new IHRs expand the scope of disease coverage, incorporate human rights principles, and institute demanding obligations for state surveillance and response. The IHRs were adopted pursuant to Article 21 of WHO’s Constitution, a fairly unique lawmaking device in the international system. Article 22 of the WHO Constitution provides that regulations adopted under Article 21 are adopted pursuant to a contracting-out procedure designed to simplify and expedite the lawmaking process. Regulations come into force automatically for all WHO Member States, except for those states that notify WHO’s Director-General, the Organization’s executive head, of any rejection or reservations. The drafters of the WHO Constitution severely circumscribed the scope of this simplified lawmaking process, however, by limiting the scope of the regulatory authority under Article 21 to traditional public health concerns (Table 3). In the case of the new IHRs, WHO Member States who do not opt out of the IHR pursuant to WHO’s Constitution are legally required to update policy and law to comport with the provisions of the new instrument. The IHR core capacities required of countries are

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Table 3 Article 21 of the Constitution of the World Health Organization The Health Assembly shall have the authority to adopt regulations concerning: a. sanitary and quarantine requirements and other procedures designed to prevent the international spread of disease; b. nomenclatures with respect to diseases, causes of death, and public health practices; c. standards with respect to diagnostic procedures for international use; d. standards with respect to the safety, purity, and potency of biological, pharmaceutical, and similar products moving in international commerce; e. advertising and labeling of biological, pharmaceutical, and similar products moving in international commerce.

to detect, assess, report, and to respond to public health risks and emergencies of national and international concern. However, progress toward implementing the core capacity provisions of the instrument has been slow at the country level, and the Health Assembly has extended the deadlines for implementation. Significantly, the IHRs do not include any financial mechanism to assist states that lack capacity to implement the broad public health system and reporting obligations of the instrument. The emergency provisions of the new IHRs have been invoked four times since the entry into force of the agreement, each time raising criticisms both of the instrument and WHO. Recently, the Organization, Member States, and the Regulations themselves faced considerable criticism in the context of the outbreak of Ebola in 2013 in West Africa and, ultimately, the United Nations led the global response to this epidemic. The Ebola outbreak, such as the HIN1 2009 outbreak, evidence that the global community is not prepared to respond to global health emergencies. In the wake of the flawed response to Ebola, commentators have called for major reforms to prevent future disasters and repair the global system for outbreak prevention and response (Moon, 2015). WHO solicited an independent assessment of its efforts during the Ebola crisis and agreed to major reforms at the 2015 World Health Assembly, including an overhaul of the IHR. Most recently, in February 2016 the WHO Director-General declared a public health emergency of international concern in the context of the outbreak of the Zika virus in order to institute a coordinated international response.

Global Code of Practice on the International Recruitment of Health Personnel

The loss of highly skilled personnel, colloquially referred to as ‘brain drain,’ has been a central concern of low-income countries for the last half century. In the context of health personnel, the global workforce shortage and the inequitable distribution of workers among and within nations has expanded in the last few decades and has now reached crisis proportions. The WHO Global Code, adopted by consensus by the World Health Assembly in 2010, marks the first time that the world community has considered and sought to respect critical and, at times, conflicting issues in this realm, including human rights issues. Such policy concerns incorporated in the Code include honoring the right to health of all persons, the right of

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low-income countries to strengthen their health systems and the right of health workers to migrate to countries that wish to admit and employ them (Taylor and Dhillon, 2011). The WHO Global Code of Practice on the International Recruitment of Health Personnel also reflects the increasing significance of nonbinding instruments in contemporary global health governance. It is only the second instrument of its kind adopted by the World Health Assembly since the 1981 WHO Code of Marketing Breastmilk Substitutes described in the section entitled ‘The Nature and Sources of International Law.’ In 2015 WHO held its first formal review of the nature and significance of the Global Code, finding that while the Code was highly relevant for global health, it was not yet widely significant in global practice due, in part, to a lack of national and international resources devoted to its implementation.

PIP Framework

An interesting example of a recent nonbinding international legal instrument in communicable disease control is the PIP Framework adopted as a resolution by the World Health Assembly in 2011. The PIP Framework was designed to address the controversy that erupted in 2007 when Indonesia reused to share samples of influenza A (H5N1) with WHO collaborating centers. Indonesian officials claimed sovereignty over a virus that was identified within its jurisdiction in part because of concerns that the country’s population would not receive a fair share of the benefits of any vaccine developed. Notably, the IHRs do not address the thorny issue of access to vaccines and other medications in the context of influenza pandemics. The PIP Framework attempts to resolve the controversy. Article 2 of the Framework sets forth the objective to improve pandemic preparedness and response systems with a benefit sharing system for influenza viruses that have human pandemic potential, and access to vaccines and other benefits including antiviral medications. Viewed as an international legal instrument, the PIP Framework has several interesting features. In particular, although adopted as a resolution of the World Health Assembly, the framework is a hybrid instrument that includes contractual instruments, designated as Standard Material Transfer Agreements, and other mechanisms designed to legally bind members of WHO’s Global Influenza Sharing Network and pharmaceutical companies involved in the production of vaccines.

The World Trade Organization This article would be remiss if it did not discuss the significant role of the WTO in international health law and policy. The connection between international trade and health is an important example of the contemporary linkage of two traditionally distinct realms of international legal concern discussed above. The growth of international trade means that the link between WTO treaties is becoming increasingly manifest in a wide range of areas, including access to medicines, health services, food security, nutrition, infectious disease control, and biotechnology. The WTO, formed at the conclusion of the Uruguay round of the General Agreement on Tariffs and Trade (1994), is the primary international institution governing international trade with over 90% of world trade conducted according to its rules.

The Uruguay round brought about a complete overhaul of the international trading system by the conclusion of a number of new international agreements addressing trade issues and by the establishment of the new WTO. Certain organizational features of the WTO make it uniquely powerful in contemporary international relations and international law. First, as a condition of membership in the new Organization, member states were required to agree and bind themselves to 24 different agreements, contained in Annexes 1–3 of the Marrakesh Agreement. Second, the WTO established a powerful dispute resolution procedure with a structured process, a prompt timetable, and the capacity to enforce rulings that is very rare in the international legal system. Pursuant to the WTO Dispute Settlement Understanding, a WTO Dispute Settlement Body is authorized to formally adjudicate trade disputes between members and can authorize the winning party to apply trade sanctions if the losing party does not modify the violating law or policy. This mandatory and enforceable dispute resolution process stands in sharp contrast to the limited implementation mechanisms established by most treaties. Notably, the WTO does not have a direct legal mandate in international health. Article III of the Marrakesh Agreement that established the WTO specifies that the Organization shall “provide a forum for negotiations among its Members concerning their multilateral trade relations ..” The WTO’s impact on health law and policy is collateral to its role in establishing a legal framework for international trade relations. Since the principal aim of the WTO is the reduction of barriers to trade and not the protection of public health, the pervasive and growing influence of WTO agreements on national and international health policy has been a subject of increasing concern. A number of the WTO trade liberalization agreements have a significant impact on health policy. For example, the WTO’s General Agreement on Trade in Services (GATS) has resulted in the liberalization of international trade in health services and has exacerbated concerns about equity and quality in the health sector in developing countries. The GATS may be applied to the international trade in health services, including health insurance and health-care provision. As a further example, the Agreement on Agriculture has had an important impact on food security through its downward pressure on nontariff barriers to trade, opening up developing country markets to food imports from industrialized states. Similarly, the General Agreement on Tariffs and Trade (1994) has expanded international trade in harmful commodities, such as tobacco, by mandating that states lower tariff and nontariff barriers to trade. The TRIPS Agreement, SPS Agreement, and TBT Agreement are discussed further below.

Trade-Related Aspects of Intellectual Property Agreement

The impact of the WTO’s TRIPS in impeding drug development capacity and access to medicines in developing countries has received the most public attention during the last decade. As discussed above in the ‘Health and Human Rights’ section, the concern about TRIPS has arisen particularly in the context of global access to HIV/AIDS antiretrovirals in poor nations. It is estimated that the vast majority of the world’s population of 36 million people living with HIV live in low- and middleincome countries, particularly in sub-Saharan Africa. Despite

Global Health Law: International Law and Public Health Policy important accomplishments over the last decade, according to UNAIDS as of 2013, only one in three persons with HIV/AIDS in sub-Saharan Africa who was eligible for treatment under WHO guidelines had access to prevention, care, or treatment with life-saving antiretrovirals. The 1994 TRIPS Agreement brought intellectual property rights under one common set of international rules for the first time and established minimum levels of protection that all members of the WTO must accord to the intellectual property of fellow members. According to the WTO, TRIPS attempts to balance long-term social objectives of providing incentives for future inventions with short-term access to such inventions. TRIPS is the most comprehensive agreement ever reached on intellectual property. Notably, TRIPS is one of the mandatory agreements that all WTO members, including developing countries, were required to ratify. Developing countries were given transition periods to bring their national intellectual property legislation in compliance with TRIPS. By 2005, all member states of the WTO, except for the poorest, were required to be TRIPS compliant. The most significant aspect of TRIPS, for public health purposes, is that it strengthened international protection of pharmaceutical patents. Prior to TRIPS, most developing countries did not recognize patents on pharmaceuticals in order to promote widespread and cost-effective access to medicines through generic competition and to strengthen the development of the local pharmaceutical industry. TRIPS requires patent protection of pharmaceuticals for 20 years. The patent monopolies established by TRIPS are a significant concern to many countries because such monopolies tend to increase the price of medicines and restrict generic competition. The TRIPS Agreement contains a wide range of safeguards that can be used to protect public health at the national level, including the possibility of overriding patents through compulsory licensing or parallel imports. These and other TRIPS flexibilities as well as the legal authority of developing countries to use them to protect public health were battled out in the WTO. A large part of the concern was settled in November 2001 in the Declaration on the TRIPS Agreement and Public Health, the socalled Doha Declaration, discussed above, in which WTO members reaffirmed the right of states to use TRIPS flexibilities to protect public health and, in particular, promote universal access to essential medications. Although it is beyond the scope of this article to provide a detailed analysis of TRIPS, it should be noted that the Doha Declaration did not solve all of the problems associated with intellectual property protection and public health. As described in the section ‘The International Lawmaking Process and the Role of International Organizations,’ dissatisfaction with TRIPS has encouraged both those who favor stronger and those who favor weaker intellectual property protection to search for alternative venues to forge agreement. Most significantly, are the ‘TRIPS-plus’ bilateral and multilateral agreements that establish intellectual property rights and obligations that are more stringent than required under TRIPS, including the recently adopted 2015 Trans-Pacific Partnership Agreement that has not entered into force at the time of this writing. The conflict between the imperatives of ensuring access to essential medications, particularly in the poorest countries and providing incentives to industry to develop

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new products through the TRIPS framework continues to dominate international public health law discourse. Despite the Doha Declaration and a subsequent, related WTO decision for countries that lack domestic generic capacity, few countries have instituted TRIPS flexibilities to expand access to essential medicines and many have come under pressure from industrialized countries to provide broader intellectual property protection than that required by TRIPS, particularly through the use of bilateral agreements. In addition, the transition period for most developing countries to become TRIPScompliant has recently come to an end in 2005, meaning that all new medicines are patentable in export-capable countries. The deadline for TRIPS-compliance has been extended several times for the poorest members, and in November 2015 the TRIPS Council agreed to an extension until 2033 for the least developed country members of the WTO allowing such members to maintain flexibility in their approach to pharmaceutical patents. The battle over universal access to antiretroviral therapy is symptomatic of the overall challenge of securing access to essential medicines for developing nations. One-third of the world’s population lacks access to basic medicines. The introduction of patent protection for drugs has made efforts to promote universal access more difficult by raising prices and reducing access. Moreover, it is estimated that, between 2000 and 2011, only 4% of new drugs or vaccines developed were designed for neglected diseases. An increasingly significant related legal challenge is the issue of patent protection for repurposed medicines. Whether called repurposing, reusing, reprofiling, or rescuing, the process of reusing previously patented medicines is expanding as an avenue for providing cost-effective and timely access to drugs in low- and middleincome countries. Granting another patent on a known product for a newly discovered use or form adds an additional layer of exclusive rights on the same chemical entity, although only for the new use. Opponents of patentability, such as MSF, have argued that granting such a new patent is a classic example of ‘ever-greening’ that considerably extends the period of patent protection for a known substance. Notably, TRIPS is silent on the issue of providing patents on new uses for old medicines. Debate on the issue of patentability of repurposed drugs is being taken up in other national and international venues, and there is no commonly accepted international legal practice. However, the Trans-Pacific Partnership Agreement, which was adopted in 2015 by 12 states and has been designed as a platform agreement for other states to join, explicitly requires patentability for new uses, new forms, and new methods of use subject to some exceptions. Finding the right balance between health, trade, and intellectual property policies to sustain innovation and ensure widespread access to life-saving technologies is one of the primary public policy challenges of our time. The failure of the international community to secure an effective mechanism under TRIPS to ensure the production and export of essential medicines to meet the health needs of developing states as well as growing recognition of the link between access to medicines and human rights has led to proposals for a radical shift in the way in which pharmaceutical research and development is undertaken, including proposals for a new research and development treaty described above.

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Global Health Law: International Law and Public Health Policy

The WTO SPS and TBT Agreements

The need to find an appropriate balance between free trade rules and the rights of states to implement measures to protect public health is a continuing challenge of the WTO regime. WTO law includes an array of constraints on domestic measures that go beyond its basic principle of nondiscrimination. In particular, the WTO codified the SPS Agreement and the TBT Agreement to address the emerging debate over the use of standards, including public health standards, in international trade. These agreements are designed to balance the competing demands for domestic regulatory autonomy and the global harmonization of product standards as well as prevent imposition of protectionist policies. Some critics contend that the harmonization provisions of these global agreements interfere with the sovereign authority of states to implement domestic public health standards and stop nations from taking preventive measures against health risks in the absence of scientific certainty. Others favor the harmonization provisions arguing that higher and more costly safety standards in high-income states can be protectionist measures that act as barrier to access to the markets of high-income states. This issue has been hotly contested, particularly in the realms of environmental health and of product standards for food safety. The SPS Agreement defines SPS measures basically as all measures instituted by states to (1) protect animal or plant life or health in its territory from the spread of pests or disease; (2) protect human or animal life or health in its territory from the risk arising from the presence of an additive, contaminant, or disease-causing organism in a food, beverage, or foodstuff; (3) protect human life or health in its territory from the risk arising from a disease-causing organisms carried by an animal or plant; and (4) prevent or limit other damage in its territory from the spread of a pest. The SPS Agreement prohibits states from imposing measures that “arbitrarily or unjustifiably discriminate between Member where identical conditions prevail” and authorizes WTO members to impose SPS measures to protect public health that may impact international if such measures are based upon internationally established guidelines and risk assessment procedures and scientific justification. When existing scientific evidence is insufficient to determine risk, states are authorized under the agreement to adopt SPS measures on the basis of available information as an interim measure, but must objectively ground their assessment of risk within a reasonable period of time. The WTO divided the issue of technical standards or barriers between the SPS and the TBT agreement, and the scope of these two treaties are mutually exclusive with the TBT Agreement applicable to all regulations not covered by the SPS Agreement. Like the SPS Agreement, the TBT Agreement is designed to balance the policy goals of national autonomy in technical regulations and free trade by obligating states to ensure their technical regulations, including product standards, do not unreasonably restrict international trade. Public health and environmental health national standards have been the subject of dispute in a number of recent TBT cases, including cases involving a ban on clove cigarettes, regulations on labeling tuna as dolphin-safe and a country-of-origin labeling scheme for meat. Most recently, Cuba and others challenged Australia’s tobacco plain packaging standards under the WTO dispute resolution mechanism primarily based on allegation that the plain packaging regulation violates TBT obligations.

Conclusion This article has provided a broad overview of the rapidly expanding field of global health law. This is an era of significant change in health policy. Over the last decade and a half, public health has emerged as an issue central to virtually all areas of multilateralism, ranging from arms control to security to human rights to trade. At the same time, the global dimensions of public health are transforming traditional approaches to public health. Globalization has limited the capacity of governments to protect health within their sovereign borders through unilateral action alone and national and international health are increasingly recognized as intertwined and inseparable. In addition, the idea that governments have human rights responsibilities to protect and promote public health and can and should be held accountable domestically and internationally for their actions is gaining widespread acceptance. In this new era of global health governance, international law has an important role to play in promoting and coordinating international cooperation and national action. Through the establishment of international health commitments, states legally bind themselves to establish, implement and, at times, coordinate national health laws and national health policy. The effective design and management of international health law will be one of the major challenges for global health governance in this century. Recent developments in international health law and diplomacy have led to increasing calls for international lawmaking in an expanding number of areas related to public health. It is important to recognize that international law is not an appropriate policy instrument for all global health problems. Given the substantial limitations of international law and the international legislative process, careful consideration should be given to the selection of global health concerns and the construction of legal regimes in future international health lawmaking enterprises. Policymakers must give high priority to identifying if and how legal strategies can contribute to the agenda in international health cooperation, including, most importantly, the major challenges that plague many developing nations. At the same time, increased attention should be paid to the impact, both positive and negative, of existing international law on population health. It is hoped that increased attention to the impact of international law, most notably international trade law, will open up critical avenues for advancing human health.

See also: Foundations in Public Health Law; Health and Human Rights: Overview; Legal Issues in Public Health.

References Attaran, A., Barry, D., Basheer, S., Bate, R., Benton, D., 2012. How to achieve international action on falsified and substandard medicines. Br. Med. J. 345, 7381l. Gostin, L., Taylor, A., 2008. Global health law: a definition and grand challenges. Public Health Ethics 1 (1), 53–63. Helfer, L.R., 2004. Regime shifting: the TRIPS Agreement and the new dynamic of international intellectual property lawmaking. Yale J. Int. Law 29 (1), 1–82.

Global Health Law: International Law and Public Health Policy Kickbush, I., 2016. Governing the global health security domain. Glob. Health Programme Work. Pap. No 12, 3–23. Mann, J.M., Tarantola, D., 1998. Responding to HIV/AIDS: A historical perspective. Health Hum. Rights 2, 5–8. Moon, S., et al., 2015. Will Ebola change the game for the next pandemic: ten essential reforms before the next pandemic. The report of the HarvardLSHTM Panel on the Global Response to Ebola. Lancet 386 (1), 2204–2221. Meier, B.M., 2011. Global health takes a normative turn: the expanding purview of international health law and global health policy to meet public health challenges of the 21st century. Glob. Community Yearb. Int. Law Jurisprudence 1, 69–108. Pannenborg, C.O., 1979. A New International Health Order: An Inquiry into International Relations of World Health and Medical Care. Sijthoff and Noordhoff, Germantown, MD. Roemer, R., Taylor, A., LaRivere, J., 2005. The origins of the framework convention on tobacco control. Am. J. Public Health 95, 936–938. Szasz, P., 1997. General law-making processes. In: Schachter, O., Joyner, C. (Eds.), The United Nations and International Law. American Society of International Law, Washington, DC, pp. 27–55. Taylor, A., 1992. Making the World Health Organization work: a legal framework for universal access to the conditions for health. Am. J. Law Med. 18, 301–346. Taylor, A.L., 2004. Governing the globalization of public health. J. Law Med. Ethics 32, 500–508.

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Taylor, A., Dhillon, I., 2011. The WHO global code of practice on the international recruitment of health personnel: the evolution of global health diplomacy. Glob. Health Gov. 1, 1–24. United Nations Commission on Human Security, 2003. Human Security Now. United Nations, New York.

Further Reading Brownlie, I.B., 1998. Principles of Public International Law, fifth ed. Clarendon Press, Oxford, UK. Human Rights and Public Health, May 2015. Toward a balanced relationship. Int. J. Hum. Rights 19 (4). Kelly, T., 2007. The Impact of the WTO: The Environment, Public Health and Sovereignty. Edward Elgar. Mcgrady, B., 2011. Trade and Public Health: The WTO, Tobacco, Alcohol and Diet. Cambridge University Press. Taylor, A., Tobias, A., Hougendobler, D., Buse, K., 2014. Non-binding legal instruments in governance for global health: lessons from the global AIDS reporting mechanism. J. Law Med. Ethics 42 (1), 72–87. WHO Commission on Intellectual Property Rights, 2006. Innovation and Public Health, Public Health, Innovation and Intellectual Property Rights. World Health Organization, Geneva, Switzerland.

Global Issues: Urban Health in Developing Countries Carolyn Stephens, UCL Institute of Health Equity, London, UK; Universidad Nacional de Tucumán, Tucumán, Argentina; and London School of Hygiene & Tropical Medicine, London, UK Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Carolyn Stephens, David Satterthwaite, volume 6, pp. 452–463, Ó 2008, Elsevier Inc.

Introduction The future of our planet now seems irrevocably urban, and we need to be sure that this urban life is healthy, equitable, and sustainable. Over 50% of the world’s population is now living in urban areas – a staggering 3.9 billion people. This article discusses the public health challenge of urbanization. It looks at existing health problems in cities of the so-called developing world and reviews some of the international policies developed to address these problems. Before looking at the health of people living in an urban context, it is important to be clear about terms. To begin it is very important to be clear about the term urbanization.

What Is Urbanization? Firstly, it is important to realize that there are widely different definitions of ‘urban’ – particularly in today’s urban context, and the type of urban setting that a person lives in can have a very different effect on that person’s life. The term ‘urban’ usually is applied to an area on the basis of a mixture of land use, area covered, and population density, but terms differ widely. For example, in the United States, settlements with 2500 inhabitants or more are defined as urban, while in Japan, which is far more densely populated, only settlements with 30 000 people or more are considered urban. For example, an urban setting today can mean anything from a small urban settlement of under 500 000 to a megacity of over 10 million – and the impacts of the urban experience on human health are very different depending on the type of urban center involved. To put this in an historical context, it is notable that few cities in the past had more than 500 000 inhabitants and, even today, many countries have smaller populations than the megacities we see of 10 million and more inhabitants. Towns and cities historically also were home to minority peoples, and depending on their social and economic conditions, urban opportunities and challenges for minorities have always existed. In 2007 the Worldwatch Institute reported that, “by 2005, the world’s urban population of 3.18 billion people constituted 49 percent of the total population of 6.46 billion. Very soon, and for the first time in the history of our species, more humans will live in urban areas than rural places” (Lee, 2007). These findings were based on United Nations projections suggesting that nearly all of the population growth in the future will be in cities and towns. Most notably, this population growth was predicted to be in low- and middle-income nations. Asia and Africa, today the most rural continents of the world, were projected to double their urban populations, from 1.7 billion in 2000 to about 3.4 billion in 2030 (United Nations Population Division, 2006; Lee, 2007; Table 1).

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Table 1 The distribution of the world’s urban population by region, 1950–2010 Region or country

1950

1970

1990

2000 a

Projected for 2010

Urban populations (millions of inhabitants) World 732 1329 2271 2845 3475 High-income nations 423 650 818 874 922 Low- and middle-income 309 678 1453 1971 2553 (‘developing’) nations ʻLeast-developed 15 41 110 166 247 nations’ Africa 33 85 203 294 408 Asia 234 485 1011 1363 1755 Europe 277 411 509 522 529 Latin America and the 70 163 315 394 474 Caribbean Northern America 110 171 214 249 284 Oceania 8 14 19 22 25 Urbanization level (percentage of population living in urban areas) World 29.0 36.0 43.0 46.8 50.8 High-income nations 52.1 64.6 71.2 73.2 75.2 Low- and middle-income 18.1 25.2 35.2 40.3 45.5 (‘developing’) nations ʻLeast-developed 7.3 13.1 21.0 24.7 29.0 nations’ Africa 14.7 23.4 32.0 36.2 40.5 Asia 16.8 22.7 31.9 37.1 42.5 Europe 50.5 62.6 70.6 71.7 72.9 Latin America and the 42.0 57.2 70.9 75.4 79.1 Caribbean Northern America 63.9 73.8 75.4 79.1 82.2 Oceania 62.0 70.8 70.3 70.5 71.2 Percentage of the world’s urban population living in: Major area, region, or 1950 1970 1990 2000 2010 country World 100.0 100.0 100.0 100.0 100.0 High-income nations 57.8 49.0 36.0 30.7 26.5 Low- and middle-income 42.2 51.0 64.0 69.3 73.5 (‘developing’) nations ʻLeast-developed 2.0 3.1 4.8 5.8 7.1 nations’ Africa 4.5 6.4 8.9 10.3 11.7 Asia 32.0 36.5 44.5 47.9 50.5 Europe 37.8 30.9 22.4 18.4 15.2 Latin America and the 9.6 12.3 13.9 13.9 13.6 Caribbean Northern America 15.0 12.9 9.4 8.8 8.2 Oceania 1.1 1.0 0.8 0.8 0.7 a

The statistics for 2000 are an aggregation of national statistics, many of which draw on national censuses held in 1999, 2000, or 2001 – but some are based on estimates or projections from statistics drawn from censuses held around 1990. There is also a group of countries (mostly in Africa) for which there are no census data since the 1970s or early 1980s so all figures for their urban (and rural) populations are based on estimates and projections. Source: Derived from statistics in United Nations 2006.

International Encyclopedia of Public Health, 2nd edition, Volume 3

http://dx.doi.org/10.1016/B978-0-12-803678-5.00480-X

Global Issues: Urban Health in Developing Countries In 2014 the United Nations Population Division (UNPD) undertook new estimates of the urban population. The world’s urban population is now close to 3.9 billion and is expected to reach 6.3 billion in 2050. Asia alone is now home to 53% of the world’s urban population (United Nations, 2014). The urban world has changed so radically from the past that in 2012 the OECD redefined the term ‘city’ to include new parameters of density, land use, and size of settlement. This new OECD definition “identified 828 (greater) cities with an urban centre of at least 50 000 inhabitants in the EU, Switzerland, Croatia, Iceland, and Norway. In addition, this methodology identified a further 492 cities in Canada, Mexico, Japan, Korea, and the United States. Half of these European cities are relatively small with a centre between 50 000 and 100 000 inhabitants. Only two are defined as global cities (London and Paris with over 5 000 000 inhabitants). These cities host about 40% of the EU population” (Dijkstra and Poelman, 2014). The UNPD (2014) describes problems of urban measurement such as:

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world’s 100 largest cities was around 6.3 million inhabitants. This compares to 2.0 million inhabitants in 1950, 728 270 in 1900, and 187 520 in 1800 (Satterthwaite, 2007). While there are various examples of cities over the last two millennia that had populations of 1 million or more inhabitants, the city or metropolitan area with several million inhabitants is a relatively new phenomenon – London being the first to reach this size in the second half of the nineteenth century. By 2000, there were 45 cities with more than 5 million inhabitants. Megacities and very large cities of today are home to millions of people, and, in some global cities, a large proportion of the population may be from diverse minorities – some cities are home to minorities from all over the world – and depending on their economic and social situation, different minorities will face very different challenges and opportunities. The 2014 analysis of urban trends by UNPD identified the following:

Administrative limits of towns and cities do not change regularly and urban populations often exceed administrative limits. For example, a metropolitan agglomeration may be considerably larger than the official administrative limits. l Different countries define the minimum size of an urban area differently.

Globally, more people live in urban areas than in rural areas, with 54% of the world’s population residing in urban areas in 2014. l Close to half of urban citizens live in settlements of less than 500 000 inhabitants, while nearly one in eight live in 28 megacities of 10 million inhabitants or more. l The number of megacities has nearly tripled since 1990; and by 2030, 41 urban agglomerations are predicted to house at least 10 million inhabitants each.

Perhaps the biggest change we now face in this discussion is that the challenges and opportunities of urban life today are simply at a completely different scale both temporally and demographically. The average size of the world’s largest cities has increased dramatically. In 2000, the average size of the

Figure 1 shows the 2014 estimates of percentage of urbanization in 2014 by region, and the location of cities and megacities in each region (United Nations, 2014). There are also the large demographic changes apparent in all nations over the last 50 years that influence urban change,

l

Percentage urban

City population

0-20%

1-5 million

20-40%

5-10 million

40-60%

l

10 million or more

60-80% 80-100% Note: Designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country, territory or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries.

Figure 1 2014 estimates of % of urbanization in 2014 by region, and the location of cities and mega cities in each region. Reproduced from United Nations, Department of Economic and Social Affairs, Population Division, 2014. World Urbanization Prospects: The 2014 Revision, Highlights (ST/ESA/SER.A/352). United Nations, Department of Economic and Social Affairs, Population Division.

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including rapid population growth rates in much of Latin America, Asia, and Africa in the mid-twentieth century, and changes in the size and composition of households and in age structures (Montgomery et al., 2003). Aggregate urban statistics can be interpreted as implying comparable urban trends across the world or for particular continents. But they obscure the diversity in urban trends between nations. In 2014, Latin America and the Caribbean and Northern America have the highest levels of urbanization, at or above 80%. Europe has 73% of its population living in urban areas, but is expected to be over 80% by 2050. Africa and Asia, in contrast, remain mostly rural, with 40% and 48% of their respective populations living in urban areas (UNPD, 2014). Aggregate urban statistics may suggest rapid urban change, but the rate of increase in urbanization levels, and the rate of increase of urban populations, has slowed in many developing countries. Many of the world’s largest cities, including Mexico City, São Paulo, Buenos Aires, Calcutta, and Seoul had more people moving out than in, during their last intercensus period. The increasing number of ‘megacities’ with 10 million or more inhabitants may seem to be a cause for concern but there are still relatively few of them. In 2014 there are 28 megacities, and they are home to 453 million people, but these agglomerations still only account for 12% of the world’s urban dwellers. Also, taking a longer-term view of urban change, it is not surprising that Asia has most of the world’s largest cities since this reflects the region’s growing importance within the world economy (and Asia has many of the world’s largest national economies).

Urban Change and Economic Change Although rapid urban growth is often seen as ‘a problem,’ it is generally the nations with the best economic performance that have urbanized most in the last 50 years. In addition, perhaps surprisingly, there is often an association between rapid urban change and better standards of living. Not only is most urbanization associated with stronger economies but generally, the more urbanized a nation, the higher the average life expectancy and the literacy rate and the stronger the democracy, especially at local level. Many of the largest cities may appear chaotic and out of control, but most provision for piped water, sanitation, schools, and health care – and consequently life expectancies that are well above their national average – even if the aggregate statistics for each megacity can hide a significant proportion of their population living in very poor conditions. Some of world’s fastest-growing cities over the last 50 years also have among the best standards of living within their nation – as was shown in a classic study of Porto Alegre in Brazil (Menegat, 2002). It is also important not to overstate the speed of urban change. Recent censuses show that the world today is also less urbanized and less dominated by large cities than had been anticipated. For instance, Mexico City had 18 million people in 2000 – not the 31 million people predicted 25 years earlier (United Nations Population Division, 2006). Calcutta, São Paulo, Rio de Janeiro, Seoul, Chennai (formerly Madras),

and Cairo are among the many other large cities that, by 2000, had several million fewer inhabitants than had been predicted (Satterthwaite, 2007).

What Drives Urban Change? Understanding what causes and influences urban change within any nation is complicated. Consideration has to be given to changes in the scale and nature of the nation’s economy and its connections with neighboring nations and the wider world economy; also to decisions made by national governments, national and local investors and the 30 000 or so global corporations who control such a significant share of the world’s economy. The population of each urban center and its rate of change are also influenced not only by international and national factors, but also by local factors related to each very particular local context – including the site, location, natural resource endowment, demographic structure, existing economy and infrastructure (the legacy of past decisions and investments), and the quality and capacity of public institutions. The immediate cause of urbanization is the net movement of people from rural to urban areas. The main underlying cause is often the concentration of new investment and economic opportunities in particular urban areas. Virtually all the nations that have urbanized most over the last 50–60 years have had long periods of rapid economic expansion and large shifts in employment patterns from agricultural/pastoral activities to industrial, service, and information activities. In developing countries, urbanization is overwhelmingly the result of people moving in response to better economic opportunities in the urban areas, or to the lack of prospects in their home farms or villages. The scale and direction of people’s movements accord well with changes in the spatial location of economic opportunities. In general, it is cities, small towns, or rural areas with expanding economies that attract most migration, although there are important exceptions in some nations, such as migration flows away from wars/conflicts and disasters. By the beginning of the twenty-first century, 97% of the world’s GDP was generated by industry and services and around 65% of the world’s economically active population work in industry and services, most of which is located in urban areas. Political changes have had considerable importance in increasing levels of urbanization in many nations over the past 50–60 years, especially the achievement of political independence and the building of government structures which were important for most of Asia and Africa but these had much less effect in most nations from the 1980s onward. Agriculture is often considered as separate from (or even in opposition to) urban development, yet prosperous high value agriculture, combined with prosperous rural populations, has proved an important underpinning to rapid development in many cities. Many major cities first developed as markets and service centers for farmers and rural households, and later developed into important centers of industry and/or services. Many such cities still have significant sections of their economy and employment structure related to forward and backward linkages with agriculture.

Global Issues: Urban Health in Developing Countries Analyses of urban change within any nation over time serve as reminders of the diversity of this change, of the rising and falling importance of different urban centers, of the spatial influence of changes in governments’ economic policies (for instance, from supporting import substitution to supporting export promotion), of the growing complexity of multinuclear urban systems in and around many major cities, and of the complex and ever shifting patterns of in-migration and out-migration from rural to urban areas, from urban to urban areas, and from urban to rural areas. International immigration or emigration has strong impacts on the population size of particular cities in most nations. But it is not only changing patterns of prosperity or economic decline that underpin these flows of people. Many cities have been impacted by war, civil conflict or disaster, or by the entry of those fleeing them.

What Is Urban Health in Developing Countries? In many of the towns and cities in Africa, Asia, and Latin America, only an urban minority lives in healthy living conditions and has access to good health services, education, and employment. Already, nearly one in two urban dwellers in developing countries live in low-income urban settlements, known pejoratively as ‘slums,’ with all that this implies in terms of living conditions and health (Lee, 2007; Stephens, 2012). Low-income settlements are areas of a town or city where people have no, or very limited, access to necessities that would secure good health: clean, and ample water, sanitation, sufficient living space, and adequate housing are all missing from these environments. Water and food are often biologically contaminated, education and work opportunities are available to a tiny minority, and the work that does exist is often in hazardous industries on a wage that does not provide a route out of poverty. Health services are often inaccessible to the urban poor – not because they are at a long distance, as in rural areas, but because poorer people in low-income settlements often do not have the financial means to access them. To make things still more difficult, low-income urban citizens often live with insecure tenure to their land and homes – making the risk of homelessness a regular threat to their well-being. Both the wealth of a country and scales of urbanization affect urban health patterns. In regions such as Asia, urban populations are huge, but the proportion of urban population in the region as a whole is still less than 50%. In the ‘least-developed’ nations, only a quarter of the population is urban. This can affect government and donor policies toward urban areas – and can mean that rural areas are prioritized for basic interventions that affect health (such as vaccination, water and sanitation, and other infrastructure). In contrast, more urbanized regions, such as Latin America, do not have this urban–rural divide in policy terms – which can mean that national policies are aligned to urban priorities. The rate of urbanization is also important for urban health: where rates of urban growth are very high, urban services are quickly overwhelmed and large proportions of the new urban population live without adequate infrastructure – including water, sanitation, housing, and transport, but also education, health, and employment.

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The Myth of the Healthy City There is still a myth among health professionals – the idea that rural peoples are less healthy than their urban counterparts. The myth of the healthy city has been linked for decades to a problem of data aggregation – where total health statistics are sometimes presented for cities with populations greater than those of nation states. Megacities suffer particularly from a problem of super-aggregation, in which health data on a city with over 10 million people can only tell part of the story. Each city’s health will depend on a range of contextual factors, just as a national health profile does. A key predictor is often the overall state of ‘development’ of the city – measured in proportions of people with clean water, sanitation, adequate housing, and access to health measures such as vaccination and primary care. Thus a megacity with a large proportion of people living in poverty will have a health profile that reflects the profile of these people. However, there is another problem: megacities account for only about 12% of total urban population of approximately 3.9 billion citizens. Almost half of the world’s city dwellers live in settlements with fewer than 500 000 inhabitants, and we still know little of the health situation in smaller towns and cities internationally (United Nations, 2014). In every town and city, data that have been broken down by income group tell a different story of urban health – it is the tale of urban inequality. Within cities and towns, disaggregated data show that there are inequalities in living conditions and in access to services such as health, water, and sanitation. There are also inequalities in access to education and work (Stephens, 2011, 2012). Thus, it is hard to generalize about urban health profiles, as each city and town may have a distinctive pattern of development and distribution of resources. Even a rich town in a rich country may have sharp inequalities that affect health drastically – for example, a classic study in New York found that black men in Harlem were less likely than men in Bangladesh to reach the age of 65 (McCord and Freeman, 1990).

Urban Health Profiles Both the physical and the social environment of cities and towns today affect urban health. The overall quality of the urban environment is important for health, and so is the extent of inequality within an urban environment. Some problems of the urban physical environment, such as ambient air pollution, may affect almost everyone in a city. Other problems, such as contaminated water, indoor air pollution, or lack of sanitation, may disproportionately affect some groups more than others. Urban violence may also affect some urban dwellers more than others. Rapid urbanization in most cases exaggerates these problems, as cities are unable to build enough infrastructure and provide enough jobs for an influx of migrants, many of whom may be fleeing war or drought (Lucchi, 2010; Cupers, 2011). In the poorer countries of Africa and Asia, a majority of urban citizens live without clean water and sanitation, and with limited public health interventions such as vaccination. This is a consequence of a complex mix of national economic situations, and of the scale and rate of urbanization. In some

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urban areas, urban health indicators can be worse than in rural areas. In poorer countries, urban areas often have the worst of all worlds – contaminated air, land, and water; deep poverty; and a health profile that includes both the infectious diseases of deep poverty and the so-called diseases of modernity (obesity, cancers, and heart disease). In these cases people carry a ‘double burden’ of disease that poses a daunting challenge for human health on an urban planet (Stephens and Stair, 2007; Stephens, 2012). In wealthier countries, such as Brazil in Latin America, most urban people have access to water and sanitation even if their housing is precarious. Urban public health interventions, such as vaccination are also widespread. In these urban areas, infant mortality rates are low, and urban health problems are linked more to social outcomes, such as educational attainment and employment, and relate to social inequality between urban groups. Urban violence is a major problem in many cities of Latin America, where rates of death from homicide affect adolescent health profiles particularly. In some cities, urban industry affects pollution levels, and the particular mix of industries affects the type of health problems that will be associated with the pollution. The key challenge for urban professionals is to understand the complex mix of urban health problems that result from the unique mix of demographic change, economic development, infrastructure, and social conditions that make up every town and city. The following sections outline some of these urban health challenges in turn.

Infant and Child Survival in Urban Areas In most low-income and many middle-income nations, infant, child or under-five mortality rates in urban areas are five to twenty times what they would be, if the urban populations had adequate nutrition, good environmental health and a competent health-care service (Satterthwaite, 2007). In some low-income nations, these mortality rates increased during the 1990s (Montgomery et al., 2003). However, there are also nations with relatively low urban infant and child mortality rates (for instance Peru, Jordan, Vietnam, and Colombia) – while there are also particular cities that have achieved low infant and child mortality rates – for instance Porto Alegre in Brazil (Menegat, 2002). Empirical studies on infant and child mortality rates in low-income urban settlements suggest that these are generally at least twice the urban average. Studies show these differentials from cities as different as Nairobi and New York (APHRC, 2002; Sohler et al., 2003). A study looking at all metropolitan areas of the United States also found infant mortality correlated strongly with income inequality in cities (Lynch et al., 1998). Minority communities can be particularly marginalized in cities and study in Yunnan Province in China found a strong correlation of low-income urban life and high infant mortality in indigenous populations in the region (Li et al., 2008; Table 2). In virtually all cities in low-income nations for which data are available, and for most in middle-income nations, there are also dramatic contrasts between different areas (districts, wards, municipalities) of the city regarding infant and child

Table 2 Examples of high infant and child mortality rates among national urban populations Urban infant (age 20 mmHg and/or pupillary abnormalities High-dose propofol (Diprivan) infusion Hyperventilation to PaCO2 25–30 mmHg

Consider hypertonic saline bolus infusion Consider decompressive craniectomy

CPP management: inotropic and pressor support to maintain CPP dopamine (Intropin) 5–20 mg kg1 min, norepinephrine (Levophed) 0.05–0.5 mg kg1 min) CPP approximately 70 mmHg Repeat head CT to exclude operable mass lesion CPP, cerebral perfusion pressure; CSF, cerebrospinal fluid; CT, computed tomography; CVP, central venous pressure; ICP, intracranial pressure; GCS, Glasgow Coma Scale.

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Head Trauma

reliably decreases ICP in patients in whom mannitol has lost its efficacy. A hyperosmolar state with serum osmolarities well above 320 mOsm l1 may develop but seems to be tolerated well as long as euvolemia and arterial normotension are maintained. Hypertonic saline infusion should only commence after preexisting hyponatremia has been ruled out in order to prevent central pontine myelinolysis (CPM). In normonatremic individuals, there have been no reported cases of CPM after hypertonic saline administration. More studies are needed to compare mannitol versus hypertonic saline in the treatment of ICP; however, one randomized trial by Battison et al. (2005) comparing equimolar concentrations demonstrated that hypertonic saline has a more profound effect on lowering ICP as well as longer duration of action.

Hyperventilation

Hyperventilation should not be used routinely in these patients because of the risk of further compromising cerebral perfusion. Hyperventilation can be used for brief periods when there is acute neurologic deterioration or if intracranial hypertension is refractory to other treatment interventions. Under these circumstances, intraparenchymal brain-tissue oxygen monitoring is utilized to titrate the degree of hyperventilation and to avoid cerebral ischemia (Table 5). The use of prophylactic hyperventilation (PaCO2 ¼ 35 mmHg) therapy during the first 24 h after severe TBI should be avoided because it can compromise cerebral perfusion during a time period when CBF is already decreased.

Prophylactic Measures

Although some centers induce prophylactic hypothermia in patients with acute TBI, the literature has failed to demonstrate a consistently positive influence on morbidity or mortality. Hypothermia is not routinely employed as a first-line therapy for TBI, and its use is reserved for long-standing, refractory ICP elevation in posttraumatic patients. In TBI patients, infection rates are increased in those on mechanical ventilation and with ICP monitoring devices. Prophylactic antibiotics are not recommended for ventilated patients so as not to select for resistant organisms. In addition, although ICP monitoring devices such as ventriculostomies should be inserted under sterile conditions, it is not recommended to continue a course of antibiotics for the duration of monitoring. It is routine to administer one to two doses of antibiotics during periprocedural insertion of these monitoring devices despite conflicting clinical studies.

Barbiturate Coma

High-dose barbiturate therapy may be considered in hemodynamically stable, salvageable, severe TBI patients with intracranial hypertension refractory to maximal medical and surgical ICP-lowering therapy. Barbiturates appear to exert their cerebral protective and ICP-lowering effects through alterations in vascular tone, suppression of metabolism, and inhibition of free radical-mediated lipid peroxidation. The risk of arterial hypotension induced by peripheral vasodilation is high. Adequate barbiturate coma therapy results in the electroencephalographic pattern of burst suppression. Near-maximal reductions in cerebral metabolism and cerebral blood flow occur when burst suppression is induced.

High-dose Propofol

Propofol (Diprivan) at low doses is commonly used for sedation in patients requiring mechanical ventilation. In recent years, high-dose propofol has gained popularity as an alternative to barbiturates in patients with intracranial hypertension refractory to maximal medical and surgical ICP-lowering therapy (Oertel et al., 2002). The main advantage of propofol is that it is short-acting. Like other anesthetics, it can cause hypotension, and, even though ICP decreases, overall cerebral perfusion pressure may drop. High-dose use of propofol can result in propofol infusion syndrome, a multiorgan and metabolic crisis that was first identified in children, but can also occur in adults. The characteristics include hyperkalemia, hepatomegaly, metabolic acidosis, renal failure, myocardial failure, and rhabdomyolysis. Hepatic and pancreatic enzymes should be monitored while on propofol and this neurosedative should not be used in pediatric patients.

Glucocorticoids

Glucocorticoids have not been shown to improve outcome after severe TBI according to Guidelines publications. A recent large prospective randomized trial has shown that corticosteroids are associated with increased rates of severe disability and death when used in the treatment of patients with TBI (Edwards et al., 2005).

Nutritional Support

Studies have shown that the failure to achieve full nutritional support within the first week after severe TBI increases mortality. Tube feedings should ideally commence within the first 2 days after TBI.

Treatment of Seizures

Posttraumatic seizures (PTS) can be divided into early (7 days after trauma). In recent TBI studies that followed high-risk patients up to 36 months, the incidence of early PTS varied between 4% and 25%, and the incidence of late PTS varied between 9% and 42% in untreated patients. Prophylactic use of phenytoin (Dilantin), carbamazepine (Tegretol), or phenobarbital is not recommended by Guidelines publications for preventing late PTS. Anticonvulsants may be used to prevent early PTS in patients at high risk for seizures following TBI. Phenytoin and carbamazepine have been demonstrated to be effective in this setting. However, the available evidence does not indicate that prevention of early PTS improves outcome following TBI. Routine seizure prophylaxis later than 1 week following TBI is therefore not recommended. If late PTS occurs, patients should be managed in accordance with standard approaches to patients with new-onset seizures. Routine seizure prophylaxis after TBI also raises concern for potential side effects such as drug fever and anaphylaxis. Fever may develop 1–8 weeks after exposure to phenytoin, phenobarbital, or carbamazepine.

Surgical Management of Acute Traumatic Brain Injury The decision as to whether an intracranial lesion requires surgical evacuation can be difficult and is based on the patient’s

Head Trauma GCS score, pupillary examination findings, comorbidities, CT findings, age, and – in delayed decisions – ICP. Neurological deterioration over time is also an important factor influencing the decision to operate. Trauma patients presenting to the emergency department with altered mental status, pupillary asymmetry, and abnormal flexion or extension are at high risk for an intracranial mass lesion, and it is our practice to notify the operating room even before obtaining a CT scan that an emergency craniotomy will most likely be necessary.

Epidural Hematoma The incidence of surgical and nonsurgical epidural hematoma (EDH) among TBI patients is approximately 3%. Among patients in coma, up to 9% harbored an EDH requiring craniotomy. The peak incidence of EDH is in the second decade and the mean age of patients with EDH is between 20 and 30 years of age. Traffic-related accidents, falls, and assaults account for the majority of all cases of EDH. EDH usually results from injury to the middle meningeal artery but can also be due to bleeding from the middle meningeal vein, the diploic veins, or the venous sinuses (Figures 3 and 4). In patients with

SDH

Arachnoid

Dura

Pia

377

EDH, one-third to one-half are comatose on admission or immediately before surgery. The classically described lucid interval, which describes a patient who is initially unconscious, then wakes up and secondarily deteriorates, is seen in approximately one-half of patients undergoing surgery for EDH. Clot thickness, hematoma volume, and midline shift (MLS) on the preoperative CT scan are related to outcome. Noncomatose patients without focal neurologic deficits and with an acute EDH with a thickness of less than 15 mm, an MLS less than 5 mm, and a hematoma volume less than 30 ml can be managed nonsurgically with serial CT scanning and close neurologic evaluation in a neurosurgical center (Figure 5). The first follow-up CT scan in stable nonsurgical patients should be obtained within 6–8 h after TBI. Temporal location of an EDH is associated with failure of nonsurgical management and should lower the threshold for surgery. Patients with a GCS score less than 9 and an EDH larger than 30 ml should undergo immediate surgical evacuation of the lesion. All patients, regardless of GCS score, should be considered for surgery if the volume of their EDH exceeds 30 ml. Patients with an EDH volume less than 30 ml should be considered for surgery but may be managed successfully without surgery in selected cases. Time from neurologic deterioration to surgery correlates with outcome. In these patients, surgical evacuation should be done as soon as possible, since every hour of delay in surgery is associated with progressively worse outcome.

EDH

Acute Subdural Hematoma

S

Falx

Figure 3 This illustration shows a subdural hematoma (SDH) below the dura mater on the left side. An epidural hematoma (EDH), between the dura mater and the skull, is shown on the right with a skull fracture and scalp hematoma overlying.

Figure 4 Head CT of a patient with a severe TBI. On the patient’s right is an acute epidural hematoma with skull fracture and scalp hematoma overlying. On the patient’s left side is an acute subdural hematoma. Note also the midline shift from left to right.

A subdural hematoma (SDH) is diagnosed on a CT scan as extracerebral, hyperdense, crescentic collections between the dura and the brain parenchyma (Figures 3 and 4). They can be divided into acute and chronic lesions. The incidence of acute SDH is between 12% and 29% in patients admitted with severe TBI. The mean age is between 31 and 47 years, with the vast majority of patients being male. Most SDHs are caused by motor vehicle-related accidents, falls, and assaults. Falls have been identified as the main cause of traumatic SDH in patients older than 75 years. Between 37% and 80% of patients with acute SDH present with initial GCS scores of 8 or lower. Clot thickness or volume and MLS on the

EDH > 30 cc or MLS > 5 mm or Thickness > 15 mm

Consider surgery

Surgery as soon as possible

EDH < 30 cc and Thickness < 15 mm and MLS < 5 mm

Nonoperative management

Consider surgery

GCS 9−15

GCS < 9

Figure 5 Graph showing considerations for nonoperative vs operative management of epidural hematomas (EDH). These are based on Brain Trauma Foundation, 2006. Guidelines for the surgical management of traumatic brain injury. Neurosurgery 58 (Suppl.), S2–S10.

378

Head Trauma

Clot thickness > 10 mm or MLS > 5 mm

Clot thickness < 10 mm and MLS < 5 mm

Early surgery

Surgery as soon as possible with post-operative ICP monitoring

Nonoperative management

Surgery if • GCS dropped 2 or more points or • ICP > 20 mmHg or • Abnormal pupils

GCS 9−15

GCS < 9

Figure 6 Graph showing considerations for nonoperative vs operative management of subdural hematomas (SDH). These are based on Brain Trauma Foundation, 2006. Guidelines for the surgical management of traumatic brain injury. Neurosurgery 58 (Suppl.), S2–S10.

preoperative CT scan correlate with outcome. Guidelines publications note that patients with SDH presenting with a clot thickness greater than 10 mm or MLS greater than 5 mm should undergo surgical evacuation, regardless of their GCS (Figure 6). Patients who present in a coma (GCS score 20 mmHg). In comatose patients or patients with progressive neurological deterioration surgical evacuation should be done as soon as possible.

Traumatic Parenchymal Lesions Traumatic parenchymal mass lesions occur in up to 10% of all patients with TBI and 13–35% of patients with severe TBI. Most small parenchymal lesions do not require surgical evacuation. However, the development of mass effect from larger lesions

may result in secondary brain injury, placing the patient at risk for further neurologic deterioration, herniation, and death. Parenchymal lesions tend to evolve over time and increase in size, which reflects the potentially devastating effect of secondary brain damage (Figure 7(a) and 7(b)). Patients with parenchymal mass lesions and signs of progressive neurologic deterioration referable to the lesion, medically refractory intracranial hypertension, or signs of mass effect on CT scan should be treated operatively. Comatose patients with frontal or temporal contusions greater than 20 ml in volume and with MLS of 5 mm or cisternal compression on CT scan, or both, and patients with any lesion greater than 50 ml in volume should be treated surgically (Mathiesen et al., 1995). Patients with parenchymal mass lesions who do not show evidence of neurological compromise, have controlled ICP, and have no significant signs of mass effect on CT scan can be managed nonsurgically.

Depressed Skull Fractures Depressed skull fractures complicate up to 6% of head injuries, and the presence of skull fracture is associated with a higher incidence of intracranial lesions, neurological deficit, and poorer outcome. Patients with open skull fractures depressed greater than the thickness of the skull should undergo surgical intervention to prevent infection. Patients with open depressed fractures should be covered with antibiotic prophylaxis according to Guidelines literature.

Decompressive Craniectomy for Control of Intracranial Hypertension Decompressive procedures such as subtemporal decompression, temporal lobectomy, and hemispheric decompressive craniectomy are surgical procedures that have been used to treat patients with refractory intracranial hypertension and diffuse parenchymal injury. Decompressive craniectomy may be very effective if it is done early after TBI in young patients who are

Figure 7 Traumatic parenchymal mass lesions occur in up to 10% of all patients with TBI and 13–35% of patients with severe TBI. Parenchymal lesions tend to evolve, which reflects the potentially devastating effect of secondary brain damage. This patient presented with a left-sided frontal contusion (a) that blossomed within 12 h and required surgical evacuation (b).

Head Trauma expected to develop postoperative brain swelling and intracranial hypertension.

Early Prognostic Indicators of Severe Traumatic Brain Injury Outcome from TBI is frequently described using the Glasgow Outcome Scale at 6 months following TBI (Table 6). This is a widely accepted and standardized scale that is of value for the clinical description of patients and also for medicolegal documentation and research purposes. The most important early presenting factors influencing outcome from severe TBI are: Age; GCS score; l Pupillary examination findings; l Arterial hypotension; l CT scan findings. l l

Studies show that the probability of poor outcome increases with decreasing admission GCS score in a continuous manner below a GCS score of 9. Patients with very low GCS scores have a mortality rate between 70% and 90%, but up to 10% may survive with Glasgow Outcome Scale scores of 4 or 5. Increasing age is a strong independent factor in prognosis from severe TBI, with a significant increase in poor outcome in patients older than 60 years of age. This is not explained by the increased frequency of systemic complications in older patients. The pupillary diameter and the pupilloconstrictor light reflex can prognosticate outcome from severe TBI. Bilaterally unreactive pupils following resuscitation on admission are associated with a greater than 90% chance of poor outcome. A systolic blood pressure less than 90 mmHg measured after severe TBI on the way to the hospital or in hospital has been associated with an almost 70% likelihood of poor outcome. Combined with hypoxia, this likelihood increases to 79%. A single recording of arterial hypotension doubles the rate of mortality from severe TBI. Among these early prognostic indicators of outcome, arterial hypotension is the only factor that can be significantly affected by therapeutic intervention. The CT scan findings associated with poor outcome from severe TBI are: Compressed or absent basal cisterns; Traumatic subarachnoid hemorrhage; l MLS greater than 5 mm. l l

Table 6

Glasgow Outcome Scale

Score

Rating

Definition

5

Good recovery

4

Moderate disability Severe disability

Resumption of normal life despite minor deficits. Disabled but independent. Can work in sheltered setting. Conscious but disabled. Dependent for daily support. Minimal responsiveness.

3 2 1

Persistent vegetative Death

Nonsurvival.

379

Following admission, ICP greater than 20 mmHg is a poor prognostic indicator. The rate of mortality from epidural hematoma requiring surgery is around 10%. The rate of mortality from acute SDH is between 40% and 60%. The mortality rate among patients with acute SDH presenting to the hospital in coma with subsequent surgical evacuation is between 57% and 68%.

Conclusion The mortality rate from severe TBI has been reduced from up to 50% in the 1970s and 1980s to between 15% and 25% in most recent series. This improvement should be attributed to more effective resuscitation in the field, rapid transport of TBI patients to trauma hospitals, more widely accepted ICP monitoring, and improvements in critical care management. In a recent study by Palmer et al. (2001) of 93 patients with severe TBI, the 6-month mortality rate was reduced 50% by the introduction of evidence-based protocol for the management of severe TBI. The treatment protocol supported ICP monitoring, adequate volume resuscitation, aggressive treatment of low blood pressure and oxygenation, avoidance of extreme hyperventilation, and early nutritional intervention. New paradigms such as direct measurement of brain tissue oxygenation hold early promise for more specific and effective management of cerebral metabolism after TBI. Multidisciplinary clinical pathways based on evidence-supported treatment guidelines for TBI streamline patient care, standardize critical care management, and hold the potential for significantly improving patient outcome and reducing hospital costs. Medical personnel in the prehospital and in-hospital setting should be aware of and trained in these principles of TBI care.

See also: Falls; Road Traffic Injuries; Sports Injuries.

References Battison, C., Andrews, P.J., Graham, C., et al., 2005. Randomized, controlled trial on the effect of a 20% mannitol solution and a 7.5% saline/6% dextran solution on increased intracranial pressure after brain injury. Crit. Care Med. 33, 196–202, discussion 257–198. Brain Trauma Foundation, 2000a. Guidelines for the management of severe traumatic brain injury. J. Neurotrauma 17, 449–554. Brain Trauma Foundation, 2000b. Hyperventilation. J. Neurotrauma 17, 513–520. Brain Trauma Foundation, 2004. Update notice: guidelines for the management of severe traumatic brain injury: cerebral perfusion pressure. Neurotrauma Crit. Care News 3, 3. Brain Trauma Foundation, 2006. Guidelines for the surgical management of traumatic brain injury. Neurosurgery 58 (Suppl.), S2–S10. Bullock, M.R., Povlishock, J.T. (Eds.), 2007. Brain Trauma Foundation, Journal of Neurotrauma Guidelines for the Management of Severe Traumatic Brain Injury, third ed., vol. 24, pp. 1–106 (Suppl. 1). Chesnut, R., Marshall, L., Klauber, M., et al., 1993a. The role of secondary brain injury in determining outcome from severe head injury. J. Trauma 34, 1–106. Chesnut, R., Marshall, L., Klauber, M., et al., 1993b. The role of secondary brain injury in determining outcome from severe head injury. J. Trauma 34, 216–222. Cruz, J., Minoja, G., Okuchi, K., 2001. Improving clinical outcomes from acute subdural hematomas with the emergency preoperative administration of high doses of mannitol: a randomized trial. Neurosurgery 49, 864–871. Cruz, J., Minoja, G., Okuchi, K., 2002. Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal papillary widening: a randomized trial. Neurosurgery 51, 628–637.

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Cruz, J., Minoja, G., Okuchi, K., et al., 2004. Successful use of new high-dose mannitol treatment in patients with Glasgow Coma Scale scores of 3 and bilateral abnormal pupillary widening: a randomized trial. J. Neurosurg. 100, 376–383. Edwards, P., Arango, M., Balica, L., et al., 2005. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet 365, 1957–1959. Fakhry, S.M., Trask, A.L., Waller, M.A., et al., 2004. Management of brain-injured patients by an evidence-based medicine protocol improves outcomes and decreases hospital charges. J. Trauma 56, 492–499, discussion 499–500. Jones, P.A., Andrews, P.J.D., Midgely, S., et al., 1994. Measuring the burden of secondary insults in head injured patients during intensive care. J. Neurosurg. Anesthesiol. 6, 4–14. Manley, G., Knudson, M., Morabito, D., et al., 2001. Hypotension, hypoxia, and head injury: frequency, duration, and consequences. Arch. Surg. 136, 1118–1123. Marmarou, A., Anderson, R.L., Ward, J.D., et al., 1991. Impact of ICP instability and hypotension on outcome in patients with severe head trauma. J. Neurosurg. 75, 159–166. Mathiesen, T., Kakarieka, A., Edner, G., 1995. Traumatic intracerebral lesions without extracerebral haematoma in 218 patients. Acta Neurochir. (Wien) 137, 155–163 discussion 163. Narayan, R.K., Michel, M.E., Ansell, B., et al., 2002. Clinical trials in head injury. J. Neurotrauma 19, 503–557. Oertel, M., Kelly, D.F., Lee, J.H., et al., 2002. Efficacy of hyperventilation, blood pressure elevation, and metabolic suppression therapy in controlling intracranial pressure after head injury. J. Neurosurg. 97, 1045–1053. Palmer, S., Bader, M., Qureshi, A., et al., 2001. The impact on outcomes in a community hospital setting of using the AANS traumatic brain injury guidelines. Americans Associations for Neurologic Surgeons. J. Trauma 50, 657–664. Robertson, C.S., Valadka, A.B., Hannay, H.J., et al., 1999. Prevention of secondary ischemic insults after severe head injury. Crit. Care Med. 27, 2086–2095. Sosin, D., Sniezek, J., Waxweiler, R., 1995. Trends in death associated with traumatic brain injury. J. Am. Med. Assoc. 273, 1778–1780. Stiefel, M.F., Spiotta, A., Gracias, V.H., et al., 2005. Reduced mortality rate in patients with severe traumatic brain injury treated with brain tissue oxygen monitoring. J. Neurosurg. 103, 805–811. Stocchetti, N., Furlan, A., Volta, F., 1996. Hypoxemia and arterial hypotension at the accident scene in head injury. J. Trauma 40, 764–767. Unterberg, A.W., Stover, J., Kress, B., et al., 2004. Edema and brain trauma. Neuroscience 129, 1021–1029.

Further Reading Anon., 2000. Early indicators of prognosis in severe traumatic brain injury. J. Neurotrauma 17, 535–627. Bardt, T.F., Unterberg, A.W., Hartl, R., et al., 1998. Monitoring of brain tissue PO2 in traumatic brain injury: effect of cerebral hypoxia on outcome. Acta Neurochir. Suppl. 71, 153–156.

Cohen, J., Montero, A., Israel, Z., 1996. Prognosis and clinical relevance of anisocoria-craniotomy latency for epidural hematoma in comatose patients. J. Trauma 41, 120–122. Hartl, R., Ghajar, J., Hochleuthner, H., et al., 1997. Hypertonic/hyperoncotic saline reliably reduces ICP in severely head-injured patients with intracranial hypertension. Acta Neurochir. Suppl. (Wien) 70, 126–129. Haselsberger, K., Pucher, R., Auer, L., 1988. Prognosis after acute subdural or epidural haemorrhage. Acta Neurochir. Suppl. (Wien) 90, 111–116. Horn, P., Munch, E., Vajkoczy, P., et al., 1999. Hypertonic saline solution for control of elevated intracranial pressure in patients with exhausted response to mannitol and barbiturates. Neurol. Res. 21, 758–764. Lee, E., Hung, Y., Wang, L., et al., 1998. Factors influencing the functional outcome of patients with acute epidural hematomas: analysis of 200 patients undergoing surgery. J. Trauma 45, 946–952. Munar, F., Ferrer, A.M., de Nadal, M., et al., 2000. Cerebral hemodynamic effects of 7.2% hypertonic saline in patients with head injury and raised intracranial pressure. J. Neurotrauma 17, 41–51. Qureshi, A.I., Suarez, J.I., Bhardwaj, A., et al., 1998. Use of hypertonic (3%) saline/ acetate infusion in the treatment of cerebral edema: effect on intracranial pressure and lateral displacement of the brain. Crit. Care Med. 26, 440–446. Qureshi, A.I., Suarez, J.I., Castro, A., et al., 1999. Use of hypertonic saline/acetate infusion in treatment of cerebral edema in patients with head trauma: experience at a single center. J. Trauma 47, 659–665. Sakas, D., Bullock, M., Teasdale, G., 1995. One-year outcome following craniotomy for traumatic hematoma in patients with fixed dilated pupils. J. Neurosurg. 82, 961–965. Schatzmann, C., Heissler, H.E., Konig, K., et al., 1998. Treatment of elevated intracranial pressure by infusions of 10% saline in severely head injured patients. Acta Neurochir. Suppl. (Wien) 71, 31–33. Shackford, S.R., Bourguignon, P.R., Wald, S.L., et al., 1998. Hypertonic saline resuscitation of patients with head injury: a prospective, randomized clinical trial. J. Trauma 44, 50–58. Valadka, A.B., Gopinath, S.P., Contant, C.F., et al., 1998. Relationship of brain tissue PO2 to outcome after severe head injury. Crit. Care Med. 26, 1576–1581. Van den Brink, W.A., van Santbrink, H., Steyerberg, E.W., et al., 2000. Brain oxygen tension in severe head injury. Neurosurgery 46, 868–876, discussion 876–878. Vialet, R., Albanese, J., Thomachot, L., et al., 2003. Isovolume hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2 mL/kg 7.5% saline is more effective than 2 mL/kg 20% mannitol. Crit. Care Med. 31, 1683–1687. Wilberger, J.J., Harris, M., Diamond, D., 1990. Acute subdural hematoma: morbidity and mortality related to timing of operative intervention. J. Trauma 30, 733–736.

Relevant Website www.braintrauma.org – Braintrauma.

Health and Disease, Concepts of Dina Czeresnia, Oswaldo Cruz Foundation (ENSP-FIOCRUZ), Rio de Janeiro, Brazil Teresa C Soares, Federal University in Juiz de Fora, Juiz de Fora, Brazil Ó 2017 Elsevier Inc. All rights reserved.

Health, Illness, and Disease Ask a person what it means to be healthy. If you repeat the question several times, you are certain to get different answers. It is impossible to provide a precise, generic definition, because there are various ways of experiencing health. The concept of health is a qualification of existence, and there are different ways of existing with quality of life. Health is not amenable to scientific definition; it is first and foremost a philosophical question and relates to each person’s life, as stated by French philosopher Georges Canguilhem (1990). Another point of view was proposed by Boorse (1977), who stated that the medical concept of health can be described by two elements: Biological function and statistical normalcy. According to Boorse, the concept of health as absence of disease provides a value-free scientific definition. Health has become a vast scientific field. Public health itself can be defined as an area of knowledge and practice focused on the health of populations. However, circumscribing health as a scientific issue and one involving the application of science-based technologies, led to a problem in the shaping of health practices. The relation between health care and other ways of expressing reality, such as art, philosophy, and politics has been overlooked (Czeresnia, 1999). The definition of health by the World Health Organization (WHO) as “a state of complete physical, mental, and social well-being, and not merely the absence of disease or infirmity” has been criticized in its philosophical manifestation on the grounds that it expresses hope for a reality free of obstacles, an ideal situation unrelated to the life of any human being. Health cannot be conceived statically, which may explain why it is almost always approached in reference to illness. Health and disease occur in a dynamic process. Ask anyone if they have ever been ill, and it is highly unlikely that you will get a negative answer. There is no such thing as perfect health, and disturbances are part of life. What is healthy in a given condition may not be in another; movement is a basic condition for adjusting to new situations. The capacity to bring about change and preserve one’s integrity under varying circumstances is a fundamental resource for health. Health is a way of approaching existence with the ability to create new forms of life, to find alternatives in order to deal with the inherent difficulties of living. In a meaning linked to biology, health is defined by Canguilhem (1975) as “a margin of tolerance for the inconsistencies of the environment.” Dubos presents a similar definition when he states, based on Claude Bernard, that health is “the ability of the organism to resist the impact of the outside world and maintain constant within narrow limits the physicochemical characteristics of its internal environment” (Dubos, 1987: p. 119). Health as the ability to withstand the difficulties of the environment is a concept that is also applied to psychology and psychiatry. The concept of resilience has been introduced

International Encyclopedia of Public Health, 2nd edition, Volume 3

recently to operationally approach individuals’ resources to face, react to, preserve themselves, and recover from adverse situations (Rutter, 1987). All these definitions highlight the inseparability between individuals and their environment. Health thus relates to living conditions, which for human beings are a set of physical, social, economic, cultural, and ecological circumstances. This observation led to health being defined as the responsibility of the state and a citizen’s right, an approach to health which is at the very basis of the institutional organization of modern public health (Rosen, 1993), reaffirmed in the discourse of health promotion in the contemporary world. Meanwhile, health as the result of a unique process of preservation of integrity in relation to the environment, highlights the meaning of health as a personal value and responsibility. Even so, health as a personal criterion is also mediated by societal values. The way a society conceives health interferes in, or even constitutes, individual options. There is no way to disassociate the value individuals create, when relating to their bodies in health or in disease, from the way society conceives health and disease and operates them in practice. Nevertheless, we need to distinguish between the feeling of being healthy or ill and the scientific concept of disease. Here, we should highlight that health can only be defined scientifically as the absence of disease, as proposed by Boorse. Thus, the difference between illness and having a diagnosed disease should have an equivalent for the concept of health. That is, there should be a way of differentiating between feeling healthy and not having a disease. However, we only have terms to designate this distinction in relation to disease, namely illness, for the subjective experience, and disease, for the scientific concept. For illness, what is expressed is suffering. Meanwhile, disease means living with a diagnosis mediated through a set of interventions by the health system. One meaning does not correspond exactly to the other. For example, there are circumstances in which a person does not feel ill, but has been diagnosed with a lesion that may not have produced clinical symptoms, characterizing the presence of a potential disease. On the other hand, the expression of suffering may not be translated as the diagnosis of a disease. There is a controversial relationship between the way a health system is structured as a field of social intervention and individuals’ need for health. The first is a peculiarity of a given concept of disease that imposes itself and creates technologies and demands. The latter involves individuals’ need from the point of view of the primary intuition that each human being experiences as a unique person. Discrepancies often arise between the way medicine intervenes and the way individuals feel their own bodies. Scientific medical knowledge is not always capable of dealing adequately with the subjective dimension of human suffering that comes from living with illness and the proximity of death. Works like The Magic Mountain by Thomas Mann and

http://dx.doi.org/10.1016/B978-0-12-803678-5.00182-X

381

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Health and Disease, Concepts of

The Death of Ivan Illich by Tolstoy have shown how literature is complementary to medicine in this sense. When people turn to a health professional or service, they are seeking relief for their pain, and not only a treatment plan based on tests and medication. Medicine needs to be humanized, as observed by those who contend that treatment technique should include a dialogical relationship: The convergence between the technique per se, communication, and affect, since treating and healing are more than simply medicating (Mann and Tarantola, 1996). Tables 1 and 2 systematize the concepts approached in this subitem. Table 1 presents the distinction between health as a scientific concept and as a philosophical issue. Table 2 provides the differences in meaning between the terms illness and disease.

Influence of Medical Science Throughout history, concepts of disease have been produced in the context of disputes between philosophical perspectives. Until the nineteenth century, the predominant idea was that of disease as an imbalance or disharmony between individuals and their environment. With the emergence of modern medicine, disease was conceptualized as clinical signs and symptoms arising from injury originating from specific causal agents. Medical science successively located diseases in organs, tissues, cells, genes, and enzymes. Diagnostic and therapeutic techniques were transformed with the progressive introduction of methods involving clinical analysis, imaging, discovery of new etiological mechanisms, and interventional technologies. The identification and localization of specific causal elements in which to effectively intervene is still the principal strategy of medical science. This perspective is reaffirmed by the search for causes in the genetic structure. The genetic origin of health problems was one of the most spectacular strides in medicine beginning in the second half of the twentieth century. Molecular biology achieved highly prominent development, and its spinoffs involved substantial changes in medical knowledge and intervention. Table 1

Health

Scientific concept

Philosophical question

Absence of disease Statistical normalcy Biological function

Value Normativeness Capacity to withstand environmental adversities

Table 2

Still, as knowledge expanded in molecular biology, new unknowns and challenges emerged in the attempt to fit the new findings into the underlying logic of modern medical thinking. The causal networks include a growing number of interacting elements – genetic, epigenetic, and environmental – and correspond to particular situations involving greater difficulty for generalization to population groups. The contemporary world is experiencing an increase in health problems that require reasoning that integrates organic, psychological, and sociocultural aspects. The modern concept of disease had been based mainly on the organic perspective. The difficulty in including the mental/symbolic dimension in knowledge on the etiology of diseases is one of the most striking characteristics of medical reasoning. This configuration leads to numerous contradictions. The world is witnessing a trend to assign organic causes to problems previously classified as mental. Meanwhile, many diseases classified as organic are clearly associated with psychological and social aspects. An increasing number of diseases fail to fit into exclusively mental or organic explanatory models and require interdisciplinary and multi-professional approaches (Czeresnia et al., 2013). Many medical, social, and behavioral studies still use the concept of stress to make the link between the biological, psychological, and social dimensions of disease. However, stress is not a highly explanatory concept, and there is no clear and accepted definition of a state of stress or how it leads to alterations in the organism’s internal functions (Hinkle, 1987). Without a doubt, a more adequate explanation is still needed for the relations between general living conditions, the psyche, and disease. The concept of somatic disease tended to circumscribe medical care mainly to specific, individualized interventions, with progressive specialization and incorporation of technology. Patients and their environment were in a sense carved out according to guidelines for medical intervention in this narrow sense and were thus relegated to a secondary plane. However, there was still a conflict between this trend and those who contended that the health/disease process required a broader approach, and that the health sector should be linked to other areas of knowledge and intervention.

Disease Prevention The preventive medicine movement emerged in the first half of the twentieth century. The work of Leavell and Clark (1965) in this context was important for the organizational structure of health systems worldwide and therefore merits our dwelling on their concept of prevention. Prevention is defined as “anticipatory action based upon knowledge of the natural history to make the onset of further progress of the disease unlikely” (Leavell and Clark, 1965: p. 20). Natural history, in turn, is defined as

Ilness  Disease

Illness

Disease

Subjective experience Suffering Primary intuition Need

Objective scientific concept Disease diagnosis Medical intervention Demand

all the interrelations of the agent, host, and environment affecting the complete process and its development, from the first forces which create the disease stimulus in the environment or elsewhere (pre-pathogenesis), through the resulting response of man, to the changes which take place leading to defect, disability, recovery, or death (pathogenesis). Leavell and Clark (1965: p. 18).

Health and Disease, Concepts of Prevention permeates all phases of intervention by the health system and appears at three levels – primary, secondary, and tertiary – from the process prior to onset of the disease until rehabilitation, including diagnostic and therapeutic measures. The origin of the disease is seen as a continuous chain of causes and effects and not merely the result of specific causes. The multicausal model proposed by Leavell and Clark is based on the relations between agent, host, and the environment. Although still heavily focused on the disease dimension and health services organization, the preventive medicine approach proposes health promotion as one level of primary prevention, defined as measures devoted to health in general, not oriented specifically to a single disease or disorder.

Epidemiology and Risk The intense changes in the demographic and epidemiological profile of populations, especially in developed countries, has raised the need to adjust the idea of multi-causality to the study of chronic, noncommunicable diseases. Epidemiology had already been structured as a scientific discipline since the early twentieth century, but after World War II, it gained a new configuration with the development and refinement of techniques and study designs for the analysis of causal factors for diseases (Susser, 1985). Epidemiological risk estimates are now the principal source for organizing scientific activity to determine disease etiology and evaluate medical procedures. Epidemiological studies build concepts and orient risk-control practices. Increasingly, statistical techniques have been developed for the evaluation of the causal nature of associations and interaction among causes and to guarantee the quality of findings by avoiding errors such as bias, chance, and confounding. Epidemiological studies contribute to legitimizing changes in the ways of conceiving diseases and acting to prevent, control, and treat them. These changes can be illustrated by gastric ulcer, the example used by Thagard (1998). A person with stomach pain who consulted a physician in the 1950s would have been advised to take it easy and drink milk. In the 1970s and 1980s, ulcer was considered a disease resulting from increased gastric acidity, and treatment was thus based

Table 3

on antacids. Beginning in the 1990s, it became an infection with Helicobacter pylori and medication shifted to a combination of antibiotics. Another important dimension of risk studies is the construction of a rationale for attributing positive or negative meanings to exposures, habits, or behaviors related to eating, exercise, sex, smoking, and various toxic agents. The concept of risk in the contemporary world is a central element for individual and collective decision making, and various authors have developed critical research on its implications (Lupton, 1999). What meanings are generated socially by establishing that given habits and behaviors risk harming health? The border between health and disease becomes tenuous: in addition to persons with established diseases, there are now individuals with merely a diagnosis of potential disease, thus raising an ethical dimension. For instance, with very few exceptions, disorders classified as genetic actually involve multiple factors. Genetic tests only indicate a statistical risk that may not even materialize, and thus end up inappropriately medicalizing the individual’s life (Melzer and Zimmern, 2002).

Health Promotion The exponential technological progress of biomedicine has led to an equivalent increase in the costs of financing medical procedures. This has helped revive the idea that health is a good that needs to be guaranteed before disease appears. In an official report in 1974, the Canadian government proposed the concept of health field, consisting of four components: Human biology, the environment, lifestyle, and organization of health care. The document, known as the Lalonde Report (1981), expresses the need to reorient health expenditures. According to the report, most costs come from the health-care component, yet most causes of disease and death are located in the other three. The reinvigorated discourse advocating the importance of investment in the promotion of better living and work conditions (to impact the structure that underlies health problems) has oriented the search for inter-sector strategies (Terris, 1990). The sector responsible for organizing health care should be linked to broader social policies. Meanwhile, health

Approaches to health and disease

Causal model

Components

Emphasis

Protection

Actors

Ecological Triad

Agent Host Environment Human biology Environment Lifestyle Organization of healthcare Statistical association between exposure and disease

Health services organization

Disease prevention

Health professionals

Inter-sectorality Empowerment

Health promotion

Individuals Social movements Governments

Risk management

Disease prevention

Empowerment

Health promotion

Individuals Health professionals and managers Individuals Social movements Health professionals and managers

Health field

Risk Vulnerability

Individual, social and health program aspects

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promotion programs emphasize the dimension of individual responsibility, that is, proposing to capacitate individuals and social groups to deal with and struggle for their health. Health promotion discourse covers from personal uniqueness to the broader dimension of state policies. Concepts and approaches such as vulnerability have been incorporated more recently in the search to innovate knowledge and instrumentalize practices aimed at interconnecting the multiple dimensions of health problems. The concept of vulnerability originated in the international human rights movement, to deal with the citizens’ rights of disempowered individuals or groups. The concept was introduced into public health to investigate conditions favoring the occurrence of HIV infection and AIDS. It takes into consideration and seeks to comprehensively integrate dimensions related to individual, social, and health-program aspects. It is important to emphasize that health promotion strategies are operationalized through the disease prevention and risk control approaches described in the sections above. This can lead to prevention and promotion practices not being distinguished. The difference between them depends on a clear understanding of the limits of scientific concepts to deal with the uniqueness of experiencing health and disease by persons and social groups (Czeresnia, 1999). Table 3 systematizes the approaches to health and disease presented in this article.

See also: Classic Concepts of Disease; Classification of Mental Disorders: Principles and Concepts.

References Boorse, C., 1977. Health as a theoretical concept. Philos. Sci. 44 (4), 542–573. Canguilhem, G., 1975. Le normal et le pathologique, third ed. PUF (Coll. Galien), Paris, France.

Canguilhem, G., 1990. La Sante: Concept vulgaire et question philosophique. Sables, Paris, France. Czeresnia, D., 1999. The concept of health and the difference between promotion and prevention. Cadernos de Saúde Publica 15 (4), 701–710. Czeresnia, D., Maciel, E.M.G.S., Malagon, R.O., 2013. Os Sentidos da Saúde e da Doença [The Meanings of Health and Disease]. Editora FIOCRUZ, Rio de Janeiro. Dubos, R., 1987. The Mirage of Health. Utopias, Progress and Biological Change, second ed. Rutgers University Press, New Brunswick, NJ. Hinkle, L., 1987. Stress and disease: the concept after 50 years. Soc. Sci. Med. 25 (6), 561–566. Lalonde, M., 1981. A New Perspective on the Health of Canadians. Ministry of Supply and Services Canada, Ottawa, Canada. Leavell, H.R., Clark, E.G., 1965. Preventive Medicine for the Doctor in His Community. McGraw-Hill, New York. Lupton, D., 1999. Risk: Key Ideas. Routledge, London. Mann, J., Tarantola, D.J.M. (Eds.), 1996. AIDS in the World II. Oxford University Press, New York. Melzer, D., Zimmern, R., 2002. Genetics and medicalisation. Br. Med. J. 324, 863–864. Rosen, G., 1993. A History of Public Health, expanded ed. Johns Hopkins University Press, Baltimore, MD. Rutter, M., 1987. Psychosocial resilience and protective mechanisms. Am. J. Orthopsychiatry 57 (3), 316–331. Susser, M., 1985. Epidemiology in the United States after World War II: the evolution of technique. Epidemiol. Rev. 7, 147–177. Terris, M., 1990. Public health policy for the 1990s. Ann. Rev. Public Health 11, 39–51. ́ Thagard, P., 1998. Explaining disease: correlations, causes and mechanisms. Minds Mach. 8, 61–78.

Further Reading Kleinman, A., Eisenberg, L., Good, B., 1978. Culture, illness, and care: clinical lessons from anthropological and cross-cultural research. Ann. Intern. Med. 88 (2), 251–258. Susser, M., 1973. Causal Thinking in the Health Sciences. Oxford University Press, New York.

Health and Human Rights: Overview Sofia Gruskin, University of Southern California, Los Angeles, CA, USA; and Harvard T.H. Chan School of Public Health, Boston, MA, USA Daniel Tarantola, Consultant in International and Global Health, Ferney-Voltaire, France Ó 2017 Elsevier Inc. All rights reserved.

Introduction What role do human rights have in public health work? Since the early stages of the women’s health, reproductive health, and indigenous health movements many have understood that public health policies and programs must be cognizant and respectful of human rights norms and standards. It has also been shown that lack of respect for human rights hampers the effectiveness of public health policies and programs. For the last two decades, an interdisciplinary ‘health and human rights’ movement has been generating scholarship and inspiring programming intended to realize ‘the highest attainable standard of health’ (UN International Covenant on Economic, Social, and Cultural Rights, 1966; Gruskin and Tarantola, 2001) with a particular focus on the most underserved and marginalized populations, and human rights language has been integrated into numerous national and international public health strategies, such as those embraced by UNAIDS and other actors (2005, 2006, 2015). Yet moving beyond the rhetoric, there is still diversity of opinion as to what this means in practice. Given that many public health practitioners are interested in the application of human rights to their work even as they are unsure what besides having a good heart this means for their efforts, as a first step an understanding of some aspects of human rights is necessary. In the present article we attempt to set out what application of these concepts has meant to date in practice, discuss ‘rights-based’ approaches to health, and suggest questions and concerns for the future. Although this article does not seek to incorporate bioethical frameworks into the discussion, it is important to recognize the long-standing relationship of those working in bioethics and those working in human rights in relation to health (see, e.g., UNESCO, 2005; Meng, 2008). The two fields are distinct, but they do overlap particularly in relation to instituting international guidelines for research via professional norm-setting modes. Human rights and ethics in health are closely linked, both conceptually and operationally (Mann, 1999; Gruskin and Dickens, 2006; Frewer and Rothhaar, 2010). Each provides unique, valuable, and concrete guidance for the actions of national and international organizations focused on health and development. Public health workers should appreciate their distinct value, but also the differences in the paradigms they represent in particular with respect to means of observance, action, and enforcement. The synergies between bioethics and human rights frameworks for strengthening protections in relation to health are beginning to be explored but are outside the scope of the present article. In the work of public health we have learned that explicit attention to human rights shows us not only who is disadvantaged and who is not, but also why this has occurred and

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whether a given disparity in health outcomes results from an injustice. Human rights are now understood to offer a framework for action and for programming, as well as providing a compelling argument for government responsibility – not only to provide health services but also to alter the conditions that create, exacerbate, and perpetuate poverty, deprivation, marginalization, and discrimination (Gruskin and Braveman, 2013). A diverse array of actors are increasingly finding innovative ways to relate human rights principles to health-related work, thereby demonstrating how a human rights perspective can yield new insights and more effective ways of addressing health needs within country settings as well as in the policy and programmatic guidance offered at the global level.

Approaches to Bringing Human Rights into Health Work Over time it has become clear that people tend to work in a variety of ways to further understanding and action at the intersection of health and human rights, and that while some take health as an entry point, others take human rights as such and no one approach has primacy as the only way to make these connections. Despite this diversity, the frameworks within which they operate can be generally assigned to four broad categories: advocacy, legal, policy, and programs. We summarize each framework briefly as follows.

Advocacy Frameworks Advocacy is a key component of many organizations’ work in health and human rights. Work in the advocacy category can be described as using the language of rights to draw attention to an issue, mobilize public opinion and advocate for change in the actions of governments and other institutions of power. Advocacy efforts may call for the implementation of rights even if they are not yet in fact established by law, and in so doing serve to move governmental and intergovernmental bodies closer to legitimizing these issues as legally enforceable human rights claims. This means also linking of activists working on issues related to health (such as groups focused on violence against women, poverty and global trade issues), reaching out to policy makers and other influential groups, translating international human rights norms to the work and concerns of local communities, and supporting the organizing capabilities of affected communities to push for change in legal and political structures. An example of an advocacy approach is the People’s Health Movement (PHM), a civil society initiative created in 2000, bringing together individuals and organizations committed to the implementation of the Alma Ata Declaration on Primary Health Care (Declaration of Alma Ata, 1978;

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The People’s Health Charter, 2000). In 2012, The PHM launched their ʻGlobal Thematic Campaign on Gendersʼ citing an essential piece for ensuring ʻbetter physical, mental and emotional healthʼ is the realization of ʻsexual rights for allʼ (Global Thematic Campaign on Genders, 2012).

Legal Frameworks This approach focuses on the role of law at international and national levels in producing norms, standards, and accountability for health. This includes engaging with law in the formal sense, including building on the consonance between national law and international human rights norms, for example, to promote and protect the rights of people living with HIV/ AIDS through litigation and other means. Pursuing legal accountability through national law and international treaty obligations often takes the form of analyzing what a government is or is not doing in relation to health and how this might constitute a violation of rights, seeking remedies in national and international courts and tribunals and focusing on transparency, accountability, and functioning norms and systems to promote and protect health-related rights. Examples of a legal approach include court cases in Latin America, specifically in Brazil and Colombia, invoking the right to health in addressing the national government’s responsibility to provide access to healthcare. In these cases, plaintiffs cited constitutional provisions – linked to international human rights treaty obligations – which required the governments to provide health goods and services including access to medications (Biehl et al., 2012).

Policy Frameworks This approach looks to instituting human rights norms and standards into the global and national policy-making bodies responsible for health and economic development. These include incorporating human rights norms or language in the documents and strategies that emanate from these bodies as well as the approach taken to operationalize human rights work within an organization’s individual programs and departments. In addition to the inclusion of human rights norms within drafts of recent global consensus documents such as the Report of the Open Working Group of the General Assembly on Sustainable Development Goals (UN, 2014), a large and growing number of national and international entities have formulated rights-based approaches to health in the context of their own efforts. Among these are several official development assistance organizations and agencies, funds, and programs of the United Nations System. (These agencies include UNAIDS, UNICEF, UNDP, UNFPA, and WHO) (Gruskin et al., 2010).

Programmatic Frameworks This approach is concerned with using human rights norms and standards in health programming. This can occur in the design, implementation, monitoring, and evaluation of health programs, and includes attention to what issues are prioritized and why, at all stages of the work. Often these efforts are carried out by large international organizations, including both

inter-governmental and non-governmental entities. In general, work in this category refers to inclusion of key human rights components within programmatic initiatives and in daily practice such as ensuring attention to the participation of affected communities, nondiscrimination in how policies and programs are carried out, attention to the legal and policy context within which the program is taking place, transparency in how priorities were set and decisions were made, and accountability for the results. As simply one example, Oxfam International, specifically, employs this approach because they “believe that respect for human rights will help lift people out of poverty and injustice, allow them to assert their dignity and guarantee sustainable development” (Oxfam International, 2015). Further examples with respect to this category are discussed in more detail below.

The Elusive Rights-Based Approach to Health As the health and human rights field has become more strongly rooted in robust human rights principles and sound public health, it is appropriate that such different interpretations and applications to practice are coming forward. This has, however, unfortunately, in many ways fueled a skeptical concern as to what added-value human rights offer to public health work. Despite significant differences, work which falls under these different rubrics is often amalgamated under what is called a ‘rights-based approach’ to health, and these are in themselves ‘all over the map,’ whether encompassing legal, advocacy, or programmatic efforts. One can say that it is a great accomplishment of all those who have fostered the dialogue around ‘rights-based approaches to health’ that this term is now being used to characterize such a wide range of activities. A great challenge is that the term is used in very different ways by different institutions and individuals. At worst, the inconsistencies in how ‘rights-based approaches to health’ are conceptualized threaten to undo major accomplishments. At best, the diversity in interpretation of what is meant by ‘rights-based approaches to health’ means the field is alive and well. Ultimately much of the work to bring human rights into public health is looking at synergies and trade-offs between health and human rights and working, within a framework of transparency and accountability, toward achieving the highest attainable standard of health. Central in all settings is application of the principles of nondiscrimination, equality, and the participation of affected communities. This does not mean a one-size-fits-all approach. In addition to differences in frameworks, the rights issues and the appropriateness of policies and programs relevant to one setting with one population might not be so in a different setting to another. Initially conceptualized in the mid-1990s as a ‘human rights based approach to development programming’ by the United Nations Development Programme (UNDP, 1998), rightsbased approaches have been applied to specific populations (e.g., children, women, migrants, refugees, and indigenous populations), basic needs (e.g., food, water, security, education, and justice), health issues (e.g., sexual and reproductive health, HIV, access to medicines), sources of livelihood (e.g., land tenure, pastoral development, and fisheries), and the

Health and Human Rights: Overview work of diverse actors engaged in development activities (e.g., UN system, governments, NGOs, corporate sector). Even as health cuts across all of these areas and is regarded both as a prerequisite for and an important outcome of development, the understanding of what a rights-based approach offers public health efforts varies across sectors, disciplines, and organizations. In order to define the core principles of rights-based approaches (RBAs) applicable across all sectors of development, including health, a ‘Common Understanding’ was elaborated by the UN system in 2003 (UN, 2003). In short, it suggests that the following points are critical for identifying a rights-based approach: all programs should intentionally further international human rights; all development efforts, at all levels of programming, must be guided by human rights standards and principles founded in international human rights law; and all development efforts must build the capacity of ‘duty bearers’ to meet obligations and/or ‘rights holders’ to claim rights (UN, 2003 May). UN Statement of Common Understanding of the Human Rights-Based Approach to Development 1. All programmes of development co-operation, policies and technical assistance should further the realization of human rights as laid down in the Universal Declaration of Human Rights and other international human rights instruments. 2. Human rights standards contained in, and principles derived from the Universal Declaration of Human Rights and other international human rights instruments guide all development cooperation and programming in all sectors and in all phases of the programming process. 3. Programmes of development cooperation contribute to the development of the capacities of ‘duty-bearers’ to meet their obligations and/or of ‘rights-holders’ to claim their rights. This Common Understanding has already shown clear potential for the implementation of health policies and programs, even as there is tremendous diversity in how these concepts are applied. A review of public health programs termed ‘rights based’ by a range of UN system actors and their partners points to several areas relevant to what implementation of a rights-based approach to health might look like (Gruskin et al., 2010). A rights based approach to health makes explicit reference to human rights from the outset, does not invent the content of rights, and does not name the relevance of rights only in retrospect; it emphasizes building capacity and does not use human rights norms as a way to name violations after they occur but as a way to promote health and prevent violations from occurring in the first place; and it is based on implementation of one or several core rights concepts, including nondiscrimination, participation, accountability, and transparency. Anchoring public health strategies in human rights can enrich the concepts and methods used to attain health objectives by bringing attention to the ways in which the legal and policy context within which health interventions occur can impact program outcomes, as well as bringing in rights principles such as nondiscrimination and the participation of affected communities in the design, implementation, monitoring, and evaluation of health systems, programs, and other interventions. In addition, it can allow for governments and

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intergovernmental agencies to be held publicly accountable for their actions and inactions. The introduction of human rights into public health work is about approaches and processes and their application toward maximum public health gains. It does not mean how the work is done or what its ultimate outcome will be is preordained to be a certain way. For example, using human rights standards with a focus on the delivery of health services requires attention to their availability, accessibility, acceptability, quality, and outcomes among different population groups (see section Annex 1 at the end of the article for the full text of the General Comment which serves as the authoritative interpretation of the right to health) (General Comment No. 14, 2000). These terms have concrete implications: Availability demands that public health and health-care facilities, goods, and services, as well as programs be offered to the maximum availability of resources available to governments. These resources may originate from public funding sources or international aid. l Accessibility requires that health facilities, goods, and services be attainable by everyone without discrimination, including gender and other recognized forms of discrimination as well as socioeconomic status, the community to which they belong, and the distance they live from an urban area. l Acceptability calls for health facilities, goods, and services to be culturally and otherwise appropriate for the intended populations. l Finally, health facilities, goods, and services must be scientifically and medically appropriate and of the optimal quality. l

Although none of the above should be unfamiliar to those working in public health, the added value of a human rights approach to health is in systematizing attention to these issues, requiring that benchmarks and targets be set to guarantee that any targets set are realized progressively, and ensuring transparency and accountability for what decisions are made and their ultimate outcomes.

Rights-Based Approaches to Health in Practice Bringing health and human rights together provides a framework within which the progress, success, or failure of a policy or program can be developed and evaluated against both public health and human rights benchmarks. In practice, the assessment, design, implementation, monitoring, and evaluation of any health policy, strategy, and program or intervention should incorporate the key components of a rights-based approach. Public health and human rights practitioners are increasingly working to transform a commitment to health and rights into an agenda for action with respect to the development, design, implementation, monitoring, and evaluation of policies, programs, and interventions. Table 1 is given as an example of how the connections between sound public health and human rights norms and standards can be explicitly established and strengthened. It represents an attempt to outline a process whereby points of convergence and possible tensions

Applying a rights-based approach to public health: examples of questions to be addressed to ensure maximum congruence between public health and human rights Participation

Attention to most vulnerable populations

Nondiscrimination

Accountability Have policies and laws been debated through political processes and in public fora? Are policies, programs, and interventions consistent with the law and human rights norms and standards? Have policies and laws been translated into decrees or other instruments to make them effective? Is a reporting mechanism in place to address claims of violations of policies and laws? Is a functioning judicial process in place to handle these claims? Have efforts been made to alert people about policies and laws specifically relevant to them? How and by whom will the results of the analysis be disseminated among political leaders, professional groups, communities, and the media? Will the situation assessment be carried out by competent and trustworthy entities? Has the existing body of evidence informed the situation assessment design? Is the presentation of results sensitive to the risk of aggravating discrimination? If so, what mechanism has been put in place to minimize this risk? Is the development of policy, program, or intervention openly discussed with vulnerable communities or their representatives? If restrictions of rights have been pronounced in the interest of public health, has there been a clear presentation of the reasons for and process applied to such decisions? Have the authorities responsible for designing the policy, program, or intervention been made known to the public? Does the policy, program, or intervention meet the criteria of availability, accessibility, acceptability, and quality in the way it responds to the needs of the population? Does the design of the policy, program, or intervention include targets and benchmarks to measure progress in relation to availability, accessibility, acceptability, and quality of services?

1. Policy and legal context

Is participation of communities and interest groups supported by law and policy? Have communities been exposed to or disproportionately affected by the health issue in question, been invited to contribute to the drafting of policies concerning them?

Do policies refer to specific vulnerable populations with regards to health, disability, and social and economic determinants? Have the structures, processes and needed resources been made available to translate these policies and laws into practice?

Are policies and laws discriminatory with regards to ill health and its recognized social and economic determinants, practices, and impacts? Are there policies and laws that specifically oppose discrimination on the grounds of health or disability status and their recognized social determinants, practices, and impacts? Are there monitoring, claims, and redress mechanisms in place?

2. Analysis of the health situation of a particular population or of a specific public health problem

Have members of concerned governmental sectors, private sector, and civil society organizations participated in the design of the study? Has attention been devoted to ensure that populations affected by ill health or their representatives have participated in the design of situation assessments?

Is the situation assessment in any way discriminatory in its aim, design, conduct, and analysis?

3. Process of devising a public policy, program, or intervention

Has public information and consultation been included in the steps taken to devise the policy, program, or intervention? Have divergent views been taken into consideration before a final decision was reached?

Has the situation assessment recognized populations most vulnerable to ill health or disability and focused on assessing their situation, needs and capacity? Have factors leading to increased vulnerability to ill-health and disability been appropriately mapped out and incorporated in the design of the situation analysis? Have communities particularly concerned with the health or disability issue participated in policy, program, or intervention design? What benefits and risks from the policy, program, or interventions could accrue to communities particularly vulnerable to or affected by the health or disability issue? Are sufficient attention and resources devoted to the meet the needs of vulnerable populations?

Is the design of the policy, program, or intervention, in any way discriminatory? Are there legitimate restrictions of rights being considered as part of the policy, program, or intervention? If so, what process has been put in place to legitimize such restrictions?

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Human rights elements public health elements

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Table 1

4. Implementation of policy, program, or intervention on health and disability

Are public information, education and participation effectively included in policy, program, or intervention implementation? Have actors in health systems and other relevant sectors been educated, trained, and equipped to implement the policy, program, or intervention in a health and human rights sensitive fashion?

Are particularly vulnerable or affected communities engaged in implementing the policy, program, or intervention? Is implementation of the policy, program, or intervention striving towards greater availability, accessibility, acceptability, and quality of services among these populations?

5. A framework within which the success or failure of a policy or program can be evaluated, against both public health and human rights benchmarks

Have targets been set and success and failure been defined with public participation?

Have targets been set and success and failure been defined with the participation of vulnerable or affected communities or their representatives? Is implementation meeting the needs of these populations to the maximum of available resources? Are monitoring and evaluation systems efficiently monitoring and evaluating availability, accessibility, acceptability, and quality of services among these populations?

Is implementation of the policy, program, or intervention discriminatory in its application? In what forms is such discrimination perpetrated? In what setting and by what actors? How can discrimination in implementation of the policy, program, or intervention be combated? What plans have been made and resources allocated to combat active discrimination? Is the monitoring and evaluation system designed to detect causes, practices, and impacts of discriminatory actions? Are claims on grounds of discrimination heard and taken into account in the monitoring and evaluation process?

Does the implementation of the policy, program, or intervention meet the criteria of availability, accessibility, acceptability, and quality in the way it responds to the needs of the population?

Health and Human Rights: Overview

Is there a mechanism to monitor and evaluate the implementation and impacts of the policy, program, or intervention according to set criteria of availability, accessibility, acceptability, and quality? Have processes been planned and resourced to measure the impact of the policy, program, or intervention put in place? Are these findings made public? Are the impacts on health of any potential violations of human rights researched and documented? Has the policy, program, or intervention contributed to the promotion of human rights, including the right to health? Has the policy, program, or intervention contributed to progress in the realization of other human rights? Are these findings used to inform needed changes or adjustments in policy, program, or interventions both within and outside the health sector?

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between health and rights practices may emerge. It schematically divides the field into five elements, including policy and legal context; situation assessment and analysis; policy, program or intervention design; implementation; and monitoring and evaluation. It proposes questions that would allow each of these elements to be examined from the perspective of key components of a rights-based approach selected for their relevance to both public health and human rights: participation, attention to the most marginalized populations, nondiscrimination, and accountability. This table is merely intended to help systematize and present examples of the questions that a rights-based approach to health would ask at each stage of engagement. It is in no way intended to be exhaustive, and if used in practice would require adaptation with respect to the specific health or disability issue considered. Additionally, careful selection and use of both health and human rights indicators can reveal trends in government and institutional compliance with human rights obligations, and reveal areas where further effort can lead to improved health outcomes (Gruskin and Ferguson, 2009). A rights-based approach to health therefore can guide choices about what should be done and how it should be done, for example when applied locally to an institutional or community setting. As with other approaches applied to public health programming efforts, it aims to achieve congruence in responding to individual and collective health needs but also seeks to advance the promotion and protection of human rights. Applying a rights-based approach is only one tool in doing effective public health work. It does not, in and of itself, for example, establish priorities among programs competing for resources, each of which arguably would improve health and the satisfaction of relevant rights, nor does it determine the best way to intervene once a particular intervention has been agreed upon. A rights-based approach will be strongest when used in conjunction with empirical assessment of the complex epidemiological, economic, management, and other information relevant to deciding how resources can most effectively be used and what kinds of improvements in population health should be emphasized.

Conclusion Considerable progress has been achieved in the last decade or so in understanding and promoting rights-based approaches to health. Nonetheless, in some quarters, paying attention to human rights is seen as too costly, and not a priority for cash strapped public health programs (Angotti, 2012). Although this notion is based on a misinterpretation of how human rights and health actually operate, the skepticism driving such arguments will need to be addressed in the coming years. Greater clarity about the central paradigms of health and human rights is essential to make this work more effective. A benefit then of considering different ways of conceptualizing and pursuing rights-based approaches to health alongside one another is that when considering different initiatives that claim to be ‘rights-based’ it is possible to get a clearer sense of what work is being done and its positive effects, but also what work is needed to move the field of health and human rights in the direction of greater clarity. The idea is not to impose

one definition of rights-based approaches to health over another, but rather to encourage a discussion about how efforts among different actors working in health and human rights can be better aligned. A preliminary step is to examine these differences rather than to obscure them. Of critical importance is documentation of the effectiveness of rights-based approaches to health; that is, presentation of solid evidence of how human rights approaches to public health initiatives have actually strengthened those initiatives and informed sound public health practice rather than acting as deterrents. This is beginning to happen, but the rightsbased approaches to health currently under way in different sorts of institutions should be examined and validated to ensure clarity in what are understood to be the strengths and limitations of the ways they bring human rights into governmental, nongovernmental, and international health work (WHO, 2013). Efforts are needed to collect and analyze data to demonstrate how human rights have been relevant with respect to each aspect of public health programming ranging from the analysis of the health and health needs of a population to the ways health systems performance assessments are done. Research is then needed not only to expand the evidence already available that infringements on human rights negatively affect health, but that the enjoyment of human rights – all human rights – has beneficial impacts on health and well-being. It is through such efforts that the ability to generate robust evidence of the effectiveness of rights-based approaches to health will occur. This will require marshalling the skills and commitment of the entire public health community. While embracing the differences in how rights-based approaches are operationalized, the task is now to ensure that public health and human rights continue to come together in strong, powerful, and practical ways.

Annex 1 The Right to the Highest Attainable Standard of Health: 11/08/2000 E/C.12/2000/4. (General Comments) Committee on Economic, Social and Cultural Rights, Twenty-second session, Geneva, 25 April–12 May 2000, Agenda item 3. Substantive Issues Arising in the Implementation of the International Covenant on Economic, Social, and Cultural Rights.

General Comment No. 14 (2000) The right to the highest attainable standard of health (article 12 of the International Covenant on Economic, Social, and Cultural Rights).

Excerpts 11. The Committee interprets the right to health, as defined in article 12.1, as an inclusive right extending not only to timely and appropriate health care but also to the underlying determinants of health, such as access to safe and

Health and Human Rights: Overview potable water and adequate sanitation, an adequate supply of safe food, nutrition and housing, healthy occupational and environmental conditions, and access to health-related education and information, including on sexual and reproductive health. A further important aspect is the participation of the population in all health-related decision-making at the community, national and international levels. 12. The right to health in all its forms and at all levels contains the following interrelated and essential elements, the precise application of which will depend on the conditions prevailing in a particular State party: (a) Availability. Functioning public health and health-care facilities, goods and services, as well as programmes, have to be available in sufficient quantity within the State party. The precise nature of the facilities, goods and services will vary depending on numerous factors, including the State party’s developmental level. They will include, however, the underlying determinants of health, such as safe and potable drinking water and adequate sanitation facilities, hospitals, clinics and other health-related buildings, trained medical and professional personnel receiving domestically competitive salaries, and essential drugs, as defined by the WHO Action Programme on Essential Drugs. (b) Accessibility. Health facilities, goods and services have to be accessible to everyone without discrimination, within the jurisdiction of the State party. Accessibility has four overlapping dimensions: Non-discrimination: health facilities, goods and services must be accessible to all, especially the most vulnerable or marginalized sections of the population, in law and in fact, without discrimination on any of the prohibited grounds. Physical accessibility: health facilities, goods and services must be within safe physical reach for all sections of the population, especially vulnerable or marginalized groups, such as ethnic minorities and indigenous populations, women, children, adolescents, older persons, persons with disabilities and persons with HIV/AIDS. Accessibility also implies that medical services and underlying determinants of health, such as safe and potable water and adequate sanitation facilities, are within safe physical reach, including in rural areas. Accessibility further includes adequate access to buildings for persons with disabilities. Economic accessibility (affordability): health facilities, goods and services must be affordable for all. Payment for health-care services, as well as services related to the underlying determinants of health, has to be based on the principle of equity, ensuring that these services, whether privately or publicly provided, are affordable for all, including socially disadvantaged groups. Equity demands that poorer households should not be disproportionately burdened with health expenses as compared to richer households. Information accessibility: accessibility includes the right to seek, receive and impart information and ideas concerning health issues. However, accessibility of information should not impair the right to have personal health data treated with confidentiality. (c) Acceptability. All health facilities, goods and services must be respectful of medical ethics and culturally

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appropriate, i.e., respectful of the culture of individuals, minorities, peoples and communities, sensitive to gender and life-cycle requirements, as well as being designed to respect confidentiality and improve the health status of those concerned. (d) Quality. As well as being culturally acceptable, health facilities, goods and services must also be scientifically and medically appropriate and of good quality. This requires, inter alia, skilled medical personnel, scientifically approved and unexpired drugs and hospital equipment, safe and potable water, and adequate sanitation.

See also: Agenda Setting in Public Health Policy; EvidenceInformed Public Health Policy; Global Health Law: International Law and Public Health Policy; Public Health Law and Public Health Policy.

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The Peoples Health, July 2012. Global Thematic Campaign on Genders (2012), Third People’s Health Assembly. Cape Town, South Africa. http://www. phmovement.org/sites/www.phmovement.org/files/IWDay%20launch%20gender %20circle.pdf (accessed March 2015). UN, 1966. International Covenant on Economic, Social and Cultural Rights. Adopted 16 December 1966, 993 U.N.T.S. 3 (entered into force 3 January 1976), G.A. Res. 2200 (XXI), 21 U.N. GAOR Supp. (No. 16) at 49, UN Doc. A/6316 (1966). See art. 11. UN, 2003a. The Statement on a Common Understanding of a Human Rights Based Approach to Development Cooperation. As agreed the Stamford Workshop and endorsed by the UNDG Programme Group. http://www.portal.unesco.org/shs/en/ ev.php-URL_ID¼7947&URL_DO¼DO (accessed March 2015). UN, 2003b. The Human Rights-Based Approach to Development Cooperation towards a Common Understanding among the UN Agencies (‘Common Understanding’) (Outcome document from an interagency workshop on a Human Rights-based Approach in the context of UN reform 3–5 May 2003). http://www.undp.org/governance/docs/HR_Guides_CommonUnderstanding.pdf (accessed December 2007). UN, 2006. Political Declaration on HIV/AIDS. GA Res. 60/262, UN GAOR, 60th Sess., UN Doc. A/RES/60/262, (2006). http://www.data.unaids.org/pub/Report/2006/ 20060615_HLM_PoliticalDeclaration_ARES60262_en.pdf (accessed December 2007).

UN, 2014. Report of the Open Working Group of the General Assembly on Sustainable Development Goals. UN Doc. A/68/970. www.un.org/ga/search/view_doc.asp? symbol¼A/68/970 (accessed February 2015). UNAIDS, August 2005. Intensifying HIV Prevention. UNAIDS policy position paper. UNAIDS/05.18E. http://www.data.unaids.org/publications/irc-pub06/jc1165intensif_hiv-newstyle_en.pdf (accessed December 2007). UNAIDS, 2006. Scaling up Access to HIV Prevention, Treatment, Care and Support: The Next Steps. http://www.data.unaids.org/Publications/IRC-pub07/jc1267-univaccessthenextsteps_en.pdf (accessed March 2015). UNAIDS, 2015. Global Aids Response Progress Reporting 2015. http://www.unaids.org/ sites/default/files/media_asset/JC2702_GARPR2015guidelines_en.pdf (accessed March 2015). UNDP, 1998. Integrating Human Rights with Sustainable Human Development. UNDP. http://www.undp.org/governance/docs/HR_Pub_policy5.htm (accessed December 2007). UNESCO, 2005. Universal declaration on bioethics and human rights. In: UNESCO Resolution Adopted on, the Report of Commission III at the 18th Plenary Meeting, on 19 October 2005. UNESCO, Paris, France. World Health Organization, 2013. Women’s and Children’s Health: Evidence of Impact of Human Rights. WHO Press, Geneva, p. 136.

Health Behavior and Risk Factors Karen Glanz, Perelman School of Medicine and School of Nursing, University of Pennsylvania, Philadelphia, PA, USA Ó 2017 Elsevier Inc. All rights reserved.

Why Health Behavior Is Important Health-related behavior is one of the most vital elements to the public’s health and well-being. Its importance has grown during the past century, as sanitation has improved and medicine has advanced so that once deadly or incurable diseases can be prevented or successfully treated. Thus, health-related behavior is an increasing focus of attention in public health and improving health-related behavior is central to public health activities. The major causes of death in the United States and other developed countries are chronic diseases such as heart disease, cancer, and stroke. The causes of each of these diseases include health risk behaviors. Behavioral factors are thought to contribute to almost half of the deaths in the United States. The most common behavioral contributors to mortality, or death, in 2000 were tobacco, poor diet and physical inactivity, and alcohol use; other significant causes of death include firearms, sexual behavior, motor vehicle crashes, and illicit use of drugs. These behaviors were responsible for nearly one million deaths in just a single year (Mokdad et al., 2004). The resurgence of infectious diseases, including foodborne illness and tuberculosis, and the emergence of new infectious diseases such as antibiotic-resistant infections, HIV/AIDS, hepatitis C, and human papillomavirus (HPV) are also influenced by human behaviors. Of the 12 leading causes of death, behavioral factors are related to all of them. The social and economic costs related to these behaviors can all be greatly reduced by changes in individuals’ behaviors. Over the past 20 years, there has been a dramatic increase in public, private, and professional interest in preventing disability and death through changes in lifestyle behaviors and participation in screening programs. Much of this interest has been stimulated by changes in disease patterns from infectious to chronic diseases as leading causes of death, the aging of the population, rapidly escalating health-care costs, and data linking individual health risk behaviors to increased rates of morbidity and mortality. Although there is more information about what constitutes healthy behavior and risk factors than ever before, this has not always led people to practice healthier behaviors. There have been some positive changes: In the United States in the late 1980s and 1990s, average daily intake of dietary fat dropped from 36% to 34% of total energy, seat belt use increased from 42% to 67%, and the number of women over the age of 40 who had breast exams and mammograms doubled. However, not all the news is favorable. More adults and children are overweight. Diabetes is increasing in near-epidemic proportions. More adolescents are sexually active. After major increases in seat belt use in the early 1990s, rates declined slightly and remain at 67%, well below the target rate of 85% (NCHS, 2001). One-fifth of children under 3 years old have not received a basic series of vaccinations for polio, measles, diphtheria, and other diseases. Ethnic minorities and those in poverty experience a disproportionate burden of preventable

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disease and disability, and for many conditions the gap between disadvantaged and affluent groups is widening (House and Williams, 2000). Patterns of risk factors and their impact on the burden of disease vary across regions of the world, with the most striking differences found between developing and developed regions. In the poorest regions, behaviors associated with childhood and maternal malnutrition, unsafe sex, tobacco and alcohol use, and personal and household hygiene are leading causes of disease burden (Ezzati et al., 2002). In both developing and developed regions, behavioral risk factors of alcohol use, tobacco, and cardiovascular risks strongly influenced by dietary and physical activity behaviors – high blood pressure and high cholesterol – are major causes of disease burden (Ezzati et al., 2002). Updated projections of global mortality and the burden of disease suggest that noncommunicable diseases will increase in the next two decades, and that tobacco-attributable deaths in particular will continue to rise. Global HIV/AIDS deaths are projected to more than double and to become the leading cause of disease burden in middle- and low-income countries by 2015 (Mathers and Loncar, 2006). Both health behavior and medical care will influence emerging disease patterns: for example, the reach of effective antiretroviral drugs and increased prevention activity have the potential to affect these projections from the World Health Organization between now and 2030 (Mathers and Loncar, 2006).

Definitions of Health Behavior Health behavior encompasses a large field of study that cuts across various disciplines, including psychology, education, sociology, public health, epidemiology, and anthropology. In the broadest sense, ‘health behavior’ refers to the actions of individuals, groups, and organizations as well as their determinants, correlates, and consequences, including social change, policy development and implementation, improved coping skills, and enhanced quality of life. Health behavior includes not only observable, overt actions but also the mental events and feeling states that can be reported and measured. Health behavior has been defined as “those personal attributes such as beliefs, expectations, motives, values, perceptions, and other cognitive elements; personality characteristics, including affective and emotional states and traits; and overt behavior patterns, actions, and habits that relate to health maintenance, to health restoration, and to health improvement” (Gochman, 1982). Gochman’s definition is consistent with the definitions of specific categories of overt health behavior proposed by Kasl and Cobb in their seminal articles (1966a,b). They define three categories of health behavior as follows: l

Preventive health behavior. Any activity undertaken by an individual who believes him- or herself to be healthy, for the purpose of preventing or detecting illness in an

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asymptomatic state, is defined as preventive health behavior. This can include self-protective behavior, such as wearing a helmet when riding a bicycle, using seat belts, or wearing a condom during sexual activity. l Illness behavior. Illness behavior is any activity undertaken by an individual (who believes she or he is ill) to define his or her state of health and discover a suitable remedy (Kasl and Cobb, 1966a). l Sick-role behavior. Any activity undertaken by an individual who considers her- or himself to be ill, for the purpose of getting well, is defined as sick-role behavior. It includes receiving treatment from medical providers, which generally involves a whole range of dependent behaviors, and leads to some degree of exemption from one’s usual responsibilities (Kasl and Cobb, 1966b). These classic definitions have stood the test of time, and continue to be used by students and public health workers alike. However, the lines between these three categories have blurred somewhat over time. For example, the period of survival after a major illness event such as a heart attack or a cancer diagnosis has become longer as treatments and disease management have improved. Cancer survivors can benefit from increased physical activity after initial treatment, both to improve quality of life and to prevent recurrence of the cancer. Diabetes self-management involves a complex set of behaviors that help to reduce health risks and prolong healthy functioning. So, a person who has been diagnosed with a serious disease may practice preventive health behavior for both disease management and prevention of further health risks. As well, classic definitions of health behavior emphasize the actions of individuals, in contrast to a public health perspective, which is concerned with individuals as part of a larger community. Also, individuals’ actions (behaviors) are what determine many of the social conditions that affect people’s health. For example, people act collectively to make laws and policies and to implement and enforce them. Additional useful distinctions can be made between ‘episodic’ and ‘lifestyle’ behaviors, or habits. Episodic health behavior can be something that is done once, or periodically, like getting immunizations or a flu shot. It can also be something that one does only to oneself, such as putting on sunscreen, or a behavior that affects others, like putting up a shade cover so children at the playground are protected from the sun. Lifestyle behaviors, or health habits, are actions that are performed over a long period of time, such as eating a healthful (or unhealthy) diet, getting regular physical activity, and avoiding tobacco use. A composite of various healthful behaviors is often referred to as a ‘healthy lifestyle.’ However, most people do not practice all healthful or risky behaviors consistently, for instance, someone might get regular, health-promoting exercise several times a week but be a cigarette smoker who seldom brushes his or her teeth. Or someone might quit smoking, only to begin overeating as a substitute. In the ideal, the person who practices a variety of behaviors in a healthenhancing manner can be described as having a healthy lifestyle. More realistically, though, many people practice some, but not all, lifestyle behaviors in a healthy manner.

At-Risk Populations as Defined by Their Health Behaviors The idea of ‘risk factors’ or ‘at-risk populations’ is complex and involves many dimensions of risk.

Biological Risk Biological risk involves risks that are part of one’s physical make-up, and may involve hereditary disorders or genetic predisposition to certain diseases. For example, some of the better-known hereditary diseases such as Tay-Sachs disease, Huntington’s disease, and cystic fibrosis are primarily biologically determined and, to date, there are no known behaviors to recommend for preventing them. Other biological risks can be addressed, at least partly, by preventive health behavior: fair-skinned people are at greater risk for skin cancer, and someone whose parent died of a heart attack in their 40s is likely to have an increased risk for heart disease. Fair-skinned people can make strong efforts to avoid exposure to ultraviolet radiation (UVR) or sunlight, and those with a family history of heart disease can avoid tobacco, maintain a healthy weight, and manage risk factors such as high blood pressure and high cholesterol. There are other biological predispositions that confer increased risk to people in combination with certain exposures – often behavioral – that are increasingly being uncovered through scientific research in molecular epidemiology, also often known as genetic epidemiology. For example, a man with a family history of colon cancer who eats a lot of red meat might be increasing his risk more than would a woman with no relatives who have had the disease.

Environmental Risk Another category of risk is environmental risk, which may or may not be within the control of individuals’ behavior. Examples include air pollution, water pollution, congested traffic, and characteristics of the ‘built environment’ such as urban sprawl. These risks may affect people’s health directly – such as when high levels of particles in the air cause asthma or allergies to flair up, or indirectly through health behavior – such as when people spend a lot of time in their cars, being sedentary, because of lengthy commuting distances to work.

Social Risk Factors Social risk factors have been increasingly recognized by social scientists and epidemiologists over the past 30 years (Berkman and Kawachi, 2000). Social isolation is thought to increase the risk of both physical and psychological health problems. Again, this can be considered a direct social risk or one that operates through behaviors such as poor self-care, and increased use of alcohol and drugs. In contrast, social support systems are believed to be protective to individuals and ‘social capital’ is a construct that describes communities that are more likely to be cohesive, trusting, and to have better health.

Behavioral Risk Factors Finally, behavioral risk factors are risks identified specifically with the practice, or failure to practice, an action or series of

Health Behavior and Risk Factors actions that are associated with health outcomes. These include tobacco use, poor diet, physical inactivity, risky sexual behavior, poor dental hygiene, drinking and driving, and many others that are important contributing causes to illness or inadequate disease management.

Determinants of Health Behavior There are many questions about how health behavior develops and is sustained. Therefore, both public health workers and scientific researchers continue to attempt to understand the nature and causes of many different health behaviors that lead to varying levels of risk for disease. An understanding of the determinants of health behavior is critical for developing effective interventions that may reinforce or change behavior. Numerous theories and models have been developed to understand health behavior and its determinants. The determinants of health behavior are complex and multifaceted, so one single theory rarely can explain a health behavior (Glanz et al., 2015). Because of this, some models have been developed that use multiple theories to help understand a specific problem in a particular setting or context.

Behavioral Theories

Broadly speaking, these theories and models can be broken down into two categories: (1) theories of behavioral prediction or explanation; and (2) theories of behavior change or action. Explanatory or predictive theories help to identify factors that may influence a health behavior; if properly specified, explanatory theories should be able to predict reasonably well who will be more or less likely to perform a given behavior. In contrast, theories and models of behavior change focus on the change process; these theories tend to detail stages through which individuals progress before achieving lasting health behavior change. Though these two types of theories often have different emphases, they are complementary. For example, knowing the reasons why someone smokes is important for the development of effective smoking cessation materials, but equally important is an understanding of how someone who has made several unsuccessful quit attempts in the past can progress to becoming a nonsmoker. The major theories can be classified into roughly three categories: (1) individual level, focusing on constructs such as knowledge and attitudes; (2) interpersonal level, emphasizing social factors such as social norms or social support; and (3) structural or environmental, emphasizing multiple levels of influence, including access to resources, laws, and policies. The most commonly used theories cut across these levels (Glanz et al., 2015; Glanz and Bishop, 2010). have conducted several reviews of health behavior theories presented in major health education, health behavior, and preventive medicine journals. The most common health behavior theories used in research published in health education, health behavior, and preventive medicine journals are briefly described here. The health belief model (Rosenstock, 1974) was originally developed to explain why people took or did not take advantage of preventive services such as disease screening and immunizations. The model suggests that when a person perceives a threat that has severe consequences, and believes she or he is likely to take action. To take action against

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that threat (i.e., change their behavior), the individual must also perceive that the benefits outweigh the costs of the preventive action. The theory of reasoned action (Ajzen and Fishbein, 1980) proposes that the most proximal indicator of actual behavior is behavioral intention. Behavioral intentions, in turn, are a function of (1) attitudes toward the behavior, and (2) subjective norms regarding the behavior. Attitudes are made up of beliefs about the positive and negative consequences associated with performing the behavior, as well as an individual’s evaluation of those consequences. Subjective norms are a function of normative beliefs that people who are important to the individual think they should or should not perform the behavior, as well as that individual’s general motivation to comply with a particular person’s wishes. An extension of the theory of reasoned action, the theory of planned behavior (Ajzen, 1985) includes the idea of perceived behavioral control. Perceived behavioral control depends on specific beliefs about the likelihood that certain conditions might affect the ability to control the behavior, and whether those conditions would encourage or constrain behavioral performance. Perceived behavioral control is similar to selfefficacy, found in social cognitive theory. Social cognitive theory (SCT) (Bandura, 1986) purports that people and their environments are thought to interact continuously. A basic premise of SCT is that people learn not only through their experiences, but also by watching the way other people act and the results they achieve. According to SCT, three primary factors affect behavior. First, individuals must have self-efficacy, or the confidence in their ability to perform particular behaviors (akin to perceived behavioral control above). Second, individuals must have personal goals that provide them with meaningful incentives for change. Third, the perceived advantages of practicing the behavior must outweigh the obstacles that hinder behavior change. Like SCT, social ecological models of behavior change emphasize the importance of the interplay between individuals and their environments. Sallis and Owen (2015) suggest the following with respect to health behavior determinants: (1) individual, social, and environmental forces determine health behavior; (2) both natural and built environments influence health behavior, including actual and perceived influence; (3) different levels of aggregation (including individuals, families, organizations, communities, and populations) need to be considered, both to understand and to change health behavior; and (4) behavior-specific ecological models may improve behavioral prediction and change. The stages of change model – or the transtheoretical model – addresses individuals’ readiness to change their behaviors from unhealthy to healthy (Prochaska et al., 2015). Its basic premise is that behavior change is a process and not an event, and that individuals are at varying levels of readiness to change. This means that people at different points in the process of change can benefit from different programs for change. In developing successful behavior change intervention, the programs work best if matched to the person’s stage at that time. For example, a smoker who has never thought about quitting will need different messages (to motivate the smoker to think about quitting) than a smoker who has made repeated unsuccessful attempts (to build self-efficacy to quit).

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It is useful to consider these various theories in context, relative to the level of analysis (individual, social, environmental) and to determine whether they focus primarily on explaining or changing behavior. The health belief model, the theory of reasoned action, and the theory of planned behavior can all be considered explanatory theories of individual health behavior, in that they all have a clearly defined set of constructs, specify the relationships between constructs, and focus on individual explanations for health behavior. SCT, which contains a larger number of constructs, and a more dynamic relationship between individuals and their environments, shares some features with the aforementioned theories, as well as similarities with social ecological models of behavior. By viewing behavior as a dynamic process, and highlighting the importance of social and environmental determinants, SCT and social ecological models are more complex, and provide a more holistic approach to behavior change. Finally, the stages of change model focuses on the behavior change process, and are best used in conjunction with other behavioral theories.

Overlap of Behavioral Theories

Various theories of health-related behavior often overlap. Not surprisingly, these explanations for behavior and models for change share several important cross-cutting issues and constructs. This section highlights a few of the most important of these.

Behavior Change as a Process

One central idea that has gained wide acceptance in recent years is the simple notion that behavior change is a process, not an event. Rather, it is important to think of the change process as one that occurs in stages. It may involve more than someone deciding 1 day to stop smoking and the next day becoming a nonsmoker for life. Also, most people won’t be able to dramatically change their eating pattern all at once. The idea that behavior change occurs gradually is not new, but it has gained wider acceptance in the past few years. Indeed, some multistage theories of behavior change date back more than 50 years (Lewin, 1935; Weinstein, 1993).

Changing Behaviors versus Maintaining Behavior Change

Even when there is good initial compliance to a health-related behavior using change advice or attempts (e.g., applying sunscreen or changing diet), relapse is very common. Thus undertaking initial behavior changes and maintaining behavior change are very different and require different types of programs and/or self-management strategies. For example, someone could quit smoking by going ‘cold turkey,’ but they will probably be tempted again, perhaps at a party where their friends are smoking. To maintain cessation behavior requires developing self-management and coping strategies, and establishing new behavior patterns that emphasize perceived control, environmental management, and improved confidence in one’s ability to avoid temptation.

Barriers to Actions, Pros and Cons, and Decisional Balance

The concept of barriers to action, or perceived obstacles, is often mentioned in theories of health behavior. An extension of the concept of barriers to action involves the net benefits of action, also referred to as ‘benefits minus barriers’ in the

health belief model (Glanz and Rimer, 2005). In the stages of change model, there are parallel constructs labeled as the pros (the benefits of change) and cons (the costs of change) (Prochaska et al., 1992). Taken together, these are known as decisional balance, or the pros minus cons, similar to the net benefits of action in the health belief model. In the theory of reasoned action and theory of planned behavior, attitudes, norms, and perceived behavioral control each consists of the sum of different positive and negative beliefs. The idea that individuals engage in relative weighing of the pros and cons has its origins in models of decision making, and has been considered important for many years (Lewin, 1935; Janis and Mann, 1977). Indeed, this notion is basic to models of rational decision making, in which people intellectually think about the advantages and disadvantages, obstacles and facilitators, barriers and benefits, or pros and cons, of engaging in a particular action.

Behavior-Change Strategies for At-Risk Populations Why Focus on High-Risk Populations?

From a public health perspective, it may be prudent to focus on high-risk populations and especially those who are at risk because of their health behaviors. There are limited resources to encourage and support risk reduction efforts, and focusing those resources (time, money, programs) on those at high risk may be more efficient. People have variable levels of need as defined by the chances that they will get sick or die prematurely, and it makes sense to concentrate efforts on those with greatest need. Intervention strategies may have a larger effect on people who are at risk, and further, the risk (and association perceptions of risk) may increase the salience of the issue and the motivation to change.

Health Risk Communication

A decision to focus behavioral interventions on high-risk populations must be accompanied by an understanding of how best to reach and communicate with these vulnerable populations. Principles of effective health and risk communication should guide the development of strategies and materials for behavior change among at-risk populations. Two key issues to focus on are (1) determining how to reach the desired audience, and (2) specific ‘message’ considerations for at-risk populations. There are two primary options for reaching an at-risk population: through targeting (or audience segmentation) or tailoring. Targeting at-risk populations is most effective when there is a channel to effectively reach those populations; that is, there is a preferred medium that is shared among the population. Many demographic variables, such as age, gender, or race/ethnicity, can be predictors both of high-risk behaviors and of channel preferences. For example, adolescents are at greater risk for smoking initiation, and there are various ways to reach this population almost exclusively, such as through teen magazines. There are also ‘psychographic’ variables that can be used for targeting at-risk populations. An example of psychographic targeting of these populations is the SENTAR, or sensationseeking targeting approach (Palmgreen et al., 2001), which has been a successful targeting strategy to reach adolescents at

Health Behavior and Risk Factors greatest risk for drug use. Researchers found that sensation seeking, or the need for novel, complex, and emotionally intense stimuli, is a personality trait that can predict: (a) adolescents at greatest risk for drug use; and (b) the types of messages that are most appealing to those adolescents. With this information, messages that appeal to at-risk adolescents can be developed and then can be inserted into programming preferred by the high-sensation seekers, thereby ensuring that messages will reach the desired population. In contrast to targeting, which focuses on delivering the same set of messages to a homogeneous group, tailoring involves delivering messages that are individualized, and based on personal assessments. Tailoring acknowledges that even among a relatively homogeneous at-risk population, there may be differences in the underlying beliefs, values, or norms that are associated with a given health behavior. After identifying these salient beliefs through an initial assessment, a computerized algorithm can be used to create individually tailored materials. Researchers have found that people may pay more attention, process more deeply, and make greater behavioral changes when messages are tailored rather than generic (Kreuter et al., 1999; Skinner et al., 1999). The disadvantage of using a tailored approach is that the messages can only be generated for those who have provided information about themselves – usually by completing a questionnaire – so tailored materials are usually more expensive to produce and typically have a smaller reach than targeted approaches. When designing messages for at-risk individuals, special attention should be paid to the way that risk is discussed. Dual processing theories (Leventhal, 1971; Witte, 1992) suggest that when individuals are faced with risky or ‘threatening’ information, they may react in one of two ways: (1) they can become fearful, which can trigger avoidance and denial; or (2) they can become alert to the danger, vigilant, and motivated to do whatever is necessary to alleviate the threat. Messages that inform people that they have an elevated risk for developing a negative health outcome, or for performing an unhealthy behavior, tend to heighten fear. If that fear is elevated, and people are not also told how they can reduce their risk, then any other messages will likely not be processed. In contrast, if fear is elevated and is coupled with efficacy messages (e.g., there is an effective response to reduce risk, and the individual is able to make the recommended changes), then individuals will be more likely to be motivated to reduce the threat.

Conclusion Understanding and improving health-related behavior is key to improving public health and individual well-being. Focusing on at-risk populations is one strategy for maximizing public health impact. In general, behavioral interventions will be more effective if they are theoretically based. Communication strategies targeting high-risk individuals should be carefully crafted and properly pretested to ensure that the messages do not trigger denial or avoidance. Whereas policies, laws, and regulations can affect health behaviors, individual beliefs and motivations must also be considered in public health efforts. Behavior change is incremental. Many people who are at greatest risk for negative health outcomes have practiced a lifetime

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of less than optimal health behaviors of one sort or another. It is unreasonable to expect that significant and lasting changes will occur during a short period of time. Public health programs need to identify and maximize the benefits or advantages of positive change, push or pull participants along the continuum of change, and consider changes in educational programs and environmental supports to help people who have made changes maintain them over the long term.

See also: Cancer Screening: Theory and Applications; Cardiovascular Disease Prevention; Cultural Issues and Linguistic Complications in Health Communication; Diabetes Mellitus Prevention; Diet and Cancer; Diet and Heart Disease; Epidemiology of the Acquired Immunodeficiency Syndrome; Health Promotion; Physical Activity and Health; Populations at Special Health Risk: Children: Children’s Mental Health Services; Smoking Cessation.

References Ajzen, I., 1985. Intention, perceived control, and weight loss: an application of the theory of planned behavior. J. Person. Soc. Psychol. 49 (3), 843–851. Ajzen, I., Fishbein, M., 1980. Understanding Attitudes and Predicting Social Behavior. Prentice-Hall, Englewood Cliffs, NJ. Bandura, A., 1986. Social Foundations of Thought and Action: A Social Cognitive Theory. Prentice-Hall, Englewood Cliffs, NJ. Berkman, L.F., Kawachi, I., 2000. Social Epidemiology. Oxford University Press, New York (. Ezzati, M., Lopez, A.D., Rodgers, A., Vander Hoorn, S., Murray, C.J., 2002. Comparative Risk Assessment Collaborating Group. Selected major risk factors and global regional burden of disease. Lancet 360 (9343), 1347–1360. Glanz, K., Bishop, D., 2010. The role of behavioral science theory in development and implementation of public health interventions. Annu. Rev. Public Health 31, 399–418. Glanz, K., Rimer, B.K., 2005. Theory at a Glance: A Guide for Health Promotion Practice, second ed. National Cancer Institute, Bethesda, MD. NIH Publication No. 05–3896. http://www.nci.nih.gov/PDF/481f5d53-63df-41bc-bfaf-5aa48ee1da4d/ TAAG3.pdf. (accessed August 2007). Glanz, K., Rimer, B.K., Viswanath, K., 2015. Health Behavior: Theory, Research and Practice, fifth ed. Wiley/Jossey-Bass, San Francisco, CA. http://www.wiley.com/ WileyCDA/WileyTitle/productCd-1118628985.html. Gochman, D.S., 1982. Labels, systems, and motives: some perspectives on future research. Health Educ. Q. 9, 167–174. House, J.S., Williams, D.R., 2000. Understanding and reducing socioeconomic and racial/ethnic disparities in health. In: Smedley, B.D., Syme, S.L. (Eds.), Promoting Health: Intervention Strategies from Social and Behavioral Research. National Academy Press, Washington, DC, pp. 81–124. Janis, I., Mann, L., 1977. Decision Making: A Psychological Analysis of Conflict. Free Press, New York. Kasl, S.V., Cobb, S., 1966a. Health behavior, illness behavior, and sick-role behavior: I. Health and illness behavior. Archiv. Environ. Health 12, 246–266. Kasl, S.V., Cobb, S., 1966b. Health behavior, illness behavior, and sick-role behavior: II. Sick-role behavior. Archiv. Environ. Health 12, 531–541. Kreuter, M.W., Strecher, V.J., Glassman, B., 1999. One size does not fit all: the case for tailoring print materials. Ann. Behav. Med. 21 (4), 276–283. Leventhal, H., 1971. Fear appeals and persuasion: the differentiation of a motivational construct. Am. J. Public Health 61, 1205–1224. Lewin, K., 1935. A Dynamic Theory of Personality. McGraw Hill, New York. Mathers, C.D., Loncar, D., 2006. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 3 (11), 2011–2030.e442. Mokdad, A.H., Marks, J.S., Stroup, D.F., Gerberding, J.L., 2004. Actual causes of death in the United States, 2000. JAMA 291, 1239–1245. Correction published in (2005) J. Am. Med. Assoc. 293 (2005), p. 298. National Center for Health Statistics (NCHS), 2001. Healthy People 2000: Final Review. Public Health Service, Hyattsville, MD. DHHS Publication No. 01–0256. Palmgreen, P., Donohew, L., Lorch, E.P., Hoyle, R.H., Stephenson, M.T., 2001. Television campaigns and adolescent marijuana use: tests of sensation seeking targeting. Am. J. Public Health 91 (2), 292–296.

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Prochaska, J.O., DiClemente, C.C., Norcross, J.C., 1992. In search of how people change: applications to addictive behaviors. Am. Psychol. 47, 1102–1114. Prochaska, J.O., Redding, C.A., Evers, K.E., 2015. The transtheoretical model and stages of change. In: Glanz, K., Rimer, B.K., Viswanath, K. (Eds.), Health Behavior: Theory, Research and Practice, fifth ed. Wiley/Jossey-Bass, San Francisco, CA, pp. 67–74. Rosenstock, I.M., 1974. Historical origins of the health belief model. Health Educ. Monogr. 2, 328–335. Sallis, J.F., Owen, N., 2015. Ecological models of health behavior. In: Glanz, K., Rimer, B.K., Viswanath, K. (Eds.), Health Behavior: Theory, Research and Practice, fifth ed. Wiley/Jossey-Bass, San Francisco, CA, pp. 43–64. Skinner, C.S., Campbell, M.K., Rimer, B.K., Curry, S., Prochaska, J.O., 1999. How effective is tailored print communication? Ann. Behav. Med. 21 (4), 290–298. Weinstein, N.D., 1993. Testing four competing theories of health-protective behavior. Health Psychol. 12, 324–333. Witte, K., 1992. Putting the fear back into fear appeals: the extended parallel process model. Commun. Monogr. 59 (4), 329–349.

Further Reading Committee on Communication for Behavior Change in the 21st Century, 2002. Speaking of Health: Assessing Health Communication Strategies for Diverse Populations. Institute of Medicine, Washington, DC. Kreuter, M.W., Farrell, D., Olevitch, L., Brennan, L., 2000. Tailoring Health Messages: Customizing Communication with Computer Technology. Lawrence Erlbaum, Mahwah, NJ.

Relevant Websites http://www.josseybass.com/WileyCDA/WileyTitle/producted-078796149.html – Health Behavior and Health Education: Theory, Research, and Practice, fourth ed (last accessed 30.05.16.). http://www.cancercontrol.cancer.gov/brp/constructs – National Cancer Institute (last accessed 30.05.16.).

Health Care of Indigenous Peoples/Nations Gerard Bodeker, University of Oxford, Oxford, UK; and Columbia University, New York, NY, USA Ó 2017 Elsevier Inc. All rights reserved.

Background

Who Are Indigenous Peoples?

Indigenous peoples have suffered from historic injustices as a result of, inter alia, their colonization and dispossession of their lands, territories, and resources, thus preventing them from exercising, in particular, their right to development in accordance with their own needs and interests. Indigenous peoples have the right to their traditional medicines and to maintain their health practices, including the conservation of their vital medicinal plants, animals and minerals. Indigenous individuals also have the right to access, without any discrimination, to all social and health services. Indigenous individuals have an equal right to the enjoyment of the highest attainable standard of physical and mental health. States shall take the necessary steps with a view to achieving progressively the full realization of this right. UN Declaration on the Rights of Indigenous Peoples (2007).

The term ‘indigenous peoples’ is widely used to characterize a reported 370 million people worldwide (WHO, 2015) – from the Arctic to the South Pacific, from the Kalahari Desert in southern Africa to Tierra Del Fuego at the southernmost tip of the Americas. With ancient roots in their local areas, these peoples are among the world’s most marginalized populations – politically, economically, and territorially – and suffer the highest burden of health challenges (Box 1).

Box 1 The health of indigenous peoples: key messages l

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Globally, indigenous peoples suffer from poorer health, are more likely to experience disability, and reduced quality of life and ultimately die younger than their nonindigenous counterparts. Indigenous women experience health problems with particular severity, as they are disproportionately affected by natural disasters and armed conflicts, and are often denied access to education, land property, and other economic resources. Differences in infant mortality between indigenous and nonindigenous populations reflect the structural inequalities of these groups on an international level. Many of the most widespread causes of mortality among indigenous children are preventable, such as malnutrition, diarrhea, parasitic infections, and tuberculosis. Indigenous youth and adolescents face particular challenges in the realization of their right to health that are often not adequately addressed, including sexual and reproductive health and rights, and mental health. Statistical and health data collection is a key challenge in addressing Indigenous health disparities across the world and within regions.

From: Inter-Agency Support Group on Indigenous Peoples’ Issues; paper for 2014 World Conference on Indigenous Peoples.

International Encyclopedia of Public Health, 2nd edition, Volume 3

Asia, according to the International Work Group for Indigenous Affairs (IGWIA), is home to an estimated 260 million (i.e., 70%) of the world’s indigenous peoples. In India alone, there are 84.3 million Advasis, or indigenous peoples. The Orang Asli, the Mon-Khmer-speaking peoples of the Malaysian peninsula, by contrast, have a population of 180 000 and claim continuous presence in the world’s most ancient rainforests. And indigenous peoples in West Asia include the Bakhtiari, Laks, Lurs, and Qashqai of Iran, and Assyrian peoples of Iran, Iraq, and Turkey. IGWIA notes that “Asian indigenous peoples face problems such as denial of self-determination, the loss of control over their land and natural resources, discrimination and marginalization, heavy assimilation pressure and violent repression by state security forces” (see Relevant Websites). Despite this large population that self-identifies as indigenous, the term ‘indigenous’ has been contested, as almost all Asians and Africans consider themselves indigenous. In Africa, the term ‘indigenous’ has come to refer to nomadic peoples, such as the Tuareg of the Sahara and Sahel, hunter gatherers such as the San people of the Kalahari, and pastoralists, including the Maasai of East Africa. Their claim to indigenous status has been endorsed by the African Union’s African Commission on Human and Peoples Rights, which has noted their status of underrepresentation in government and the need for affirmative action to ensure their survival. In North and South America, where every nation has indigenous peoples, violence, marginalization, and isolation on native reservations, and in remote locations reduced access to traditional food supplies and increased susceptibility to disease. From the seventeenth century to the early twentieth century, there were a reported 93 waves of epidemics that devastated native populations with diseases such as typhoid, malaria, smallpox, measles, cholera, a range of sexually transmitted infections, pneumonia, and yellow fever, resulting in population declines of up to 90–95% (Encarta, n.d.). In the United States, census data indicate that there are approximately 2 million Native Americans. And in Canada, where Aboriginal people, including the Inuit of the Arctic region, have been designated as members of First Nations, the population is approximately 1.4 million. In Latin America, indigenous populations now range from Bolivia and Peru with just over 40% of the nation, to 60% in Guatemala, to Uruguay where, according to the 2011 Census, 2.4% of the population reported having indigenous ancestry (Da Silva and Santiago, 2011). The total indigenous population of Latin America is estimated at 40 million (IGWIA: see Relevant Websites). In Greenland, a self-governing country within the Danish Realm, with a total population of 56 000, the Inuit, the indigenous people of the polar region, number 50 000. Other indigenous European groups include the Kumandin Peoples of Russia and the Sami of northern Scandinavia.

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Oceania, which includes Australia, New Zealand, Papua New Guinea, and approximately 25 000 Pacific Islands, including the Marshall Islands, is home to indigenous groups from Polynesian, Melanesian, and Micronesian origins, as well as to Torres Straits Islanders. It is also home to indigenous Australians, who have at least 40 000–50 000, and potentially up to 70 000 years presence on the continent, with genetic linkages to the peoples of Papua New Guinea. Indigenous Australians now represent approximately 3.0% of Australia’s population (Australian Bureau of Statistics, 2011). Appropriation of land and water and the introduction of disease were two early features of colonial presence in Australia. Introduction of alcohol, opium, and tobacco began a problem of substance abuse that has continued in epidemic proportions. In New Zealand, there were similar patterns of conflict between British settlers and the Maori, as well as the introduction of new diseases. There were, however, formal treaties covering land acquisition and ownership (Minority Rights Group International, 2008). The lives of the majority of the world’s 370 million indigenous peoples are characterized by extreme conditions of social and environmental risk and historical injustice. Through remoteness, poverty, landlessness, and political marginalization, they have minimal access to health care and are underrepresented in national health-care statistics.

among adolescent women is estimated to be at 50% (see Relevant Websites). Yet, there can also be significant regional differences in population health, arising from individual population histories, lifestyle factors, environmental pollution, and underlying biological variation (Snodgrass, 2013). This variation in health status across indigenous populations has been borne out further by a landmark study describing the health and social status of Indigenous and tribal peoples relative to benchmark populations, Anderson et al (2016) studied 28 populations across 23 countries. Data showed poorer outcomes for Indigenous populations, although the size of the rate of difference varied across populations. The study found: l l

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Public Health Status Low levels of identification of indigenous people in national vital statistics and administrative data collections constitute a global barrier to the development of accurate indigenous health information. This in turn hinders a public health response. Indigenous populations are growing rapidly in many countries, and there is a higher child-to-adult dependency ration compared to nonindigenous populations. Sexual health is of great relevance to indigenous youth and adolescents. The United Nations Population Fund (UNFPA) notes: “A special mention needs to be made with respect to indigenous adolescents, given the higher proportion of adolescent maternity that reveals ethnic-related unequal access to reproductive rights.” A report from the Inter-Agency Support Group on Indigenous Issues (2014) reports that in Latin America, the proportion of young mothers in the indigenous population is higher than that of the nonindigenous population. The countries in this region with the greatest disparity between indigenous and nonindigenous adolescent mothers are Brazil (27% vs 12%), Costa Rica (30% vs 12%), Panama (37% vs 15%), and Paraguay (45% vs 11%), respectively. The rate of pregnancies for adolescent women in indigenous communities is inextricably linked to social norms and attitudes regarding sexual protection and family planning. Thus, precautions against sexually transmitted infections and HIV/AIDS are often forgone, resulting in high rates of sexually transmitted infections among indigenous youth. In Latin America, rates of HIV infection among women have risen from 4% in 1990 to 30% in 2007; in countries like Haiti, Guyana, and Dominican Republic, the rate of infection

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life expectancy at birth for 16 of 18 populations with a difference greater than 1 year in 15 populations; infant mortality rate for 18 of 19 populations with a rate difference greater than one per 1000 livebirths in 16 populations; maternal mortality in ten populations; low birth-weight with the rate difference greater than 2% in three populations; high birth-weight with the rate difference greater than 2% in one population; child malnutrition for ten of 16 populations with a difference greater than 10% in five populations; child obesity for eight of 12 populations with a difference greater than 5% in four populations; adult obesity for seven of 13 populations with a difference greater than 10% in four populations; educational attainment for 26 of 27 populations with a difference greater than 1% in 24 populations; and economic status for 15 of 18 populations with a difference greater than 1% in 14 populations.

The authors recommend that national governments, in the context of the UN Sustainable Development Goals, develop targeted policy responses to Indigenous health, improving access to health services, and Indigenous data within national surveillance systems. An accompanying Editorial in The Lancet commented: “Policy makers should follow Australia’s lead and make Indigenous disadvantage a national policy priority. Without that, the situation will remain unchanged, with 300 million people continuing to die much earlier than they should and women dying unnecessarily in childbirth” (Editorial, Lancet, July 9, 2016, p.104). The health status of indigenous Australians drew world headlines in 2007. The Australian Government, mobilized by a report highlighting high levels of child sexual abuse and violence in indigenous communities (Northern Territory Government, 2007), declared a state of emergency in the Northern Territory, banning alcohol in indigenous communities and mobilizing police and armed forces to enter indigenous communities to seize computers and other sources of pornography held to be the source of child sexual abuse. Part of a sequenced strategy, this was designed to be followed by teams of doctors to examine children and for possible referral for placement in foster care outside their communities. Such a drastic response led to strong condemnation by indigenous leaders, while others supported

Health Care of Indigenous Peoples/Nations the action as overdue and needed in the face of endemic abuse (see Relevant Websites). A change in federal government led to a review of this policy and, in February 2008, to a national apology to indigenous Australians for past injustices: see Relevant Websites. Reiterating themes found across the literature on indigenous health, the Overview of Australian Indigenous Health (2014) notes that in Australia,

There is a clear relationship between the social disadvantages experienced by Aboriginal people and Torres Strait Islander people and their current health status. These social disadvantages, directly related to dispossession and characterised by poverty and powerlessness, are reflected in measures of education, employment, and income.

Indigenous infant mortality rates varied by state, ranging from a third higher to more than double the rate for nonindigenous infants. Newborns of indigenous women were more than twice as likely to be of low birth weight as those born to nonindigenous women; the lowest average birth weights for infants were those whose mothers used marijuana with tobacco or with both tobacco and alcohol. Overall, life expectancy was lower by 17 years for indigenous women and men. The leading cause of death among males and females in most states was cardiovascular disease (CVD), with rates up to 30% higher than the nonindigenous population. The next leading cause of death for indigenous males was injuries. These included automobile accidents, intentional self-harm and assault (3.0 times that of the total male population), cancer (1.3), respiratory diseases (3.9), and endocrine, nutritional, and metabolic disorders (primarily diabetes) (7.3). The most frequent causes of death for indigenous women, after CVD, were cancer (1.6 times the total female population), endocrine, nutritional, and metabolic disorders (11.7), injuries (2.9), and respiratory diseases (3.6). Lung cancer is among the leading forms of cancer for indigenous males and females, and cervical cancer is an important cause of death for indigenous women; the death rate in several Australian states is more than seven times that of nonindigenous women. Leading communicable diseases among indigenous peoples are tuberculosis, hepatitis A, B, and C, sexually transmitted infections, HIV/AIDS, Haemophilus influenza type b, pneumococcal disease, and meningococcal disease. Poverty, overcrowding, malnutrition, smoking, alcohol, and drug abuse rank high as key risk factors for this constellation of communicable diseases. The incidence of tuberculosis, for example, is 15 times higher than that of the wider Australian-born population. Diarrheal disease, eye and ear problems, and skin infections are also significantly higher among indigenous people and especially so among young children. Levels of disability and handicap are estimated to be at least double that of the general population. Despite uncertainty over definitions of mental health/ illness and inadequate data on mental health problems, indigenous people have high levels of mental health challenges and stress. A prominent manifestation of this is the rate of suicide. Based on sex-specific rates for the Australian population, suicide rates are more than 2.8 times that expected for

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indigenous males and 1.9 times more than expected for indigenous females. MacRae et al. (2012) note that these rates mask a very high youth suicide rate: indigenous to nonindigenous ratios are 3.4 for males and 6.1 for females in the 15–24 age groups. Health risk factors include high tobacco, alcohol and other drug use, poor nutrition, low income, limited education, high unemployment, high levels of stress, social marginalization, inadequate working conditions and housing, and gender-related challenges. These, in turn, interact with cultural and traditional factors to influence behavior, health status, and health outcomes.

Intervention Programs A key theme in communities is that self-management, self-policing, and culturally based solutions offer the most viable means of tackling socially based health problems. Native North American communities have been incorporating traditional forms of treatment into health programs for some years. In the United States, Indian Health Service (IHS) alcohol rehabilitation programs include traditional approaches to the treatment of alcoholism. An early analysis of 190 IHS contract programs revealed that 50% of these programs offered a traditional sweat lodge at their site or encouraged the use of sweat lodges. Treatment outcomes improved when a sweat lodge was available (Hall, 1986). Often these sweat lodges include the presence of medicine men or healers, and the presence of a traditional healer greatly improved the outcome when used in combination with the sweat lodge. Partnerships between traditional healers and mental health professionals have been reported and advocated in the Latin American context as well (Incayawar, 2009). Although reliable data on indigenous mental health are scarce, the World Health Organization has highlighted the inevitable mental health consequences of trauma and grief resulting from invasion, dislocation, and, not infrequently, genocide (Cohen, 1999). Generational experience of these and associated trauma such as family separations, Aboriginal deaths in custody, and high levels of imprisonment are linked with the high levels of substance abuse in many indigenous communities (Thomson et al., 2006). Culturally sensitive research methodology is essential in studying indigenous mental health issues. An ethnographic and participatory approach is basic in ensuring that meaningful data are generated (Kirmayer et al., 2000). A Canadian study on indigenous mental health used a participatory research design to survey causes of sadness and happiness. It found that children and adolescents (ages 7–18) judged school and victimization as sources of sadness more frequently than did other age groups and cited alcohol less frequently. Women cited death and relatives as sources of sadness, whereas males cited boredom (Bopp, 1985). The Arctic Climate Impact Assessment has also highlighted that alterations of the physical environment can lead to rapid and long-term cultural changes and loss of traditional culture. This, in turn, can create psychological distress and mental health challenges in indigenous communities (Berner et al., 2004).

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In Australia, as noted, substance abuse and violence rank high among health concerns of many indigenous communities (Thomson et al., 2006). In the early 1990s, Yuendumu, a remote Aboriginal township on the edge of the Tanami Desert, was gripped by an epidemic of petrol sniffing among young people. This northern Australian indigenous community adopted a ‘zero-tolerance’ policy when violence and property damage fueled by petrol sniffing was destabilizing the community. With up to 70 regular ‘sniffers’ in a community of 400, elders sent young petrol sniffers to Mt. Theo, an outstation 160 km from their remote township of Yuendumu and 50 km from the nearest road. A program of recovery from addiction and instruction in traditional culture, matched by a comprehensive youth program in Yuendumu offering alternatives to petrol sniffing, succeeded in breaking the cycle of addiction and violence. Within a decade, there were no petrol sniffers in Yuendumu and the Mt. Theo program is now viewed as a model for other communities afflicted by petrol sniffing (Australians for Native Title and Reconciliation, 2007). With time, new directions have begun to be forged in Australia and in Queensland, for example, the Urban Institute for Indigenous Health conducts a number of programs on urban Aboriginal health designed and led by Aboriginal and Torres Strait Islander health workers. These include dedicated health clinics, a comprehensive maternal and child health service, prevention education such as nutritional education, smoking prevention, and an Indigenous Ambassadors school and community based education program, “which encourages Indigenous people to be healthy role models for family, friends and broader community networks” (www.iuih.org.au, 2015).

Environmental Factors Biodiversity and Human Health The environmental impact of landscape changes on health is now gaining attention in both public health and conservation arenas, where it is recognized that environmental disturbance affects the ecological balance of the hosts of diseases as well as of disease-causing pathogens and parasites. The World Health Organization has recorded over 36 new emerging infectious diseases since 1976, many of which, particularly malaria and dengue, are the direct result of landscape influencing the ecology of disease (Taylor et al., 2001). As has been noted by the Harvard Project on Biodiversity and Health, human health, biodiversity, and poverty reduction represent a nexus of interrelated issues that lie at the center of human development; biodiversity, in turn, is dependent upon human health, as undernourished communities and those weak with disease will draw heavily on their surroundings for wild food resources and fuelwood (Epstein et al., 2003; Box 2). In addition to losing traditional hunting and cultural territory, deforestation exposes indigenous forest-dwelling communities to new diseases. For example, in the case of malaria and other mosquito borne diseases such as dengue fever, the process of deforestation is known to reduce the diversity of forest mosquitoes. Yet, those species that do survive have been found to transmit malaria more effectively than the forest-dwelling species that had previously been prevalent. This outcome has been observed in all areas of

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People in developing countries face particularly heavy health burdens from a loss of biodiversity, with impacts on food supply and quality, medicines, and cultural and religious values. It has been estimated that approximately 80% of the world’s population from developing countries rely mainly on traditional medicines derived from plants and that 25% of prescriptions dispensed in United States pharmacies contained plant extracts or active ingredients derived from plants. Also, as the number of crop varieties has shrunk in the past 50 years: with 90% of the world’s calories coming from a dozen crops, people’s diets have been simplified and nutritional diseases have arisen in part as a result. Obesity and diabetes, as well as many other emerging plagues such as mental health ailments, including depression, can all in part be connected to biodiversity loss.

FROM: CBD factsheet from: Chivian, E., Bernstein, A. (Eds.), Sustaining Life: How Human Health Depends on Biodiversity. Oxford University Press, New York, NY. World Health Organization.

high malaria risk – the Amazon, East Africa, Thailand, and Indonesia (see Relevant Websites). Deforestation can affect the emergence and spread of human infectious diseases in other ways as well. With forest loss comes a loss of habitat and food for some species that serve as reservoirs for human diseases. For example, an outbreak of Nipah virus infections in Malaysia resulted from forest loss and a change of behavior of fruit bat species that are reservoirs of human disease. With the loss of forest habitats, the bats moved to mango trees surrounding large pig farms at the edge of forests and fed on these. Their infected saliva on fallen fruit and their feces were consumed by pigs who contracted the Nipah virus for which the fruit bat is a vector. This was, in turn, passed on to humans resulting in 257 human infections and 105 deaths (Looi and Chua, 2007). Deforestation also leads to disturbance of soil borne pathogens. “Approximately one-half of the people of Southeast Asia living in poverty have one or more soil-transmitted helminth infection. Indigenous populations, such as the Orang Asli communities in peninsular Malaysia, are disproportionately affected, with high levels of community prevalence and intensities” (Hotez et al., 2015) to improve the health situation of indigenous peoples, it is critical to recognize that their health and well-being are linked to their collective rights, such as rights to conserve and practice traditional knowledge. Water is a common source of infection for those living in poverty, especially indigenous communities. In Southeast Asia, intestinal protozoa such as toxoplasmosis is common among the Orang Asli indigenous communities of Malaysia (Lim et al., 2009; Romano et al., 2010; Ngui et al., 2011). Prevalence data are not available for intestinal protozoan infections or toxoplasmosis, but it is presumed that similar trends are found in other impoverished communities across Southeast Asia (Hotez et al., 2015). “To improve the health situation of indigenous peoples, it is critical to recognise that their health and well-being are linked

Health Care of Indigenous Peoples/Nations to their collective rights, such as rights to conserve and practice traditional knowledge” (State of the world’s indigenous peoples, 2010). A program in India involving indigenous (so-called ‘tribal’) communities and landless and marginal farmers promoted the concept of home herbal gardens (HHG) as a means of decreasing family health problems and reducing high expenditures on health care (Hariramamurthi et al., 2007). This was part of a wider program to promote medicinal plant conservation and the forests that are their home. Medicinal plants were selected to address such common ailments as cold, cough, fever, diarrhea, dysentery, cuts and wounds, irregular menstruation and other menstrual conditions, joint pain, insect bites, indigestion and gastric complaints, mouth ulcer, and urinary infections and disorders. In each setting, a village resource person was trained in how to grow and use the medicinal plants, and she, in turn, trained the households. An independent evaluation showed that the HHG program was adopted by the poorest of the poor, namely landless (33%), marginal landholding (37%), and small landholding (21%) farmers; 86% of adopters belonged to socially deprived communities, particularly indigenous communities. HHGs benefited mainly women and children in poor communities as a first response to common conditions such as cold, cough, and fever. HHG participants reported economic benefits in the form of savings from PHC-related expenses by use of home remedies. Health expenditures by non-HHG households was approximately five times greater than for HHG households.

Climate Change and Indigenous Health Climate change is being reported globally as a challenge to indigenous communities. More than a decade ago, the Arctic Climate Impact Assessment (ACIA) evaluated Arctic climate change and its impact for the region and the world (Berner et al., 2004). Indigenous people make up approximately 10% of the total Arctic population, which includes populations from Norway, Sweden, Finland, Denmark, Iceland, Canada, Russia, and the Untied States. ACIA argued that changing weather conditions, resulting in increased storms, reduced sea ice, and thawing ground, and the accompanying reduction in species’ ranges and availability, will affect human health and food security and possibly the survival of some indigenous cultures. Of the 4 million who presently live in the Arctic, 400 000 are indigenous people. Inuit communities have reported massive drops in walrus and seal populations, both species vital to the nutritional well-being and survival of the Inuit. In Alaska, melting permafrost has undermined foundations of buildings leaving indigenous communities facing crumbling infrastructure, damaged sewage systems and destroyed schools and public facilities (Ferris and Hu, 2015). Changes in climate are occurring faster than traditional knowledge is able to adapt. Across the Arctic indigenous people are reporting changes in climate and in the fish and animal and bird populations on which they depend for food. Melting ice makes travel to traditional hunting areas difficult and reduction in summer sea ice makes ringed seals

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harder to find. Elevated ultraviolet (UV) light levels will lead to UV exposure of young people by more than 30%, thus increasing the risk of skin cancers, cataracts, and immune system disorders. Drought and associated desertification are also risks of climate change and threats to the health and livelihoods of indigenous communities. In western Arnhem Land in northern Australia, indigenous people are reviving traditional landscape burning patterns, begun soon after the rains, to reduce combustible material that can cause far larger, damaging fires and to regenerate useful plants and animals. Supported by a gas refinery, required by environmental law to reduce its greenhouse emissions, a unique carbon trading agreement has been forged with government and indigenous communities. The agreement recognizes that if, in 1 year, indigenous people could reduce the area burned in wildfires by just 7%, they would create the equivalent of at least 100 000 tonnes in greenhouse gas savings. Starting in 2007, the refinery owner, Conoco-Phillips, has contracted to pay a $1 million a year for 17 years to employ Arnhem Land people and support their fire management. Known as the West Arnhem Land Fire Abatement (WALFA), the project was the first Savanna Fire Management project using traditional fire management practices together with scientific knowledge and research to better control the extent and severity of savanna wildfires and thereby reducing greenhouse gas emissions (see Relevant Websites). The money has been used to support community health and education programs. Enhanced self-sufficiency in health care has been won through a revival of traditional practices, also contributing to reduced carbon emissions, improved global health, and environmental security – surely a sound contemporary model for integrated indigenous health development. Coastal communities in West Africa are vulnerable to the impact of rising sea levels. Desertification in the Sahel is forcing farming and pastoralist populations further south, away from their traditional lands. The resulting relocation to fringe settlements in urban centers heightens conditions of poverty, disease, including exposure to HIV/AIDS, and exploitation, including heightened risk of violence against women. Abandonment of pastoralist lifestyles in Cameroon’s Mbororo community, for example, has resulted in men moving to urban centers, with women and children being left behind in desertifying areas. Encroachment of invasive plant species has resulted from reduced grazing and land use has become further restricted. In Mauritania, drought and food insecurity have become permanent challenges associated with climate change and depletion of natural resources, with 20 and 30% of the population suffers from high food insecurity according to the World Food Program. The result has been a rapid increase in urbanization with all of the attendant problems. Examples from Pacific communities demonstrate that local solutions are also being employed with success. According to the Secretariat of the Pacific Regional Environment Program (SPREP), ‘adaptation to climate change is becoming a Pacific way of life.’ This has included installation of storage tanks and innovative drainage systems, which has helped to diffuse water contamination and potential health risks arising from unusually long periods of drought and saltwater intrusion. It

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is now widespread among Pacific communities to work on strengthening their biodiversity, planting dense vegetation and building sea walls, aware of the risks of erosion and landslides to the densely populated areas along their coastlines. In Samoa, training local people in the design and building of traditional Samoan dwellings has led to promotion of resilient housing and reduced need for relocation. Indigenous customs and knowledge have also been recognized as a tool to tackle the effects of climate change. In the Philippines, a UNESCO-led project has studied indigenous cultural practices to help policy makers devise better disaster preparedness strategies in coastal areas. According to a Minority Rights (2015) report: “The study identified a number of traditions that were used to accurately predict disasters, such as typhoons or tsunamis, and later integrated with scientific approaches. The study found that indigenous communities have developed various ways to strengthen their houses and store food ahead of disasters, offering useful lessons in strengthening local resilience.” (Minority Rights, 2015; see Relevant Websites).

Conclusion The health of indigenous people is typically influenced by histories of social injustice, loss of territorial rights, marginal social status, and limited employment and income opportunities. Overall, the intractability of indigenous health determinants and health status warrants a comprehensive global strategy, based on a human rights approach, with local action by governments in partnerships with indigenous organizations. The challenge by several governments – with significant indigenous populations – to the eventual passage on 13 September 2007, of the UN Declaration on the Rights of Indigenous Peoples through the UN General Assembly underscores the obstacles ahead in any such global strategy. Another challenge is the need for comprehensive local, national, and regional data collection, inclusive of indigenous peoples and their health conditions, as an epidemiological framework for action. Despite repeated challenges from indigenous peoples for stronger action, the World Heath Organization, through a number of World Health Assembly (WHA) resolutions, is mandated to accord special attention to the health of indigenous peoples. There is also commitment to convene partners and catalyze action to improve indigenous peoples’ health and human rights. As for the basic prerequisites for improvement and development, Health Unlimited has outlined priorities for indigenous health development: 1. Train local people to provide basic health services in remote areas. 2. Ensure that traditional practitioners are involved and that their views are appreciated, so new ideas about health are more likely to be taken on board in isolated, indigenous communities. 3. Provide safe water and improve sanitation. 4. Provide information regarding indigenous peoples’ rights and entitlement to health care (see World Directory of Minorities and Indigenous Peoples: see Relevant Websites).

5. Work with state health providers to ensure indigenous peoples are not discriminated against when it comes to accessing health services (see Relevant Websites). As the global rural–urban drift continues and indigenous peoples join marginal groups living in urban poverty, the future would seem to hold a mix of trends: continued intractability in the determinants of poor health, accompanied by isolated models of success. Where solutions do present themselves, success would seem to be based on self-sufficiency, recourse to traditional cultural practices, and equitable partnerships with agencies receptive to new models of work.

See also: Populations at Special Health Risk: Indigenous Populations.

References Anderson I, Robson B, Connolly M, et al. Indigenous and tribal peoples’ health (The Lancet–Lowitja Institute Global Collaboration): a population study. Lancet 2016; published online April 20. http://dx.doi.org/10.1016/S0140-6736(16)00345-7. Australians for Native Title and Reconciliation, 2007. Success Stories in Indigenous Health. ANTR, Rozelle, NSW, Australia. Australian Bureau of Statistics, June 2011. Estimates of Aboriginal and Torres Strait Islander Australians. http://www.abs.gov.au/ausstats/[email protected]/mf/3238.0.55.001 (accessed 19.07.15.). Berner, J., Furgal, C., Bjerregaard, P., et al., 2004. Human health. In: ACIA (Ed.), Impacts of a Warming Arctic: Arctic Climate Impact Assessment, Ch. 15. Cambridge University Press, Cambridge, UK. Bopp, M., 1985. Developing Healthy Communities: Fundamental Strategies for Health Promotion. Four Worlds Development Project: University of Lethbridge, Lethbridge, UK. Cohen, A., 1999. The Mental Health of Indigenous Peoples: An International Overview. Department of Mental Health, World Health Organization, Geneva, Switzerland. Da Silva, V., Santiago, K., August 27, 2011. “Censo 2011. Organizaciones Sociales Llaman a Decir “Sí” Para Reconocer sus Etnias – Censo: afrodescendientes e indígenas hacen campaña”. Matías Rotulo (in Spanish). LaRed21 Comunidad. Editorial, Lancet, July 9, 2016, 338, 104. Epstein, P.R., Chivian, E., Frith, K., 2003. Emerging diseases threaten conservation. Environ. Health Perspect. 111 (10), A506–A507. Ferris, E., Hu, A.C., May 29, 2015. Climate change, indigenous peoples, and mobility in the Arctic. Harv. Int. Rev. http://www.hir.harvard.edu/archives/11386 (accessed 21.07.15.). Hall, R.L., 1986. Alcohol treatment in American Indian communities: an indigenous treatment modality compared with traditional approaches. Ann. N.Y. Acad. Sci. 472, 168–178. Hariramamurthi, G., Venkatasubramanian, P., Unnikrishnan, P.M., Shankar, D., 2007. Kitchen herbal gardens: biodiversity conservation and health care at the local level. In: Bodeker, G., Burford, G. (Eds.), Traditional, Complementary and Alternative Medicine: Policy and Public Health Perspectives. Imperial College Press, London. Hotez, P.J., Bottazzi, M.E., Strych, U., Chang, L.-Y., Lim, Y.A.L., Goodenow, M.M., et al., 2015. Neglected tropical diseases among the Association of Southeast Asian Nations (ASEAN): overview and update. PLoS Negl. Trop. Dis. 9 (4), e0003575. http://dx.doi.org/10.1371/journal.pntd.0003575 (accessed 19.07.15.). International Work Group for Indigenous Affairs. http://www.iwgia.org/regions/asia (accessed 19.07.15.). Incayawar, M., 2009. Future partnerships in global mental health- foreseeing the encounter of psychiatrists and traditional healers. In: Incayawar, M., Wintrob, R., Bouchard, L. (Eds.), Psychiatrists and Traditional Healers: Unwitting Partners in Global Mental Health. Wiley-Blackwell, London, pp. 251–260. Kirmayer, L.J., Macdonald, M.E., Brass, G.M., 2000. The mental health of indigenous peoples. Proceedings of the Advanced Study Institute, the Mental Health of Indigenous Peoples. In: McGill Summer Program in Social and Cultural Psychiatry and the Aboriginal Mental Health Research Team May 29–May 31. Culture and Mental Health Research Unit, Montreal, Quebec. Montreal; Report No. 10.

Health Care of Indigenous Peoples/Nations Lim, Y.A., Romano, N., Colin, N., Chow, S.C., Smith, H.V., 2009. Intestinal parasitic infections amongst Orang Asli (indigenous) in Malaysia: has socioeconomic development alleviated the problem? Trop. Biomed. 26, 110–122 pmid:19901897. Looi, L.M., Chua, K.B., December 2007. Lessons from the Nipah virus outbreak in Malaysia. Malays. J. Pathol. 29 (2), 63–67. MacRae, A., Thomson, N., Anomie, Burns, J., Catto, M., Gray, C., Levitan, L., McLoughlin, N., Potter, C., Ride, K., Stumpers, S., Trzesinski, A., Urquhart, B., 2012. Overview of Australian Indigenous Health Status. Retrieved 21 July, 2015 from: http://www.healthinfonet.ecu.edu.au/overview_2013.pdf. Minority Rights Group International, 2008. World Directory of Minorities and Indigenous Peoples – New Zealand: Maori. Available at: http://www.refworld.org/docid/ 49749cd8c.html (accessed 19.07.15.). Minority Rights, 2015. State of the World’s Minorities and Indigenous Peoples. http:// www.minorityrights.org/13061/attachments/_MRG-state-of-the-worlds-minorities2015-FULL-TEXT.pdf (accessed 19.07.15.). Ngui, R., Lim, Y.A., Amir, N.F., Nissapatorn, V., Mahmud, R., 2011. Seroprevalence and sources of toxoplasmosis among Orang Asli (indigenous) communities in Peninsular Malaysia. Am. J. Trop. Med. Hyg. 85, 660–666. http://dx.doi.org/ 10.4269/ajtmh.2011.11-0058 pmid:21976569. Northern Territory Government, 2007. Report of the Northern Territory Board of Inquiry into the Protection of Aboriginal Children from Sexual Abuse. Northern Territory Government, Darwin, Australia. Romano, N., Nor Azah, M.O., Rahmah, N., Lim, Y.A., Rohela, M., 2010. Seroprevalence of toxocariasis among Orang Asli (Indigenous people) in Malaysia using two immunoassays. Trop. Biomed. 27, 585–594 pmid:21399601. Snodgrass, J.J., 2013. Health of Indigenous Circumpolar Populations. Annual Review of Anthropology 42, 69–87. http://dx.doi.org/10.1146/annurev-anthro-092412155517. Taylor, L.H., Latham, S.M., Woolhouse, M.E., 2001. Risk factors for human disease emergence. Philos. Trans. R. Soc. Lond. 356, 983–989. UN Declaration on the Rights of Indigenous Peoples, 2007. http://www.un.org/esa/ socdev/unpfii/documents/DRIPS_en.pdf (accessed 21.07.15.). WHO, 2015. WHO End TB Strategy. http://www.who.int/tb/post2015_strategy/en/ (accessed 20.07.15.).

Further Reading Ahmad, A.F., Hadip, F., Ngui, R., Lim, Y.A., Mahmud, R., 2013. Serological and molecular detection of Strongyloides stercoralis infection among an Orang Asli community in Malaysia. Parasitol. Res. 112, 2811–2816. http://dx.doi.org/ 10.1007/s00436-013-3450-z pmid:23666229. Al-Harazi, T., Ghani, M.K., Othman, H., 2013. Prevalence of intestinal protozoan infections among Orang Asli schoolchildren in Pos Senderut, Pahang, Malaysia. J. Egypt. Soc. Parasitol. 43, 561–568. http://dx.doi.org/10.12816/0006413 pmid:24640856. Australian Bureau of Statistics, 2014a. Australian Aboriginal and Torres Strait Islander Health Survey updated results, 2012–13-Australia: table 6.3 [data cube]. http://www.abs.gov.au/ausstats/[email protected]/Lookup/by%20Subject/4727. 0.55.0032012-13Main%20FeaturesFeature%20article:%20%20Chronic %20disease%20results%20for%20Aboriginal%20and%20Torres%20Strait% 20Islander%20and%20non-Indigenous%20Australians134 (accessed 20.07.15.). Australian Bureau of Statistics, 2014b. Feature Article: Chronic Disease Results for Aboriginal and Torres Strait Islander and Non-indigenous Australians. http://www.abs. gov.au/ausstats/[email protected]/Lookup/by%20Subject/4727.0.55.0032012-13Main %20FeaturesFeature%20article:%20%20Chronic%20disease%20results%20for% 20Aboriginal%20and%20Torres%20Strait%20Islander%20and%20non-Indigenous %20Australians134 (accessed 19.07.15.). Bodeker, G., 2007. Traditional medicine. In: Cook, G., Zumla, A. (Eds.), Manson’s Tropical Diseases, twenty-second ed. WB Saunders, Elsevier Health Sciences, London. Bodeker, G., Burford, G. (Eds.), 2007. Public Health and Policy Perspectives on Traditional, Complementary and Alternative Medicine. Imperial College Press, London. Bodeker, G., Ong, C.-K., Burford, G., Grundy, C., Shein, K. (Eds.), 2005. World Health Organization Global Atlas on Traditional and Complementary Medicine, 2 vols. World Health Organization, Geneva, Switzerland. Canadian Development Corporation (CDC), 2008. International Group for Indigenous Health Measurement Terms of Reference. http://www.cdc.gov/nchs/data/isp/ IGIHM_Terms_of_Reference.pdf (accessed 19.07.15.).

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Chivian, E., Bernstein, A. (Eds.), 2008. Sustaining Life: How Human Health Depends on Biodiversity. Oxford University Press, New York, NY. World Health Organization. Pan American Health Organization (PAHO), n.d. Health of Indigenous Peoples. http:// www.paho.org/english/ad/ths/os/Indig-home.htm (accessed December 2007). UNICEF India, 2015. Nutrition and Tribal Peoples- A Report on Nutrition Situation of India’s Tribal Children. http://www.unicef.in/tribalchildren/Story-Nutritionand-Tribal-Peoples-A-Report-on-Nutrition-Situation-of-India-s-Tribal-Children-. html (accessed 20.07.15.). UN Permanent Forum on Indigenous Issues, 2009. WHO, n.d. The Health and Human Rights of Indigenous Peoples. http://www.who.int/ hhr/activities/indigenous/en/ (accessed December 2007). WHO, 2003. Indigenous Peoples and Participatory Health Research: Planning and Management/Preparing Research Agreements. WHO, CINE, Geneva, Switzerland. World Factbook, 1997. Central Intelligence Agency, Washington, DC. http://www.odci. gov/cia/publications/factbook/ (accessed 25.01.08.). World Factbook, 2007. CENIMAR, Troy Studios, Loomis, California. http://www. seminar.com/factbook/index.jsp (accessed 25.01.08.).

Relevant Websites http://www.hc-sc.gc.ca/ahc-asc/activit/strateg/fnih-spni/ahhri-irrhs_e.html – Aboriginal Health Human Resources Initiative – (Canada). http://www.aph.gov.au/house/news/news_stories/news_sorry.htm – APH Government Organization. http://www.healthinfonet.ecu.edu.au/ – Australian Indigenous Health InfoNet. http://news.bbc.co.uk/2/hi/asia-pacific/6229708.stm – BBC news Organization. http://www.chgeharvard.org/sites/default/files/resources/182945%20HMS% 20Biodiversity%20booklet.pdf – Biodiversity Resources. http://www.unfpa.org/webdav/site/global/shared/documents/events/2011/IASGBriefingNote. pdf – Economic Commission for Latin America and the Caribbean (ECLAC), 2007. Information on the Permanent Forum on Indigenous Peoples Issues and the Upcoming UNFPA Hosted Inter-agency Support Group Meeting on Indigenous Peoples Issues. http://www.frlht.org – Foundation for Revitalization of Local Health Traditions. http://www.iphrc.ca/ – Indigenous People’s Health Research Centre, (Canada). www.iuih.org.au – Institute for Urban Indigenous Health. http://www.un.org/en/ga/president/68/pdf/wcip/IASG_Thematic%20paper_Health.pdf – Inter-Agency Support Group on Indigenous Peoples’ Issues. Thematic Paper towards the Preparation of the 2014 World Conference on Indigenous Peoples. http://www.iwgia.org/regions/latin-americaiwgia – International Work Group for Indigenous Affairs (IWGIA) – Asia. http://www.iwgia.org/regions/latin-americaiwgia – International Work Group for Indigenous Affairs (IWGIA) – Latin America. http://www.iwgia.org/regions/asiaiwgia – International Work Group for Indigenous Affairs. http://www.iwgia.org/regions/latin-americaiwgia – International Work Group for Indigenous Affairs in America. www.minorityrights.org; www.minorityvoices.org – Minority Rights Group International. http://www.minorityrights.org/13061/attachments/_MRG-state-of-the-worlds-minorities2015-FULL-TEXT.pdf – Minority Rights International, 2015. State of the World’s Indigenous Peoples. http://www.nailsma.org.au/walfa-west-arnhem-land-fire-abatement-project – NAILSMA Organization. http://www.oxfam.org.au/campaigns/indigenous/health.php – Oxfam: Close the Gap: Indigenous Health in Crisis. http://www.new.PAHO/WHO.org/hq/dmdocuments/2009/tool%20box%2010069_ IndigPeople.pdf – PAHO/WHO, 2008. Human Rights and Health: Indigenous Peoples, p. 2. http://www.un.org/esa/socdev/unpfii/documents/SOWIP/en/SOWIP_web.pdf – Symbols of United Nations Documents. http://www.who.int/gb/EBWHA/PDF/WHA55/EA5535.pdf; http://www.un.org/esa/socdev/ pfii/index.html; www.unesco.org/culture/indigenous/index.shtmlwww.who.int/gb/EB %20WHA/PDF/WHA55/EA5535.pdf – UN Decade of Indigenous Peoples. http://www.un.org/en/ga/president/68/pdf/wcip/IASG_Thematic%20paper_Health.pdf – UN Organization. http://www.who.int/healthsystems/topics/financing/healthreport/IHNo33.pdf – World Health Report, 2010. Background Paper 33: Indigenous Health – Australia, Canada, Aotearoa New Zealand and the United States – Laying Claim to a Future that Embraces Health for Us All.

Health Inequalities Catherine Chittleborough, School of Public Health, University of Adelaide, Adelaide, SA, Australia Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Paula Braveman, volume 3, pp. 189–197, Ó 2008, Elsevier Inc.

Working Definition of Health Inequalities

Introduction Child under-five mortality, the focus of a United Nations Millennium Development Goal (MDG), has halved between 1990 and 2015, resulting in about 19 000 fewer children dying every day (UNICEF et al., 2015). Despite these gains, child mortality differences persist around the world. In sub-Saharan Africa 1 child in 12 dies before his or her fifth birthday, far higher than the average ratio of 1 in 147 in high-income countries (UNICEF et al., 2015). Within Africa there is a wide range of child mortality rates; for example, 26 deaths per 1000 live births in Algeria compared to 157 deaths per 1000 live births in Angola (UNICEF et al., 2015). Substantial differences also exist within countries. In Indonesia, children in the poorest one-fifth of the population are 2.4 times as likely to die before reaching age 5 as children in the wealthiest fifth (Hodge et al., 2014). In Australia, an Aboriginal or Torres Strait Islander child is twice as likely to die before age 5 than a non-Indigenous child (Australian Institute of Health and Welfare, 2014). What do these between- and within-country comparisons have in common? What concepts and values underlie such comparisons and the inequalities they represent? How should we measure inequalities in health outcomes? What are the implications for policy and action of making such comparisons? Should societies routinely measure, monitor, and seek to reduce such inequalities? This article explores the concept of health inequalities, the values behind it, and the implications for how we understand, measure, and take action to address those differences.

What Do We Mean by Health Inequalities? Health inequalities are generally understood to refer to differences in health between groups of people who are better or worse off socioeconomically, as reflected by, for example, their occupational standing, levels of income, wealth, or education, or by economic characteristics of the places where they live. Increasing attention has also been given to health inequalities by gender, ethnicity, or immigration status. The term health ‘disparities’ is more often used than health ‘inequalities’ in the United States to refer to racial or ethnic differences in health (Braveman et al., 2011), or to worse health among economically disadvantaged people within different racial or ethnic groups (Braveman, 2014). Disaggregation of health information by race or ethnic group and not by socioeconomic indicators contributed to ill-founded but widespread assumptions that racial or ethnic differences in health were genetically based. These assumptions tend to have reinforced racial stereotypes, despite the fact that racial discrimination is illegal, and distracted attention from persisting structural barriers to socioeconomic opportunity.

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Dictionaries define inequality as ‘the quality of being unequal or uneven’ and disparity as ‘difference,’ without specifying the nature of the difference or to whom it may apply. Based on these definitions, health inequalities or disparities encompass the entire discipline of epidemiology – in other words, the study of the distribution of diseases and risk factors compared across groups within populations, without restrictions on the kinds of groups considered relevant. For example, epidemiologists might study why residents of two equally affluent neighborhoods had very different rates of a particular disease, or why breast cancer occurred more frequently among women of European background than among women with family origins in Africa. Although these examples involve differences in health between population groups, they reflect concerns much broader in scope than those motivating efforts to describe and understand health inequalities or disparities. In her seminal paper ‘The Concepts and Principles of Equity and Health’ (Whitehead, 1992), Margaret Whitehead defined health inequalities as differences in health that are not only unnecessary and avoidable but also unfair and unjust. Social justice, a desire to improve everyone’s health with faster improvements for those groups that have faced economic and social disadvantage, was a central concern. An expanded definition, updated in Paula Braveman’s previous version of this article, complemented Whitehead’s definition and made explicit some key concepts necessary for clarity and accountability in measurement of health inequalities: A health inequality or disparity is a particular type of difference in health (or in the most important influences on health) that could potentially be shaped by policies. It is a systematic difference in health (or in modifiable health risks) according to social advantage, meaning one’s relative position in a social hierarchy determined by wealth, power, and/or prestige. It is a difference in which disadvantaged social groups (such as the poor, racial/ethnic minorities, women, or other groups that have persistently experienced social disadvantage or discrimination) systematically experience worse health or greater health risks than more advantaged social groups. Health inequalities or disparities include comparisons not only between the best- and worst-off groups in a given category (e.g., the richest versus the poorest), but between the most socially advantaged group and all others. Braveman (2006).

According to this definition, a ‘health inequality’ does not refer generically to any health difference but to a particular type of potentially avoidable difference in health or in important influences on health that can be shaped by policies. This corresponds to Whitehead’s criterion that health inequalities are avoidable or unnecessary, but the extent to which a given condition could be influenced by policies is debated. For example, it is unlikely that policies will be enacted to redistribute resources in favor of less advantaged groups in countries

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Health Inequalities where there is little public, media, or political support for such egalitarian action (Smith, 2014). Despite this, it is reasonable to maintain that the relevant differences are those that could be influenced by policies given political will, assuming that such political will is at least theoretically possible in the future. The criterion of health inequalities being systematic, first articulated by Starfield (2007), restricts the possibilities to those health differences that are routinely and persistently patterned across social groups; an occasional or random association between a given social characteristic and ill health would not qualify as a health inequality. This definition restricts relevant differences to those seen across groups with different levels of underlying social advantage/disadvantage or social position, that is, one’s position relative to others within social hierarchies. Across the world, social position varies according to economic resources, power or control over resources, and prestige or social standing, which are often reflected by measures including: income or expenditures; wealth; education; occupational standing; residential location (e.g., rural/urban; slum/non-slum; and less/more advantaged neighborhoods); racial/ethnic, tribal, or religious group or national origin; gender; and sexual orientation (Braveman, 2006). Disadvantaged social groups include the poor, racial/ethnic minorities (or, as in South Africa, disenfranchised majorities), women, physically or mentally disabled persons, or other groups that have persistently experienced social disadvantage, discrimination, or exclusion. Age can be relevant as well; in many societies the elderly and/or children are disadvantaged by policies or traditions. The biological constraints posed by physical or mental disability are often compounded by social exclusion or marginalization. Social advantage and disadvantage are powerful determinants of health, both directly and indirectly, insofar as they determine the conditions in which people live and work, the resources they have, their relationships with others, and, potentially, how they view themselves (Marmot et al., 1997). The proposed definition specifies that in order to be a ‘health inequality,’ a health difference must be observed among groups with different levels of underlying social advantage, and the a priori disadvantaged groups must also do worse on that health indicator. This distinction is important as we do not always observe poorer health among the more disadvantaged groups. An example is the gender inequality in life expectancy in affluent countries, with women generally living on average several years longer than men. This difference illustrates a public health issue that deserves attention as part of a broad public health agenda, but is not defined as a health inequalities issue, because men have more social advantage (wealth, power, prestige) than women in almost all societies. Other examples include breast cancer mortality being higher among higher educated groups in Europe (Strand et al., 2007) and some groups, particularly women, with higher education levels being more likely to drink alcohol at hazardous levels in many OECD countries (OECD, 2015). Similarly, an Australian study observed typical income gradients for obesity, but not for overweight, where no income gradient was observed among females, and a reverse gradient was observed among males (Markwick et al., 2013). In Korea, the magnitude of educational inequality varied across causes of mortality, and by gender (Khang et al., 2004).

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Ethical Values and Human Rights Principles Underlying the Concept of Health Inequalities Examining the values underlying a concern for health inequalities is helpful for focusing on important measurement issues that reflect differing values, and to consider the practical consequences that might result from pursuing different approaches. Principles of human rights, justice, sustainability, inclusion, and peace form the basis of the post-2015 United Nations Sustainable Development Goals that remain committed to the MDGs and include economic, social, environmental, education, and health objectives (United Nations, 2015).

Injustice, Unfairness, and Avoidability The terms ‘injustice,’ ‘unfairness,’ and ‘avoidability’ in Whitehead’s definition of health inequalities are open to varying interpretations, which can be problematic. For example, while most people in the United States and Europe believe it is unjust and unfair for women to not be able to vote, to be required to have their faces veiled in public, and to be forbidden to work outside the home, in some other countries these circumstances are viewed by the ruling groups as appropriate, just, and fair in light of women’s unique role in society. Given a long history of racial/ethnic discrimination that has systematically put people of color at a disadvantage in multiple spheres of life, many believe that justice and fairness are served by affirmative action to increase racial/ethnic diversity in professional positions; others, including some vocal members of the underrepresented groups, feel that such efforts are unjust, constituting ‘reverse discrimination’ that unfairly disadvantages people of European origin. Health differences where socially disadvantaged groups systematically fare worse than their more socially advantaged counterparts are particularly unjust. This is because they place groups of people who are already at an underlying disadvantage in society – for example, because they were born into poor families, belong to a particular racial/ethnic group, or are women – at further disadvantage with respect to their health. Health in turn is essential for well-being and for escaping from social disadvantage. This is consistent with the concern developed in Amartya Sen’s work regarding human capabilities (Sen, 1999). If health, along with education, is a basic human capability and is essential to fulfill one’s human potential, then being doubly disadvantaged – first in virtue of one’s social group and then in virtue of having worse health – is particularly unacceptable from an ethical perspective of fairness and justice. In the previous version of this article, Braveman argued that the term ‘health inequality’ rather than ‘health inequity’ should be used, even though health inequalities are considered a subset of health differences that are particularly unfair. Braveman stated that when the causes of a given health inequality are known, and are due to social disadvantage, it would be appropriate to call it a health inequity, but that there are cases when we cannot determine whether an observed difference in health that is systematically associated with social disadvantage is unfair or unjust in itself. For example, the causes of the disparity in preterm birth between African-American and non-Hispanic white women in the United States are

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multifactorial and not well understood (Kramer and Hogue, 2009), so we cannot say to what extent it is unjust, unfair, or unavoidable. However, on the definition proposed here, that difference qualifies as a health inequality deserving attention because it is an important health difference adversely affecting an a priori disadvantaged social group, resulting in further disadvantage for that group in terms of health. Even though the specific causes are uncertain, and therefore we cannot be certain about avoidability, we would still view intensive research to understand the causes as a high priority because preterm birth is a strong predictor of health in infancy and across the life course. The proposed definition specifies that the differences in health or health determinants need only be theoretically avoidable; it must be reasonable to believe, based on current knowledge, that the differences could be avoidable, but evidence does not have to be provided empirically. The term ‘inequity’ is often used to distinguish socially caused inequalities from biological variations that are not considered unjust (Marchman Andersen et al., 2013). Preda and Voigt (2015) observe a normative assumption throughout the health inequalities literature where only ‘social’ inequalities in health are unfair, but also note that it is difficult to distinguish between health inequalities that are unfair or unjust and those that are not. A further distinction is that inequality is the construct that is measured, while inequity is a political concept communicating a moral commitment to social justice (Kawachi and Kennedy, 2002). While there is general agreement on the unfairness in the underlying determinants of health – conditions in which people live and work, their homes and communities, their schools and education, and their access to health care (Marmot et al., 2010) – researchers are beginning to question whether it necessarily follows that health inequalities per se are unfair, because health is not a ‘good’ that can be redistributed (Mackenbach, 2012). What remains unfair is the social circumstances and the opportunities to be healthy from which the health inequalities arise.

Ethics and Health Inequalities Ethical concerns regarding health inequalities generally focus on theories of justice, which – along with beneficence (doing good), nonmaleficence (not doing harm), and autonomy (respect for individuals as agents) – is one of the four basic principles of ethics. A common ethical thread in reviews of ethical concepts relevant to health inequalities is the notion that, given that health is a necessity of life rather than a luxury, justice requires that there should be equitable opportunities to be healthy (Daniels, 2001, 2006; Peter and Evans, 2001; Ruger, 2006). The late political philosopher Rawls (1985) argued that priority should be given to improving the situation of the most disadvantaged in a society. Although he did not explicitly address health, he reasoned that an egalitarian distribution of the resources needed for the essentials of life was justified by considering what one would want to be the prevailing rules for distribution of essential goods and services if those rules were to be chosen behind a ‘veil of ignorance’ about whether individuals had been born into socially advantaged or disadvantaged families. Based on the principle of fair equality of opportunity for everyone to be healthy, American philosopher

Norman Daniels (1982) explored how to systematically assess the fairness or equity of health-care systems to guide resource allocation policy decisions. His approach attracted considerable interest in part because the process of assessing equity of health-care systems in a given country is in itself an important tool for building the societal consensus needed to ensure the necessary political will to implement equity-promoting policies (Daniels et al., 2000). Daniels and others have also explored ethical and pragmatic arguments for justice or equity in other factors influencing health, including but not limited to health care (Daniels et al., 1999). Nobel Prize-winning economist Amartya Sen has written that human development should be measured not just in economic terms, which has been the rule, but in terms of indicators of human capability to freely pursue the quality of life, with health and education being among the best indicators of that capability (Sen, 1999).

Health Inequalities and Human Rights In addition to ethical concepts, international human rights principles can provide both a valuable theoretical basis for understanding and defining health inequalities and a rationale for reducing them. Human rights are a set of entitlements for all people in the world, regardless of who they are or where they live. When human rights are mentioned, most of us think about civil and political rights, such as freedom of speech, freedom of assembly, and freedom from torture. However, there are also economic, social, and cultural rights, such as the right to a decent standard of living, which in turn includes rights to adequate food, water, shelter, and clothing requisite for health, as well as the right to health itself. International human rights agreements also include the right to participate in one’s society and the right to dignified and safe working and living conditions. By now, almost every country in the world has signed one or more agreements that include important health-related rights. Sadly, in many places in the world, agreed-upon human rights are generally breached more than enforced, and it would thus be naïve to think that human rights laws, as legal instruments, ensure the reduction of health inequalities. However, the analytic frameworks of human rights can be a powerful source of conceptual and practical guidance for social policies (Braveman and Gruskin, 2003; Gruskin and Kass, 2002; Mann et al., 1999). One cross-cutting human rights principle with particular relevance to concepts of health inequalities is nondiscrimination – an individual’s right to be treated equally as a person, without discriminatory treatment based on his or her social group in terms of race/ethnicity, religion, refugee status, gender, or age. Because groups in power, for example, the dominant racial/ethnic group, men, or adults, have sometimes questioned or failed to acknowledge the disadvantaged status of the minority racial/ethnic groups, women, and/or children and their resulting need for special measures to protect their rights, agreements have been developed that explicitly recognize these groups as historically disadvantaged. Globally, such agreements have proved to be very important in practice. Human rights principles such as nondiscrimination provide a universally recognized frame of reference for initiatives to reduce health disparities between more and less advantaged social groups.

Health Inequalities The economic, social, and cultural rights codified in international human rights agreements and laws also provide a powerful tool for conceptualizing health inequalities and justifying action to reduce them. Physical and social environments in which one lives and works, including conditions in homes, neighborhoods, workplaces, and communities are powerful influences on health. In developing countries, factors such as adequate and safe food supply, clean water, sanitation, exposure to known biological pathogens and environmental toxins, and unsafe conditions at work and in transportation are obvious major factors. In affluent countries, poor quality (rather than quantity) of nutrition, inadequate physical activity, tobacco use, and excessive alcohol consumption feature more prominently (McGinnis and Foege, 1993; Mokdad et al., 2004). These risk factors are powerfully shaped by socioeconomic resources and opportunities. Medical care can also be an important determinant of health, particularly for those who have become ill; even when it cannot cure disease or extend life, medical care can improve functional status and relieve suffering. Inequalities in all aspects of medical care should be addressed, including the allocation of resources for health care as well as the utilization, quality, and financing (particularly with respect to the burden of payment on individuals or households) of services. Medical care, however, is neither the sole determinant of health nor the most powerful determinant of whether one becomes sick or dies prematurely. Ethical and human rights principles provide a strong rationale for addressing inequalities in both the medical and nonmedical determinants of health. Human rights call for a decent standard of living for all and for safe and dignified working conditions. Both ethical and human rights principles call for equal opportunities for all people to be as healthy as possible. Opportunities to be healthy extend far beyond the availability of medical care to buffer the health-damaging effects of underlying unjust living and working conditions. Thus, based on human rights principles, the definition of health inequalities proposed at the beginning of this article refers not only to differences in health itself, but also in the most important determinants of health that could at least in theory be influenced by policies. As one of the economic, social, and cultural rights addressed by international human rights agreements, the right to health is a cornerstone underlying efforts to reduce health inequalities. The World Health Organization (1946) defined the right to health as the right of everyone to enjoy the highest possible level of health. While this definition has been criticized for being vague and difficult to operationalize, the right to health can be defined operationally as the right of all social groups (defined by social position) to attain the level of health enjoyed by the most privileged group in society (Braveman and Gruskin, 2003). The right to health thus provides the basis for comparing the health experienced by different social groups. Drawing upon human rights concepts, pursuing health equity means removing obstacles to good health for groups of people who experience disadvantage – for example, in terms of their income, education, gender, or sexual orientation – and who have historically had more obstacles preventing them from realizing their rights to health and other human rights.

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What Difference Could a Definition Make for Measuring Health Inequalities? Measurement of health inequalities is essential for assessing whether we are making progress toward reducing them. A range of methods has been used to quantify health inequalities, each reflecting implicit assumptions about definitions (Braveman, 2006; Carr-Hill and Chalmers-Dixon, 2002; Harper and Lynch, 2005; Kakwani et al., 1997; Mackenbach and Kunst, 1997; Manor et al., 1997; Wagstaff et al., 1991). Normative judgments about whether certain inequalities are unfair underlie descriptive and measurement strategies aiming to determine the magnitude of, and trends in, health inequalities (Harper et al., 2010). It is worth explicitly mentioning some of these methodological issues because they have implications for how the magnitude of health inequalities is interpreted, and what recommendations are made for intervention and policy action. An example is the debate over the World Health Report (World Health Organization, 2000) recommendation that health inequalities be measured across all individuals in a population, as with indices like the Gini coefficient. While this might aid comparability between countries, this approach removes comparisons between more and less advantaged social groups from the agenda and ignores the selection of social groups on a priori moral, ethical, and human rights grounds (Braveman et al., 2000; Kawachi et al., 2002). Clarity about concepts is needed to inform measurement approaches for ongoing surveillance to determine whether health inequalities are widening or decreasing over time and to evaluate policies aimed at reducing these inequalities (Chittleborough et al., 2009). Public health surveillance of health among more and less advantaged groups is not sufficient to reduce health inequalities, but it is required for accountability for differential effects of policies in all sectors. In order to measure health inequalities, our definition can guide us in deciding on indicators of social disadvantage, such as income, education, employment status (Galobardes et al., 2007), ethnicity, or gender at the individual or area level (Galobardes, 2012) and over the life course (Chittleborough et al., 2006). Decisions on how to group individuals require consideration of the moral and political relevance of the groupings, and how these groupings might be involved in the etiology of health inequalities. Decisions about whether to use absolute or relative measures of inequality also require consideration of whether health equality is a valuable goal in itself. Presenting only relative health inequalities reflects an implicit judgment that the relative gap is unfair and avoidable, and equality takes precedence over considerations of absolute levels of health (Harper et al., 2010). This has implications for interpreting progress toward health equality. For example, after attempts by England’s Labour governments from 1997 to tackle health inequalities via an ambitious cross-cutting approach on the broader determinants of health, it was concluded that while overall health had improved, the health of disadvantaged groups had not improved as quickly as that of more advantaged groups (Department of Health, 2008). The inability to meet the target to reduce inequalities in infant mortality by 10% by 2010 could be viewed as a failure. However, this target was based on a relative measure of health inequality – a reduction of

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10% in the gap between ‘routine and manual’ occupational groups (lower supervisory and technical occupations, and routine and semi-routine occupations) and the population as a whole (Department of Health, 2003). The relative gap, expressed as a percentage and calculated as the infant mortality rate per 1000 live births in the ‘routine and manual’ group (6.6 in 1995–97; 5.6 in 2004–06) divided by the rate in the whole population (5.8 in 1995–97; 4.8 in 2004–06), increased from 14% in 1995–97 to 17% in 2004–06 (Gray et al., 2009). The absolute difference in infant mortality between ‘routine and manual’ groups and the whole population remained constant at 0.8 deaths per 1000 live births in 1995–97 and 2004–06. These relative and absolute inequalities all occur in the context of a decreasing overall infant mortality rate, from 5.8 to 4.8 deaths per 1000 live births between 1995–97 and 2004–06 (Gray et al., 2009). The infant mortality rate decreased for all occupation groups over this time period. From a public health point of view, it is difficult to interpret an increase in relative inequality as a failure when absolute inequality has not increased and overall health has improved. Similarly, observing a reduction in health inequality due to the deterioration of health in a healthier, more advantaged group would be inconsistent with public health principles (Harper and Lynch, 2007). There is a perception that the possibility of population health improving while inequalities increase is not very explicitly addressed in health inequalities literature (Preda and Voigt, 2015). It is therefore recommended that both absolute and relative measures are reported for clarity in interpretation of health inequality trends (Kelly et al., 2007; King et al., 2012).

What Difference Could a Definition Make for Acting to Reduce Health Inequalities? Measuring the magnitude of health inequalities and monitoring whether the health gap is increasing or decreasing is necessary, but there is a need to move beyond this description of health inequalities, to focus on strategies to reduce them. This is increasingly being attempted. A shift was noted in the English government commissioned reports on health inequalities – the 1980 Black Report, 1998 Acheson Enquiry, and 2010 Marmot Review – from descriptive research, to research exploring etiological pathways of health inequalities, to prescriptive research developing and evaluating evidence-based interventions that might reduce health inequalities (Bambra et al., 2011). The recommendations of the Marmot review arose from an understanding that health inequalities result from inequalities in society, in the conditions in which people are born, grow, live, work, and age (Marmot et al., 2010). The policy objectives for improving population health and reducing inequalities, with the exception of strengthening early childhood interventions, have been criticized because they appear aspirational. Chandra and Vogl (2010) argue that we do not have the evidence on whether these recommendations would actually reduce health inequality. Alternative reasons related to social justice for modifying policies in education, employment, taxes, communities, and health care (Commission on the Social Determinants of Health, 2008)) are likely to support implementation of these prescriptions (Preda and Voigt, 2015), but

the available evidence to justify their ability to influence health inequalities is weak. The systematic review evidence based on the effect of interventions and policy regimes targeting social determinants of health on improving health and reducing health inequalities is limited (Bambra et al., 2010; Borrell et al., 2014). Highly developed ‘welfare states’ in Western Europe, with their efforts to redistribute income and provide access to housing, education, health care, and leisure facilities for all, have reduced inequalities in socioeconomic outcomes such as income and housing but inequalities in health outcomes have persisted (Mackenbach, 2012). Perhaps we have not yet seen social changes of the scale required, and perhaps it is unrealistic to expect such dramatic changes within current political systems (Preda and Voigt, 2015). Pega et al. (2012) argue that given the goal of most welfare state interventions is to redistribute wealth rather than redistribute health, we should not assume such interventions would necessarily have any effect on health and health inequalities. In addition, it may be that these analyses at the welfare regime level are too broad to capture differential effects on population subgroups. Financial credits, for example, may have no health effect among low income groups who receive them, but may improve health among middle or high income non-recipients via ‘welfare security’ (Pega et al., 2012), in which higher socioeconomic groups benefit from welfare interventions via subjective employment security. We may therefore not observe any change, or a worsening, in overall health inequalities. A series of recent reviews (Horton et al., 2015) have continued to highlight the general lack of studies investigating the effectiveness of public health interventions to reduce health inequalities. Interventions that have been studied commonly focus on individual behavior change rather than the socioeconomic, political, and cultural context of society (Horton et al., 2015). While relatively rapid changes in population health and health inequalities have occurred, these have often been in the context of major economic or political events, such as recession or war, or infectious disease outbreaks (Frank and Haw, 2013). The claim that social policies to reduce inequalities in income, wealth, and education are the most effective interventions to improve health outcomes and reduce health inequalities is problematic because there are also interventions that have targeted behaviors that have successfully reduced health inequalities (Preda and Voigt, 2015). Examples include public health legislation to change supply of cooking oil (Dowse et al., 1995), ban smoking in public places (Liu et al., 2013), and increase cigarette prices (Purcell et al., 2015), resulting in changes to population exposure to cardiovascular risk factors and related health outcomes. Addressing inequalities in social conditions such as income, wealth, and education is important for social justice, but relying solely on this to reduce health inequalities may not be effective (Preda and Voigt, 2015). Furthermore, the theory that social inequality determines health inequality, in which socially disadvantaged groups experience worse health, does not acknowledge the dynamic nature of the association between social factors and health. The association of social disadvantage with both increased and decreased health risks, depending on the health outcome, historical time period, and geographical location under investigation (Harper et al., 2011), is an important observation in our

Health Inequalities attempts to explain changes in population health over time. Classifying health inequalities as those where socially disadvantaged groups experience worse health defines these inequalities under the ethical and justice principles described above. We should also acknowledge the dynamic nature of how various health outcomes are distributed among social groups across time and place as this offers hope that the link between social disadvantage and poor health is not fixed. Policies that do aim to tackle social determinants of health and reduce health inequalities, for example, goals to end child poverty, or to reduce inequalities in life expectancy, require long-term, ‘joined-up government’ approaches that allow consistency and collaboration across departments over long periods of time (Exworthy and Hunter, 2011). Health in All Policies, implemented in various forms in many countries, is an approach that builds intersectoral relationships for policy development to address health inequalities by recognizing that responsibility for the determinants of health cross over multiple government departments (Delany et al., 2015). In order to have a chance at success, Health in All Policies needs to be part of a centrally mandated framework, with dedicated staff and resources, and have intersectoral accountability for targets related to health inequality (Delany et al., 2015). Such joined-up approaches are not normally associated with government activity and have been difficult to achieve. For example, the ‘Close the Gap’ campaign for Indigenous Health Equality is supported by the Australian Human Rights Commission and includes commitment by the Commonwealth, State and Territory Governments (Council of Australian Governments, 2008). In addition to a focus on health outcomes, the strategy also includes national partnership agreements and action plans for early child development, education, housing, and remote area service delivery. The Indigenous Advancement Strategy coordinated by the Department of the Prime Minister and Cabinet has programs aimed at improving employment, schooling, and safety of communities (Australian Government Department of the Prime Minister and Cabinet, 2014). However, this recent strategy does not include the majority of health programs that remain located in the Department of Health, resulting in a call for closer alignment of the Advancement Strategy and Close the Gap to articulate how the two approaches can mutually support priorities to reduce health inequalities between Indigenous and non-Indigenous Australians (Holland, 2015). While there is commendable attention being paid to broader determinants of health inequalities at the policy level, there are still barriers to coordinating these approaches across multiple government departments. There is a disconnect between valuing social justice and rights to health and other economic, social, and cultural rights, and the remit of government departments responsible for improving health and reducing health inequalities (Smith, 2014). Organizational location of responsibility for reducing ‘health’ inequalities has limited the influence of research-informed ideas about the wider determinants of health (Exworthy and Hunter, 2011). It is much easier to convince a health department to evaluate a smoking intervention than to be involved in assessing a housing, education, or transport policy (Smith, 2014). Carey and Crammond (2015) suggest that rather than giving up on policy action on health inequalities because joined-up

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approaches are too difficult, researchers should try to work within the structural confines of government. The risk with this model is that the focus of researchers, policy makers, and practitioners will drift away from social determinants such as income, education, housing, and employment and back to individual behaviors (Popay, 2012). In addition, examples from the early child development field reveal difficulties in implementing efficacious interventions into routine practice and service delivery, even within discrete government agencies (Lynch et al., 2010). The challenge is to gain clarity on the interventions aimed at risk factors, behaviors and consumption that are effective at improving overall population health and reducing health inequalities, while simultaneously not losing sight of the social, economic, cultural, and political circumstances in which these risk factors occur. This requires balancing what is achievable in the shorter term, within the ‘health’ focused current government organizational constraints, with longer term goals to reduce social inequalities. In addition to reducing health inequalities via action directed at either the social determinants of health, or personal behaviors and risk factors, there is not only an opportunity to improve health for everyone, but also to focus on bringing up those who started off furthest behind. This approach, has been described as ‘leveling up’ (Whitehead, 1992) and more recently in a service provision context as proportionate universalism (Marmot et al., 2010). This approach is used, for example, in early child health and development policy where universal services are provided for all, with more intensive support offered to those with greater need (Lynch et al., 2010). Value judgments are implicit in determining eligibility criteria for these progressively intensive services, with social factors sometimes not considered in defining vulnerable groups who might benefit from such programs (Chittleborough et al., 2011).

Conclusion At times, defining terms can be largely a semantic matter, without practical consequences. At other times, however, definitions can indeed matter. In the case of health inequalities, definitions determine what will be measured and monitored by local, national, and international governments and nongovernmental organizations; and measurement is crucial for accountability. Definitions also can matter insofar as they clarify – or obscure – key concepts such as distributive justice and the concept of equal opportunities to be healthy as a fundamental human right. The concept of health inequalities draws heavily from epidemiologic notions, but it is not just a technical concept. It inherently reflects social values from the fields of ethics and human rights. If we do not understand a concept, we are likely to be less effective in pursuing its fulfillment; in the case of health inequalities, we can easily be sidetracked by attempts to pull the agenda away from social justice concerns. Concepts can determine what will get the attention and support of the public and policy makers, and whether that attention and support will be sustained on policy agendas. Health inequalities are differences in health (or differences in important influences on

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health) that are systematically associated with being socially disadvantaged (e.g., being poor, a member of a disadvantaged racial/ethnic group, or female), and that put already disadvantaged groups at further disadvantage. We need to pursue the evidence base demonstrating that reducing social disadvantage and social inequalities results in less health inequality and greater health and human capability. Pursuing health equity – that is, striving to eliminate health inequalities associated with social disadvantage – means striving for equal opportunities for all social groups to be as healthy as possible, and selectively focusing on those groups that have had fewer opportunities. Health inequalities are also defined here as potentially avoidable differences in health, or determinants of health, that can be shaped by policies. We should therefore continue to work toward providing effective interventions to reduce health inequalities that target social and economic factors, risk behaviors, and personal characteristics, and at providing interventions and services to vulnerable groups within proportionate universal systems. The ultimate goal is equal opportunity for health for all, regardless of the social conditions in which people are born, live, and work.

See also: Codes of Ethics in Public Health; Cultural Competence in Public Health; Cultural Epidemiology; Educational Attainment and Health: Survival; Foundations in Public Health Ethics; Gender in Health and Illness; Health and Human Rights: Overview; New Public Health; Social Determinants of Health, the United Nations Commission of; Social Epidemiology; Social Gradients and Child Health.

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Mokdad, A.H., Marks, J.S., Stroup, D.F., Gerberding, J.L., 2004. Actual causes of death in the United States, 2000. J. Am. Med. Assoc. 291, 1238–1245. OECD, 2015. Tackling Harmful Alcohol Use. Economics and Public Health Policy. OECD Publishing, Paris, France. Pega, F., Blakely, T., Carter, K., Sjöberg, O., 2012. The explanation of a paradox? A commentary on Mackenbach with perspectives from research on financial credits and risk factor trends. Soc. Sci. Med. 75, 770–773. Peter, F., Evans, T., 2001. Ethical dimensions of health equity. In: Evans, T., Whitehead, M., Diderichsen, F., Bhuiya, A., Wirth, M. (Eds.), Challenging Inequities in Health: From Ethics to Action. Oxford University Press, New York, pp. 24–33. Popay, J., 2012. The knowledge needed to deliver social Justice and health equity. Int. J. Qual. Methods 11, 59–60. Preda, A., Voigt, K., 2015. The social determinants of health: why should we care? Am. J. Bioeth. 15, 25–36. Purcell, K.R., O’Rourke, K., Rivis, M., 2015. Tobacco control approaches and inequitydhow far have we come and where are we going? Health Promot. Int. 30, ii89–ii101. Rawls, J., 1985. Justice as fairness: political not metaphysical. Philos. Public Aff. 14, 223–251. Ruger, J.P., 2006. Ethics and governance of global health inequalities. J. Epidemiol. Community Health 60, 998–1003. Sen, A., 1999. Development as Freedom. Random House, New York. Smith, K.E., 2014. The politics of ideas: the complex interplay of health inequalities research and policy. Sci. Public Policy 41, 561–574. Starfield, B., 2007. Pathways of influence on equity in health. Soc. Sci. Med. 64, 1355–1362. Strand, B.H., Kunst, A., Huisman, M., Menvielle, G., Glickman, M., Bopp, M., et al., 2007. The reversed social gradient: higher breast cancer mortality in the higher educated compared to lower educated. A comparison of 11 European populations during the 1990s. Eur. J. Cancer 43, 1200–1207. UNICEF, World Health Organization, World Bank, United Nations Department of Economic and Social Affairs Population Division, 2015. Levels and Trends in Child Mortality 2015. United Nations Children Fund, New York. United Nations, 2015. Transforming Our World: the 2030 Agenda for Sustainable Development. UN Department of Economic and Social Affairs, New York. Wagstaff, A., Paci, P., van Doorslaer, E., 1991. On the measurement of inequalities in health. Soc. Sci. Med. 33, 545–557. Whitehead, M., 1992. The concepts and principles of equity and health. Int. J. Health Serv. 22, 429–445. World Health Organization, 1946. Constitution of the World Health Organization. World Health Organization, New York. World Health Organization, 2000. World Health Report 2000: Health Systems; Improving Performance. World Health Organization, Geneva, Switzerland.

Health Information on the Internet Rehema Chande-Mallya and Sydney Enock Msonde, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania Wulystan Pius Mtega, Sokoine University of Agriculture, Morogoro, Tanzania Edda Tandi Lwoga, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania Ó 2017 Elsevier Inc. All rights reserved.

Introduction Advancements in information and communication technologies (ICTs) including Internet have accelerated the search for health-related information and become a common practice worldwide. It has brought a change in people’s lifestyle and has a greater impact compared to any other communication tools. A study by Alghamdi and Moussa (2011) noted that, a majority of people rely on Internet to search for health information, social, business, and other information available online. The evolution of Internet and its utilization has improved access and retrieval of health information. Alghamdi and Moussa (2011) observed that patients used various sources of information such as newspapers, books, and colleagues to search for health information in previous days. Modern search engines and platforms (e.g., social networks, websites, portals, health databases) have made health information easily accessible using various devices such as smart phones, tablets, laptops, and computers (Hong et al., 2015). Health information is now available at fingertips. The Internet is a powerful tool for empowering patients in making decision on health-related matters, and it facilitates patients to communicate easily in health-care services. It is also observed that limited patient communication is associated with poor patient health outcomes and low patient satisfaction. However, Internet is viewed as a medium for patient empowerment; although some websites are not rated as trustworthy or validated (Beck et al., 2014). The public health impact of the Internet is wide reaching, affecting many aspects of people’s social lives and practice. For example, university students used the Internet to search for health information on various aspects especially on specific illness, fitness, and nutrition compared to other online users. In higher learning institutions and health-care centers, Internet has been a crucial tool in exchanging information using various online platforms such as social media tools (e-mails and other interactive tools). Telemedicine and video conferencing are useful tools in transferring information from one part to another (e.g., in facilitating hospital communication) in relation to clinical aspects such as medical diagnosis, treatment, transferring of data, and monitoring patients’ health-care delivery services. This article focuses on the use of Internet for public health, and it covers the following subtopics: accessibility, quality, prospects, efficacy, and challenges of accessing health information on the Internet.

Accessibility of Health Information on the Internet The Internet has increased accessibility of health information among stakeholders. Ajuwon (2015) defines Internet as a global network of networks that enables computers of all

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kinds to directly and transparently communicate throughout the world. The usage of Internet has been increasing over time. The literature indicates that there were 400 million Internet users in the year 2000, the number of users rose to over 1 billion people in 2005 and to 3.2 billion by the end of 2015. This fast increase in usage of Internet is due to its informative power. The Internet plays a crucial role in facilitating interactions between people and the health care–delivery system and as an important source for the public, patients, and health-care professionals to obtain information about health, diseases, and medical treatment. Internet enhances access to health information to people regardless of their geographical locations. It enables users to have access to health information from anywhere and during anytime of the day. Through modern search engines, people easily access information stored in servers found around the globe. The amount of online health information available to users keeps growing on daily basis (Ajuwon, 2015). Song et al. (2016) found that through research and case studies, doctors and health professionals contribute to online health information. Song et al. (2016) reported that patients have a great contribution to health information through sharing individual experiences of their health conditions. Online health information affects health-related decisions, enables better management of chronic health conditions; and fuels discussions with health-care providers. Patients use Internet to access health information and share that information with their doctors during treatment and diagnosis as a second opinion for improving health-care services. With Internet usage patients can find answers to frequently asked health queries. The Internet is an important platform for obtaining and sharing online health information among health-care providers (Song et al., 2016). It also facilitates easy accessibility of health information as the message can be transferred through different formats (audio, film, text, image, and video). Therefore, through Internet both health-care providers and patients become better informed. Advancements of Internet technology have brought about second generation of the Internet commonly known as Web 2.0 technologies. Applications of Web 2.0 tools including the social media are widely used among people. Social media can be defined as Internet-based tools that allow individuals and communities to communicate; share information, ideas, personal messages, images, and other content in a timely manner. In the health sector, health-care providers and patients have been accessing and sharing health information through social media. Basically, social media increases the level of interactions among and between patients and health-care providers in enhancing provision of health-care services delivery. In most cases, if people become dissatisfied with support received from offline contacts they are more likely to contact social media for more information.

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Health Information on the Internet

Quality of Health Information in Improving Public Health The quality and reliability of health information on the Internet is highly variable. Some of the health websites are of poor quality, incorrect, and contain misleading content (Alsaiari et al., 2016; Fahy et al., 2014). These websites are also biased especially when the content is supported by profit organizations (Alsaiari et al., 2016). Some health websites may mislead the public into nonevidence-based practices, and unwarranted self-diagnosis (Chumber et al., 2015). The poor quality content may negatively affect the patient–doctor relationship and lead to anxiety or stress among patients (Alsaiari et al., 2016). These websites also provide large amounts of information, which may be overwhelming to patients to be able to recognize inaccurate information, especially those without a high school education or medical training (Chumber et al., 2015). These concerns have recently resulted in the need to assess the quality of health information available on the web. Fortunately, there are a number of criteria and instruments that are used for measuring the quality of health content on the web. The two most widely used instruments for assessing the quality of health information include the Health On the Net Foundation (HON) certification; the Journal of the American Medical Association (JAMA) scoring system and the DISCERN tool. The HON code is the oldest tool created by the Health on the Net Foundation in 1995. It measures and accredits websites that adhere to the eight principles of authorship, complementarity, privacy, attribution, justifiability, transparency, financial disclosure, and advertising policy (Net Hot, 2016). The HON code certification is a voluntary certification aimed to encourage the dissemination of quality health information on the web (Net Hot, 2016). The JAMA criteria evaluate the quality of a website based on four main criteria that must be matched: authorship, attribution of references, and sources for all content, date of publication, and author disclosures of ownership or financial support. DISCERN is a tool created by the Division of Public Health and Primary Care at Oxford University, London, in 1998. It comprises a 16-item questionnaire for patients to complete for each site they want to assess. Other criteria that are commonly used include whether the website is readable (Alsaiari et al., 2016), and user-friendly in terms of interactivity (Chumber et al., 2015). Although many tools and instruments have been developed, there is no agreed standard for measuring the quality of health information on the web. Studies indicate that these tools (JAMA score, the HON certification, and DISCERN) may not be adequate for evaluating health websites (Chumber et al., 2015; Fahy et al., 2014). None of these instruments or tools individually addresses each of the above-mentioned criteria, and thus researchers use multiple tools to comprehensively evaluate quality of health information available on the web (Nasser et al., 2012). This calls for a need to have a standard approach to measure the quality of health information in the health websites. The majority of health information on the web is still of poor quality. It is imperative to improve the quality of health information if the Internet is to meet its potential to improve health. There is still a need to have a standardized approach to present

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health information to enable even people with low level of education to comprehend. Health-care workers can identify the best websites with the most complete, readable, updated information, and recommending these website patients with appropriate guidance on how to access these websites. Health-care workers should play an active role in the development of reliable and informative health websites and design guidelines to assist patients to access health information.

Prospects and Efficacy of the Internet in Promoting Health-care Services Advances in ICT and the practices that grow around them create an explosion of health information made available on the Internet. The use of Internet for accessing health information is rapidly increasing across the world (Wald et al., 2007; Silver, 2015). The enormous adoption of mobile and social media technologies have revolutionized the way people think and in promoting health-care services. Currently, unlike the practices experienced in the 1990s, there is a huge demand for patients (the public) to use and access timely online health information (Silver, 2015), that would address their medical problems. The Internet has now become the catalyst for the seismic shift in the doctor–patient relationship (Jeannot and Bischoff, 2015), and it is bringing a profound impact on improving health-care services. In the past few decades, it was not clear what impact the Internet could bring on clinical care. It is now evident that the Internet has the capability to offer several applications that improve health-care services in clinical settings. For example, the Internet is increasingly used in hospitals for storing and accessing patient health records, which in turn give physicians, evidence for informed clinical decision making. In the same line, hospitals can use the Internet as a medium to share patient health records in order to improve health care and hospital performance. Very recently, the use of remote video consultation provides patients with extensive opportunity to get access to skilled health professionals irrespective of their geographical location. Virtual reality is another form of tools that are supported by the Internet to help surgeons plan and implement surgical procedures more successfully than before. The Internet also plays a key role in transferring medical images to expert for interpretation which culminates into improved patients’ diagnostic process. The linkage of various Internet applications in clinical settings widen the repertoire of getting high-quality medical information on complications of thousands of conditions (Beck et al., 2014), and increases the likelihood of getting evidencebased information for confident clinical decision making. In most cases, individuals do access important websites that provide information about diseases outbreak, medical treatment, and other health-related issues (Wald et al., 2007). In other words, patients are able to identify potential health problems using the Internet and they become comfortable communicating with health providers (doctors) about their illness via the Internet (Silver, 2015). Therefore, access to health information on the Internet enables individuals to make informed decision about how to take care of their illness and whether or not to visit a doctor (Wald et al., 2007).

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Health Information on the Internet

The unprecedented rise of the Internet informed-health consumers affects the physician–patient relationship in many ways. The availability of health information on the Internet may create a strong relationship between patients with their physician in managing patient health-care (Wald et al., 2007). Patients are increasingly using the Internet as a source of health information before or after seeing a physician (Beck et al., 2014). They also expect physicians to provide interpretations of health information they acquire from the web. In such a case, the physician feels the patients are challenging their authority (Beck et al., 2014), and that some of the information requested may not be appropriate for improving their health. Sometimes, patients may have greater access to information on various health conditions and fail to acknowledge the physician’s clinical expertise. The way, in which medical information is made available and discussed in the Internet, it is likely to influence (jeopardize) the physician–patient relationship. The Internet can therefore not be considered as a threat for physician, rather as an opportunity to strengthen the physician–patient relationship. While the ecology of health information and how it flows was not evident in the 1990s, recent advances in technologies (Web 2.0), particularly the emergence of social media tools have transformed the communication ecology. The use of social media tools has increased the likelihood of connectivity among people within a community. The use of social media has direct impact on promoting health communication between physician–patient, which leads to improved public health (Vance et al., 2009). Most hospitals and health care–providing organizations across the world have recognized the value of social media tools for promoting communications between patient–patient and between physician– patient (Hanson et al., 2014). The tools also enhance interactions between researchers–patient as well as public health consumer. The use of social media in health-care settings focuses on facilitating patients to acquire relevant information about disease and their associated treatments. It also helps to connect two or more people with the same illness and share their experiences on how to address common health problems. Patients are increasingly using social media tools to find medical advice and share information about their condition using social media platforms (Hanson et al., 2014). This leads to improved relationship among patients as well as with health providers. It is not surprising to see patients using social media to communicate their health problems. Therefore, appropriate use of these tools and the Internet by the community is likely going to improve the public health. Although, we are witnessing a huge shift in technology use in promoting public health but still we do not know how new technological invention and media convergence will affect what the Internet is capable of today. As the Internet converges in particular with television and mobile technologies, it is crucial to explore how such convergence would bring positive impact to public health. Apart from social media tools, the public may also use more sophisticated forms of media to provide the opportunity with ability to communicate with people from a broader range of backgrounds. The use of virtual reality tools, for example, may help surgeons undertake medical procedures in more successful way. In fact, many

revolutionary changes could well lie ahead, driven to a large extent by the technology currently called the Internet. While we do not know what technological innovations will emerge tomorrow, some things will not change, or atleast, they will not change quickly. For example, major illness and injury will still be crises that cause immense suffering. People affected by them will still need expert support, information, and communication, often for many years. These needs will remain, but within the framework of evolving systems and relationships. Historically, patient information has tended to be paternalistic, assuming ignorance on the part of patients together with a need for them to be protected from uncertainty and distressing information: patients should be directed about what they should know, what they should think, and what they should do. This remains, to a significant extent, a feature of patient information. That is not in the end consistent with empowerment through information, and it is inconsistent with the open and revealing nature of the Internet. As more people become better educated about their health and how to use information, the slow historical trend toward increasing patient autonomy can be expected to at least continue to be upgrade. Most likely, it will be sped up substantially by the Internet.

Challenges of Accessing Health Information on the Internet Access to Internet services in the health sector is limited by several factors. Ajuwon (2015) mentions some of the factors to include computer and Internet illiteracy; limited access to computers; and slow Internet speed in some geographical settings. The level of investment in ICT infrastructure influences accessibility of Internet. Due to ICT infrastructure in developing countries, Internet penetration is low. However, due to the well-developed ICT infrastructure in most developed countries, usage of Internet and the level of accessibility of e-health information are quite high. Moreover, patients in developed countries have developed a habit of searching for health information through the Internet compared with health-care providers. This means that the Internet is the first source of health information for many people including patients. In addition, other factor limiting Internet usage include unreliable sources of power, limited budget and lack maintenance culture, lack of information-searching skills, and limited bandwidth especially in rural and remote areas. Generally, most of these factors have limited most people from developing countries from accessing e-health services.

Summary This article discusses access to and use of Internet in promoting public health. It provides a background and overview of the Internet, accessibility of health information on the Internet, and quality of health information in improving public health. It also covers prospects and efficacy of the Internet in supporting health care–delivery services as well as challenges in accessing health information from the Internet. Lastly, it concludes by providing a summary.

Health Information on the Internet

References Ajuwon, G.A., 2015. Internet Accessibility and Use of Online Health Information Resources by Doctors in Training Healthcare Institutions in Nigeria. Library Philosophy and Practice, pp. 1–20. Available at: http://www.search.proquest.com/ docview/1744626494/abstract/6554E60F01EB4E2EPQ/1/nhttp://media.proquest. com/media/pq/classic/doc/3887018661/fmt/pi/rep/NONE?hl¼&cit%3Aauth¼ Ajuwon%2CþGraceþA&cit%3Atitle¼InternetþAccessibilityþandþUseþofþ OnlineþHealthþInformationþ. Alghamdi, K.M., Mouss, N.A., 2011. Internet use by the public to search for healthrelated information. Int. J. Med. Inf. 81, 363–373. http://dx.doi.org/10.1016/j. ijmedinf.2011.12.004. Alsaiari, A., et al., 2016. The content and quality of health information on the Internet for patients and families on Adult Kidney Cancer. J. Cancer Educ. Off. J. Am. Assoc. Cancer Educ. Beck, F., et al., 2014. Use of the Internet as a health information resource among French young adults: results from a nationally representative survey. J. Med. Internet Res. 16 (5), e128. Available at: http://www.jmir.org/2014/5/e128/. Chumber, S., Huber, J., Ghezzi, P., 2015. A methodology to analyze the quality of health information on the Internet: the example of diabetic neuropathy. Diabetes Educ. 41 (1), 95–105. Fahy, E., et al., 2014. Quality of patient health information on the Internet: reviewing a complex and evolving landscape. Australas. Med. J. 7 (1), 24–28.

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Hanson, C.L., et al., 2014. Understanding and predicting social media use among community health center patients: a cross-sectional survey. J. Med. Internet Res. 16 (11). Hong, T., et al., 2015. The impact of Internet health information on patient compliance: a research model and an empirical study. J. Med. Internet Res. 17 (6). Jeannot, J.G., Bischoff, T., 2015. Patients, doctors and the Internet. Rev. Méd. Suisse 11 (474), pp. 1064, 1066–8. Nasser, S., Mullan, J., Bajorek, B., 2012. Assessing the quality, suitability and readability of Internet-based health information about warfarin for patients. Australas. Med. J. 5 (3), 194–203. Net Hot, 2016. The HON Code of Conduct for Medical and Health Web Sites (HON code). Silver, M.P., 2015. Patient perspectives on online health information and communication with doctors: a qualitative study of patients 50 years old and over. J. Med. Internet Res. 17 (1), e19. Song, H., et al., 2016. Trusting social media as a source of health information: online surveys comparing the United States, Korea, and Hong Kong. J. Med. Internet Res. 18 (3), e25. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi? artid¼4810010&tool¼pmcentrez&rendertype¼abstract. Vance, K., Howe, W., Dellavalle, R.P., 2009. Social Internet sites as a source of public health information. Dermatol. Clin. 27 (2), 133–136. Wald, H.S., Dube, C.E., Anthony, D.C., 2007. Untangling the web – the impact of Internet use on health care and the physician-patient relationship. Patient Educ. Couns. 68 (3), 218–224.

Health Insurance Plans and Programs: An Overview Stefan Greß, University of Applied Sciences, Fulda, Germany Juergen Wasem, University of Duisburg Essen, Essen, Germany Ó 2017 Elsevier Inc. All rights reserved.

Introduction

Design of Health Insurance Programs

The purpose of this article is to provide an overview on the principles of health insurance plans and programs. (On a system level, we use the term health insurance program. On the level of the individual health insurance entity, we use the term health plan. It is important to note that this article does not cover the tax-financed schemes that are predominant in some parts of Europe such as Scandinavia, the UK, Italy, and Canada.) In doing so, we endeavor to discuss the major theoretical issues that make the design of health insurance plans and programs difficult. The diversity of health insurance designs around the world is the consequence of these difficulties. One of these theoretical problems is adverse selection in competitive health insurance markets: as a consequence of market failures, comprehensive coverage by health insurance is difficult if not impossible to obtain. Another important problem is to ascertain the value of health insurance: while comprehensive coverage of health insurance is valued highly in many countries, the incomplete coverage in the United States can – among other reasons – be explained by the conviction that health insurance leads to wasteful overconsumption of health care because the price of health services for the consumer is too low. This article is organized as follows. The section Design of Health Insurance Programs provides a summary and nontechnical discussion about the research that has been conducted on two of the most important theoretical problems of health insurance: the value of health insurance and adverse selection in competitive health insurance markets. This section also provides an analytical framework to classify real-world health insurance programs. The following sections analyze real-world health insurance programs in more detail. The section Private Health Insurance Programs discusses the design of private health insurance (PHI) programs that typically calculate risk-related premiums. We find that even in the United States supposedly purely PHI is not dominant: typically designers of health insurance programs prefer comprehensive coverage, which is difficult to obtain by using PHI with risk-related premiums. Therefore, section Social Health Insurance Programs reviews the more predominant social health insurance programs. Social health insurance implies that extensive regulation – most importantly premium rate restrictions, standardization of benefits, and mandatory coverage – leads to comprehensive coverage. However, some important differences between social health insurance programs can be established, most importantly the difference between competitive multipayer programs and noncompetitive single-payer programs. Finally, ‘Health Insurance in Low- and Middle-Income Countries’ reviews the evidence on the health outcomes of health insurance programs.

This section discusses two of the most important theoretical problems of the design of health insurance programs: the trade-off between comprehensive coverage and wasteful overconsumption of health care and the trade-off between competition and selection. The section Calculation of Premiums in Health Insurance Programs introduces an analytical framework to classify real-world health insurance programs.

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Value of Health Insurance The value of health insurance is derived from the uncertainty and unpredictability of health spending. Of any given population, only a very small fraction of individuals incurs a very large fraction of health spending. The distribution of health spending at any given time (and over time as well) is highly skewed. Although individuals have some information about their health status and their needs for health spending, the exact amount is highly uncertain. As a consequence, health insurance is an important tool to spread risks and by this to enhance welfare. Insurance is superior to borrowing and saving (Cutler and Zeckhauser, 2000). Individuals might borrow money when they are sick and repay their loans when they are healthy again. However, individuals might not be able to live long enough to pay back their loans. Moreover, savings might be able to cover everyday health expenses. However, medical episodes will possibly incur very substantial health expenses, which cannot be covered by savings. As a consequence, risk spreading of health insurance is highly valuable for individuals. Moreover, it is highly valuable from a societal perspective as well. In most developed industrial countries, comprehensive coverage against the financial risk of health spending is highly valued by society. Since the “Obama health care reform,” this is true even for the United States. Moreover, comprehensive mandatory coverage avoids market failures such as adverse selection and free-rider behavior (see the section Adverse Selection in Competitive Health Insurance Markets). The value of health insurance, determined by spreading medical risks, is, however, diminished by incentive problems caused by health insurance. There is a substantial body of literature that presumes that the existence of health insurance leads to overspending (Pauly, 1968). Individuals with health insurance use more health services than they would if they were paying for these health services themselves. This behavior is called moral hazard. The term does not refer to some moral failure of individuals. Moral hazard simply implies that individuals adapt their behavior to incentives set by health insurance: “The response of seeking more health care with insurance than in its absence is a result not of moral perfidy, but of rational economic behaviour” (Pauly, 1968: p. 535).

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Health Insurance Plans and Programs: An Overview The economic analysis of the welfare implications of moral hazard actually led to the conclusion that moral hazard substantially reduces the value of health insurance, and consumers might even incur a negative value from health insurance if the coinsurance rate is very low (Manning and Marquis, 1996). This welfare loss occurs because with health insurance patients consume additional services that provide little benefit to them (Rice, 2002). A rather famous natural experiment found that (higher) coverage of health insurance indeed leads to higher utilization rates of health services. The RAND Insurance Experiment randomized about 6000 individuals in six areas in the United States into different insurance programs. The insurance programs differed by coinsurance rates – between 0% and 95% (see Table 1). Without coinsurance, total health spending per capita was considerably higher than with some degree of coinsurance (Manning et al., 1987; Newhouse and Insurance Experiment Group, 1993). However, the RAND Insurance Experiment also found that individuals are unable to distinguish between highly effective and less effective treatments. In other words, more coinsurance may indeed lead to less utilization of health services – useful services as well as useless services “. cost sharing did not seem to have a selective effect in prompting people to forgo care only or mainly in circumstances when such care probably would be of relatively little value” (Lohr et al., 1986: p. S36). The design of health insurance programs involves a tradeoff between risk spreading and appropriate incentives. More generous health insurance programs spread risk more broadly but also led to more overspending due to moral hazard. Several studies simulate optimal coinsurance rates, ranging between 25% and 58% (Cutler and Zeckhauser, 2000). From a societal point of view, these coinsurance rates are – at least outside the United States – difficult to accept. Still, modest coinsurance rates are part of most social health insurance programs. Therefore, most countries accept some degree of moral hazard in order to gain the benefits which are due to risk spreading: “Perhaps the most persuasive empirical evidence regarding the value of health insurance is the extent to which health insurance is purchased voluntarily, or provided to the citizens of democratic states. This evidence, represented by the high proportion of U.S. consumers who are insured and the high proportion of developed democracies that have some form of national health insurance, suggests that the value of health insurance is overwhelmingly positive” (Nyman, 2006: p. 102).

Table 1

Results of the RAND health insurance experiment

Outpatient Inpatient Co-insurance expenses expenses rate (1984$) (1984$)

Total expenses (1984$)

Physician visits

Admissions

0 (free) 25% 50% 95%

749 634 674 518

4.55 3.33 3.03 2.73

0.128 0.105 0.092 0.099

340 260 224 203

409 373 450 315

From Manning, W.G., Newhouse, J.P., Duan, N., et al., 1987. Health insurance and the demand for medical care: evidence from a randomized experiment. Am. Econ. Rev. 77 (3), 251–277, with permission from American Economic Association.

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Adverse Selection in Competitive Health Insurance Markets In the previous section we discussed the trade-off between risk spreading and appropriate incentives. In this section, we discuss another trade-off that is essential for the design of health insurance programs: the trade-off between competition and selection. Of course, this trade-off is not relevant for noncompetitive single-payer health insurance programs. However, designers of health insurance programs in many countries rely on competition as a means to stimulate innovation and – at least to some degree – to enhance consumer choice as a way to meet individual preferences. As a consequence, consumers who are shopping around for the lowest price and the best product at least theoretically stimulate price competition and the development of new products. The benefits of competing health insurers are similar to the benefits of competition in other markets (Cutler and Zeckhauser, 2000). Unfortunately, health insurance is different. In contrast to other markets, some characteristics of the consumer of health insurance programs most probably affect the price of the product. If health insurance programs are charging riskrelated premiums (see the section Calculation of Premiums in Health Insurance Programs), sick individuals pay more for an identical product than healthy individuals. Moreover, sick individuals prefer health plans with more generous benefits and low coinsurance rates. Since individuals also tend to have more information about their health status than the health plan, the latter is unable to calculate actuarially fair premiums. As a consequence, health plans charge some kind of average price. However, more generous health plans attract a high share of sick individuals and less generous health plans attract a high share of healthy individuals. As a result of this process of adverse selection, premiums of more generous health plans go up, which drives out the remaining healthy individuals, which in turn increase premiums even further. The empirical evidence for adverse selection is rather strong and unambiguous (Cutler and Zeckhauser, 2000; Geoffard, 2006). Adverse selection makes it extremely difficult – if not impossible – to reach market equilibrium that ensures risk spreading for both groups, sick individuals as well as healthy individuals. Moreover, health plans have incentives to distort benefits in order to make themselves unattractive for sick individuals. What is more, they face disincentives to develop product innovations that are likely to attract sick individuals. This outcome is rather undesirable from a societal point of view. As a consequence, designers of social health insurance programs in many countries strive to prevent the consequences of adverse selection. They do so by introducing mandatory coverage, standardizing benefits, and abolishing risk-related premiums. (Alternatively, health insurance programs could also charge risk-related premiums if bad risks (sick individuals) received premium subsidies, for example, by the government: the sicker an individual, the higher the premium subsidy (see Zweifel and Breuer, 2006). (However, this solution is not applied in practice.) However, the trade-off between competition and selection remains an important issue in highly regulated health insurance programs as well, because some kind of risk adjustment system needs to neutralize incentives for

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risk selection (see the sections Private Health Insurance Programs and Social Health Insurance Programs).

Calculation of Premiums in Health Insurance Programs We have seen in the previous section that adverse selection is an important reason why the design of health insurance plans is regulated quite heavily. One of the most important fields of regulation is the method of premium calculation in health insurance plans. In this section, we introduce some basic distinctions of premium calculation in health insurance programs and discuss the implications. Table 2 displays the basic methods of premium calculation and some real world examples of health insurance programs. Adverse selection is an important reason for the regulation of health insurance programs. Moreover – and maybe even more importantly – societies in many OECD countries place a high priority on fairness or solidarity as a policy objective in health-care financing (Wagstaff and van Doorslaer, 1992; Wagstaff and van Doorslaer, 2000). Several dimensions of solidarity need to be distinguished (van de Ven and Ellis, 2000), the most important being risk solidarity and income solidarity. The most basic dimension of solidarity is risk solidarity. Looking in more detail, it can be distinguished in ex-ante risk solidarity and ex-post risk solidarity between the healthy and the sick. Ex-post solidarity means that there is a limited redistribution of resources from the unexpectedly healthy toward the unexpectedly sick. Ex-post risk solidarity between the healthy and the sick can also be considered to be the basic (health) insurance function, which can even be achieved in PHI programs that calculate risk-related premiums. For the sake of simplification we classify health insurance programs as private if they primarily rely on risk-related premiums. If health insurance programs are required to calculate community-rated premiums or income-dependent premiums, we classify them as social insurance programs. The private US group health insurance programs are somewhere in between. Note that the classification ‘private’ does not refer to the legal status of insurance companies: in the Netherlands, the social health insurance program is now carried out by PHI companies.

Table 2

Calculation of premium in health insurance programs

Method of premium Income-related calculation contributions Health insurance program

Community rating

Germany (social) Switzerland

France Netherlands

United States (group)

Risk-related premiums United States (individual) Germany (private)

Netherlands

Based on Wasem, J., Greß, S.,Okma, K.G.H., 2004. The role of private health insurance in social health insurance countries. In: Saltman, R., Busse, R., Figueras, J. (Eds.), Social Health Insurance in Western Europe. Open University Press, London, pp. 227–247.

Ex-ante risk solidarity implies a redistribution from those who are expected to be healthy to those who are expected to be sick. This cannot be achieved with risk-related premiums, as they charge those expected to be sick higher premiums. This is the natural result that can be observed on more or less unregulated health insurance markets. However, OECD countries do not want to restrict their health-care system to expost risk solidarity. Therefore, designers of social health-care financing systems prefer to implement modes of financing, which provide an enhanced degree of solidarity and redistribution. The introduction of premium rate restrictions, for example, community rating (community-rated premiums are the same for all enrollees in the same health plan) – and mandatory enrollment lead to ex-ante risk solidarity as well as ex-post risk solidarity between the healthy and the sick, because health insurance programs have to refrain from charging higher premiums for high health risks (see section Social Health Insurance Programs for the implications this regulatory requirement has for the trade-off between competition and selection). Moreover, income solidarity between the rich and the poor may be another fundamental feature of health insurance programs as well, but not necessarily so. If health insurance programs are required to calculate community-rated premiums, these premiums are independent of income. As a consequence, these health insurance programs do not redistribute resources from the rich to the poor. What is more, the consequences of community-rated premiums are regressive: the higher the income, the smaller the share which is spent for health insurance premiums. In those OECD countries that use social health insurance as the predominant mode of health-care financing, these consequences are not acceptable to designers of health insurance programs. Therefore, they either implement a system of community-rated premiums and tax-financed and needstested premium subsidies to the poor (Switzerland) or use income-dependent premiums as a mode of financing (the social health insurance market in Germany, France). In the Netherlands, both approaches are applied, as half of the contribution in social health insurance is income-dependent, half is community-rated. The income consequences of communityrated premiums with tax-financed and needs-tested premium subsidies on the one hand and income-dependent premiums on the other hand can be equivalent (Breyer, 2002).

Private Health Insurance Programs Compared to other sources of health-care finance, PHI programs are of minor importance in most OECD countries. Within the OECD, it is only in the United States that PHI programs account for more than 30% of health spending. Still, adequately regulated PHI programs are attractive alternatives to so-called socialized medicine for proponents of marketoriented reforms not only in the United States (Pauly and Herring, 1999) but also in Western Europe (Henke, 1999). What are then the problems of adequate regulation of PHI programs? The next section briefly describes the various functions PHI programs can perform in health-care systems. The section Regulation of Private Health Insurance Programs analyzes regulation of PHI programs. Finally, we will discuss

Health Insurance Plans and Programs: An Overview the relationship of PHI programs with health-care providers (see section Provision of Health-Care Services).

Functions of Private Health Insurance Programs PHI programs cover a wide range of arrangements. PHI programs are supplied by commercial insurance firms (both stockholder and mutual; among them also plans owned by the state) as well as not-for-profit agencies. Insurance business can be run by conventional indemnity plans, which only reimburse costs, as well as by more innovative plans, which provide some form of managed care. On the demand side of PHI markets, individuals as well as groups or corporate actors (e.g., employers, professional organizations) may ask for insurance. In general, contracts between insurer and enrollee are voluntary for both sides. However, mandatory contracts (for one or both sides) are realized in some countries (and discussed in others) as well. Risk spreading between the parties involved (insurer, insured, health-care providers, and employers) varies considerably. Regulation of PHI programs in different countries results from specific historical national as well as international developments. In the past, international developments have been of minor importance for PHI regulation. However, in Europe European Union regulation is of increasing importance. The third EU directive on Non-Life Insurance has forced several member states to adapt their regulatory framework for PHI programs. However, they also reflect the particular function of PHI programs. Basically three functions of PHI in healthcare systems can be observed in international comparisons. PHI programs may be the only system of coverage available for some part of the population, because these people are not included in public schemes. PHI programs thus perform the function of an alternative to public arrangements. This is the case particularly in countries with means-tested public health benefit schemes (Medicaid in the United States) or if eligibility to social health insurance programs depends on income and/or employment status (Germany) or age (Medicare in the United States). The need for regulation of alternative PHI programs is particularly high, because an unregulated market does not guarantee that people who are not entitled to the public system will receive adequate insurance coverage (see section Adverse Selection in Competitive Health Insurance Markets). The second function of PHI programs is to supplement public schemes. Supplementary PHI programs can offer coverage for services not covered in the public system (e.g., dental care for adults in the Netherlands as well as dental care and pharmaceuticals in Canada but also upgraded hospital services such as private or semiprivate rooms in almost every country). Supplementary PHI programs also offer coverage for services not completely covered by public schemes and thus reduces co-payments and deductibles (e.g., Medigap insurance in the United States, coverage for co-payments in France, dental care in Germany). If benefit schemes of the public system are rather comprehensive and of good quality, supplementary PHI programs basically cover luxury goods (e.g., more comfortable board and lodging in hospitals in Belgium). As a consequence, a smaller degree of regulation for supplementary PHI programs than for

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alternative PHI programs is more justifiable in terms of social acceptability. The third function of PHI programs is to complement public schemes. Thus PHI programs provide double cover: people who are entitled to benefits of the public system might buy private insurance that covers at least partly the same benefits as the public system. People purchase complementary PHI programs for a variety of reasons: they want to get services quicker than in the public system (queue jumping), they want to get better or more comfortable services, or they want to contact health-care providers who are excluded from delivering services within the public system. Complementary PHI programs seem to occur primarily in tax-financed health-care systems – for example, in the United Kingdom, Australia, and Canada (Flood et al., 2005) – but play a role in systems with mandatory social health insurance programs as well, for example, in the Netherlands (Brouwer et al., 2003). Regulation of complementary PHI programs primarily concerns the question whether it may be supplied at all. In Canada, 100% of the population is covered by the public health insurance scheme, which is run by the provinces. Most provinces prohibit the supply of complementary PHI programs. However, this regulation was challenged by the Supreme Court in June 2005. In a narrow 4:3 decision, the Supreme Court of Canada struck down Quebec laws prohibiting the sale of complementary PHI on the basis that they violate Quebec’s Charter of Human Rights and Freedoms. The result makes further Charter challenges to similar laws in other provinces inevitable, but the question of whether they will succeed remains unanswered for the time being (Flood et al., 2005).

Regulation of Private Health Insurance Programs We have shown that unregulated PHI markets would not lead to socially desirable outcomes (see section Design of Health Insurance Programs). In this section, we review the regulation of (mostly alternative) PHI programs that aim to increase access for unfavorable risks. The term unfavorable risks is applied to individuals who are expected to have high health spending in the future. To increase access to PHI programs for unfavorable risks, a variety of approaches is possible and many have been tried during the last few decades. Most of them have been implemented only for alternative PHI programs or (in the case of Ireland) for complementary PHI programs. Discrimination against unfavorable risks in supplementary PHI programs is widespread, which might become less acceptable the more benefits in public schemes are limited. The attempt of the French government to increase access for low-income persons to supplementary PHI programs by providing means-tested subsidies (Turquet, 2004) and the initiative of the European Parliament for the revision of European regulation for supplementary PHI programs (Rocard, 2000) are first indicators for more regulation in that particular area of PHI programs. One possible way to safeguard access to health care for unfavorable risks is to offer access to a public scheme for those individuals. Deficiencies of the risk spreading capabilities of competitive PHI programs thus would be compensated for. This type of approach has been realized in parts of the United

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States. Premium income generally covers only parts of health spending for high risks in these schemes. The deficit is covered by the fiscal budgets (Achman and Chollet, 2001). Instead of implementing a public scheme for unfavorable risks, PHI programs may be directly regulated in order to increase access: mandatory open enrollment, prohibition of preexisting condition limitations, and/or prohibiting or premium rate restrictions are instruments of direct regulation. Similar to the first approach, most of these measures imply a subsidization of unfavorable risks. Here, subsidies would be financed not through taxes but by favorable risks insured with PHI programs. A similar approach was applied in alternative PHI programs in the Netherlands before the 2006 health insurance reform and will be applied in alternative PHI programs in Germany in 2009. Even the United States has implemented federal legislation in order to increase access for unfavorable risks, especially for small group and individual contracts. Since 1996, the extent to which private health insurers may impose preexisting conditions limitation was limited. Furthermore, private health insurers in the United States were not allowed to discriminate against unfavorable risks in group contracts (Jost, 2001). It is also core to the Affordable Care Act (ACA), with which the Obama Health Care Reform was implemented. The approach followed by the ACA is to improve access for those individuals who are uninsured or underinsured by introducing health insurance exchanges which are supposed to facilitate consumer choice between different health plans. Insurance policies offered by these exchanges need to offer a minimum benefits package. They are run either by individual states or national government (Greer and Singh, 2014). At the same time the ACA obliges individuals to take out health insurance and provides subsidies to low-income individuals and families to buy health insurance. Although initially political resistance against the ACA has been fierce (Jost, 2014, 2015) and the health insurance exchanges did not run smoothly at first, the number of uninsured individuals in the United States has dropped from 42.7 million individuals in 2013 to 25.9 million individuals in 2015. About 11 million individuals took out insurance at health insurance exchanges – the remainder is due to the expansion of public tax-financed programs such as Medicaid (Carman et al., 2015). Mandatory open enrollment, prohibition of preexisting condition limitations, and premium rate restrictions are important tools to increase access in PHI programs. However, they also create new incentives for adverse selection. Favorable risks could seek very low coverage first and change to more comprehensive coverage when they happen to become unfavorable risks. It is difficult to neutralize these incentives for adverse selection. One way is to restrict access to PHI programs to a limited time period, for example, after losing coverage in public schemes or in social health insurance programs. Regulation to increased access for unfavorable risks in PHI programs does not only produce problems of adverse selection. It might also produce problems of unequal risk distribution and incentives for risk selection (cream skimming) between competing health insurers, which would not occur if insurers could exclude unfavorable risks or charge them an extra premium reflecting their unfavorable health status. As a consequence, some type of risk adjustment scheme needs to

neutralize incentives for risk selection (van de Ven and Ellis, 2000; Glazer and McGuire, 2006). With the Obama reform for the first 3 years, a mandatory system of high cost pools was implemented for this purpose (ACA, 2013). Also in Ireland, the incentives for risk selection in PHI are limited by a risk adjustment system. This is true also for Germany, where a ‘basic plan’ has to be offered by private insurers, and there is a risk adjustment system established among these insurers (Weber, 2010). In most other countries, where private insurance is only supplemental, regulation does not forbid to charge higher premiums for the sick, therefore, incentives for cream skimming are insofar reduced.

Provision of Health-Care Services Traditionally, PHI programs – in the United States and elsewhere – do not influence incentives on the supply side, for example, remuneration systems for physicians. One important exception is the development of managed care insurance in the United States (Glied, 2000; Barnes et al., 2014; Fang and Rizzo, 2009; Lewis et al., 2013; Ehlert and Oberschachtsiek, 2014). However, managed care has been developed because thirdparty payers (employers, government) put pressure on PHI programs to contain health spending. Managed care is virtually nonexistent in individual PHI programs in the United States. In general, PHI programs instead use instruments at the demand side to influence costs. Insurance contracts include mechanisms such as co-payments and deductibles to increase consumers’ cost-consciousness. These mechanisms in turn are supposed to put indirect pressure on the behavior of providers. Moreover, PHI programs usually are unable to influence the supply of health-care providers. The market power of PHI programs in most cases is too small to play an active role in determining the supply of health-care providers. Moreover, policy makers (at least in most of Europe and in Canada) are first of all interested in the viability of public schemes (Stabile and Thomson, 2014; Thomson et al., 2009). Thus, they want to cut expenditures and growth rates of expenditures primarily within these systems. Cost containment in PHI programs is of secondary importance to them. Therefore, we often observe that the attempt to contain costs in the public sector leads to cost shifting toward PHI programs. It is very common that health-care providers compensate for budgets, spending cuts, and the like in the public sector by raising volume and/or prices for services in PHI programs. Governments may even purposefully shift costs from public schemes to PHI programs by allowing higher fee levels in PHI programs to compensate providers for cost-containment measures in the public sector.

Social Health Insurance Programs Designers of competitive multipayer health insurance programs in many countries strive to prevent the consequences of adverse selection. This problem can be avoided by designing single-payer health insurance programs (such as in Korea) or noncompetitive multiple-payer health insurance programs (e.g., in France and Austria). In the case of Austria, potential selection problems have been the main reason for not adopting

Health Insurance Plans and Programs: An Overview Table 3

Typology of social health insurance programs

Competitive Noncompetitive

Single payer

Multiple payers

– Korea

Germany, Netherlands, Switzerland France, Austria

a German-style competitive system (Leiber et al., 2015). As a consequence, potential benefits of competitive health insurance markets can also not be achieved (Table 3). In competitive multi-payer social health insurance programs (e.g., Germany, Switzerland, and the Netherlands), adverse selection is prevented by introducing mandatory coverage, standardizing benefits, and abolishing risk-related premiums. However, the trade-off between competition and selection remains an important issue in these health insurance programs as well, because some kind of risk adjustment system needs to neutralize incentives for risk selection by health insurers. In this section, we analyze the relationship between risk adjustment and consumer choice in three social health insurance programs in Germany, the Netherlands, and Switzerland (Greb, 2006; Thomson et al., 2013; van de Ven et al., 2013).

Risk Adjustment The objectives guiding health-care reforms in Germany, Switzerland, and the Netherlands leading toward more competition in social health insurance programs in the middle of the 1990s have been quite similar. These objectives can be summarized as efficiency and consumer satisfaction in the provision of healthcare services while maintaining solidarity of health-care financing and effective containment of health-care costs (van de Ven et al., 2003). One of the most important prerequisites for competition in social health insurance programs to be successful is an effective mechanism for risk adjustment (van de Ven et al., 2013). Since premium rate restrictions prohibit risk-rated premiums in any of the three social health insurance programs, without risk adjustment health plans have ample incentives for the selection of risks. If risk adjustment is absent or incomplete, it is more profitable for health plans to select risks than to manage health services. This behavior may be rational from the viewpoint of health plans. However, it definitely contradicts the objectives of the health-care reforms mentioned above. Systematically, three adverse effects of incentives to select risks can be separated (van de Ven et al., 2004). First, health plans face a disincentive to react to the preferences of bad risks. It is rational for health plans to provide good service for profitable, i.e., favorable, risks. Moreover, it is also rational for health plans to provide bad service for unprofitable, i.e., unfavorable, risks since investments in preferred risk selection (cream skimming) have higher returns than investments in improving the efficiency of health services. From a public health point of view, these disincentives are fatal, since unfavorable risks are usually patients who are chronically ill and need services that are better than average. Neither health plans nor health-care providers have incentives to gain a reputation for treating the

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chronically ill efficiently and effectively (van de Ven and Ellis, 2000; van de Ven et al., 2013). Second, if cream skimming is successful, it will eventually lead to market segmentation. Unfavorable risks (high-risk patients) will be members of sickness funds with high contributions. Conversely, favorable risks (low-risk patients) will be members of sickness funds with low contributions. This situation is not compatible with the idea of solidarity in social health insurance programs since in fact it paves the way for riskrelated premiums. Third, preferred risk selection strategies that are highly rational from an individual health plan point of view create welfare losses for society. Investments for the identification of favorable risks (e.g., information technology) and investments for the attraction of favorable risks and the deterrence of unfavorable risks (e.g., resources used for developing effective marketing strategies) do not create any societal gains. Therefore, resources spent on preferred risk selection represent a welfare loss (van de Ven and Ellis, 2000). Moreover, preferred risk selection strategies may create an unstable market if some sickness funds refrain from selecting risks. These funds may be forced to declare bankruptcy due to adverse selection of risks. This consequence also represents a welfare loss to society. Research is unanimous in concluding that adjusters based on sex and age (demographic adjusters) predict actual healthcare expenditures of individuals very poorly (van de Ven and Ellis, 2000). If the risk adjustment formula takes into account information of prior diagnosis and/or prior costs, the risk adjustment formula predicts actual health-care expenses of individuals more accurately. Thus, it neutralizes incentives of sickness funds to select risks more effectively. The difference between actuarially predicted expenses and revenue from contributions and the risk adjustment mechanism is much smaller (Drösler et al., 2011). In all three social health insurance programs – in Germany, the Netherlands, and Switzerland – risk adjustment system has been implemented. All three countries started with age-andgender-only risk adjustment and moved to more advanced systems, measuring risk by health-based variables later on (Prinsze and van Vliet, 2005; van de Ven et al., 2004; Beck et al., 2010; Buchner et al., 2013).

Consumer Choice Another important prerequisite for competition to be successful is free consumer choice (van de Ven et al., 2013). Consumers – the insured – need to have an exit option in order to search successfully for more efficient sickness funds: “. the exit option is widely held to be uniquely powerful: by inflicting revenue losses on delinquent management, exit is expected to induce that ‘wonderful concentration of the mind’ akin to the one Samuel Johnson attributed to the prospect of being hanged” (Hirschmann, 1970: p. 21). Free choice of health plans – open enrollment – has been established in all three health insurance programs. Open enrollment implies that consumers are able to switch health plans and each health plan must accept all applicants. Usually there is an open enrollment period during which consumers can switch to another fund. Incentives for consumer choice are enhanced if the

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benefits of switching (lower premiums) are substantial enough to outweigh the costs of switching (information costs, search costs, administration costs). Moreover, incentives for consumer choice are enhanced if consumers can realize the full benefits of lower premiums after switching health plans. If this is not the case, consumers may refrain from switching, although they might do so if they were able to collect the full benefits of switching. Free consumer choice of health plans has been established in Germany, the Netherlands, and Switzerland. However, incentives for consumer choice vary. Open enrollment has been established in all countries. Whether consumers can realize the full benefits of switching to a lower-priced health plan depends on the manner premiums are calculated (see the section Calculation of Premiums in Health Insurance Programs). In Switzerland, contributions are communityrated and independent of income. Therefore, consumers can realize the full benefits of switching to another health plan. The same is true in the Netherlands, since health plans have different community-rated premiums. In Germany, social health insurers differ in income-related contributions; if consumers switch to a lower-priced health plan, the size of their savings depends on their income therefore. Price differences between health plans in Germany, Switzerland, and the Netherlands reflect differences in efficiency as well as differences in the risk structure on members. Since risk adjustment does not neutralize incentives for risk selection effectively in Germany and Switzerland, price differences are high and constitute powerful incentives for consumers to switch. In contrast to Germany (Tamm et al., 2007), it is quite surprising that consumers in Switzerland in fact are very reluctant to switch to lower-priced health plans, since incentives to switch are high. This might be partly explained by poor consumer information (Beck et al., 2003). Moreover, the analysis of incentives for consumer mobility does not explain why healthy consumers switch more often than less-healthy consumers in all three countries, in Germany and Switzerland more so than in the Netherlands. Since sickness funds do not calculate risk-related premiums, price differences are the same for healthy and less-healthy consumers. Moreover, open enrollment applies to all consumers. Different switching behavior of different risk groups therefore points to risk selection of sickness funds (Laske-Aldershof et al., 2004).

Provision of Health-Care Services Even if there were few incentives for health plans to select risks in a competitive environment and incentives for consumer choice were high, health plans are only able to influence the efficiency of the provision of health service if they have sufficient instruments do so. Otherwise, “. under competition dissatisfaction takes the form of ineffective flitting back and forth of groups of consumers from one deteriorating firm to another without any firm getting a signal that something has gone awry” (Hirschmann, 1970: p. 26). In order to avoid this “ineffective flitting back and worth of consumers,” health plans need to be able to develop innovative contractual arrangements with health-care providers that

take into account consumers’ preferences. Accordingly, health plans must be able to decide which providers to contract with and must be able to negotiate freely about the content of those contracts. If health plans are not able to contract selectively with health-care providers they will not be able to gain competitive advantages. The potential for developing innovative arrangements for the provision of health care will instead be small when health plans are obliged to contract collectively, i.e., with every willing licensed health-care provider. Even if health plans are able to contract selectively, contractual freedom can be diminished by public regulation intended to contain costs. However, public regulation to contain costs (restrictions on prices, budgets, and other contract parameters) may severely restrict the contractual freedom of health plans and healthcare providers. There is some opportunity for health plans to contract selectively with health-care providers in all three social health insurance programs. However, these opportunities are limited. In the Netherlands, health plans are legally allowed to choose health-care providers. However, a governmental agency determines maximum tariffs for prices in ambulatory care and hospital care. In contrast to the Netherlands, collective contracting is still the legal norm in Germany and in Switzerland. In Switzerland and Germany, sickness funds are only allowed to contract selectively with health-care providers if their insured enroll in managed care plans. In both countries, insurers cannot exclude providers in collective contracts, which prevail by large – in Germany more so than in Switzerland (van de Ven et al., 2013).

Health Insurance in Low- and Middle-Income Countries The trade-offs between risk spreading and appropriate incentives and between competition and selection that we focused on in this article are relevant for low- and middle-income countries as well as for high-income countries. For low- and middleincome countries, however, specific chances but also specific challenges exist, with regard to the implementation of health insurance. In the last few decades, quite a large number of low- and middle-income countries have started to implement mechanisms of health insurance as an approach to solve their often dramatic health funding problems. Implementing health insurance has been identified as a strategy to contribute to the solution of these problems for three reasons (Carrin and James, 2005a,b; Carrin et al., 2007; Hsiao and Shaw, 2007; McIntyre, 2007; Mathauer and Carrin, 2011; Wagstaff, 2010).

Revenue collection: It is well known that low- and middle-income countries spend even smaller portions of their GDP on health than high-income countries. Many low-income countries spend considerably less than the 5% of GDP. Often an underfinanced health sector with poor performance is financed by taxes, and private (formal but often as well informal) payments add some resources. Social health insurance has been seen by several countries as an instrument to increase available resources for health. Especially if people feel that they are getting value for money and draw additional benefit from health insurance, they often are willing to contribute.

Health Insurance Plans and Programs: An Overview Mandatory social health insurance, however, is easier to implement in the formal sector of the economy. If most of the labor force is in the informal sector, small-scale, voluntary community health insurance may be a more appropriate approach; its main obstacle, however, is adverse selection (as described in more detail in the section Health Insurance Programs and Health Outcomes), as the healthy might wait until they join. Pooling of funds: Often medium-size and large expenditures for medical treatment lead to impoverishment, debts, etc., in low- and middle-income countries. This is because, even if a tax-financed health system exists, its coverage for expensive surgery and drugs is often rather limited or available only in certain regions or for certain groups of the population. As we analyzed in more detail in the section The Value of Health Insurance the value of health insurance is derived from the uncertainty and unpredictability of health spending. At the time of illness, health insurance is pooling funds from many contribution payers to cover the costs of treatment. It is sharing risks. Poor people pay small contributions to health insurance regularly and are entitled to receive services in case of illness. Health insurance is enabling medical treatment for parts of the population who would not be able to finance it without insurance. Pooling of resources might be accompanied by ex-ante redistribution of resources, from the healthy to the sick, from higher income to the poor. Health insurance might therefore contribute to narrowing somewhat the often extreme gap between the large majority of rather poor and a small minority of rich in lowand middle-income countries. Purchasing of health-care services: Health insurance agencies buy health services for their insured on health-care markets. They therefore have some market power and can negotiate for quality and cost-effective services, whereas the individual, especially when in need of health services, cannot. As performance of the health sector in low- and middleincome countries often is low, implementing health insurance might be a strategy, therefore, to increase quality of services. Also, as the insured have paid contributions to health insurance, they can argue that they are entitled to services of a certain quality. Although there are some strong arguments that implementing health insurance might contribute to quantity and quality of health services and a fair distribution of the burden of finance, health insurance is far from being a deus ex machina, which would solve all the health sector’s problems easily. Whether implementing health insurance will be a success story in low- and middle-income countries depends on a variety of factors. In particular, there must be a political framework and a climate in society that allows success for health insurance (Carrin and James, 2005b).

Health Insurance Programs and Health Outcomes The final section of this article reviews empirical research about the relationship between different health insurance programs and health outcomes. First of all, it is quite evident that the health consequences of not having insurance at all can be quite dramatic. Research on the consequences of being uninsured in

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the United States has shown consistently that individuals without health insurance “receive fewer preventive and diagnostic services, tend to be more severely ill when diagnosed, and receive less therapeutic care” (Hadley, 2003: p. 3S). More importantly, having health insurance would decrease mortality of the uninsured in the United States significantly. One might expect that similar findings are available for differences between health insurance programs. For example, enrollment in more generous health insurance programs – such as high-coverage and low coinsurance plans – might result in superior health outcomes compared to enrollment in less generous health insurance programs, such as managed-care insurance and high coinsurance plans. However, there are also tendencies counteracting these assumptions. For example, fee-for-service plans might increase incentives for the overuse and misuse of services, which might be beneficial for the income of the health-care provider but may be harmful for the patient’s health. What is more, the use of evidence-based guidelines in managed care might decrease the overuse and misuse of health services, which might be beneficial for health outcomes (Cutler and Zeckhauser, 2000). Evidence on the health consequences of different health insurance programs is scarce and rather ambiguous. The RAND Health Insurance Experiment has found some relationship between the level of coinsurance and health outcomes, although the findings were less dramatic and less conclusive than the relationship between the level of coinsurance and health spending (see the section The Value of Health Insurance). Actually, health outcomes did not differ across plans for most individuals. However, it has to be noted that the RAND Health Insurance Experiment was limited to a short time period: “Increased primary and preventive care, even if strongly beneficial, might not be so important in such a short period of time” (Cutler and Zeckhauser, 2000: p. 629). Moreover, maybe even more importantly, “health among the sick poor – approximately the most disadvantaged 6 percent of the population – was adversely affected .. In particular, the poor who began the experiment with elevated blood pressure had their blood pressure lowered more on the free care plan than on the cost-sharing plans. The effect on predicted mortality rates – a fall of about 10 percent – was substantial for this group. In addition, free care marginally improved both near and far corrected vision . and increased the likelihood that a decayed tooth would be filled” (Newhouse and Insurance Experiment Group, 1993: p. 339). Evidence on the health outcome of managed care insurance is ambiguous as well. A review of the empirical literature comparing health outcomes of managed care insurance and fee-for-service indemnity insurance did not find clear differences. About half of the studies have found that managed care improves health outcome (quality of care), while the other half have found that managed care has a negative impact on health outcomes (Miller and Luft, 2002). Moreover, there is no clear empirical evidence of health outcomes in PHI programs compared to health outcomes in social health insurance programs (e.g., comparing health outcomes in Germany social health insurance and in German alternative PHI).

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Conclusions The design of health insurance programs and plans is determined by important trade-offs. First, designers of health insurers need to consider the trade-off between risk spreading and appropriate incentives. More generous health insurance programs spread risk more broadly but may also lead to more overspending due to moral hazard. However, most countries – with the notable exception of the United States – accept some degree of moral hazard in order to gain the benefits stemming from risk spreading and comprehensive coverage. Even in the United States, government intervention implemented by the ACA considerably raised the number of individuals covered by health insurance. Second, designers of health insurance programs need to consider the trade-off between competition and selection. Many countries rely on competitive health insurance programs as a means to stimulate innovation and – at least to some degree – to enhance consumer choice as a way to meet individual preferences. However, if health insurance programs are calculating risk-related premiums, adverse selection makes it extremely difficult – if not impossible – to reach market equilibrium, which ensures risk spreading for both groups: sick individuals as well as healthy individuals. As a consequence, designers of health insurance programs in many countries strive to prevent the consequences of adverse selection. Mandatory open enrollment, prohibition of preexisting condition limitations, and premium rate restrictions are important tools to increase access to PHI programs. However, regulation also creates new incentives for adverse selection. Moreover, regulation might also produce problems of unequal risk distribution and incentives for risk selection (cream skimming) between competing health insurers. Moreover, regulation of PHI programs reflects the particular function of PHI programs. The need for regulation of alternative PHI programs is particularly high, because an unregulated market will not guarantee that individuals who are not entitled to the public system will receive adequate insurance coverage. In contrast, lessextensive regulation for supplementary health insurance is socially acceptable. Discrimination against unfavorable risks in supplementary PHI programs is widespread. However, it might become less acceptable the more benefits in public schemes are limited. Adverse selection can be prevented by designing singlepayer or noncompetitive multiple-payer social health insurance programs. Designers of competitive multiple-payer social health insurance programs prevent the consequences of adverse selection by introducing mandatory coverage, standardizing benefits, and abolishing risk-related premiums. However, the trade-off between competition and selection remains an important issue in these health insurance programs as well, because some kind of risk adjustment system needs to neutralize incentives for risk selection by health plans. Even if there were few incentives for health plans to select risks in a competitive environment and incentives for consumer choice were high, health plans are only able to influence the efficiency of the provision of health service if they have sufficient instruments to do so. Evidence on the health consequences of different health insurance programs is scarce and rather ambiguous. The health consequences of not having insurance at all can be quite dramatic. Having health insurance would decrease mortality

of the uninsured in the United States significantly. The RAND Health Insurance Experiment has found some relationship between the level of coinsurance and health outcomes, although the findings were less dramatic and less conclusive than the relationship between the level of coinsurance and health spending. Evidence on the health outcome of managed-care insurance is ambiguous as well. Moreover, there is no clear empirical evidence of health outcomes in PHI programs compared to health outcomes in social health insurance programs. Health insurance can contribute to the problems of health sector financing in low- and middle-income countries as well. In particular, it can make revenue collection easier and therefore allow for an increase in quantity and quality of services, it may support the pooling of risks and therefore avoid impoverishment because of illness, and it may be a vehicle for prudent purchasing of health care. Whether implementing health insurance in low- and middle-income countries will be a success story depends on many factors, however, political and societal support being the most important among them.

See also: Transition to Universal Coverage in Developing Countries.

References American Academy of Actuaries, 2013. Fact Sheet: ACA Risk Sharing Mechanisms. The 3 Rs (Risk Adjustment, Risk Corridors, and Reinsurance) Explained. www.actuary.org. Achman, L., Chollet, D., 2001. High Risk Pools of Limited Help to the Uninsurable. The Commonwealth Fund, New York. Barnes, A.J., Unruh, L., Chukmaitov, A., van Ginneken, E., 2014. Accountable care organizations in the USA: types, developments and challenges. Health Policy 118 (1), 1–7. Beck, K., Spycher, S., Holly, A., Gardiol, L., 2003. Risk adjustment in Switzerland. Health Policy 65 (1), 63–74. Beck, K., et al., 2010. Risk adjustment in health insurance and its long-term effectiveness. J. Health Econ. 29, 489–498. Breyer, F., 2002. Einkommsbezogene versus pauschale GKV-Beiträge – eine Begriffsklärung. Schmollers Jahrbuch 122, 605–616. Brouwer, W., Exel, J.V., Hermans, B., Stoop, A., 2003. Should I stay or should I go? Waiting lists and cross-border care in the Netherlands. Health Policy 63, 289–298. Buchner, F., et al., 2013. The new risk adjustment formula in Germany: implementation and first experiences. Health Policy 109, 253–262. Carman, K.G., Eibner, C., Paddock, S.M., 2015. Trends in health insurance enrollment, 2013–15. Health Aff. 34 (6), 1044–1048. Carrin, G., James, C., 2005a. Key performance indicators for the implementation of social health insurance. Appl. Health Econ. Health Policy 4 (1), 15–22. Carrin, G., James, C., 2005b. Social health insurance: key factors affecting the transition towards universal coverage. Int. Soc. Secur. Rev. 58 (1), 46–63. Carrin, G., James, C., Adelhardt, M., et al., 2007. Health financing reform in Kenya – assessing the social health insurance proposal. So. Afr. Med. J. 97 (2), 130–135. Cutler, D.M., Zeckhauser, R.J., 2000. The anatomy of health insurance. In: Culyer, A.J., Newhouse, J. (Eds.), Handbook of Health Economics. Elsevier, Amsterdam, the Netherlands, pp. 563–643. Drösler, S., et al., 2011. Evaluationsbericht zum Jahresausgleich 2009 im Risikostrukturausgleich. Endfassung. Download unter. http://www.bmg.bund.de/fileadmin/ dateien/Publikationen/Forschungsberichte/2011/Evaluationsbericht_morbi-rsa. pdf. Bonn. Ehlert, A., Oberschachtsiek, D., 2014. Does managed care reduce health care expenditure? Evidence from spatial panel data. Int. J. Health Care Finance Econ. 14 (3), 207–227. Fang, H., Rizzo, J.A., 2009. Has the influence of managed care waned? Evidence from the market for physician services. Int. J. Health Care Finance Econ. 10, 85–103. Flood, C., Sossin, L., Roach, K. (Eds.), 2005. Access to Care Access to Justice: The Legal Debate Over Private Health Insurance in Canada. University of Toronto Press, Toronto, Canada.

Health Insurance Plans and Programs: An Overview Geoffard, P.-Y., 2006. Incentives and selection effects in health insurance. In: Jones, A. (Ed.), The Elgar Companion to Health Economics. Edward Elgar, Cheltenham/Northampton, UK, pp. 104–113. Glazer, J., McGuire, T., 2006. Optimal risk adjustment. In: Jones, A. (Ed.), The Elgar Companion to Health Economcis. Edward Elgar, Cheltenham/Northampton, UK, pp. 279–285. Glied, S., 2000. Managed care. Handbook of health economics. In: Culyer, A.J., Newhouse, J. (Eds.), Handbook of Health Economics. Elsevier, Amsterdam, the Netherlands, pp. 707–753. Greß, S., 2006. Regulated competition in social health insurance: a three-country comparison. Int. Soc. Secur. Rev. 59 (3), 27–47. Greer, S.L., Singh, S.R., 2014. Obama’s Health Reform: what is it, and what does it mean for the future of health care in the United States? Gesundh ökon Qual manag 19 (02), 53–56. Hadley, J., 2003. Sicker and poorer. The consequences of being uninsured: a review of the research on the relationship between health insurance, medical care use, health, work, and income. Med. Care Res. Rev. 60 (Suppl. 2), 3S–75S discussion 76S–112S. Henke, K.-D., 1999. Socially bounded competition in Germany. Health Aff. 18 (4), 203–206. Hirschmann, A., 1970. Exit, Voice and Loyalty. Responses to Decline in Firms. Organizations and States Harvard University Press, Cambridge, MA. Hsiao, W., Shaw, P., 2007. Social Health Insurance for Developing Nations. World Bank, Washington, DC. Jacobs, K., Reschke, P., Cassel, D., Wasem, J., 2002. Zur Wirkung des Risikostrukturausgleichs in der gesetzlichen Krankenversicherung. Nomos, Baden-Baden. Jost, T.S., 2001. Private or Public Approaches to Insuring the Uninsured: Lessons from International Experience with Private Insurance. University Law Review, New York, pp. 419–493 vol. 76 (2). Jost, T.S., 2014. Implementing health reform: four years later. Health Aff. 33 (1), 7–10. Jost, T.S., 2015. The affordable care act returns to The US Supreme Court. Health Aff. 34 (3), 367–370. Laske-Aldershof, T., Schut, F.T., Beck, K., et al., 2004. Consumer mobility in social health insurance markets: a five-country comparison. Appl. Health Econ. Health Policy 3 (4), 229–241. Leiber, S., Greß, S., Heinemann, S., 2015. Explaining different paths in social health insurance countries – health system change and cross-border lesson-drawing between Germany, Austria and the Netherlands. Soc. Policy Admin. 49 (1), 48–108. Lewis, V.A., et al., 2013. Accountable care organizations in the United States: market and demographic factors associated with formation. Health Serv. Res. 48 (6 Pt 1), 1840–1858. Lohr, K., Brook, R., Camberg, C., 1986. Effect of cost sharing on use of medically effective and less effective care. Med. Care 29 (Suppl. 9), 31–38. Manning, W., Marquis, S., 1996. Health insurance: the trade-off between risk pooling and moral hazard. J. Health Econ. 15 (5), 609–640. Manning, W.G., Newhouse, J.P., Duan, N., et al., 1987. Health insurance and the demand for medical care: evidence from a randomized experiment. Am. Econ. Rev. 77 (3), 251–277. Mathauer, I., Carrin, G., 2011. The role of institutional design and organizational practice for health financing performance and universal coverage. Health Policy 99 (3), 183–192. McIntyre, D., 2007. Learning from Experience: Health Care Financing in Low and Middle-Income Countries. Global Forum for Health Research. http://www. globalforumhealth.org (accessed October 2007). Miller, R.H., Luft, H.S., 2002. HMO plan performance update: an analysis of the literature, 1997–2001. Health Aff. 21 (4), 63–86. Newhouse, J.P., 1993. Insurance Experiment Group, Free for All? Lessons from the RAND Health Insurance Experiment. Harvard University Press, Cambridge, MA. Nyman, J., 2006. The value of health insurance. In: Jones, A. (Ed.), The Elgar Companion to Health Economics. Edward Elgar, Cheltenham/Northampton, UK, pp. 95–103. Pauly, M., Herring, B., 1999. Pooling Health Insurance Risks. AEI Press, Washington, DC. Pauly, M.V., 1968. The economics of moral hazard: comment. Am. Econ. Rev. 58 (3), 531–536. Pauly, M.V., 1986. Taxation health insurance, and market failure in the medical economy. J. Econ. Lit. XXIV, 629–675. Prinsze, F.J., van Vliet, R.C.J.A., 2005. Health-Based Risk Adjustment: Improving the Pharmacy-Based Cost Group Model by Addition of Diagnostic Cost Groups. Rotterdam Institute of Health Policy and Management, Erasmus Medical Centre. Rice, T., 2002. The Economics of Health Reconsidered. Health Administration Press, Chicago, IL.

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Rocard, M., 2000. Report on Supplementary Health Insurance (A5–0266/2000). European Parliament, Brussels, Belgium. Stabile, M., Thomson, S., 2014. The changing role of government in financing health care: an international perspective. J. Econ. Lit. 52 (2), 480–518. Tamm, M., Tauchmann, H., Wasem, J., Greß, S., 2007. Elasticities of market shares and social health insurance choice in Germany – a dynamic panel data approach. Health Econ. 16 (3), 243–256. Thomson, S., et al., 2013. Statutory health insurance competition in Europe: a fourcountry comparison. Health Policy 109 (3), 209–225. Thomson, S., Foubister, T., Mossialos, E., 2009. Financing Health Care in the European Union. Challenges and Policy Responses. WHO, Copenhagen. Observatory Studies Series No. 19. Turquet, P., 2004. A stronger role for the private sector in France’s health insurance? Int. Soc. Secur. Rev. 57 (4), 67–90. van de Ven, W.P.M.M., Ellis, R., 2000. Risk adjustment in competitive health plan markets. Handbook of Health Economics. In: Culyer, A.J., Newhouse, J. (Eds.), Handbook of Health Economics. Elsevier, Amsterdam, the Netherlands, pp. 755–845. van de Ven, W.P.M.M., Beck, K., Buchner, F., et al., 2003. Risk adjustment and risk selection on the sickness fund insurance market in five European countries. Health Policy 65 (1), 75–98. van de Ven, W.P.M.M., van Vliet, R.C.J.A., Lamers, L.M., 2004. Health-adjusted premium subsidies in the Netherlands. Health Aff. 23 (3), 45–55. van de Ven, W.P.M.M., et al., 2013. Preconditions for efficiency and affordability in competitive healthcare markets: are they fulfilled in Belgium, Germany, Israel, the Netherlands and Switzerland? Health Policy 109 (3), 226–245. Wagstaff, A., 2010. Social health insurance reexamined. Health Econ. 19, 503–517. Wagstaff, A., van Doorslaer, E., 1992. Equity in the finance of health care: some international comparisons. J. Health Econ. 11, 361–387. Wagstaff, A., van Doorslaer, E., 2000. Equity in health care finance and delivery. Handbook of Health Economics. In: Culyer, A.J., Newhouse, J. (Eds.), Handbook of Health Economics. Elsevier, Amsterdam, the Netherlands, pp. 1803–1857. Wasem, J., Greß, S., Okma, K.G.H., 2004. The role of private health insurance in social health insurance countries. In: Saltman, R., Busse, R., Figueras, J. (Eds.), Social Health Insurance in Western Europe. Open University Press, London, pp. 227–247. Weber, R., 2010. Risikoausgleichsverfahren in der privaten Krankenversicherung. In: Göpffarth, S., Greß, K., Jacobs, J., Wasem, J. (Eds.), Jahrbuch Risikostrukturausgleich 2010-Von der Selektion zur Manipulation? D. Heidelberg, Medhochzwei Verlag, pp. 117–135. Zweifel, P., Breuer, M., 2006. The case for risk-based premiums in public health insurance. Health Econ. Policy Law 1, 171–188.

Further Reading Drechsler, D., Jütting, J., 2007. Different countries, different needs: the role of private health insurance in developing countries. J. Health Polit. Policy Law 32 (3), 497–534. van Doorslaer, E., Wagstaff, A., 1999. The redistributive effect of health care finance in twelve OECD countries. J. Health Econ. 18 (3), 291–313. Eanthoven, A., Fuchs, V., 2006. Employment-based health insurance: past, present, and future. Health Aff. 25 (6), 1538–1547. Gottret, P., Schieber, G., 2006. Health Financing Revisited. A Practitioner’s Guide. The World Bank, Washington, DC. Goodmann, J., 2006. Employer-sponsored, personal and portable health insurance. Health Aff. 25 (6), 1556–1566. Hussey, P., Anderson, G.F., 2003. A comparison of single- and multi-payer health insurance systems and options for reform. Health Policy 66, 215–228. Maarse, H., Paulus, A., 2003. Has solidarity survived? A comparative analysis of the effect of social health insurance reform in four European countries. J. Health Polit. Policy Law 28 (4), 585–614. Mossialos, E., Thomson, S., 2004. Voluntary Health Insurance in the European Union. World Health Organization on Behalf of the European Observatory on Health Systems and Policies, Copenhagen, Denmark. The OECD Health Project, Private Health Insurance in OECD Countries, 2004. OECD, Paris, France. Sekhri, N., Savedoff, W., 2004. Private health insurance: implications for developing countries. Bull. World Health Organ. 83, 127–134. Woolhandler, S., Himmelstein, D., 2002. Paying for national health insurance – and not getting it. Health Aff. 21 (4), 88–98.

Health Literacy Roy W Batterham, Alison Beauchamp, and Richard H Osborne, Population Health Strategic Research Centre, School of Health and Social Development, Deakin University, Geelong, VIC, Australia Ó 2017 Elsevier Inc. All rights reserved.

What is Health Literacy? Health literacy is a concept that recognizes that people have different capacities to find, understand, and use health information, with different experiences that shape their willingness and confidence to do these tasks, and different ways in which they prefer to receive and engage with information. It is a humbling concept for health service providers and health educators because it carries within itself the recognition that there are many people whose needs we have failed to meet because we have not fully understood those needs. The drive to incorporate health literacy into public health practice is intrinsically linked with the concept of equity (Paasche-Orlow and Wolf, 2010). A health literacy approach can meet the needs of people who are not responding to current approaches to improve their access to health services, to change their health behaviors, and/or to increase their participation in actions and advocacy to improve health in their communities. Health literacy is less of a concern for people with whom current health-care approaches are already effective. The concept of health literacy has evolved considerably since it was first coined in 1974, as have the means to measure it. Consequently, there has also been an expansion in the number and breadth of health literacy interventions. Modern definitions include multiple dimensions of health literacy, consider multiple settings, and recognize that there are social as well as individual components to health literacy. While there are many definitions, those that are more recent overlap substantially. A review by Sorensen et al. (2012) produced a definition that covers most of the elements included in earlier definitions: health literacy relates to “people’s competencies to access, understand, appraise and apply information to make health decisions in everyday life throughout the life course”. An earlier definition by Kickbusch in 2001 does, however, include an additional element, which is the concept of settings: “Health literacy is the ability to make sound health decisions in the context of everyday life – at home, in the community, at the workplace, the healthcare system, the market place and the political arena.” Consideration of settings is of particular importance in determining how health literacy can contribute to the Sustainable Development Goals (see Table 4) and other major policy objectives.

Evolution of the Concept The term ‘health literacy’ was first coined by SK Simonds in 1974. As has been noted by several authors, the timing of the emergence of health literacy coincided with the emergence of a term related to general education and literacy: ‘functional literacy.’ Functional literacy referred to people having sufficient reading and writing skills to be able to undertake the tasks of

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citizenship and to participate in society (Freebody and Luke, 1990; Resnick and Resnick, 1977). However, this is not the only antecedent of the concept of health literacy. Simonds was one of a group of academics in the field of health education who, in the 1950s and 1960s, were working to develop the concept of ‘educational diagnosis’ for health education. The following quote typifies their thinking: If we group patients for learning according to their disease or illness, then we must also take into account the differences in individuals and provide a variety of learning experiences. To teach all patients the same thing in the same way as if their needs and experiences and perceptions are identical and to call this good education is comparable to giving all cardiac [sic] the same drug, diet, and activity schedule and calling it good medical care (Research Committee of the Society of the Public Health Educators, 1968). Kasey and MacMahan, 1965

With reference to this acknowledged responsibility, Simonds argued that the job of health educators is to convey relevant information and to understand the problems of the patient (as a learner) on as systematic a basis as possible (Simonds, 1963). This remains the role of much of the health literacy research and development work to this day. In some ways, the evolution of the concept of health literacy can be thought of as a back-to-the-future journey. The concept traveled far from its original intention of understanding the diversity of needs (to attempting systematic measurement of numeracy and literacy) but has recently returned to its origins. There are also areas in which the concept has outgrown its origins. In particular, health literacy is recognized as important not only for health education and individual use of health knowledge, but also for people’s ability to access and use health services and to participate in debates and advocacy about issues that affect the health of their families and communities. These diverse functions of health literacy correspond to three forms of health literacy proposed in one of the most widely used classification systems (Nutbeam, 2000). Functional health literacy involves having the reading, writing, and information processing abilities to effectively participate in one’s own care, and it relates strongly to one’s personal use of health information. l Interactive health literacy relates to how a person obtains and applies health information through interaction with others, including health professionals, and is a major factor in how effectively people access and use health services. l Critical health literacy is the skills that support critical reflection about information or advice received, including recognition of the influence of wider social determinants of health. These include the ability to obtain, understand, and critically appraise different sources of information, and the ability to engage in shared decision-making. Critical health l

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Health Literacy literacy is strongly related to people’s ability to participate in debates and advocacy about issues that affect the health of their families and communities. At times, the broadening of the concept of health literacy has been contentious. There are those who have argued that by losing its specific focus on reading and writing, it becomes too difficult to distinguish from related concepts such as health education (Tones, 2002). There are, however, arguments against health literacy being defined in a more limited way. The first is that focusing only on reading and writing implies that people who are illiterate have a health literacy of zero even if they are able to obtain and use health information well. The second is that such a definition introduces an element of arbitrariness in that, even among people who read and write well, there are those who respond better to information presented through discussion, pictures, or demonstration. Finally, such a constraint on the term is inconsistent with other literacies such as computer literacy and financial literacy, which invariably include the ability to do a certain set of core tasks, not just to read related terminology. At the conceptual level, an inclusive view of health literacy has prevailed. Until recently, however, this has not been reflected in the measurement of health literacy. Before 2012, the most widely used tools measured primarily reading, comprehension, and numeracy tasks. This, in turn, limited the development and evaluation of interventions that responded to a broader view of health literacy. In the 1990s and early 2000s, a way of thinking about health literacy emerged that sought to study the prevalence and effects of ‘low health literacy.’ This approach was troubled by wide and sometimes arbitrary variations to determine thresholds for ‘low health literacy’ (Barber et al., 2009; Wolf et al., 2010), and was tied to attempts to target interventions to people with low health literacy. There was strong pushback against this approach, particularly by researchers in the United States led by Rudd and others, who argued that all people can have difficulties with aspects of health literacy, depending on the circumstances in which they find themselves (Batterham et al., 2016; Brown et al., 2004; DeWalt et al., 2010). These researchers developed the universal precautions approach to health literacy, for particular use in health services. They argued that it is not always possible or necessary to know the details of a person’s health literacy and that health services can still make themselves friendly and usable to all people regardless of their level of health literacy. Proposed interventions include simplifying signage, forms and printed materials; using diverse forms of presentation of education materials; providing navigation assistance to users of health services; and training health-care personnel in a range of skills, including how to create a trusting atmosphere with patients, how to present information such that it relates to the actual tasks a patient needs to do, and how to check that a patient understands information and instructions provided. In recent years, conceptual development has informed the way in which health literacy is applied in health promotion, health service delivery, and policy development. One important aspect is an increasing appreciation for the way in which health literacy, and its importance within people’s lives, varies across the life course and across people’s health and illness

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journeys (Edwards et al., 2012). This view argues that health literacy is relative to the demands a person faces. For example, a level of health literacy that was perfectly adequate for a person to care for themselves and their families the day before they were diagnosed with cancer may be completely inadequate the day after diagnosis. Another important conceptual development relates to recognition of the social context of health literacy. There are two key aspects to these developments. The first is an increasing recognition of the importance of health literacy in different settings such as homes, communities, health services, work places, and schools (WHO Regional Office for Europe, 2013). The second is an increasing recognition that the discussions that people have in their families and social groups have a substantial impact on when and where they seek health information, how they interpret it, what they choose to believe, and how they go about applying it. This includes the recognition that many decisions about health are made by people other than the individual. In this way of thinking, health literacy is as much a characteristic of groups as it is of individuals, particularly in societies that are more communally than individually oriented. This could mean, for example, that the average health literacy of all the women in a village may be a more important determinant of a child’s health outcomes than the individual health literacy of the child’s mother (Edwards et al., 2013; Parashar, 2005; Sentell et al., 2014). These developments have led to calls for definitions of health literacy and the development of measurement tools and intervention strategies that are more explicitly socially oriented and targeted at public health (Freedman et al., 2009; Guzys et al., 2015).

Different Purposes and Emphases of Health Literacy in Different Contexts The reasons underlying debates about the concept of health literacy often relate simply to points of view and the purposes for which people seek to engage with the concept in the first place (Berkman et al., 2010). While there are many ways of classifying these different points of view, two distinctions are particularly important: 1. Research versus an applied orientation 2. Health services versus broader community settings.

Research versus Applied Orientation

In general, researchers tend to want precise definitions that distinguish one concept from others. Their work often requires measurement of concepts so that, in practice, the concept is often defined by the measurement tools available. By contrast, in applied settings – be it within health services or communities, or in the development of major healthadvertising campaigns – the primary objective is the concept’s ability to help service providers fully understand the needs of their target group.

Health Services versus Broader Community Settings

Much of the conceptual development of health literacy has occurred among the health promotion community, whereas a great deal of intervention development has occurred within

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health services. This has led to a focus on health literacy interventions that are health service orientated. For example, the Universal Precautions approach is particularly valuable for assisting health services to be responsive to their whole patient group (Brown et al., 2004; DeWalt et al., 2010). It is less relevant, however, to guide health promotion and community development workers to engage with local communities to build health awareness and assets. In this latter situation, it is critical that workers have an understanding of the health literacy diversity and health literacy strengths and weaknesses in the community. Similarly, in situations where a health service has a responsibility to a whole community and not just its patient group, the Universal Precautions approach is not sufficient to engage people who are not using the service at all. This is important because there are substantial differences between countries in the extent to which a health service is responsible for the care of the whole community versus being responsible only for the patients who use the service.

How is Health Literacy Different to Other Concepts? There is often confusion about the scope of the concept of health literacy and the way in which it is differentiated from a range of related concepts, such as patient education, patient empowerment, health beliefs, and many others. As noted previously, health literacy is often functionally defined in terms of the ability to do a set of health-related activities, including the following: Access, understand, and use health information; Engage with others, including health service providers, to care for one’s health or the health of those for whom you feel responsible; l Participate in community debates about issues and decisions that impact on health. l

problems of the patient (as a learner, as an active agent engaging health providers and as a participant in health decisionmaking processes in the community) on as systematic a basis as possible” (modified from (Simonds, 1963) additions in italics).

Measurement of Health Literacy As discussed above, the way in which health literacy is measured can determine how it is applied in practice. There are a multitude of health literacy measures. At the time of writing the website called The Health Literacy Toolshed (see section Relevant Websites) contained 112 measurement tools. Most of these relate to one or two aspects of health literacy and many assess knowledge related to a particular disease or other health issue. Five of the listed tools cover multiple domains of health literacy although one of these uses questions that are specific to one country (China). These multidimensional tools are newly popular. Prior to 2012, however, health literacy measurement was dominated by two families of tools: tools based on the Rapid Estimate of Adult Literacy in Medicine (REALM), and tools based on the Test of Functional Health Literacy for Adults (TOFHLA). While these measures had proven useful in many projects, by 2004 the limitations of the available measures were already widely recognized. In a systematic review, the Committee on Health Literacy of the Institute of Medicine (IoM) of the National Academies in the United States concluded that:

l

Health literacy is, therefore, not a single cognitive characteristic of individuals but a set of interacting cognitive, affective, experiential, and social processes that either help or hinder a person to engage with health information. From this perspective, health literacy is inclusive of many other concepts. For example, it clearly has a large cognitive component related to health knowledge, beliefs, and knowledge-acquisition skills. However, it is not a solely cognitive ability because issues such as the ability to trust health professionals, prior experience in successfully navigating health services, and comfort in discussing one’s health issues with family and friends also have an impact.

Back to the Future: Returning to a Needs Diagnostic Approach In the past few years, there has been increased recognition that health literacy has multiple components and that people can have varying health literacy strengths and weaknesses. In addition, a few multidimensional measurement tools have been developed that allow these strengths and weaknesses to be assessed. This has opened the way for a return to a needs diagnostic approach to health literacy. Rather than just trying to assess the prevalence of low health literacy, these tools and approaches enable the identification of specific needs in individuals and groups. To paraphrase the earlier quote from Simonds, “health literacy is now about working to understand and respond to the

[Finding 2–4] While health literacy measures in current use have spurred research initiatives and yield valuable insights, they are indicators of reading skills (word recognition or reading comprehension and numeracy), rather than measures of the full range of skills needed for health literacy (cultural and conceptual knowledge, listening, speaking, numeracy, writing and reading). Committee on Health Literacy, 2004 (see Altin et al., 2014 for a more recent review of available tools).

A further limitation of the earlier tools is that they appeared to lack sensitivity to change. In both the 2004 review and in an updated review in 2011, the IoM reviewers found little evidence of interventions that improved health literacy in general: most of the successful interventions included in the reviews sought to improve health outcomes specifically for people with low health literacy. The lack of evidence for improvements in health literacy, however, may have been due to the use of tools which did not measure all aspects of health literacy. Subsequently, tools that measured interactive and critical health literacy were published but it was not until 2012 that the first truly multidimensional tools emerged. These are discussed in below (see Tables 1 and 2).

Purposes of Health Literacy Measurement Health literacy measurement is not only used for research purposes. There is increasing interest in measuring health literacy for care planning and service planning purposes at the level of individual patients, specific target groups, whole communities, and national populations. Table 1 presents

Health Literacy Table 1

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Purposes for health literacy measurement and analysis at different levels

Levels at which health literacy can be measured

Potential purposes for measuring health literacy

Health service settings 1. Individual patients

l l

2. Patient groups

l l l

3. Individual health services

l

l

Community and population settings 4. Local areas (both health and community services/ authorities)

l

5. National surveys (to compare regions and groups)

l

l

l

l

6. Countries (international comparisons)

l l

To solve problem for complex patients To train staff in responding to differing health literacy needs To identify common factors that contribute to poor access and health outcomes To plan for services to respond to health literacy needs To inform advocacy activities To diagnose health literacy strengths and limitations of target populations and how these strengths and limitations contribute to known inequalities of access, participation in health and health outcomes To develop specific strategies for responding to common health literacy limitations To plan marketing and education strategies across services To assess the ability of community members to participate in community-based health planning activities (critical health literacy) and develop suitable approaches to enable their participation To identify relationships between health literacy and access, equity and outcomes, in order to develop appropriate health service and public health policies and strategies Plan health education campaigns, or campaigns to support the introduction of new services, screening initiatives (e.g., bowel or skin cancer) or vaccination programs. Assess regional ‘patient difficulty’ for planning and funding purposes (assuming that it takes more intensive resources to improve health outcomes for people with low health literacy than it does for people with higher health literacy) Advocacy for governments in countries where there is systemic low health literacy Identify countries that are role models for how to improve health literacy levels of populations

Source: Batterham, R.W., Hawkins, M., Collins, P.A., Buchbinder, R., Osborne, R.H., 2016. Health literacy: applying current concepts to improve health services and reduce health inequalities. Public Health 132, 3–12.

Table 2

Three multidimensional questionnaires or tests of health literacya

Name

Domains reported

Purpose

Chinese Resident Heath literacy scale (Shen et al., 2015) European health literacy survey (EU-HLS) (Sorensen et al., 2013) Health literacy questionnaire (Osborne et al., 2013)

1. Knowledge and attitudes, 2. Behavior and lifestyle, and 3. Health-related skills 1. Access, 2. Understanding, 3. Appraisal, and 4. Application of health information 1. Feeling understood and supported by health care providers, 2. Having sufficient information to manage my health, 3. Actively managing my health, 4. Social support for health, 5. Appraisal of health information, 6. Ability to actively engage with health care providers, 7. Navigating the health care system, 8. Ability to find good health information, 9. Understand health information enough to know what to do

Guides understanding of community health-related knowledge. Health literacy of populations Provides information on individual, group, and population health literacy needs and outcomes.

a

See the Health Literacy Toolshed for a full list of published health literacy tests and scales www.healthliteracy.bu.edu.

a range of purposes for which health literacy measurement has been applied or proposed at different levels.

Uses of Health Literacy Measurement in Different Populations and Settings Children, Adolescents, Families, Schools

Given that health literacy primarily relates to ability or opportunity to understand, find, and use health information and health services, infants’ and children’s health literacy is primarily related to the parental and school environments.

Overall, several association studies indicate that children with low literacy have worse health behaviors; parents with low literacy have less health knowledge and have more behaviors that are disadvantageous for their children’s health, compared with parents with higher literacy; and children whose parents have low literacy often have worse health outcomes (DeWalt and Hink, 2009; Keim-Malpass et al., 2015). For adolescents and young people, peer groups are strong determinants of an individual’s health literacy, as is the educational background of their parents (Zhang et al., 2016). There is the potential for school health education programs to assist

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children to recognize and choose healthy options and influence the home environment. In large population-based health literacy studies of sixth grade students (11–12 years old) in Taiwan, Shih et al., 2016 argue “that in order to enable children to participate in their own health management in the long term, as well as being able to avoid the temptations of junk foods such as sugar beverage in their daily environments, we need to improve children’s health literacy.” There is also the possibility of children being the agents of change within families by bringing new knowledge about health to the family, including through incongruence between habits at home and those promoted at school being discussed by the family. However, policy and programs driving school health education have the potential to generate unintended effects. The uptake and success of such programs are more likely to occur in well-resourced schools or where comfortable nuclear families enable discussions about health, therefore school health programs have the potential to increase social inequalities in health if not well implemented. In adolescents and young adults, while their individual health literacy, and the health literacy of their parents is important, for many, the health literacy of the most influential individuals in their peer group may be even more important (Sanders et al., 2009).

General Population

Most studies of health literacy in populations have focused on classifying the proportion of individuals who may have inadequate functional health literacy. To date, the cut-offs or benchmarks have not been directly linked to clinical or social impacts. For example, the Adult Literacy and Life Skills Survey (ALLS) (Australian Bureau of Statistics, 2009) provides a statistical snapshot of the performance and abilities of the adult population in relation to a reading-based test of literacy, numeracy, and problem solving. Despite providing limited guidance on the nature of the health literacy problem and how to solve it (other than improve overall education), the ALLS and other tests have generated estimates of inadequate health literacy to be as high as 60% and as low as 7% within the same population, depending on the test used (Barber et al., 2009). The upper estimates are often cited and draw attention to an alarming problem and call for nonspecific responses such as improving the quality of reading materials, improving organizational health literacy, and improving health-care professional communication skills. More recently, the newer multidimensional health literacy questionnaires have been applied in population surveys (see Table 2). The Chinese Resident Health Literacy Scale comprises 64 items that test an individual’s knowledge about information, lifestyle, and health behaviors (Shen et al., 2015). The tool comprises questions with one (or more) correct responses and provides planners with specific information about the healthrelated knowledge on issues of concern. The test is tied to local health issues or educational needs. The European Health Literacy Survey (EU-HLS) comprises 47 questions that cover access, understanding, appraisal, and application of health information in different contexts (community through to hospital) (Sorensen et al., 2013). Responses to the scales are classified as insufficient, problematic, sufficient, and excellent based on response scales linked to each question. When associations between the EU-HLS and demographic factors are explored, the EU-HLS total and scale scores have been found to

be lower in less-educated people, younger people, and migrants compared with the general population. The 44-item Health Literacy Questionnaire (HLQ) generates information about health literacy needs and strengths across nine domains (see Table 2) with no classification of high or low health literacy nor a total score. In a similar way to the EU-HLS, it has shown health literacy differences across social gradients (Beauchamp et al., 2015), but it has also shown further differences across disease groups after controlling for education (Friis et al., 2016). The HLQ is also widely used to inform the development of public health interventions (Batterham et al., 2014, 2016).

Health-Care Settings

Despite the ever-increasing availability of health information, individuals, communities, and organizations cannot be fully prepared for all health-care situations. An individual’s health literacy will play a big role in the way they proceed through care and disease pathways. An individual’s (or a family’s) health literacy will affect in the following ways: the recognition of overt or latent symptoms and signs; decisions of when, how, and even whether or not to seek care; and l the ability to understand information provided during an encounter with a health service, to identify what is relevant, to seek clarification, and to identify concrete actions. l l

These effects will also be modified by the health literacy responsiveness of the health services. Many studies have found that health-related literacy and numeracy are correlated with use of acute services. These have been summarized in a systematic review by Berkman et al. (2011). Table 3 provides some exemplar acute care settings or conditions where health literacy may play a strong role in generating suboptimal health outcomes or where an inadequate response by health services may adversely affect individuals. While these gaps in health care may pertain to patientrelated factors, such as not understanding the value of care or not being able to follow medicine regimens, they may also be the result of how health-care options are presented. If health advice is not presented in a way that gives people a fair chance of understanding the value of treatment, or the clinical environment generates mistrust or fear, poor outcomes and health Table 3 Associations between health-related literacy and numeracy and health care outcomes Inadequate health literacy skills or a service that does not sufficiently respond to users’ needs may result in the following: l Late presentation l Presentation at EDs for primary care preventable conditions l Excess unplanned hospital admissions and readmissions l Prevent community members acting safely with emergent diseases, e.g., treatment of Ebola-infected or deceased family members l Reduced medication adherence and increased adverse medication events l Poor disease outcomes l Poor quality communication with health care professionals l Excess mortality Source: Berkman, N.D., Sheridan, S.L., Donahue, K.E., Halpern, D.J., Crotty, K., 2011. Low health literacy and health outcomes: an updated systematic review, Ann. Intern. Med. 155 (2), 97–107.

Health Literacy inequalities are likely to occur. The way in which health services make their information, environments, resources, and supports available and accessible to the people they serve can be termed health literacy responsiveness (Dodson et al., 2015).

Community Settings

While much of the conceptual development around health literacy has emphasized health literacy in community settings, the amount of research conducted in communities is small. In part this may be because measurement tools have emphasized following medical instructions and understanding materials provided by health professionals and materials such as medication labels. The most active area for measuring community health literacy has been for mental health literacy where the relationship between community awareness and stigmatization, willingness to engage with mental health services, participation in monitoring and engagement with e-mental health services have all been studied (Gulliver et al., 2012; Jorm, 2012). Another area where health literacy has been assessed in community settings is for maternal and child health. These studies have considered both the health literacy of mothers and the health literacy of the network of women in a community or family (Parashar, 2005). These types of studies led Edwards et al. (2013) to propose the concept of ‘distributed health literacy’ which suggests that the health literacy that influences health outcomes may not be just an individual cognitive phenomenon but may reside in social networks that discuss, develop norms, and make decisions related to health through their interactions. They catalog a number of examples of situations where some sort of communal health literacy has a substantial impact on health actions and outcomes. More recent of authors have continued to investigate this phenomenon and to propose methods for assessing, engaging with, and improving community health literacy (Batterham et al., 2016; Sentell et al., 2014).

Health Literacy Interventions Health literacy interventions include a broad range of activities, many of which are not called health literacy interventions Table 4

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at all. Patient education activities; the development of Web portals by governments to provide access to trustworthy information; the use of health volunteers in rural villages as health brokers between health services and villagers; and the use of SMS messaging in conjunction with call centers to provide education to traditional midwives can all be considered health literacy interventions. In general, health literacy interventions fall into two categories: interventions aimed at improving health literacy, and interventions aimed at improving service delivery and outcomes for people with low health literacy or with specific health literacy limitations. The number of interventions in the second group is larger than in the first and, in the large systematic reviews of health literacy interventions, most of the interventions that showed benefits were also in the second category (Berkman et al., 2011; Dewalt et al., 2004). This may, however, have been due to limitations in the ability of the health literacy measurement tools used at the time to measure change. Table 4 shows examples of interventions with each of these aims, including interventions that are likely to be called health literacy interventions and those that are not. Broadly speaking, health literacy interventions are used in support of four categories of outcomes for the target groups. These are shown in Figure 1. Developing and implementing health literacy interventions does not necessarily mean creating new ideas and techniques. Within an organization or a community there are often skilled people who have developed strategies to assist people with a variety of health literacy strengths and weaknesses to improve in one or more of the four areas shown in Figure 1. Health literacy interventions are often about assisting local agencies to turn the best practice of these skilled practitioners into normal practice. In such cases, the intervention can be seen as a quality improvement process in which staff in the health service or community agency are assisted to (1) understand the diversity of health literacy needs in their community, (2) develop a repertoire of strategies to respond to those needs, and (3) receive authorization, support, and resourcing from their organization to implement these strategies.

Examples of health literacy interventions organized by the broad aim of the intervention Interventions aiming to improve people’s health literacy

Interventions called health literacy interventions

Audits of health service premises Audits of printed materials l Specific communications strategies (e.g., photos of medicines) l Reminders and prompts (e.g., SMS) l Communication skills training for health professionals l Teach-back methods l Patient education l Prepacked medication packs organized by l Public education campaigns daily administration times l Chronic disease self-management support l Cultural competence training l Village health volunteers l Village disease leaders (e.g., diabetes) l Family health leaders l l

Other interventions in which health literacy has a major role Community-based interventions that aim to both improve health literacy and assist those with low health literacy

Training patients in how to talk to doctors Carer skills training

Interventions to accommodate different peoples’ health literacy needs l l

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Figure 1 Causal pathways through which health literacy influences health outcomes. Source: Batterham, R.W. Hawkins, M., Collins, P.A., Buchbinder, R., Osborne, R.H., 2016. Health literacy: applying current concepts to improve health services and reduce health inequalities. Public Health 132, 3–12.

In these situations health literacy interventions involve an interaction of change processes at multiple levels including the following:

Table 5 Examples interventions at the consumer and staff levels to provide consumers with experiences that respond to their health literacy needs

patients or community members, health-care staff or community workers and leaders, l health care or community organizations.

Changed consumer experience

The intervention

Consumer offered the opportunity to participate in a peer support group where they receive support and ideas for translating general advice for specific health actions into their life as well as motivational support Consumer is invited by staff members to explain exactly how they will act on advice they receive. This provides the staff member with an opportunity to assist the consumer to translate advice into specific practical actions Consumer experiences a change in attitude from staff with specific invitations to ask questions, time taken to explain and discuss printed materials. Consumer no longer feels like a failure if she/he fails to understand everything immediately

A peer support group (consumerlevel intervention)

l l

The starting point for thinking about an intervention is understanding what needs to change for patients or community members with specific health literacy weaknesses, not just how they need to change but what needs to change in the experiences they have while looking after their health issues, or while interacting with health service personnel. This leads directly to the question, What do staff in the health service or community agency need to do differently to provide the people in the target group with the necessary experiences? Sometimes this will involve specific new interventions but sometimes it will just involve a change in the staff member’s interaction with the consumer, based on training that the staff member has received. Table 5 provides examples of interventions that involve new services provided to consumers, and interventions that are targeted primarily at staff to enable them to work in new ways to provide more beneficial experiences to the people they are serving. Enabling the staff of an organization to provide new services and to work in new ways requires organizational authorization, support, training, and resourcing, which means that interventions typically also have an organizational component.

Health Literacy Policy and Programs to Impact on Health, Inequalities and Poverty through the Sustainable Development Goals (SDGs) The Sustainable Development Goals (SDGs) (see Table 6), which came into effect January 2016, set out 17 goals with 169 targets (United Nations, 2015). They were designed to be relevant to all people in all countries to ensure that “no one is left behind.” They also focus on improving equity to meet the needs of women, children, and the poorest, most disadvantaged people. This agenda requires that all three dimensions of sustainable development – economic, social, and environmental – are addressed in an integrated manner. Almost all the goals

Training staff in Teach-back methods (staff-level intervention focused on specific techniques)

Staff trained to understand and appreciate health literacy diversity and adopt a constructive rather than a judgmental orientation (staffand organizational-level intervention has focus on developing deeper understanding, constructive attitudes, and a positive culture)

are directly related to health or will have an indirect impact on health. Health literacy can be considered a foundation block for health- and equity-related SDGs. In the coming years, governments will need to develop comprehensive policy and programs to improve health literacy to assist with their responses to the SDGs. Action is not only required across ministries of health but policy development and coordination will need to be undertaken across other sectors including education, urban and rural development, security, immigration, environment, and others. Consequently, programs will need to develop capacities in individuals and communities, as well as strengthening health systems such that they are more responsive to

Health Literacy Table 6

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The role of health literacy in supporting countries to meet a selection of the sustainable development goals (SDGs)

SDG1 No poverty People with health literacy strengths and resources are likely to have many health-enhancing behaviors and be able to recognize, receive, and act on health information and services. Being healthy and staying healthy protects individuals, their family, and their community, against the onset of communicable and noncommunicable diseases, and makes them more resilient to sudden change (e.g., poor health event, extreme weather events, loss of income). The loss of health increases the risk of being driven into poverty due to, for example, the inability to maintain paid work, being unable to support and care for others who generate household income, and chronic or catastrophic out-of-pocket health expenditures. Poverty can become entrenched in families or local communities when children stop going to school to earn an income to look after ailing family members or assist with generating basic subsistence income. People with high health literacy are more likely to respond to health problems early and to engage with primary care services, reducing the likelihood of requiring secondary and tertiary care that is expensive and likely to involve significant loss of income. People with high health literacy may be able to better manage the need to work long hours without resorting to practices that are deleterious to their health, for example, using various drugs as well as high sugar foods and drinks, in an attempt to manage their energy levels. SDG3 Good health and well-being Health literacy is required at the individual and community level to ensure health and well-being for all. To end the epidemics of AIDS, tuberculosis, malaria, and other communicable diseases, we need culturally appropriate health messages and services to be delivered, understood, and taken up. To achieve universal health coverage, and to provide access, understanding and uptake of safe and effective medicines and vaccines for all, the unique health literacy profile of each community needs to be considered and responded to. People and communities with high health literacy are more likely to be able to recognize and choose healthy lifestyle behaviors.

SDG10 Reduce inequalities People with limited education and/or who are poor tend to get more exposure to and are more often affected by potentially healthharming advertising than their more educated and wealthier counterparts. Many minority groups also tend to get less exposure to health-promoting information to counter unhealthy behavior options such as tobacco use and high sugar foods. Healthpromoting messaging, when restricted to written information, tends to have weak penetration in low socioeconomic groups, but higher in more educated sectors and this may increase inequalities. Health literacy needs to be considered when designing health messaging, taking care to provide information not only in plain language, but also in other formats accessible to people with low literacy such as oral and visual formats, delivered through a range of media, including through local trusted peers. As countries work toward achieving Universal Healthcare (UHC) for their people, health-care organizations need to consider the health literacy of all the people in the communities they serve. As the range and reach of health services increases, people in communities need to develop new knowledge and skills to access, use, and cooperate with these services appropriately. Conversely, organizations need to ensure they know and respond to the health literacy needs of vulnerable and disadvantaged groups. Without strong health literacy, people’s ability to work and get back to work when ill or injured can be hampered. The loss of health leads to loss of income, increased burden of medical expenses, or being forced to forego care. This leads to entrenched poverty and inequality in communities. Finally, health literacy is linked to empowerment. Clearly, inequality is linked to reduced material access to services, however, pervasive customs and social attitudes can further entrench inequality. Stigma can be experienced by people with, or families experiencing, TB, HIV, and other diseases due to beliefs that blame the person or family for the disease. This can lead to reduced participation in treatment and reduced ability to implement strategies that address the potentially modifiable causes of disease. Health literacy, and the empowerment of individuals, families, and wider communities, including community and religious leaders, is required to combat health inequalities.

the health literacy strengths and weaknesses of the people they serve. Table 6 outlines potential roles of health literacy in meeting SDG1 No poverty and SDG3 Good health and well-being. Improvements in health literacy will also have substantial contributions to other SDGs, including SDG2 Zero hunger through food choices, including communal health literacy related to decisions about both consumption and production of food. SDG4 Quality education needs to include health literacy in curricula, so that teachers and educators at all levels are resourced to integrate health literacy concepts across the lifespan (from new mothers, preschools, schools, universities, and adult education) as well as in mass and social media. Postgraduate training in doctor–patient and doctor–community communication are aspects of SDG4 Quality Education that in turn contribute to SDG3 Good health and well-being.

Conclusion The capacity for health literacy to be applied in ways that facilitate equity of access and improve health outcomes is now greater than it has ever been. The concept is well developed and for the most part there is an agreement about its definition and scope. Measurement tools are now available to assess most aspects of health literacy. The impacts of low health literacy on many health-related outcomes are well understood. Standards of practice for developing written education materials, managing consultations with patients, and creating health services that are easy to navigate have been developed and there are many resources available to assist health information providers and health services to apply these. In community settings, the role of social groups in determining health literacy is becoming more widely understood.

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Techniques that enable health service providers and community development workers to understand and respond to the health literacy strengths and weaknesses of their constituency continue to be developed and refined. At the same time, the insights that health literacy can offer to engage hard-to-reach populations, are now particularly evident in light of the many ambitious targets that have been set for health and health care globally. These targets address a wide range of issues including tuberculosis treatment, participation in antenatal care, diabetes control, reduction of road accidents, and universal access to health care. In each of these areas, the gains made by standard approaches are tending to plateau while wide gaps between current performance and agreed targets remain. Marginal improvements will not lead to the attainment of the desired targets, therefore new approaches that effectively engage those who are not responding to the current standard methods are required. This, in turn, requires public health professionals, policy makers, and many others to have a better understanding of how people think about health and health services, the forces that shape this and how these can be influenced in order to affect how people receive and process health messages, what they choose to believe, how they judge its applicability to them, and the success with which they can translate it into action. The concept of community health literacy, tools for assessing health literacy at the group or community level, and strategies to engage in the community conversations and relational dynamics that shape health beliefs will be important in bridging the gap between the current situations and targets. While there are many opportunities, there are also trends that tend to work against health literacy responsiveness. Health literacy responsiveness implies the ability to be sensitive and accommodate different cultures, diversity in cognitive styles, approaches to information processing and learning preferences. Many trends in service delivery encourage increased standardization and reduction of options. The recent trend to encourage self-service health care places heavy cognitive demands on users and may disadvantage those who have a highly interactive learning style or who have low literacy. The critical application of a health literacy lens to these sorts of developments is essential if we are to avoid them producing newly disengaged groups in the community. The relatively new concept of eHealth Literacy will be increasingly important in a world where engaging with health information and health services increasingly requires engagement with technology. While there are many opportunities and needs for health literacy interventions, there is an ongoing need for research and advocacy to highlight the importance of understanding health literacy diversity and of service delivery strategies that are sufficiently flexible and responsive to meet people where they are.

Acknowledgments The authors wish to thank Melanie Hawkins for editing assistance. Richard Osborne is a recipient of an Australian National Health and Medical Research Council Senior Research Fellowship #1059122.

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Relevant Websites www.ahrq.gov/professionals/quality-patient-safety/quality-resources/tools/literacytoolkit/ – Universal Precautions Toolkit (last accessed 05.07.16.). http://www.healthliteracy.bu.edu – Health Literacy Toolshed (last accessed 05.07.16.). https://www.sustainabledevelopment.un.org/post2015/transformingourworld – Sustainable Development Goals (last accessed 05.07.16.).

Health Policy: Overview Calum Paton, Keele University, Newcastle-under-Lyme, UK Ó 2017 Elsevier Inc. All rights reserved.

Introduction This article provides an overview of health policy, a basis for understanding what it is, and key definitions relevant to the subject; the various factors that can be used to explain policy making; how policy is or is not rationalized in practice; how health policy affects health systems, exemplified by analyzing how they are financed and governed; and the politics of health policy in the world today. A conclusion is then provided. Clearly health policy is – both in theory and in practice – an application of public policy more generally. It is therefore important to set it in the context of public policy and politics. It is equally important to appreciate that a global review of health policy with potential reference and relevance worldwide must concentrate on generic factors, yet with selective illustrations: principles of analysis, generic global trends, and illustrations of policy making and actual policy in different parts of the world.

Key Definitions Health It is crucial to define policy but also to give a brief account of how health is being defined and treated. Doing the latter first, health is defined, in the spirit of this Encyclopedia, in terms of its public aspect: The health of the public and therefore the responsibility and role of government and other agencies to meet public objectives for the public health. Public health is sometimes defined in a more specific way, that is, the particular set of programs and activities that seek to make an impact upon the promotion of better health, the prevention of ill health, and also environmental health. Rather than the latter definition, this article refers to health policy in the broadest sense – affecting the health of the public – ranging, for example, from the effect of policy upon individuals’ access to care, on the one hand, to policy made overtly in pursuit of social goals for both the health-care system and health outcomes for the population, on the other hand. Its focus is upon policy, policy making, and the implementation of policy, but it is as well to be clear at the outset as to policy’s scope in terms of health. Policy can be negative as well as positive; for example, different health and health-care systems may affect health care for – and the health of – individuals, groups, and the whole population by what it omits as well as what it provides. With this in mind, let us turn to policy as the basis for understanding health policy.

Policy A pragmatic definition of public policy would be what the government does (just as the British Cabinet Minister in the post-war government, Herbert Morrison, defined socialism as what Labor governments do!). This puts the emphasis as much upon public as upon policy: On its own, policy can be

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used in relation to any organization, public or private (e.g., it is the policy of the firm to specialize in luxury goods). But we need to go beyond such a pragmatic definition in order to unpack and examine the concept.

Politics, Policy, and Administration

Our concern here is indeed with public policy (as the means to understanding health policy). Policy comes from the Greek polis, which meant a city or more relevantly city-state and also gave rise to the term polity, that is, political unit of self-government or the political part of a society, that is, (in classical terms) the state. Policy came to mean the statecraft of the (modern) state. Etymologically it is bound up intricately with politics. But this is not just of historical curiosity. For public policy is embedded in politics – the politics embodied by the government, the politics of those who advise the government, the political ideologies that shape one’s political ideas, the political structures required to pass legislation, and the administrative, managerial, and social structures and personnel required to implement policy (that is, to produce social outcomes from policy outputs). In the French language, for example, la politique can mean either politics or policy; the two are not distinguished (Hill, 1997). In traditional British language referring to the traditional British approach to statecraft, on the other hand, the word was often missing: There was politics, on the one hand, and administration, on the other hand. Hence the salience of the academic subdiscipline, public administration, which persists to this day, even in an age when the real world rather disparages administration, turning first to management and then to leadership. It persists no doubt in part because of convention (see e.g., the spread from the United States to the rest of the world of MPAs – Masters degrees in Public Administration – even when the subject matter is modern business, management, and leadership). But it may also persist because there is a healthy skepticism in certain parts of academe about whether or not we should merge (private sector-derived) concepts of management and leadership with the overall terrain of government and its output – which may well be called public administration with some degree of accuracy (Hood and Scott, 2000). Between these two extremes (French and British) above, there is the domain of public policy, which is different from politics (although intertwined with it) and also different from administration with the connotation of the civil service that takes politics/policy, codifies it, and translates it into systems capable of being implemented in the field. This domain recognizes policy’s intimate relations to other domains but still thinks it worthwhile to give it a domain of its own. That is my perspective, broadly, in this article.

Public Policy Going beyond the pragmatic definition of public policy as what the government does, it can be defined as the outputs from

International Encyclopedia of Public Health, 2nd edition, Volume 3

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Health Policy: Overview a process geared to making laws, enactments, and even regulations that are intended to affect society, that is, produce social outputs and outcomes as a result of the outputs from the political system that we may call policy. Note that, in some countries, systems, and cultures, policy even by this definition may not be handled primarily by the politicians, but this is in itself a (political) characteristic of the political system. On this approach to the process, the inputs are various (Paton, 2006). They range from ideas and ideologies, through the political culture, through political movements or parties, through the effect of political institutions and structures generally, through social movements, interests, and pressure groups, through dominant modes of behavior (whether rational or otherwise), to the administrative or bureaucratic culture. Below, I examine the key factors involved. Meanwhile, selectively, the following section defines some more terms.

General Terms l

l

l

l

l

Environment/context: The external climate and actual constraints, or pressures, which influence policy. For example: In the economic environment of global capitalism, it is difficult for individual countries to create or maintain progressive taxation systems with high tax rates, and the prospects for expanding public health-care systems are therefore diminished. Actors/agents/stakeholders: All those individuals, groups, interests, agencies, and organizations that are involved with, concerned with, or affected by, a specific policy (see Kingdon, 1984 and Buse et al., 2005). Agenda: The terms of debate on which an issue is developed in the policy process, or the prioritizing of one issue rather than another – or none – in the political process, or in an agent’s schedule (see Kingdon, 1984). Problem: Seemingly straightforward (e.g., “the primary problem with the British NHS in the 1990s was long waiting times”) but useful when considering how agendas are formed (e.g., is there agreement as to what the problem(s) is/are), and how politics, problems, and policies interact (John, 1999; Paton, 2006). Power: The ability of Actor A to win in an overt political battle (Dahl, 1980) (in our case, in the health policy arena) with B; or the ability of A to prevent B from raising an issue (effectively) within the political process (Bachrach and Baratz, 1970); or the ability of A to prevent B from even being aware he has a grievance or should have a grievance (see Crenson, 1971 and Lukes, 1974); or the effect of the dominant (or prevailing, or pervasive) discourse upon the perception of issues (in the poststructuralist sense, in terms of the effects of language upon concepts and thought) (Peck and Coyle, 2002: pp. 214–219). Note that the last definition de-centers the actor – power is less a conscious attempt to win, by an agent, than an effect.

Practical Terms for the (Health) Policy World l

Regulation: A framework of rules (e.g., a legally backed code) or practices (e.g., by an inspecting agency) that define

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permitted activity, or type and mode of activity, in a field, as opposed to planning or management, which intervene directly rather than set a framework for self-action. For example, the new regulation in health care sets out the rules for markets or quasi-markets, in formerly directly managed health-care systems. Day and Klein (1987) argued that a regulator is external (so that, e.g., a higher tier within a public health-care system does not regulate but instructs or manages). l Strategy: Often contrasted with (on the one hand) tactics, it refers to the means of achieving a direction of travel or goal (as in military strategy), for example, “the strategy for involving the public more in decision-making is to set up local self-governing units in the healthcare system”; contrasted (on the other hand) with an operational focus on keeping things running, as in “the Health Authority’s Director of Strategy will ensure that our plans are consistent with our goal of improving access to the under-served; whereas the Director of Operations will seek to increase throughput in the wards to meet government targets.” l Governance: Within public services such as health care, the adoption of an appropriate structure and culture of oversight of the organization (as in corporate governance, which seeks to assure that the organization is run and controlled ethically, soundly, sustainably and appropriately; or clinical governance, which is the corporate governance of the clinical process in particular).

Explaining Public Policy Through one interpretation, actors (e.g., policy makers) are rational. This might be in the sense of either maximizing their utility (the neoclassical microeconomic viewpoint) or planning a coherent – perhaps evidence-based – route to achievement of objectives, that is, the tailoring of means to ends. This latter view is found in political and administrative science, for example, in Allison (1971). The question is begged as to whether such rationality commands consensus (the unitarist view, or Allison’s Model 1 when applied to policy making within the portals of central government) or whether different interests, elites, structural interests, or economic classes – either in government or across the wider polity and society – have different objectives (respectively, the pluralist, elitist, corporatist, or Marxist views) (Paton, 2006). These different objectives might be rational on the terms of the individuals and groups who have them, and they may be pursued rationally in terms of the instrumental tailoring of means to needs. Yet the overall effect is not consensual pursuit of universally acknowledged rational outcomes. Instead there may be pluralism, with compromise as the basis for outcome – leading, perhaps, to incremental, small-scale policy changes overall even when each group or interest seeks radical, large-scale change. (Compromise is a very different thing from consensus, although there may be eventual consensus upon the need for, and nature of, compromise.) Or indeed there may be domination by an elite or ruling class, which creates a dominant agenda. This may look like rationalism, not least in terms of the passage of comprehensive policy rather than cautious adjustment, but is a very different thing, once again.

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One may also consider actors seeking to achieve their chosen outputs and outcomes (as defined above), but tailoring their behavior in line with the incentives created or enhanced by the institutions’ way of working. This is institutional rational choice (Dunleavy, 1989). But perhaps the culture created or encouraged by structures, and the behavior they encourage, takes on a life of its own: There is a mobilization of bias (Schattschneider, 1995; Paton, 1990) in policy. This may be due to the effect of external structures upon people’s expectations and ways of thinking (i.e., cognitive structures) rather than (just) upon the calculations of autonomous rational actors whose thought processes and agency are unaffected by structures. Indeed there is a difficulty with assuming that humans have an unchanging, rational, or maximizing nature – what Archer calls Modernist Man (Archer, 2000). While it has the merit of preventing the agent from being (implausibly) completely subsumed by society, it begs the question as to where this intrinsic nature comes from. Not only are the assumptions behind rational man questionable (an ontological matter), but their origin is too (an epistemological matter). Structuralism (Peck and Coyle, 2002: pp. 211–214) arguably solves the dualism by going too far in the other direction. It either removes man’s autonomy, positing that deep cognitive or real (natural or social) structures dominate agency. Poststructuralism posits that structures are linguistically determined but variable, indeed arbitrary (Peck and Coyle, 2002: pp. 214–219). On this approach, varying discourses and perspectives that are thus based are constitutive of the individual. The paradox is that the agent is no longer determined by deep or unchanging structures but that there seems no basis for agency other than by changing language. On this basis, agents qua policy makers are neither rational nor irrational: There is no objective basis for evaluating their actions. Other approaches point to the actor’s autonomy being limited but not eradicated. In public administration, this might provide a useful reminder of the role of cultures, ideologies, and ideas in policy studies. Particular structures of relevance to health policy are political institutions, governmental and administrative structures, and specific health agencies. We may wish to define culture separately from structure, or to interpret cultures, habits, and beliefs (including ideologies and ideas) as structures for the present purpose – identifying external factors when seeking to explain or influence policy. The literature concerning the factors that influence, shape, and even cause public policy is now immense. It is necessary to walk the tightrope between theory, on the one hand, and plausible explanation of what is actually happening in the real world, on the other hand. Rhodes (in Stoker, 2000) stated memorably that social science can cope with a lot of hindsight, a little insight, and almost no foresight! Thus it is with explanations of public policy. The policy process (Hill, 1997) is a phrase that characterizes the story of how policies develop, are implemented, in often unpredictable or even perverse ways, and are amended, in a process that is less linear than (variously) wave-like, stew-like, cyclical, and even circular. It should also be understood to encapsulate how politics both shapes and is shaped by policy and the social outcomes that result from policy outputs.

Explanatory Factors (Illustrated for Health) The key factors used in political science and public administration to explain outputs and outcomes in public policy are: 1. Political economy (generally, and also embracing regime or regulation theory) (Aglietta, 1979; Jessop, 2002): Political economy can be defined as the way in which wealth is produced and distributed. It is a crucial backdrop to understanding the underlying pressures and constraints upon health policy. The global capitalist economy puts significant pressures upon public health systems, as well as (for some countries) generating wealth and income that can be used for both private and public purchasing of health care. Additionally, effects upon health outside the health-care system altogether can affect health both positively and negatively. How public policy generally and health policy in particular interact in this environment is crucial. For most but not all countries of the world, current international political economy as opposed to purely national political economy is more important than during the period from 1945 to 1975, which was an era of expansion of economies and of the welfare state in what was then called the industrialized West; expansion which had knock-on effects elsewhere around the globe. Subsequent retrenchment, plus a (related) change in dominant type of political economy (or regime), has had significant effects on health-care systems. The first wave of global health sector reform in the 1940s and 1950s (WHO, 2000a) consisted in the establishment of national health-care systems in many countries. The second wave (1960s and 1970s) consisted in primary health care as a strategy for affordable universal coverage (given already-experienced cost pressures) in developing countries. The third wave – moving into the 1980s and beyond – consisted in a move away from statist public systems to either public or mixed systems relying more on market, quasi-market, or new public management mechanisms (WHO, 2000a). 2. Socioeconomic factors. These are distinguished from (1), although they are related in that they refer to data and demographics, such as the level of wealth of a country and the distribution of wealth and income. Health and welfare expenditure, for example, has been correlated to the former (see Wilensky, 1974 and Maxwell, 1982). 3. Institutionalist, new institutionalist, and structural explanations, which give primacy to the effect of political institutions (and the behavior and incentives that they create) in explaining policy outputs (Dowding, 1990; Paton, 1990). In health policy, policy may result both from the way institutions operate and also how they create a dependency that constrains future policy or directs it in a particular way. 4. Institution-based rational choice. Individuals may act in groups or share interests which influence their behavior, yet have goals and objectives that are determined independently of political structures (institutions) and of cultural factors (e.g., a putative dominant ideology). Nevertheless, their behavior is influenced by institutions and the incentives to which the latter give rise, as they seek to achieve their objectives in the most rational manner. This is a version of institutional rational choice (which, as

Health Policy: Overview Dowding (1990) points out, need not be methodologically individualist). Original or pure rational choice theory as applied to politics was individualist. Public choice theory was based on the view that both individuals and agencies (collectivities of individuals) are selfish maximizers. The implications were that bureaux and bureaucracies would seek to maximize their budget beyond the point of efficiency or effectiveness. For example, the chiefs of a health department – or publicly funded hospital system – would use the political process (perhaps in coalition with politicians, civil servants, and doctors, all building their empires) to expand. This was one of the rationales for the purchaser/provider split (Osborne and Gaebler, 1993), which has featured significantly in both the theory and practice of health sector reform since the late 1980s and 1990s. The trend started in developed countries, particularly the United Kingdom and New Zealand (Paton et al., 2000). Countries with public or publicly regulated insurance in central Europe systems, such as the Bismarckian systems of social insurance (Paton et al., 2000), always had financier/provider splits in the tautologous sense that payers and insurers were separate entities from providers. But this is merely the traditional system that operated through guilds (self-governing providers, professions, and payers regulated by the state) relating to each other without much competition. It is not the same thing as a deliberately created quasi-market or new public management reform. The latter has also been used to reform Bismarckian systems by instigating competition between payers and insurers (whether public or private) for subscribers. Providers of services would have to justify their product (effectiveness) and their costs (efficiency) through tendering competitively in order to win a contract, or at least, if competition was not possible, through setting out clearly their services in response to a specification that might be contestable in the longer run if it was unacceptable in cost or quality. The trouble with this was that purchasing authorities and agencies would also be selfish maximizers if the theory were right. Who would control them? The answer – especially in health care – has often been a system regulator (Saltman et al., 2002). But the same applies to the regulator! So we are driven back to government, as the regulator of regulators. And who controls government? The answer is (idealistically) the people or (realistically) special interests or the ruling class. There is no technical solution – such as purchaser/ provider splits – to what is in essence a political problem. 5. Issues of power, of how power is distributed in society and within the political system, and how it influences public policy. For example, is power distributed pluralistically, or are decisions taken by – or in the interests of – the ruling elite or a ruling class? Here, it is important to distinguish instrumentalism (arguing that, if politics and policy benefit a group, elite, or class, how this occurs must be actually demonstrated) and functionalism (which implies that means that are functional for ends somehow are realized). An example of using functionalism to defend Marxism, for example, was found in Cohen (1978) A strong variant of functionalism is evolutionism, which draws an analogy with Darwinism in natural science to imply that the policies that

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come to dominate are those best suited to surviving in their (political) environment (John, 1999). Functionalism implies that policies develop because they are functional for the external environment, whereas evolutionism implies that policies develop if the external environment is functional for them. Neither stance is satisfactory, as the how is missing. And evolutionism in particular – in social science and policy studies – is either tautologous or vacuous. This is because, unlike in the natural world, the environment is human-made and mutable and can be made functional for policies. Anything can therefore be explained in this manner. The classic example of power in health policy has concerned the medical profession and its relationship both with other actors in health-care systems (especially managers) and with the state. Network theory, whether sociological, political, or managerial, has had prominence recently. To some it is descriptive rather than analytical (Dowding, 1995), although if integrated with power studies (i.e., networks explained in terms of power and influence) it can be useful (Marsh, 1998). At its best, it has the potential to explore how regimes at various levels of government (international, national, and local) are responsible for investment and consumption, and therefore to link political economy with institutional and behavioral analysis. For example, the corporatist approach – which depicts iron triangles of business, government, and labor in policy decision making (e.g., Cawson, 1986) – was extended to depict how national government organizes investment and local government organizes consumption. More recently, in the global and European era, local and regional government and governance are responsible for investment to a greater extent, with national government ironically increasingly controlling or circumscribing consumption. This is related to a (concealed) change in power relations in the economy, with corporatist trilateralism replaced with the bilateralism of business and the state. 6. Ideas and ideologies, which are important, but often linked to wider social factors (and political economy), and in complicated ways. An approach emphasizing the primacy of ideas may sound rational. On the other hand, an approach emphasizing ideology may be ambiguous. Ideology can suggest moral goals and a program to achieve them, or it can suggest false consciousness of agents who are cultural dupes. In health, the primary care movement is sometimes seen as ideologically motivated. Equally Navarro (1978) has argued that high-technology medicine is a means of buying off workers given the disadvantages of (and lack of effective public health in) capitalist society.

A Synthesis Clearly, different factors can be combined in explaining public (and health) policy. Different typologies are available to aid with this task (see Table 1 and Table 2). Two examples are provided: 1. Policy may be made for health, or it may be made with other factors in mind (e.g., trade, the economy). We can call these, respectively, internal and external policy. Additionally, power

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Table 1

Internal

Power Pluralism

Elitism/ruling class

Pluralist conflict within health systems over priorities

Domination of power and resources by the medical profession or business Use of the health system to benefit the capitalist economy, as in promotion or private provision not for health system reasons but to support or subsidize corporations

External Pluralist conflict within local communities or districts over control of health agencies for political purposes

Table 2

Type and degree of rationality Unitarist

Rationalist

Incrementalist

Pluralist

Government pursuing system-wide reform on the basis of agreed objectives

Each interest group or stakeholder pursues its goals rationally, but the overall result has to be a compromise Disjointed incrementalism, Government gradually amending policy on the where mutual adjustment (and its basis of agreed objectives (perhaps with direction) depends upon a conservative bias by the resolution of different agendas on the civil servants) part of different actors behaving incrementally

may be distributed widely in making – or implementing – policy, or it may be concentrated. We can call these, respectively, pluralism and elitism (or ruling class theory). Table 1 shows four possibilities, with four health examples. The aim is not to develop grand theory but to provide a checklist or an aide mémoire when examining empirical possibilities. 2. Policy may be made from a zero base on the basis of seeking means to achieve ends on which there is agreement (either within government or in wider society). This can be called rationalism. Alternatively, it might be made incrementally, on the basis of minor adjustments to previous policy (see the second paragraph in ‘Explaining Public Policy’ above). Additionally, policy may be made consensually (or with only one viewpoint featuring, not the same thing), which variants can all be termed unitarism. This in turn can be contrasted with pluralism (defined as in Example 1). This time, the latter refers more to the breadth of influence upon central government than to the nature of social power more generally. Table 2 shows four possibilities. As with Table 1, it illustrates and clarifies rather than helps decide, which must be done on a context-specific basis, that is, empirically rather than a priori.

Explaining Implementation A framework for explaining implementation can begin simply, analyzing inputs, outputs, and outcomes. Inputs

draw on aspects of the explanatory factors described above, translated into concrete terms. It is helpful to categorize these as ideas, institutions, and political behavior (e.g., by political parties). At root the structure versus agency debate in social science (Archer, 2000) is at the heart of the issue: Individuals operating in (structural) contexts, individually or collectively, help to determine outputs and outcomes. While ideas versus institutions has long been a talking point in policy analysis (King, 1973; Heidenheimer, 1975), these inputs produce outputs in the form of public policy. Implementation concerns the process by which such outputs (e.g., laws; an organization’s objectives) are translated into social outcomes. For example, health policy may concern the creation of a publicly funded national health service (NHS). The effect of the NHS upon access to services and health inequalities (for example) occurs as a result of how, where, and when the policy is implemented. It is possible to have good policy but bad implementation and vice versa (Paton, 2007: Chapter 5). The former may occur when policy is designed (and enacted) rationally, but without taking into account opposition that later is mobilized effectively during the implementation phase. The latter may occur when policy is enacted after significant, possibly debilitating, compromise, but then implemented in a straightforward manner, as all opposition has already been taken into account. Regulation is a means of seeking to achieve goals and objectives though a process of implementation, which occurs through self-modification of behavior in response to external rules rather than by direct command and control. Clearly, this is a pertinent issue in health policy, where international trends overtly embrace the new governance through regulation rather than direct control. The recent reorganization of the UK Department of Health (Greer, 2007) (which administers the English NHS but not those of Scotland, Wales, and Northern Ireland) reflects the creation of many quangos (external public agencies) allegedly to replace direct control by government. There are, broadly, three systems of governance for implementing health policy. Firstly, there is what economists call by the catch-all term of hierarchy (i.e., one word as an alternative to markets) but which may be better described, on examination, as classical bureaucracy or – not the same thing – planning. This is sometimes described as command and control. Often this has pejorative overtones, but it need not: Bureaucracy has advantages in both normative and practical terms. These may include equity, consistency, and transparency (normative) as well as an ability to rationalize systems, reduce inappropriate discretion, and minimize unintended outcomes from local action (practical). Furthermore, the term hierarchy may be inappropriate to describe planning, in health care at least: The latter may eschew the market (see below), but allow considerable devolution of responsibility in meeting goals (Paton et al., 1998; Paton, 2007). Secondly, there is the market. Many countries have recently sought to use both market incentives within the public sector (Paton et al., 2000) and private provision to reshape their health-care systems. Thirdly, there is guild self-regulation. This approach has historically existed in central Europe and also some countries in Latin America as the basis by which the government guarantees access (National Health Insurance) but providers, payers,

Health Policy: Overview and professionals self-regulate to a large extent, often in the context of a corporatism in which quasi-official, nongovernment agencies manage agreement about pay, the prices of services, and market entry. It has been argued that providers (especially professionals) have knavish as well as knightly tendencies and that guild self-regulation requires both an assumption of altruism (Le Grand, 2003) and the assumption that providers respond to the correct signals in supplying services. Generally policy advocates such as Le Grand (2003) suggest the market as the answer. Yet it is vital to examine what happens when politics meets economics in market-driven health systems, which notoriously produce perverse results (Paton, 2007). Furthermore, hierarchy, or command, need not be based on the assumption that providers (and managers in health care) only behave in a self-interested (knavish) manner. Planning approaches in health care, with official targets, may be a means of coordinating altruistic public service as well as providing material incentives for compliance. Clinical networks, bringing together professionals from different institutions, may (for example) require both (internal) coordination and (external) compatibility with wider policy and managerial objectives. To replace these with atomized market incentives may encourage knavish behavior rather than channel it. In terms of global health policy, we have the paradox that the ideology of the market sometimes continues to be on the ascendant but that its effects upon implementation are complex and often perverse (Segall, 2000; Blas, 2005).

Policy in Practice The seemingly random interplay of ideas, groups organized around ideas, interests or advocacy (combining both values and interests; Hann, 1995), and opportunities for policy decisions leads us to the garbage can approach (Cohen et al., 1972). Policy now seems an arbitrary mess. And it may be, at one level or for some of the time. Agendas are successful, in this approach, not because of rationality but because of time or timing and chance (Kingdon, 1984). Policy, politics, and problems are separate streams rather than components of a rational process, and only when they flow together is policy created. This might, for example, be when politicians seize an answer (i.e., a policy) because it is available, trendy, and (coincidentally rather than logically) seemingly an answer to a problem that is perceived to be pressing. The question then arises: If policies emerge haphazardly, one after another, how is policy rationalized, if indeed it is, to ensure that the aims of the state are realized or that policy outputs, at least to a minimal extent, achieve the social outcomes required for both the legitimacy of the state and the requisite stability of institutions? This is a more fundamental question than one about the aims of government. Clearly individual governments’ aims simply may not be realized. Nor should one assume that there is some teleology or functionalism favoring the aims of the state. My argument is a different one, which can be illustrated from health policy. An institution such as the British NHS is only politically legitimate and economically viable if it satisfies

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several conditions: Investment in cadres of domestic workers occupying salient niches in the international economy; acceptability to the demanding middle classes, in terms of both quality and financial outlay (i.e., comparable to what they would pay if only insuring themselves); and fulfillment of its egalitarian founding mission at least to the extent that it seems worth the moral bother of protecting in the first place. How can action by the state or its agents seek to fulfill these conditions? How in other words does the political realm ensure the compatibility of social institutions (such as the NHS) with economic reproduction? This is the crucial question for the sustainability of public health systems in the era of global capitalism. There is no inevitability here. The state may act effectively to square the circle – not just of competing social demands in the conventional sense, but of the competing agendas listed two paragraphs above. If it does not or cannot – for example, if a country’s public health service does not satisfy employers’ needs and demands for healthy employees – employers will seek to finance their own occupational health. If doctors fail to cooperate at least adequately to prioritize the outputs and outcomes that the state requires, then either they will be coerced into doing so within the NHS or they will be disciplined by market forces outside the NHS, as corporations take responsibility for health care on a sectional basis (perhaps taking advantage of European Union Law). What this does, then, is give governments that are sympathetic to preserving at least publicly financed health care an interest in ensuring that the state coordinates policy at the end of the day, so that a complex amalgam of aims can be furthered. There is in practice a major conflict between the garbage can that produces continual waves of incompatible, media-driven policy, mostly in the developed world (Paton, 2006) or policy distorted by the predatory state (Martinussen, 1994), mostly in the developing world, on the one hand; and the need for effective coordination, on the other hand. The latter means tight control of resources given the ambitiousness and complexity of aims, which means political centralism against all prevailing rhetoric. Most devolution and decentralization in state-dominated health systems is devolution of responsibility for functions, not devolution of power. Again, we can see that, in order to explain public policy outputs, we have to consider, respectively, the backdrop of political economy; social power; the structure of the state and political institutions; and how individuals, groups, interests, and classes behave in the context of the structures they must use. For example, Allison’s (1971) Model 1 posits a unified executive pursuing the national good, having been developed empirically to explain the US Government’s behavior during the Cuban missile crisis. It is therefore a kind of grounded theory that is context-specific, and therefore the model may be less suitable for wider explanation of social decision making, interest-group politics, and power. The challenge is to incorporate different explanatory factors at different levels of analysis. These levels can be considered to be a hierarchy in that there is a move from the underlying to the immediate in terms of their causal nature as regards policy outputs, but this is heuristic rather than wholly empirical. It is important not to be too rigid about (for example) what is

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undoubtedly a two-way relationship between political structure and social power: The latter will exert itself, except in exceptional circumstances, through different forms of structure, it is true; but the former’s mode of channeling power may alter the nature of that power in so doing. For example, the medical profession was powerful, as a stratum within a social and economic elite in the 30 post-war years of the last century, in both the United Kingdom and the United States. It was capable of exerting its power through the then very different political institutions of the United Kingdom and the United States. In the centralized, executive-heavy United Kingdom with (then) a political culture of insider networks that were relatively invisible (like all effective power!), an implicit bargain was made through informal channels between the state and the profession (Klein, 1990), which meant a symbiotic relationship in governing the NHS. In the United States, with its decentralized interest-group politics as the stuff of the system, the profession preserved its power using different institutions in different ways, primarily by blocking reform (in the way that the insurance industry did with the Clinton Plan in the 1990s (Mann and Ornstein, 1995; Paton, 1996), by which time it had replaced the now toothless tiger of the American Medical Association (AMA) as the lobby feared by reforming legislators). The question that arises is: Is power economically rooted at base, with the decline in the AMA’s – and the wider medical profession’s – power caused by a surplus of doctors, on the one hand, by comparison with the 1950s and 1960s (when access to health care was extended by government, and the medical profession’s fears of socialization were shown to be ideological rather than economic), and by new corporate approaches to purchasing and organizing health care for their workers, on the other hand? There is clearly truth in this. Yet it is not the whole story. The centralist UK political system was capable of more systematic reform – including the creation of the NHS itself – than in the United States, when the UK state was governed by a strong political party with clear and comprehensive aims, in other words, majority rule rather than the passage of policy by the painstaking assemblage of winning coalitions in the legislature. The latter creates a mobilization of bias (Schattschneider, 1995) away from comprehensive or rationalist reform as opposed to incremental reform, which in turn alters mindsets and limit ambitions. That is, structures can have cultural and ideological effects. It is important to study an issue such as health policy over a long enough period (subjectively, about 20–30 years, in today’s world) to allow different eras to register and therefore the changing salience of different explanatory factors in public policy. In a nutshell, the 1970s was the era of political structures, as the prevailing political economy was nationally based; the 2000s are the era of political economy, as capitalist globalism reduces the salience of nations and their institutions. In other words, political economy is at the top of the hierarchy of salient factors in delimiting and explaining public policy. It sets the background, environment, and constraints. Depicting a regime in political economy shows how the state and other elements of the polity come together to steer the economy in a particular way. It is Marxist, in that it prioritizes economic production, situates political viability and legitimacy

in terms of the political economy and has crisis as the motivation to move from one type of regime to another (e.g., from the Keynesian national welfare state to the Schumpeterian workfare state, in the language of Jessop (2002)). It is, however, post-Marxist or non-Marxist in that regimes vary within capitalism, i.e., a regime is less than a mode of production in the Marxist sense. Institutions and political structures shape behavior, partly by channeling rational behavior (i.e., institutional rational choice) but also by changing cultures and expectations, which feed into future ideas for policy, reform, or whatever, as outlined above. For example, in the United States, the failure of successive attempts at federal health reform, foundering on the rocks of established structures and interests inhabiting them, has lowered expectations for future action on the part of many reformers even without them realizing. Power is exerted, that is, through institutions overtly and covertly, but the latter equates neither to Lukes’ (1974) nor to the poststructuralist vision of dialogues that are enclosed and arbitrary. Loss of ambition in reform ideas is a fatalism, in this sense, rather than a false consciousness, perhaps because elites are systematically lucky (in Dowding’s (1990) arresting oxymoron). In the end, it is just that, an oxymoron, because – with reflexivity of actors and even of passive public(s) – those who are systematically lucky are likely to go beyond luck, that is, to build on it in a deliberate strategy to maximize their instrumental power. Political structures and institutions vary between countries (as well as sub- and supranational levels). Thus executives vary in structure, scope, salience, and power, within the political system in general and state in particular. Regimes are more than governments and less than state systems. In health policy, regimes embody the prevailing orthodoxy in ideas (or ideology) as adapted to, and amended by, political institutions and social structures.

Policy for Financing Health Care and Structuring Health Systems We can illustrate how health policy reflects a variety of different influences by examining how health systems may be financed and governed.

Financing Options The main options for financing health care (ranged along a continuum from private to public) are as follows: 1. private payment (out of pocket), including partial private payment, that is, co-payments (coinsurance or deductibles) (coinsurance means the consumer paying a proportion of the cost, e.g., 20%; a deductible means the consumer paying a fixed amount on each claim, e.g., £50); 2. voluntary private insurance, including partial versions (e.g., supplementary and complementary insurance, to be discussed below); 3. statutory private insurance regulated by the state (including partial versions such as substitutive insurance, meaning – in

Health Policy: Overview

4. 5. 6. 7.

this option – mandatory private contributions by certain categories of citizen (generally the better-off) toward core rather than supplementary or optional health services. That is, everyone is covered, but the better-off pay a form of insurance that is obligatory; community pooling; public/social insurance; hypothecated (earmarked) health taxation; general taxation.

Assessment of Options Against Criteria A specific policy analysis would assess options, one by one, against identified criteria and (perhaps) incorporate a weighting procedure to rank the options. From the viewpoint of understanding how policy is actually made, however, this would only be part of the picture. It might constitute an attempt at rational policy making, that is, an attempt to provide a basis for scientific consensus among the key actors holding power in either the policy process generally or government in particular. Alternatively, it might seek to build in to the criteria for judging options (or even, to the options themselves) pragmatic or political factors (such as the political feasibility of an option in a particular political context). Either way, it is important to be explicit about the range of factors likely to affect a policy’s success as regards both enactment and implementation (i.e., outputs and outcome, respectively), as explored in the sections titled ‘Explaining public policy’ and ‘Policy in practice’. Otherwise, there is a divorce in the policy dialogue between what might be termed technocrats (such as economists), on the one hand, and political scientists on the other. The divorce between such worlds is often responsible for extremes of optimism and disillusionment, respectively, in assessing policy ex ante and ex post, as with recent health reform programs in England, for example.

Governance There are fundamentally three categories of system: 1. statist systems; 2. market systems (whether private, public, or mixed); 3. self-governing systems (with varying degrees of state regulation) (Arts and Gelissen, 2002), in which either guilds or organized functional interests or networks (of providers, financiers, and employees) organize the delivery of care. Statist systems have replaced the market with public planning, whether it is dominated by politics, the public, or experts. Market systems rely on either private markets that have evolved historically or on the creation of market structures and incentives within (formerly) publicly planned systems. Self-governing systems are systems where central state control is limited or weak or both, but where guild-like relationships rather than market relationships between key actors predominate. For example, physicians’ associations, insurers’ associations, and the state will thrash out deals in a corporatist manner, with corporatism meaning (in this context) the institutionalization of major social interests into a reasonably stable decision-making machinery overseen by – but not dominated by – the state.

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Clearly most advanced health-care systems are hybrids in varying degrees. The question is whether the degree of hybridity is dysfunctional or not, that is, whether cultures and incentives are adequately aligned throughout the system. Using the language of incentives, it is important to distinguish between macro and micro incentives. Statist systems, for example, are generally good (often too good!) at macro cost control; their record in terms of micro-level allocations (e.g., to providers or clinical teams) to achieve objectives is variable (a statement that should be taken at face-value; some are good at it; others are not). Those systems that allow meso-level planning authorities, such as regions, to avoid the excesses of both central control and local capture by unrepresentative interests, often have the capacity to square the circle in terms of incentives, as long as attention is paid to steering the system to achieve desired outcomes. While all systems are likely to be hybrids, it is important to ensure that the dominant incentives, geared to achieving the most important objectives agreed by government on behalf of society, are not stymied by cross-cutting policies with separate incentives. This has been an occupational hazard of (for example) England in recent years, arguably, with four different policy streams vying for dominance: The purchaser/provider split inherited from the 1990s’ old market and deepened by the creation of Primary Care Trusts; local collaboration as an alleged third-way alternative to state control and markets; central control through myriads of targets; and the new market of patient choice implemented alongside payment by results (Paton, 2005a,b). In consequence, in considering structures, attention ought to be paid to the central structure, that is, how the political level is and is not distinguished in terms of governance from the top management, that is, health executive level. There is no one answer (again, as the United Kingdom and especially England’s volte faces on whether or not health ought to be managed strategically at arm’s length from government or not probably show). Nevertheless, the question ought to be considered in terms of roles and functions of the different levels within a coherent governance structure: Is the system capable of articulating consistent policy?

The Politics of Policy Analysis and Policy Outcomes Policy studies have evolved the term path dependency to illustrate how historical choices create paths that constrain (although do not necessarily determine) future options. This is sometimes allied with the concept of the new institutionalism, which is actually just a way of emphasizing that agency, ideas, and ideologies are only part of the picture. For example, policy debates vary from country to country – say, in terms of how to reform health services or with regard to the best type of health-care systems – for reasons that do not involve only the cultural relativism of ideas. There are relatively universal typologies of health-care systems, analyzed along dimensions such as how universal coverage is, how comprehensive services are, and how payment is made. Yet these debates are handled very differently, with different results, in domestic policy communities in different countries, even when these countries might seem fairly similar in global terms

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(e.g., France, Germany, Switzerland, Sweden, and the countries of the United Kingdom). Political institutions and their normal functioning constrain and direct policy (Paton, 1990). The field of policy studies also analyzes how different policy communities and networks (both insider and outsider) influence policy. Even in an era of globalization and (in particular) global capitalism, “global policy debates arrive at local conclusions.” This observation was made by political scientist Hugh Hedo in commenting on a book by Scott Greer (2004), which explores how – even within the United Kingdom – territorial politics and local policy advocacy after devolution have produced diversity within the UK’s National Health Services. This is such that one can now talk about four distinctive NHSs (England, Scotland, Wales, and Northern Ireland). To make an analogous observation, a rational approach to policy analysis may seek to combine (for example) universalism, comprehensiveness, and prepayment (whether by tax or insurance) in different ways. In the abstract, there may be little to choose, for example, between a rationally designed NHS and a rationally designed social insurance system. Yet the proof of the pudding is in the political digestion. How viable a system is in practice depends not just on technical factors such as efficiency (which are rarely only technical, in any case), but also upon how the politics of both policy design and policy implementation play out. It could be argued, for example, that England’s confused and overloaded health reform agenda is destabilizing its NHS, unlike, say, in Finland. Or that France’s social insurance system is being adapted to reap the benefits of an NHS-type system. Globalization constrains, but policy and implementation are affected by politics and political structures. As a result, whether or not a system is viable in the global era depends upon practice as well as theory. For example, is an NHS capable of spending money efficiently and effectively enough to make the requisite taxation rates for a comprehensive service viable? The answer, in theory, is yes. The answer, in practice, is we do not know until we have examined if and how different policy objectives, and policy strands, are rendered compatible (Paton, 2006).

The Politics of Health Policy in the World Today In order to analyze health policy, it is necessary to analyze politics in health, a better phrase than the politics of health. That is, while there may be certain respects in which the politics of health is unique to health, it is generally true that the effect of general political factors upon health, health-care systems, and the delivery of health care is more significant. In other words, political economy (both national and international), political structures, and political systems condition health-care systems and indeed the prospects for health. Control and conflict over resources for both health and health care put health at the center of politics. Consider also the role of the state. Moran (1999) has talked of the health-care state, with echoes of the welfare state, and the implication both that the state affects health care (and health) and that health-care systems in turn affect the state and political life more generally. The traditional concerns of political science – ranging from normative political theory (concerning

the nature of the good society and the role of the state) to both analytical political theory and public administration analyzing the nature of, distribution, uses, and consequences of power – are fairly and squarely replicated in analyzing the field of health and health care. Political history is also important. The twentieth century saw the expansion of health systems, often (especially in the developed world, including the communist block, but also in much of South America) into universal systems (i.e., open to all) if not always fully comprehensive (i.e., covering people for everything). (The United States was a notable exception.) This in itself reflected the politics of the twentieth century in which (from a Western perspective) laissez-faire gave way to the interventionism of either social democracy or at least increased government activism. While this may seem like a characterization of the developed world, in the developing world, the expansion of schemes of health insurance in South America and the export to colonies and ex-colonies in Africa and Asia of health-care systems from the developed world make it a broader picture.

Health Sector Reform The logic of globalization has been transmitted directly to the world of health policy (even if the detail that emerges is politically conditioned). For example, a think tank of leading businessmen from multinational corporations in Europe in the mid-1980s, setting out just this rationale (Warner, 1994), had as one of its members a certain Dekker, from the Phillips group in the Netherlands, who also chaired the Dutch health reform committee leading to the Dekker plan of 1987 (which was partially implemented over the 1990s albeit in a restricted form). The Dutch model of managed competition became the prototype for reform of Bismarckian social insurance schemes in Europe and beyond (including South America), as well as for the failed Clinton Plan in the United States (Paton, 1996). The UK model of internal markets and purchaser/ provider splits in tax-funded health systems became the prototype for reform of NHS and government systems both in developed and developing worlds. It was devised by right-wing political advisers and politicians who advocated commercialization in the public sector. This model (shared with health sector reform in New Zealand) even became the prototype, somewhat incredibly, for health system reform in the poorest countries of Asia and Africa. Later in the 1990s and early 2000s, the World Bank sought to broaden the framework by which reform ideas and criteria were assessed, but the watchwords were still competition, market forces, and privatization. The World Health Organization has sought a broader basis for evaluating (and therefore, implicitly, exporting) health system reform. The WHO (2000b) has sought to evaluate health systems around the world by a variety of criteria, including quality, cost-effectiveness, acceptability to citizens, and good governance. The World Bank’s approach, as stated, is heavily influenced by the neoliberal economic agenda applied to health and welfare, an agenda itself influenced by public choice theory (Dunleavy, 1989), especially purchaser/ provider splits between buyers and sellers of health services, managed competition, and quasi-commercial providers.

Health Policy: Overview The assumption is that publicly funded health care has to be delivered more efficiently, or cheaply, and has to be more carefully targeted. In Western countries such as the Netherlands, the latter could be done by advocating publicly funded universal access for a restricted basket of services (i.e., universality but not comprehensiveness). In the developing world from the 1980s onward, usually under the aegis of multilateral agencies such as the World Bank and bilateral aid departments such as Britain’s Overseas Development Administration (which became the Department for International Development in 1997), Western policies promoting market forces in health care have been advocated and partially implemented. In other developing countries, the watchword has been decentralization, but the political intention has frequently been both to limit the role of the state in health care and to make communities more responsible for their own health (which sounds culturally progressive but is likely to be fiscally regressive). As for the whole world, the key question for developing countries is: How is better health (care) to be financed? The options range from private payment through private insurance, through community self-help or cooperative activity, through public insurance, to national systems financed from government revenues, whether operated from the political center or from devolved, decentralized or deconcentrated agencies. (The last refers to field agencies of the central government.) In developing countries, the infrastructure for modern tax-based or national insurance systems often does not exist. Moreover, the decline of tax and spend in the developing as well as developed world means that third-way solutions (meaning neither traditional state or fully public services nor unregulated markets) are also sought in the third world, irrespective of the names or slogans used. In health, the poorest countries have focused upon building social capital (as in the West): Communities, with aid from bilateral and multilateral agencies as well as nongovernmental organizations (NGOs), have sought to create mutual or cooperative local (informed) insurance schemes. The priorities for investment in health are often set through a mixture of expert-based needs assessment and local choice via rapid appraisal of local people’s needs. Not surprisingly, this offer leads to a focus upon the key determinants of public health such as sanitation, immunization, reproductive and sexual health (embracing maternal and child health), and so on. Regarding access to more expensive and acute or secondary health services, the key issues are the availability of pharmaceuticals at affordable prices (with both state and market solutions such as parallel imports being attempted); the provision of integrated primary and secondary care, often through actually siting primary care facilities at hospitals; and the charging policy of public hospitals (i.e., should they be free, should they implement user charges, and if so, how can equity be protected?). Politics is important in all of these areas. For example, if the private sector in hospital provision is encouraged, it may undermine public hospitals’ ability to raise revenue from user charges for better-off patients.

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The Changing Capitalist State and Health System Reform Paradoxically, the capacity of the health-care state (Paton et al., 2000) is increasing in proportion to the complexity of social regulation, while the state’s autonomy from economic interests is diminishing. Either the new managerialism (i.e., business systems to replace public administration (Exworthy and Halford, 1999) or direct politicization of public sector targets (Paton, 2006)) is used is to seek to tailor health services to both economist needs and economically filtered social needs. Use of the central state to extract maximum additional surplus value for private business from health-care provision can reach its apotheosis in the NHS model. Two paradoxes therefore arise. Firstly, the most progressive and egalitarian model for health services (the NHS model) is also the most easily subverted. (The central state can be used and abused.) Secondly, where the NHS model is off the political agenda (as in the United States) because of a pro-business ideology, the surrogate policy for taming health care in the interests of business (i.e., managed care) is much less cost-effective. Consider the hypothesis that state-funded health services (such as the NHS) are a cheap means of investment in the workforce and the economy. If firms derive extra profit (surplus value) as a result of healthier workers that is due to social spending, then that extra profit can be thought of as the total extra income minus the costs of the social spending (e.g., corporate tax used to contribute to the NHS) that firms make. The residual – the extra profit – is composed of two elements: The contribution that workers make to their own health-care costs and social expenses (e.g., through tax), which increases their productivity and firms’ profits; and the exploitation, that is, surplus value extracted from, for example, health-care workers. This latter element, if it exists, derives from the incomes of health-care workers being less than the value they create, that is, the classic Marxist definition of surplus value. It might be objected that governments do not plot such a scenario or situation. But sociopolitical pressures help to produce such an underlying reality. The changing socioeconomic structure of Western societies, and the international class structure produced under global capitalism, leads to pressures on publicly financed health systems. This is inter alia because more inequality and more complex differentiation of social structures leads to different ability and willingness to pay tax and/or progressive social contributions on the part of different strata. Either private financing of (say) health care will increase or public services will have to please affluent consumers and satisfy corporate expectations for their employees, as well as investing in health on behalf of the economy’s needs. The latter may not be equitable, if equity means equal access to services on the basis of equal need. Put bluntly, health-care consumption demands by the richer and investment in the health of skilled, scarce employees, will conflict with egalitarianism in health services. Greater social inequality plus the absence of a left-of-center electoral majority thus puts pressure on egalitarian policy and institutions such as an NHS available to all irrespective of ability to pay. Attempts to defend such a service tend to be forced onto the terrain of economic justifications, to the argument that international competitive advantage requires a healthy workforce. But the workforce is not the same as

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the whole of society. Nor is a post-Fordist workforce (that is, a national class structure shaped by international capitalism) an undifferentiated structure: Some workers are more equal than others when it comes to prioritizing health for economic reasons. It is here that arguments about social capital are sometimes used: A healthy workforce requires a healthy civil society. But this in turn may be a zero-sum game between regions and communities. At this point, it is worth bringing in the classic Marxist dispute about the nature of the state: Is it a (crude) committee of the bourgeoisie and does it manage the long-term viability of capitalism; or is it an area of hegemonic struggle. In health and health care, what would the rational capitalist state do? If the state is the rationalizing executive board of the capitalist class, one can imagine the board’s secret minutes saying, it makes economic sense for us for the state to fund and provide health care. That way, we will pay less than if we directly provide health benefits for our workforce, company by company or industry by industry. It makes sense because taxation is less progressive than it used to be (so workers pay more; we pay less); the state can force hospitals and other providers to do more for less, that is, exploit the health workforce to produce additional surplus value for most of us; and the said public services can invest in the productive using allegedly technocratic means of rationing. At this point, however, if the country’s health-care providers were private, for-profit concerns, they might object, on the grounds that the broader interests of (the majority of) capitalists went against their interests, namely, to derive as much profit as possible from a generously funded health system (broadly, the US position). Equally corporate insurers in the United States resist a single-payer or statist model. Note that such a situation does not pertain in the United Kingdom, with the commercial sector in health care being less economically and therefore politically salient and essentially content with marginal income from the NHS (important as that is in its own terms). Additionally, leaving investment in the workforce to individual firms means a system whereby there is a problem of collective action: Firms will not do it for fear of simply fattening up workers who then move to another firm; or rather, they will only do it in order to recruit and retain the most valuable workers. Again, this is broadly the US situation. On the other hand, if the state finances and provides a common basket of health services for all (the European model), mechanisms will have to be put in place to limit that basket and to increase productivity in its production. This will mean that wider benefits will be sought privately by individuals or employers. This, very broadly, is the agenda driving European health system reform. If the state is more than a committee of capitalists (whether with or without the health-care industry) then ironically the hard-nosed longer-term agenda of competitiveness may be easier to implement; hence the continuing viability of the British NHS on economic as opposed to ethical lines, rather than the messy and expensive US system. (Note how New Labor – in defending the NHS – points to how European social insurance taxes business directly.) The choice between state health care to promote selective investment rather than equitable consumption is glossed over in the rhetoric of the third way, whereby the former becomes

social investment and the latter is downplayed either as old tax and spend or as failing adequately to emphasize health promotion, and so on. Overall, the state in the developed world balances the claims of individual firms, the overall capitalist system and particular laborist or welfarist claims. But in today’s international capitalism, securing inward investment is the crucial imperative. Health policy is not determined by political economy, but it is influenced and constrained by it. This occurs in two ways: It affects the money available and its distribution, and policy regimes (associated with regimes in political economy) influence governments and policy makers, with policy transfer across ministries.

Conclusion This article has defined and explored public policy, applying general concepts to ensure that health policy is not treated in too exceptional or parochial a manner. It has gone on to explore some of the complexities in making (and understanding) policy and in implementation. Policy analysis can be defined in two ways. The first is the systematic but normative examination of situations and options in order to generate choice of policy. The second is the academic analysis of how policies originate and where they come from; who and what shapes them; how power is exerted; and what the consequences or outcomes are. There is often confusion between those two domains both in theory and in practice, perhaps based on the fact that the two meanings are linked psychologically if not logically. Analysts and advocates who wish to find an analytical basis for policy choice (first domain) often have a subconscious picture of the policy process as rational. That is, they assume there is some basis through which evidence can create consensus as a direction or a decision. Yet the reality is often that interests, ideologies, or both determine policy choice. These choices (by individuals, groups, or classes) may be rational in that the means are chosen (the policies) for the ends or goals. It is just that there is no scientific basis for adjudicating among ends, especially now that teleologies such as Marxism do not hold sway and would-be universal values such as capitalist liberalism are revealed to be partisan rather than universal. That is, health policy, like public policy generally, is made as a result of the interplay of powerful actors influencing politicians to make decisions (politics), on the basis of policies that are available and currently salient, either because they are trendy or because they are seen as convenient solutions to those problems that currently dominate agendas. Rationality, in the sense of evidence-based tailoring of means to ends, is only consensual if the key decision makers agree as to ends. This may occur if there is wide and genuine social consensus, or – a very different state of affairs – if those who disagree are excluded from a powerful role in the policy process. In health policy, as in other spheres, we see – locally, nationally, and globally – that orthodoxies wax and wane over decades. (For example, in what used to be called Western countries, the era of public administration gave way to the new public management in the 1980s, 1990s, and beyond, with the

Health Policy: Overview latter subsequently being influenced in a harder market direction by both globalization per se and the mission of supranational block such as the European Union.) We may call these orthodoxies policy regimes. They are regimes because they combine elements of the dominant political economy and the (usually related) current political orthodoxies i.e., they are more than just a policy yet less than an evidence-based certainty.

See also: Agenda Setting in Public Health Policy; Role of the State in Public Health Policy; United Kingdom, Health System of; Western Europe, Health Systems of.

References Aglietta, M., 1979. The Theory of Capitalist Regulation. New Left Books, London. Allison, G., 1971. Essence of Decision. Little, Brown, Boston, MA. Archer, M., 2000. Being Human: The Problem of Agency. Cambridge University Press, Cambridge, UK. Arts, W., Gelissen, J., 2002. Three worlds of welfare capitalism or more? A state of the art report. J. Eur. Soc. Policy 12, 137–158. Bachrach, P., Baratz, M., 1970. Power and Poverty. Oxford University Press, New York. Blas, E., 2005. 1990–2000: A Decade of Health Sector Reform in Developing Countries. Nordic School of Public Health, Göteborg, Sweden. Buse, K., Mays, N., Walt, G., 2005. Making Health Policy. Open University Press, Buckingham, UK. Cawson, A., 1986. Corporatism and Political Theory. Basil Blackwell, Oxford, UK. Cohen, G., 1978. Karl Marx’s Theory of History: A Defence. Clarendon, Oxford, UK. Cohen, M., March, J.G., Olsen, J.P., 1972. A garbage can model for rational choice. Admin. Sci. Q. 1, 1–25. Crenson, M., 1971. The Un-politics of Air Pollution. Johns Hopkins University Press, Baltimore, MD. Dahl, R., 1980. Dilemmas of Pluralist Democracy. Yale University Press, New Haven. Day, P., Klein, R., 1987. Accountabilities. Five Public Services. Tavistock, London. Dowding, K., 1990. Power and Rational Choice. Edward Elgar, London. Dowding, K., 1995. Model or metaphor? A critical review of the policy networks approach. Polit. Stud. XLIII, 136–158. Dunleavy, P., 1989. Democracy, Bureaucracy and Public Choice. Harvester Wheatsheaf, London. Exworthy, M., Halford, A. (Eds.), 1999. Professionals and the New Managerialism in the Public Sector. Open University Press, Buckingham, UK. Greer, S., 2004. Territorial Politics and Health Policy. Manchester University Press, Manchester, UK. Greer, S., 2007. The UK Department of Health: From Whitehall to Department to Delivery to What? Nuffield Trust, London. Hann, A., 1995. Sharpening up Sabatier. Politics 15, 19–26. Heidenheimer, A., Heclo, H., Adams, C., et al., 1975. Comparing Public Policy. Macmillan, London. Hill, M., 1997. The Policy Process in the Modern State. Harvester Wheatsheaf, London. Hood, C., Scott, C., 2000. Regulating Government in a ‘Managerial’ Age: Towards a Cross-National Perspective. Centre for Analysis of Risk and Regulation. London School of Economics, London. Jessop, B., 2002. The Future of the Capitalist State. Polity, Cambridge, UK. John, P., 1999. Analysing Public Policy. Pinter, London. King, A., 1973. Ideas, institutions and the policies of governments. Br. J. Polit. Sci. 3, 291–313. Kingdon, J., 1984. Agendas, Alternatives and Public Policies. Little, Brown, Boston, MA. Klein, R., 1990. The state and the profession: the politics of the double bed. Br. Med. J. 301, 700–702. Le Grand, J., 2003. Motivation, Agency and Public Policy. Oxford University Press, Oxford, UK. Lukes, S., 1974. Power: A Radical View. Macmillan, London. Mann, T., Ornstein, N.J., 1995. Intensive Care: How Congress Shapes Health Policy. Brookings Institute, Washington, DC. Marsh, D. (Ed.), 1998. Comparing Policy Networks. Open University Press, Buckingham, UK. Martinussen, J., 1994. Samfund, stat og marked. Mellemfolkeligt Samvirke, Copenhagen, Denmark.

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Maxwell, R., 1982. Health and Wealth. Kings Fund, London. Moran, M., 1999. Governing the Health Care State. Manchester University Press, Manchester, UK. Navarro, V., 1978. Class Struggle, the State and Medicine. Martin Robertson, London. Osborne, D., Gaebler, T., 1993. Reinventing Government. Plume, New York. Paton, C., 1990. US Health Politics: Public Policy and Political Theory. Avebury, Aldershot, UK. Paton, C., 1996. The Clinton plan. In: Bailey, C., Cain, B., Peele, G., Peters, B.G. (Eds.), Developments in American Politics. Macmillan, London. Paton, C., May 19, 2005a. Open Letter to Patricia Hewitt. Health Serv. J. 21. Paton, C., 2005b. The state of the health care system. In: Dawson, S., Sausman, C. (Eds.), Future Health Organisations and Systems. Palgrave, Basingstoke, UK. Paton, C., 2006. New Labour’s State of Health: Political Economy, Public Policy and the NHS. Avebury, Aldershot, UK. Paton, C., 2007. Visible hand or invisible fist? Choice in the English NHS. J. Health Econ. Policy Law 2 (3). Paton, C., Birch, K., Hunt, K., et al., 1998. Competition and Planning in the NHS, the Consequences of the Reforms, second ed. Stanley Thornes, Cheltenham, UK. Paton, C., et al., 2000. The Impact of Market Forces Upon Health Systems. European Health Management Association, Dublin, Ireland. Peck, J., Coyle, M., 2002. Literary Terms and Criticism. Palgrave, London. Saltman, R., Busse, R., Mossialos, E. (Eds.), 2002. Regulating Entrepreneurial Behaviour in European Health Care Systems. Open University Press, Buckingham, UK. Schattschneider, E.E., 1995. The Semi-Sovereign People: A Realist’s View of Democracy. Holt, London. Segall, M., 2000. From co-operation to competition in national health systems – and back? Impact on professional ethics and quality of care. Int. J. Health Plan. Manage. 15, 61–79. Stoker, G. (Ed.), 2000. The New Politics of Local Governance. Macmillan, London. Warner, M., Lee, K. (Eds.), 1994. Health Care Systems: Can They Deliver? Keele University Press, Keele, UK. Wilensky, H., 1974. The Welfare State and Equality. University of California Press, Berkeley, CA. World Health Organization, 2000a. The World Health Report. World Health Organization, Geneva, Switzerland. World Health Organization, 2000b. The World Health Report 2000 Health Systems: Improving Performance. World Health Organization, Geneva, Switzerland.

Further Reading Altenstetter, C., Björkman, J. (Eds.), 1997. Health Policy Reform, National Variations and Globalization. Macmillan, London. Bell, D., 1960. The End of Ideology. Free Press, Glencoe, IL. Braverman, H., 1998. Labour and Monopoly Capital. Monthly Review Press, New York. Department of Health, 2002. The NHS Plan: Next Steps for Investment, Next Steps for Reform. Department of Health, London. Galbraith, J.K., 1992. The Culture of Contentment. Sinclair-Stevenson, London. Gough, I., 1979. The Political Economy of the Welfare State. Macmillan, London. Gray, J., 1998. False Dawn: The Delusions of Global Capitalism. Granta, London. Jessop, B., 1994. The transition to post-Fordism and the Schumpeterian workfare state. In: Burrows, R., Loader, B. (Eds.), Towards a Post-Fordist Welfare State? Routledge, London. Lowi, T., 1964. American business, public policy, case studies and political theory. World Polit. XVI, 677–715. O’Connor, J., 1973. The Fiscal Crisis of the State. Harper and Row, New York. Paton, C., 1995. Present dangers and future threats: some perverse incentives in the NHS reforms. Br. Med. J. 310, 1245–1248. Paton, C., 2000. World, Class, Britain: Political Economy, Political Theory and Public Policy. Macmillan, London. Paton, C., 2001. The state in health: global capitalism, conspiracy, cock-up and competitive change in the NHS. Public Policy Admin. 16 (4), 61–83. Poulantzas, N., 1973. Political Power and Social Classes. New Left Books, London. Price, D., Pollock, A., Shaoul, J., 1999. How the World Trade Organization is shaping domestic policies in healthcare. Lancet 354, 1889–1892. Skocpol, T., 1997. Boomerang: Health Care Reform and the Turn against Government, second ed. W.W. Norton, New York. Stockman, D., 1986. The Triumph of Politics. Harper and Row, New York. Taylor-Gooby, P., 1985. Public Opinion, Ideology and State Welfare. Routledge, London.

Health Promotion Maurice B Mittelmark, University of Bergen, Bergen, Norway Ilona Kickbusch, Graduate Institute of International Studies, Geneva, Switzerland Irving Rootman, University of Victoria, Victoria, BC, Canada Angela Scriven, Brunel University, Uxbridge, UK Keith Tones, Leeds Metropolitan University, Leeds, UK Ó 2017 Elsevier Inc. All rights reserved.

Introduction and Overview A metaphor that is often used to describe health promotion is that of a stream, into which people may fall. Downstream, at the waterfall’s edge, plucking out near-drowned unfortunates is likened to the treatment of illness. Upstream, on the riverbank, a protective barrier that keeps people from falling in the water is likened to health policy that helps people avoid becoming ill. Extending the metaphor, providing a safe entry point at the river’s edge and training people in self-rescue can be likened to health promotion’s focus on capacity-building and empowerment. The practice of involving people in decision making about access to the stream and safety issues illustrates the participatory approach to health promotion. For many, the defining characteristic of health promotion is that it works upstream, in participatory ways that empower people to control their own health. But not all agree. Health professionals working downstream as well as upstream may declare themselves ‘health promoters.’ In some parts of the world, health promotion is closely equated with disease prevention and the terms may even be used synonymously. Elsewhere, health promotion is viewed as having more to do with policy-level work to intervene on the macrodeterminants of health, such as ensuring access to basic needs (e.g., shelter, clean water, sufficient food, security). Health promotion can be downstream, upstream, or anywhere along the stream because it is perhaps more usefully conceived as a way of working, regardless of where on the stream one finds oneself. As an extreme example, the staff of a hospice work seemingly in a place of hopelessness. However, they can choose to work in ways that empower the patients to manage their remaining time in ways that are the most meaningful to patients. That is a counterpoint to a professional style in which the experts know best and the patients are ‘managed.’ This article reviews key concepts, historical developments, and practice and research strategies of health promotion, with an emphasis on capacity-building and empowerment processes aimed at reducing health inequity in society.

Health Inequality and Inequity Due to many reasons, people experience different levels of health, they suffer differently from diseases and disability, and they die at different ages. Inequality in health is a fact of life. Some of the inequalities in health within and between societies are due to forces beyond an individual’s control, such as variations in natural resources and geography. However, some health inequalities are due to social injustice – unfair circumstances that society should not tolerate. Examples include discriminatory practices based on race, gender, and

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culture, and a society’s failure to provide basic health care to all people irrespective of their economic circumstances. Health inequity arising from social injustice should not be tolerated. Health is a basic human and societal need, and health equity is therefore a basic human right. One’s ability to function physically, mentally, socially, and, in many cultures, spiritually has critical implications for one’s autonomy. Furthermore, the health of a society’s members has important implications for the quality of functioning of the society as a whole. Thus an important aim – many would say the main aim – of health promotion is the elimination of health inequity and a narrowing of health inequality to the smallest possible margin. The practical challenges in this undertaking are daunting, to say the least. One could conceive narrowing the health inequality gap by a reduction in the level of health among the healthiest, as well as by improving the level of health of those with poor health, but the former approach would be absurd. Further, the determinants of health have much to do with how resources are distributed in a society. Any redistribution of resources intended to reduce health inequality requires political action, taking health promotion beyond the confines of what is usually thought of as public health practice.

Health Promotion Defined There is no simple answer to the question ‘What is health promotion?’ People who consider themselves health promoters may have very different professional roles, backgrounds, and perspectives on the nature of health itself. The definition of health promotion given by the World Health Organization (WHO) in 1986 is in the Ottawa Charter for Health Promotion, and reads: Health promotion is the process of enabling people to increase control over, and to improve, their health. To reach a state of complete physical, mental and social wellbeing, an individual or group must be able to identify and to realize aspirations, to satisfy needs, and to change or cope with the environment. Health is, therefore, seen as a resource for everyday life, not the objective of living. Health is a positive concept emphasizing social and personal resources, as well as physical capacities. Therefore, health promotion is not just the responsibility of the health sector, but goes beyond healthy lifestyles to wellbeing. The definition of health promotion given by the American Journal of Health Promotion (AJHP) in 1989 stands in contrast on several points of comparison (Table 1): Health promotion is the science and art of helping people change their lifestyle to move toward a state of optimal health. Optimal health is defined as a balance of physical, emotional,

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Contrasting definitions of health promotion World Health Organization

American Journal of Health Promotion

What is health?

Resource for everyday life

What is health promotion? What is health promotion’s aim? How does health promotion reach its aim?

Process Go beyond healthy lifestyle to well-being Enable people to increase control over their health

Optimal state balancing physical, emotional, social, spiritual, and intellectual aspects Science/art Lifestyle change Help people change their lifestyle

social, spiritual, and intellectual health. Lifestyle change can be facilitated through a combination of efforts to enhance awareness, change behavior, and create environments that support good health practices. Of the three, supportive environments will probably have the greatest impact in producing lasting change. (see Relevant Websites). It is also evident that health promotion can be conceived in ways that defy comparison with either the WHO or the AJHP perspectives. As a particularly illustrative example, the United States’ prestigious Centers for Disease Control and Prevention (CDC) Coordinating Center for Health Promotion was created as a result of the changes in the landscape of public health. Today, many of the leading causes of death and disability are preventable through lifestyle modifications and better understanding of family history. To meet the needs of these new challenges in the area of disabilities, chronic diseases, and birth defects, CDC has strategically created Coordinating Centers that allow the agency to be more responsive and effective when dealing with the public whose health we protect. (see Relevant Websites). Thus, the ‘legitimate’ territory of health promotion can range from empowerment to the prevention of birth defects. Many critics decry the present lack of precision and agreement about the definition of health promotion, but it is clear that one view is growing in influence worldwide – that of the WHO as expressed in the Ottawa Charter for Health Promotion.

underlie a large number of diseases. It is argued that a whole-person approach to disease prevention is more logical than a disease-specific approach. Health promotion is less concerned about specific diseases, although much of what is labeled as health promotion does include disease prevention as characterized above. However, health promotion places great emphasis on how individuals’ choices are limited by circumstances beyond their control. It is believed that policies are needed in all societal sectors, including the private sector, that create environments that support healthy living. There is also emphasis on empowering people to control their own health, and building individuals’ and communities’ capacities to identify and solve the health issues that are their own priorities. Because health inequalities within and between societies are exacerbated by social injustice, health promotion is compelled to enter the political arena, and advocacy for social change is an important health promotion strategy. The distinctions between disease prevention and health promotion can perhaps be best appreciated by considering an example. A typical disease prevention program in a school might target tobacco use, and include education and behavior change interventions aimed at stopping youth from starting a tobacco habit, as well as helping students quit. However, a health promotion program in a school might follow the guidance of the Health Promoting Schools movement, in which a health-promoting school:

Contrasting Health Promotion and Disease Prevention

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Although the terms are often used in tandem, health promotion is distinguishable from disease prevention. Disease prevention has in practice mostly to do with reducing the burden of chronic and infectious diseases by preventing their expression in the first place, by reducing the levels of risk factors for the diseases, and by intervening at early stages so diseases do not progress to more serious stages. Since unhealthy lifestyles can increase risk for many diseases, lifestyle modification is an important element in disease prevention. Education about the lifestyle-disease link, and ways to live a healthier lifestyle, aim to help individuals make healthy choices. There is also some attention to making changes in peoples’ environments, to facilitate healthy lifestyles. Disease prevention efforts tend to be compartmentalized, with specialists working exclusively or almost exclusively with heart disease prevention, cancer prevention, diabetes prevention, and so on. This situation is often criticized, because many of the same risk factors

l

l

l

l

“Fosters health and learning with all the measures at its disposal. Engages health and education officials, teachers, teachers’ unions, students, parents, health providers and community leaders in efforts to make the school a healthy place. Strives to provide a healthy environment, school health education, and school health services along with school/ community projects and outreach, health promotion programs for staff, nutrition and food safety programs, opportunities for physical education and recreation, and programs for counseling, social support and mental health promotion. Implements policies and practices that respect an individual’s well being and dignity, provide multiple opportunities for success, and acknowledge good efforts and intentions as well as personal achievements. Strives to improve the health of school personnel, families and community members as well as pupils; and works with community leaders to help them understand how the community contributes to, or undermines, health and

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education.” (WHO, 1995). (The settings approach to health promotion is taken up in greater detail later in this article.) Health promotion and disease prevention are complementary rather than alternative approaches to improve public health. In recent times health promotion ideas have become more mainstream in public health practice, and sharp distinctions are fading. Yet there remains an important discourse about the ‘right’ balance between individual-oriented versus systems-oriented approaches to improving the public’s health.

History of Health Promotion and Its Key Concepts The Ottawa Charter for Health Promotion, adopted by an international WHO conference in Ottawa Canada in November 1986 (Ottawa Charter for Health Promotion, 1986) was constructed with a strong sense of history and yet was fully rooted in the seminal changes of the latter part of the twentieth century (Kickbusch, 2003). As is the case with all intellectual endeavors the Charter was shaped by its context. It emerged during a time of extraordinary cultural innovation, economic growth, and political change. The Charter provided a new framework on how to approach the ‘sanitation challenge’ of the twentieth century, which had been classified as ‘lifestyles conducive to health.’ It established that “health is created in the context of everyday life: where people live, love, work and play” and introduced a very active and interactive understanding of health. According to the Charter, health was considered a resource for living – it was not just an output of other social forces but became an input, a dynamic force of its own. Lester Breslow (1999), the great epidemiologist, argued that the Ottawa Charter and its view on health constitute the third public health revolution (the first and second being the advances against communicable and noncommunicable diseases). The Charter was built on many historical sources from the golden age of public health, and was indebted in particular to the work of Thomas McKeown who had shown with great clarity the extent to which improved living conditions and nutrition contributed to the increase in life expectancy in the late nineteenth and early twentieth centuries. Many of the best public health traditions established in the nineteenth century had become eclipsed by medical strategies or a focus on individual behavior and the Charter aimed to put the spotlight back on population health and its determinants. In doing so it further reinforced the primary health-care approach adopted by the WHO in 1978 at the seminal health conference in Alma Ata (in the former USSR). However, no single public health action – such as the famous removal of the handle of the Broad Street pump by John Snow – could resolve the twentieth-century epidemics of chronic disease. Instead, the Charter proposed a synergy between five essential areas of public health action: (1) healthy public policies; (2) personal skills; (3) supportive environments; (4) community action; and (5) reorientation of health services. The aim of health promotion was to combine a social determinants approach (the old public health) with a commitment to individual and community empowerment (the new public health). This consensus emerged through a 5-year discussion process involving professionals, academics, and

community members from all around the world. The Ottawa Charter gave expression to many ideas as well as on-the-ground practices in the health arena, which were waiting to be recognized and legitimized. The Ottawa Charter was very much inspired by the social movements of the 1960s and 1970s: the women’s health movement, the newly emerging ecological movement, liberation theology, the gay pride movement, as well as the freedom movement around the globe. The age of colonialism was coming to an end: in the Civil Rights movement in the United States black Americans were fighting for their rights as citizens, Solidarnosc and other opposition movements were emerging in Eastern Europe, Africans were fighting against apartheid, and the first attempts at global solidarity were emerging. For example, a global boycott against South Africa was put in place and Bob Geldolf organized the first big concert for Africa – ‘We Are the World.’ The North South Dialogue was chaired by Willy Brandt and Our Common Future by Gro Harlem Brundtland. This was the time of writings such as Silent Spring by Rachel Carson, and the Club of Rome’s Limits to Growth and Limits to Medicine by Ivan Illich. The year 1986 also saw the Chernobyl disaster and a new killer – HIV AIDS – had entered the world of public health. It became clear that all progress carried its own seeds of disaster. Frequently forgotten are the many intellectual roots of the Ottawa Charter that stem in particular from the social sciences. Sociological theories of how everyday life is constructed, anthropological research into the importance of context and meaning for individual action, critiques of medicalization and the role of health as a means of social control, the relevance of a sense of control and belonging – all the richness of the social discourse of the late 1960s, the 1970s, and the early 1980s fed into the document and provided its scholarly context. Sources of inspiration include Michel Foucault, Anthony Giddens, Gregory Bateson, Aron Antonovsky, Margaret Mead, Hannah Arendt, and Marie Jahoda, to name but a few. Finally, the policy innovations that had emerged in a number of countries also strongly influenced the Charter: the Lalonde Report from Canada, the Health Objectives for the Nation from the United States, and the experiences gained with major health promotion and prevention projects, for example, the North Karelia Project in Finland, the Minnesota Heart Health Program in the United States, and Heartbeat Wales in Wales. Any new discourse needs an institutional space and in the 1980s the WHO provided such a space. At the global level it was led by a visionary director general, Halfdan Mahler, who was supported by the extraordinary public health intellectual Joshua Cohen. They had led the WHO into a phase of innovation that it has since not experienced. Exemplary for their approach was the Alma Ata Declaration on Primary Health Care and the Health for All Movement, the latter of which was committed to reducing significantly the health inequalities around the globe. At the WHO Regional Office for Europe, the regional directors Leo Kaprio and Jo Asvall provided the space to develop both health promotion and the many projects that followed – such as WHO’s Healthy Cities initiative. It was critical for the health promotion movement that it had the full support of the WHO leadership in its first phase and could establish a process whereby health promotion was

Health Promotion strongly recognized in the institutional structure of the WHO. New projects could be developed – the many settings projects are cases in point – and key strategic documents such as the European Action Plans on Tobacco and Alcohol were based on the Ottawa Charter principles and five action areas. Health promotion development was showcased and discussed through a series of international conferences, exploring the five action strategies of the Ottawa Charter in depth. The idea was to hold conferences every 2–3 years in different parts of the world, thus systematically making the health promotion approach and movement ever more global and ever more rooted in local and regional experience and practice. A global program on health promotion was established to lead this development and was run first from Copenhagen and then from Geneva. The series of conferences that followed were Healthy Public Policies (Adelaide in 1988), Supportive Environments (Sundsvall in 1991), New Players in a New Era (Jakarta in 1997), Inequalities in Health (Mexico City in 2000) and Globalization (Bangkok in 2005). The generation that developed the Ottawa Charter for Health Promotion set out to classify what it takes to address public health in modern societies, not only in the twentieth but even more so in the health society of the twenty-first century. The Ottawa Charter was very much ahead of its time and its full importance and potential has not yet been fully recognized. In an age of globalization, consumerism, and rapid change of living and working conditions, the dimensions of the Ottawa Charter take on a new life. The challenges abound: how to respond to global marketing assaults on children, how to address obesity as a societal rather than an individual problem, how to address the rapidly growing mental health challenges in modern societies, and how to link environment sustainability with health sustainability. The Ottawa Charter still provides some of the best guidance we have in public health about these matters. In a society in which most dimensions of everyday life – including health – have become commodities, new answers are needed about how to make the healthy choice the easier choice, how to make health everybody’s business, and, in particular, how to ensure equity. Health in the twenty-first century is transnational and all attempts to create health and control risks lead into the new global arena. The territorially bounded settings approach – schools, workplaces, hospitals, cities, villages, marketplaces – needs to be complemented by strategies to counteract unbounded global ‘healthscapes’ – fashion images, advertisements, internet pornography, and the like. The five action areas of the charter now need to be complemented with a global dimension that recognizes health as: a global public good; a key component of collective human security; l a key factor of good global governance; l responsible business practice and social responsibility; l a key defining factor of global citizenship. l l

International Union for Health Promotion and Education Just as the WHO has played a critical role in the development of health promotion as it is found around the world today, other

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organizations have made important contributions that warrant mention. At the national level, ever more countries are establishing national competency centers in health promotion, and this trend seems to be accelerating. At national and international levels, the best-established infrastructure for health promotion professionals is the International Union for Health Promotion and Education (IUHPE). The IUHPE is a leading global network to promote health worldwide and contribute to the achievement of equity in health between and within countries. With its home office in Paris, the IUHPE is half a century old, and the only global nongovernmental organization (NGO) entirely devoted to advancing public health through health promotion and health education. The IUHPE is a leading global network to promote health worldwide and contribute to the achievement of equity in health between and within countries. It has an established track record in advancing the knowledge base and improving the quality and effectiveness of health promotion and health education practice. For example, an ongoing project of the IUHPE is the Global Programme for Health Promotion Effectiveness (McQueen and Jones, 2007). Members range from government bodies, to universities and institutes, to NGOs and individuals across all continents. The IUHPE offers regional and global conferences, has dedicated journals both in print and online versions, and offers others resources to health promotion practitioners, researchers, and policy-makers (for more information on the IUHPE, see Relevant Websites).

Health Promotion Practice Health promotion has systematically drawn its strategies from health education, the self-care movement, social and preventative medicine, and psychology, among other sources. Before 1986 – when the WHO consolidated the various influences on health promotion in the Ottawa Charter for Health Promotion – the following five strategies strongly influenced the direction that health promotion practice has taken. 1. Building a healthy public policy is a key strategy for population health improvement, ensuring that health becomes the responsibility of policy makers in all sectors, and that policies outside of the health sector take account of their health impact. There was a stated need to identify the obstacles to the adoption of healthy public policies in nonhealth sectors and a challenge set to find ways of removing them. At the second International Conference on Health Promotion (Adelaide, 1998), the set of recommendations for healthy public policies in part clarified what the term healthy public policy means and how it might be facilitated. The Adelaide recommendations define healthy public policies as those concerned with health and equity at all levels of policy and accountable for health impact. The aim of healthy public policies is to create supportive environments that make health choices possible (or easier), so that people can lead healthier lives. Healthy public policies therefore aim to make social and physical environments health enhancing. The recommendations also suggest that in pursuit of healthy public policies, government

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departments concerned with agriculture, trade, education, industry, and communications need to take into account health as an essential factor when formulating policy. Developing personal skills focuses on supporting personal and social development through providing information, education for health, and enhancing life skills for people throughout the course of life. By so doing it increases the options available to people to exercise more control over their own health, which in turn enables choices conducive to health. A practical example is that of empowering disadvantaged groups through training and education. Creating supportive environments makes the link between people and their environments to improve health. It involves addressing the cultural values, social norms, physical surroundings, and political and economic structures that make up the home, workplace, and community environments in which individuals and groups live. Practical examples include the European Networks of Health Promoting Schools and Workplaces, discussed in the following section of this article. Strengthening community action involves the empowerment of communities through strengthening social networks, building social capital, and building capacity for social change by providing information, learning opportunities, and a broad range of resources. Reorienting health services involves working toward a health-care system that contributes to the pursuit of health. Reorienting health services requires strong attention to health research and evidence as well as changes in professional education and training. This must lead to a change of attitude and organization of health services, which refocuses on the total needs of the whole person. It moves the health sector beyond providing only medical and clinical services toward meeting the more holistic needs of people using a multisector approach.

The Settings Approach The Ottawa Charter introduced the notion of the settings approach to health promotion because health is created within the settings of everyday life, where people learn, work, play, and love. The WHO has declared schools, the workplace, hospitals, prisons, cities and towns, and islands, among the priority settings for health promotion.

Schools Schools have an important role to play in fostering the health of children and young people at a formative point in their physical, social, mental, and attitudinal development. Consequently, schools form a significant setting and have been the focus of a major global initiative based on a social model of health. The Health Promoting School emphasizes the entire organization, as well as focusing on the individual. At the heart of the health-promoting school is the young person, who is viewed as a whole individual within a highly supportive dynamic environment that influences the visions, perceptions, and actions of all who live, work, play, and learn in the school. This generates a positive climate that influences how young

people form relationships, make decisions, and develop their values and attitudes. Healthy, well-educated young people can help to reduce inequities in society, thus contributing to the health and wealth of the population at large. Because the determinants of education and health are inextricably linked, health promotion seeks to integrate the policy and practice of the health-promoting school into the wider health and education sectors. Worldwide, regional health-promoting schools networks have been established, such as the European Network of Health Promoting Schools. The Network functions at three levels – school, national, and international – with more than 40 countries in the European Region as members. The countries that have embraced the initiative have established national networks and frameworks that set out the criteria that schools should meet to be designated as health-promoting schools.

Workplace In its Luxembourg Declaration, the European Network of Health Promoting Workplaces (ENHPW) conceives workplace health promotion as combining the efforts of employers, employees, and society to improve the health and well-being of people at work through a combination of improving work organization and the working environment, promoting active participation, and encouraging personal development. This perspective was given further substance by the Barcelona Declaration on Developing Good Workplace Practice in Europe (ENHPW, 2002). Workplace health promotion has several aspects: Commitment to a healthier workforce by providing information on health promotion; l Implementation of policies and practices that assist employees to make healthy choices; l Recognition of the impact that organizations can have on individuals. l

A healthy organization successfully balances corporate and individual goals. It promotes health actively and in a holistic manner, by focusing on health and safety requirements, developing an open and flexible culture with systems that seek to reduce workplace health risks, rewarding achievement, ensuring effective communication, and monitoring, reviewing, and evaluating how the workplace affects health.

Hospitals and Health Care Health-promoting hospitals and primary health-care settings go beyond the traditional role of diagnosis, treatment, and rehabilitation, by positively influencing the health of not just patients, but also staff, relatives of patients, and the communities in which they are situated. In 2004, the WHO set five standards for health-promoting hospitals: There must be a written policy for health promotion, implemented as part of the overall quality system, aimed to improve outcomes, and including patients, relatives, and staff. l There must be assessment of patients’ needs for health promotion, disease prevention, and rehabilitation. l

Health Promotion Patients must be provided with significant information about their health situation, and health promotion interventions should be established for all patients. l Hospital management must establish the conditions for the development of the hospital as a healthy workplace. l There must be a planned approach to collaboration with other health service sectors and institutions, for continuity and collaboration in the provision of health care. l

Not only hospitals, but all health-care settings – primary care, walk-in clinics, school and workplace health services, rehabilitation centers, hospices, and long-term care facilities – have the potential to promote the health of all who receive and provide care. In addition to the many hundreds of hospitals worldwide that subscribe to the ideals of the healthpromoting hospital, many other types of health-care settings are adopting similar approaches and standards. (Information about health promotion in health-care settings is available from the WHO Collaborating Centre for Health Promotion in Hospitals and Health Care in Vienna; see Relevant Websites).

Prisons The current emphasis in health promotion practice on tackling inequalities and addressing social inclusion makes prisons important settings for promoting health. In 1996 the WHO held the first international conference on the subject of healthy prisons, in the United Kingdom, and since then the healthy prisons movement has spread across Europe. Some of the principle actions that are recommended to prisons are to: l l l l l l

Establish a health promotion steering group supported by top management; Actively involve prisoners in developing programs; Commit resources, staff, and training; Use a range of health-related approaches; Set achievable goals and undertake annual evaluation; Make a long-term commitment (3–5 years recommended) to programs.

(Further details are available on the WHO websites; see Relevant Websites).

Combined Settings Approach While healthy settings have become a key element of health promotion strategy, there is no common frame of reference and many settings initiatives have developed in isolation from others. It seems desirable that bridges be built between various settings, so that as people move from setting to setting in a community, the health-promoting aspects of community living are ever present (Dooris, 2004). However, the movement toward combined settings in health promotion is still in its infancy.

Media

Mass media used by health promoters includes radio, television, newspapers, magazines, and billboard posters. The strengths of the mass media in promoting health lies in putting issues on the public agenda, in reinforcing local efforts, in raising consciousness about health issues, and in conveying simple information. The media is also useful in

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countering the well-resourced, often one-sided messages that come from industries promoting health-damaging products, such as alcohol. The limitations of the mass media are that they are less effective in conveying complex information in teaching skills, shifting attitudes and beliefs, and changing behavior in the absence of other enabling factors (Hill, 2004). An explicit objective of many mass media campaigns is to influence the social context and to create a favorable climate in which interventions can be received (Wellings and Macdowall, 2000).

Coalitions, Partnerships, Collaboration, Alliances, and Participation

Participatory approaches involving collaboration and partnership are well established in health promotion practice (Scriven, 2007). As early as 1978, the full participation of the community in the multidimensional work of health improvement became one of the pillars of the Health for All movement, launched at the Alma Ata conference. The declaration from this conference confirmed that people have not only the right but also the duty to participate individually and collectively in the planning and implementation of their health care and in their health generally. This was further developed in 1986 when the Ottawa Charter identified strengthening community action as one of five key priorities for proactive health creation. A wide range of international policies has followed which have adopted and reaffirmed these ideas. The Bangkok Charter, for example, prioritizes local partnerships and calls for the strengthening of the capacity of civil society and decision makers to act collectively to exert control over the factors that influence health. The Charter asserts that active participation, especially by the community, is essential for the sustainability of health promotion efforts. The formation of partnerships with public, private, and NGOs is designed to create sustainable actions across sectors to address the determinants of health (WHO, 2005; see Relevant Websites).

Planning, Implementing, and Evaluating Health Promotion Programs Health promoters use planning tools to guide them through the steps of planning, implementing, and evaluating programs in various community settings. These tools vary greatly in details and complexity, but in general they are composed of three steps. The first step is planning, during which a careful study is undertaken of a community’s or setting’s needs, resources, priorities, history, and structure. Planning takes place in partnership with community members, and this participatory approach is consistent with health promotion’s underlying philosophy of ‘doing with’ rather than ‘doing to.’ After a plan of action has been agreed on, the required resources are gathered, implementation begins, and monitoring of action and change processes is undertaken. Importantly, plans are just that – plans – and frequently require revision as implementation unfolds. Fluidity in planning and implementation helps meet the demands of new or changing conditions and constant surveillance of, and reflection over practice, change processes, and outcomes, inform better practice. Finally, health promotion practice tools stress the importance of evaluation,

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and dissemination of best practices, with attention to maintaining and improving quality as dissemination unfolds (see Health Promotion Research). The exact form of a health promotion intervention rests on many considerations, including the skills and aptitudes of all the people involved, the type of health issue that is being addressed, the community setting or group context, the type and extent of resources, and so forth. However, the health promoter’s general approach to intervention is relatively invariant – stimulate peoples’ capacity and control over their own health through collaborative work.

Models of Health Promotion The Nature of Models A model provides a simplified and abbreviated version of a complex reality. Models typically derive from theory. They are useful and effective insofar as they accurately represent their theoretical base and capture all of the key elements of the underlying complex reality. Broadly, there are two varieties of model: models that are ideological and models that are technological. In the context of health promotion, the ideological variant is well illustrated by the case of the much maligned medical model. Apart from its failure to take into account ‘social’ health, it has been criticized by health promotion workers for its narrow focus on specific causality and individual behaviors, when both health and disease are in reality typically determined by broader social and environmental factors. Moreover, as Illich (1976) vigorously asserted, the medical model may actually damage health in that it is ‘depowering,’ whereas health promotion intends to empower people to control their own health.

The Primacy of Empowerment Empowerment is both a process and an end state. It is not only viewed as central to the approach to health promotion outlined in this article, but is considered a sine qua non, based on the following truisms: Health – including the experience of disease – is influenced by a dynamic process of interaction between individuals and their environment (physical, social, and economic). l Research demonstrates unequivocally that the most powerful and overriding negative effects on health are due to the existence of inequity and inequality; accordingly, the pursuit of equity is health promotion’s overriding purpose. l Effective health promotion must take account of both individual and environmental factors and adopt action strategies designed to produce positive change at both individual and environmental levels. l Health promotion has important political, as well as philosophical and professional, dimensions. l

The values position and central ideology of the health promotion models described below is therefore quite unequivocal. However, in addition to ideological commitment, health promoters require a toolbox of strategies and methods that are technically sound. Without the technical understanding associated with sophisticated radicalism, health promoters

are at risk of self-congratulatory posturing. In short, a technological model is needed which identifies the key psychological, social, and environmental factors that facilitate or inhibit genuine empowered health-related decision making by individuals and communities. Two complementary models that contribute to the theory and practice of effective health promotion are taken up here, one focused at the level of individuals, the other at the level of communities.

The Health Action Model The health action model (Tones and Tilford, 2004) identifies the major psychological, social, and environmental determinants of individuals’ health- or illness-related actions. It comprises two key sections: first, the system that contributes to behavioral intention, and secondly, the factors that determine the likelihood that behavioral intention will be translated into practice (Figure 1). Behavioral intentions are governed by a complex interaction of beliefs, motivations, and normative influences together with a more holistic but separately identifiable construct described as the self, which has traditionally been described as ‘personality.’ Beliefs are cognitive and viewed as probability judgments – for example, the extent to which individuals accept that smoking causes cancer or potential activists consider that they are capable of joining a march to protest against poor housing. The motivation system, on the other hand, is affective; it has to do with feelings, emotions, attitudes, and values. There is interaction between behavioral intention and motivation. For instance, people who believe that the tobacco industry has bribed a political party might feel outrage, and outrage might lead them to selectively focus on evidence that the tobacco industry engages in bribery. The importance of social pressure on behavioral intention has been well recognized. There is also an interaction between cognition and affect in this context. Individuals’ intention to act may be influenced when they (1) believe that a course of action will result in disapproval from other people and (2) have a strong attraction to the normative source, and are therefore motivated to comply with it. There may, of course, also be interaction between any or all of the above influences and the global notion of personality. For instance, a ‘sensationseeking’ personality trait may be associated with certain beliefs and motivation that influence health actions. As can be seen from Figure 1, it is useful to identify three situations which make the healthy choice the easy choice, so to speak. The simplest of these involves the provision of knowledge. In many instances people may be quite eager to adopt a healthy course of action but merely lack knowledge of what to do, where to go, and so forth. A health promoter simply needs appropriate communication skills to achieve a successful outcome in such cases. Rather more difficult is the situation in which particular skills may be needed. These might include (1) psychomotor skills, such as competence in proper use of a condom, (2) social interaction skills, such as the capability to act assertively, and (3) self-regulatory skills, such as quitting smoking. However, the environmental system as identified in Figure 1 has the greatest relevance for individuals’ behavior; this is taken up in the following section.

Health Promotion

Figure 1

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Health action model.

The Community Empowerment Model The community empowerment model (Figure 2) extends and redefines Freire’s classic notion of conscientizacao, roughly translated as ‘critical consciousness-raising.’ The approach identifies the role of a community worker – one who works with the community, and, by means of small-group work, leads them to analyze critically their lives and their predicaments until they are able to view them in a different, more realistic and critical way. If effective, a state of praxis is achieved. The notion of praxis is central to the classic work of Paulo Freire (1972), and the strategy of community development is strongly associated with Freirean ideas. However, like the pure Freirean approach, it has limitations. Accordingly, the community empowerment model identifies measures to maximize the likelihood that praxis results in vigorous and successful political activism, which will in turn result in the genuine achievement of healthy public policy. Three key strategies in this regard are (1) the strengthening of social interaction skills, (2) the use of media advocacy, and (3) the development of coalitions.

Social Interaction Skills

An extended system of social interaction skills should be used to complement and facilitate plans for social and political action. A variety of resources has been developed to provide such skills. Reference has been made in Figure 2 – by way of example – to two such resources (designed primarily for use in secondary schools in the United Kingdom and Denmark). Their purpose is to teach health and life skills such as, for instance, assertiveness skills. The result of training that provides a range of these fundamental social skills should be the achievement of what have been termed action competences, which in turn should motivate and facilitate social and political action.

Media Advocacy

Rather than seeking to use mass media to change the attitudes and behaviors of mass audiences, which is usually ineffectual, media can be used locally to achieve radical outcomes, particularly by targeting unhealthy situations in specific communities and seeking to influence key decision makers (Wallack et al., 1993).

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Figure 2

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Community empowerment model.

They provide access to a wide range of talent and resources and can enhance groups’ leverage. l They are a vehicle for recruiting additional groups to a cause. l Their flexibility enables them to draw on new resources as situations change.

Development of Coalitions

l

They spread responsibility across a number of organizations. l They demonstrate and mobilize public support for an issue. l They can maximize the power brought to bear on an issue and achieve a critical mass. l They can minimize duplication of effort.

Education and Social Action

The third strategy is building coalitions of the ‘great and the good.’ Butterfoss et al. (1993) have provided a definitive list of the importance of coalitions: l

In recent years, theoreticians, philosophers, and sociologists have questioned the relevance of health education for promoting public health. Indeed some have seen health

Health Promotion education as counterproductive – as an activity associated with ‘victim blaming.’ There is also concern with the paradox that health education has the potential to widen the health equity gap, if it succeeds in reaching advantaged people and fails to reach disadvantaged people. However, health education can be made available to all, if imaginative strategies are used. For example, in sub-Saharan Africa street theater is used, even in the most disadvantaged communities, to deliver health education messages to people at every level in the community in entertaining ways that fit local context and culture. Indeed, the position taken here is that health education is an essential element in health promotion as illustrated by this formula: Health Promotion ¼ Healthy Public Policy  Health Education Health Promotion ¼ Healthy Public Policy  Health Education. The term healthy public policy received emphasis at a time when those who were dissatisfied with the limitations of health education argued for a more vigorous and radical political approach. They proposed that a prime goal for public health was to put pressure on politicians and others with power, to achieve implementation of public policy measures that were health promoting. However, politicians and those in power were often notably unwilling to implement healthy policies in the face of competing political pressures. Secondly, the implicit definition of education was too narrow, often conceived as having merely to do with individuals’ health-related attitudes, beliefs, knowledge, and behavior. Setting aside philosophical points, education may be defined as any deliberate and, hopefully, competent attempt to achieve learning outcomes. The central question – frequently not addressed – is what kind of learning is most relevant to health promotion? Certainly, the least important health promotion learning tasks are related to individuals’ lifestyle changes (though important to many in their own right). The vital educational goals for health promotion are radical and political – to influence beliefs, provide skills, and generate motivation by a process of critical consciousness-raising. In this way the achievement of healthy public policy might be attainable as a consequence of effective advocacy by an enlightened citizenry.

Health Promotion Research In contrast to most of public health, health promotion research has tended to draw mainly from the social and behavioral sciences rather than the biomedical sciences. This is not surprising in that health promotion as it has developed over the past two decades has had a distinctly social and behavioral focus. Indeed, most people associated with the field would argue that this is entirely appropriate given that health promotion is primarily about trying to influence social and behavioral change in health-enhancing directions. Thus, the kind of research that is undertaken is inevitably social and behavioral, and there is a strong emphasis on intervention research, and finding appropriate ways to evaluate the various approaches to promoting change. Today, one of the most influential compendia on health promotion evaluation illustrates a number of the points made above (Rootman et al., 2001). Most of the authors of

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its 23 chapters are social or behavioral scientists and most of the contents are focused on social and behavioral issues related to the evaluation of health promotion interventions. The book’s framework for evaluation (Figure 3) identifies principles related to evaluation in health promotion, recommendations for policymakers and others, issues that need to be resolved, and critical considerations in health promotion evaluation. One of the most important considerations in health promotion research and evaluation is the extent to which the objects of the research or evaluation should be involved in the research or evaluation process. Today, there is wide consensus in the field that meaningful opportunities should be provided for all of those with a direct interest in health promotion initiatives to participate in all the processes, including planning, priority setting, implementation, and evaluation (although there is some debate about the extent to which community participation in all research and evaluation efforts is feasible). A second critical consideration is methodological. In particular, there has been considerable debate in the field regarding the extent to which quantitative or qualitative approaches are preferable. Although most researchers in health promotion agree that qualitative methods are useful and appropriate in research and evaluation in health promotion, depending on the questions to be answered and the context, there is still some debate over whether a qualitative paradigm is preferable to a quantitative one. It is likely that this debate will continue. In any case, there now appears to be wide acceptance of the need to use a broad range of approaches and models for research and evaluation in health promotion, including experiments, although community-based health promotion hardly ever allows experiments to be mounted. There is also growing acceptance of the need to use multiple methods in the same study to triangulate findings (mixed methods designs). As in all community-based research, health promotion research faces the dual challenge of maximizing validity (confident in a study’s results) and reliability (confidence that the study can be replicated). Mixed-methods research designs can help researchers to better assess and to improve validity and reliability. A third critical consideration is the choice of level of measurement. Clearly, the field requires measurement at both individual and collective levels, given that changes to enhance health need to occur at different levels – from the individual to society. However, at this point in time, there is a tendency to rely more on individual measures than aggregate ones, if for no other reason that the former are more common and tested than the latter. If, however, we are to make progress in understanding the collective processes that lead to change we need to put greater emphasis on the development and testing of collective measures, especially given the emphasis on settings-based approaches to health promotion. A fourth critical consideration is the role of culture. Often, minority cultural groups are the most disadvantaged and vulnerable and therefore are most in need of health promotion interventions. However, we have a long way to go in terms of understanding how cultural beliefs and norms operate in a health promotion context. This complicates both the design of research studies and evaluations, and the interpretation of results. In comparison studies that include communities from

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Figure 3 Framework for evaluation. Reproduced from Rootman, I., Goodstadt, M., Hyndman, B., et al., (Eds.), 2001. Evaluation in Health Promotion. Principles and Perspectives. WHO Regional Publications European Series, No. 92. WHO Regional Office for Europe, Copenhagen, p. 530.

different cultures, for example, it can be difficult to translate both interventions and survey instruments in ways that convey equivalent meaning. A fifth and related critical consideration is the relative paucity of research and evaluation of health promotion initiatives in less developed countries. The field needs to do much better than it has so far in building research and evaluation capacity in the southern part of the world. The IUHPE Global Program on Health Promotion Effectiveness, mentioned previously in this article, is one step in the right direction, but it is not sufficient. We need to find more resources for the work and do a much better job than we have to date in building this capacity. Finally, one critical consideration that continues to plague research and evaluation efforts in health promotion is the lack of an integrated, overarching, theoretical framework for health promotion. The health action model and the community empowerment model, described earlier, stand alongside a number of other models, and are therefore illustrative, but do not represent ‘received wisdom’ in the field of health promotion. Perhaps we are doomed to this, because health promotion is an intensely multidisciplinary enterprise, but there is a growing consensus in the field that we need to put

more effort, intelligence, and creativity into developing approaches to theory that integrates our knowledge of health promotion change processes.

Evidence, Effectiveness, and Quality Over the past decade, there has been increasing discussion and use of the concepts of evidence, effectiveness, and quality within health promotion. This is stimulated by the perceived need among people working in the field to better justify health promotion, so the decision makers holding the purse strings will prioritize health promotion. There is also genuine interest among people working in the field to improve what they are doing though the collection and sharing of relevant information. With regard to the concept of evidence, there has been discussion in the field regarding its relevance for health promotion. This concept has various meanings in the different academic disciplines that contribute to health promotion, and the evidence concept cannot be reduced to a single meaningful concept in health promotion. In spite of this, the concept of evidence continues to be used in health promotion in at least a common sense way, to refer to information related to

Health Promotion a particular problem or situation that allows one to assess what is occurring. It is likely that this will continue to be the case for the foreseeable future. The concept of effectiveness, on the other hand, has been used in a much more systematic and sustained manner in health promotion over the past decade. Specifically, there have been a number of regional and international conferences on the topic of effectiveness in health promotion, mostly in developed countries. In addition, there have been several major projects focused on the effectiveness of health promotion, perhaps the best known being the European Commission–sponsored project on health promotion effectiveness undertaken by the IUHPE. This project reviewed evidence on the effectiveness of health promotion that was generated mostly in developed countries. Although it did not provide a clear and specific definition of the concept of effectiveness, it did provide a substantial review of relevant research attesting to the value of health promotion efforts in developed countries in relation to a number of key political (aging, mental health, out-of-school youth), health (heart disease, tobacco, alcohol, and illicit drugs), and social challenges (nutrition, safety), in three different settings (workplace, schools, health-care sector) (IUHPE, 1999). Moreover, it led to the establishment of the IUHPE Global Program on the Effectiveness of Health Promotion.

Summary The reader of this article deserves to come away from it having a succinct grasp of what health promotion is, in the context of public health. Yet that objective eludes the authors, for a number of reasons, almost all of which can be illustrated by an imaginary visit to a health promotion conference. One will listen to talks by, and have discussions with, sociologists, psychologists, physical therapists, nurses, physicians, teachers, among other disciplinary types. Very few have education in health promotion per se, and therefore did not grow up learning a common academic language and culture. Each individual would vary on dimensions of, for example, length and depth of education, degree of social activism and interest in advocacy, devotion to practice, attention to policy making, level of ecological attention from macro to micro, and on extent of professional experience. They would come from all over the world, and their cultures (national, professional, organizational) and daily contexts (work, home, recreation, spiritual) would shade their personal views of health promotion. They could not agree on a common definition of health promotion, except perhaps at the most idealistic level – for example, the WHO definition cited near the beginning of this article – and many would reject even that. Thus health promotion does not occupy a point, but rather a multidimensional space, with rough boundaries that shift constantly. Because such a space cannot be reduced to a point, any effort to define health promotion definitively is futile, and also unnecessary. But though we cannot define it, we can do it, we can discuss it, we can engage in dialog about it. Like other complex ideas, part of its allure is its complexity.

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See also: Alma-Ata and Primary Health Care: An Evolving Story; Disease Prevention: An Overview; Happiness, Health and Altruism; Peoples Health Movement.

References Breslow, L., 1999. From disease prevention to health promotion. J. Am. Med. Assoc. 281, 1030–1033. Butterfoss, F.D., Goodman, R.M., Wandersman, A., 1993. Community coalitions for prevention and health promotion. Health Edu. Res. 8 (3), 315–330. Dooris, M., 2004. Joining up settings for health: a valuable investment for strategic partnerships? Crit. Public Health 14 (1), 37–49. European Network of Health Promoting Workplaces (ENHPW), 2002. The Barcelona Declaration on Developing Good Workplace Health Practice in Europe. European Network of Health Promoting Workplaces, Barcelona, Spain. Freire, P., 1972. Pedagogy of the Oppressed. Penguin, Harmondsworth, UK. Hill, L., 2004. Alcohol health promtoion via mass media: the evidence on (in)effectiveness. In: Eurocare Bridging the Gap Conference Warsaw, Poland, 16–19 June. Illich, I., 1976. Limits to Medicine. Medical Nemesis: The Expropriation of Health. Penguin Books Boyars, London. International Union for Health Promotion Education (IUHPE), 1999. The Evidence of Health Promotion Effectiveness: Shaping Public Health in a New Europe. Parts One and Two. ECSC-EC-EAEC, Brussels and Luxembourg. Kickbusch, I., 2003. The contribution of the World Health Organization to a new public health and health promotion. Am. J. Public Health 93 (3), 383–388. McQueen, D.V., Jones, C.M. (Eds.), 2007. Global Perspectives on Health Promotion Effectiveness. Springer Science and Business Media, New York. Rootman, I., Goodstadt, M., Hyndman, B., et al. (Eds.), 2001. Evaluation in Health Promotion. Principles and Perspectives. WHO Regional Publications European Series, No. 92. WHO Regional Office for Europe, Copenhagen, p. 530. Scriven, A., 2007. Developing local alliance partnerships through community collaboration and participation. In: Lloyd, C.E., Handsley, S., Douglas, J., Earle, S., Spurr, S.M. (Eds.), Policy and Practice in Promoting Public Health. Sage, London, pp. 257–285. Tones, K., Tilford, S., 2004. Health Promotion: Effectiveness, Efficiency and Equity, third ed. Nelson Thornes, Cheltenham, UK. Wallack, L., Dorfman, L., Jernigan, D., Themba, M., 1993. Media Advocacy and Public Health: Power for Prevention. Sage, Newbury Park, CA. Wellings, K., Macdowall, W., 2000. Evaluating mass media approaches to health promotion: a review of methods. Health Edu. 100 (1), 23–32. WHO, 1995. http://www.who.int/school_youth_health/gshi/hps/en/index.html.

Further Reading Barry, M., Jenkins, M., 2007. Implementing Mental Health Promotion. Churchill Livingstone/Elsevier, London. Crosby, R.A., DiClemente, R.J., Salazar, R.F., 2006. Research Methods in Health Promotion. Jossey-Bass, San Francisco, CA. Earle, S., Lloyd, C.E., Sidell, M., Spurr, S., 2007. Theory and Research in Promoting Public Health. Sage, London. Herrman, H., Saxena, S., Moodie, R. (Eds.), 2005. Promoting Mental Health: Concepts, Emerging Evidence, Practice. WHO, Geneva, Switzerland. Kickbusch, I., 2007. Health promotion – not a tree but a rhizome. In: O’Neill, M., Pederson, A., Dupere, S., Rootman, I. (Eds.), Health Promotion in Canada: Critical Perspectives. Canadian Scholars’ Press, Toronto, pp. 363–366. McQueen, D., Kickbusch, I., 2007. Health and Modernity: The Role of Theory in Health Promotion. Springer Science and Business Media, New York. Mittelmark, M.B., Wise, M., Nam, E.W., et al., 1997. Mapping national capacity to engage in health promotion: overview of issues and approaches. Health Promot. Int. 21 (Suppl. 1), 91–98. Moodie, R., Hulme, A. (Eds.), 2004. Hands-on Health Promotion. IP Communications, Melbourne. O’Neill, M., Pederson, A., Dupere, S., Rootman, I. (Eds.), 2007. Health Promotion in Canada: Critical Perspectives. Canadian Scholars’ Press, Toronto. Scriven, A., Garman, S., 2005. Promoting Health: Global Perspectives. Palgrave, Basingstoke, UK. Tones, K., Green, J., 2004. Health Promotion: Planning and Strategies. Sage, London.

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Relevant Websites http://www.who.int/healthpromotion/conferences/previous/adelaide/en/index.html – Adelaide Recommendation on Healthy Public Policy. http://www.healthpromotionjournal.com – American Journal of Health Promotion. http://www.whoint/healthpromotion/conferences/6gchp/bangkok_charter/en/index.html – Bangkok Charter for Health Promotion in a Globalized World. http://www.cdc.gov/cochp/about.htm – CDC’s Coordinating Centre for Health Promotion. http://www.utoronto.ca/chp – Centre for Health Promotion, University of Toronto. http://www.socialjustice.org – Centre for Social Justice. http://www.vichealth.vic.gov.au/cochrane – Cochrane Health Promotion and Public Health Field. http://www.cmhealth.org – Commission on Macroeconomics and Health. http://www.eurohealthnet.org – EuroHealthNet. http://www.hpmulti.net – European Multilingual Thesaurus on Health Promotion. http://www.euro.who.int/ENHPS – European Network of Health Promoting Schools. http://www.enwhp.org – European Network for Workplace Health Promotion. http://www.euteach.com – European Training in Effective Adolescent Care and Health. http://www.euro.who.int/prisons – Health in Prisons Project. http://www.phs.ki.se/hprin – Health Promotion Research Internet Network. http://www.american.edu/academic.depts/cas/health/iihp/index.html – International Institute for Health Promotion.

http://www.iseqh.org – International Society for Equity in Health. http://www.iuhpe.org – International Union for Health Promotion and Education (IUHPE). http://www.ldb.org/iuhpe/jakdec.htm – Jakarta Declaration on Health Promotion into the 21st Century, 1997. http://www.who.int/healthpromotion/conferences/previous/mexico/statement/en/index. html – Mexico Ministerial Statement for the Promotion of Health. http://www.ldb.org/iuhpe/ottawa.htm – Ottawa Charter for Health Promotion, 1986. http://www.publications.paho.org – PAHO/WHO Online Bookstore. http://www.healthpromotingschools.co.uk – Scottish National Health Promoting Schools. http://www.euro.who.int/document/e82490.pdf – Standards for Health Promoting Hospitals. http://www.ldb.org/iuhpe/sundsval.htm – Sundsvall Statement on Supportive Environments for Health, 1991. http://www.hph-hc.cc – WHO Collaborating Centre for Health Promotion in Hospitals and Health Care. http://www.who.int/topics/health_promotion/en – WHO Geneva Health Promotion. http://www.who.int/healthpromotion/conferences/previous/ottawa/en/index.html – World Health Organization. http://www.ldb.org/vl/top/glossary.pdf – WHO Health Promotion Glossary. http://www.ldb.org/vl/index.htm – WWW Virtual Library: Public Health.

Health Surveys Jennifer H Madans, National Center for Health Statistics, Hyattsville, MD, USA Ó 2017 Elsevier Inc. All rights reserved.

Information on health status, risk factors, health insurance, and health-care utilization is used to plan, conduct, and evaluate public health programs, to inform policies, regulations, and legislation, and to conduct research to better understand the determinants and consequences of health and health care. Much of this information is collected through health surveys. Although some surveys focus on only one aspect of health, others are multipurpose and attempt to gather at least some information on the range of factors that define health so that the interconnections among these factors can be studied. Although surveys may differ in content, sample design and data collection methodologies, the general issues that guide survey development apply to most health surveys.

How to Measure Health Health is as much a social as a biologic concept. There is no question that the biologic aspects of health are of great importance to individuals and to society, but how these objective aspects of health affect social functioning is perhaps even more important. In addition, although the biologic aspects of health lend themselves to objective measures, the social aspects present a much greater challenge. Characteristics of the environment and the individual affect how objective health is perceived and reported. The same objective health states can have very different impacts on an individual’s ability to function and perform social roles. Health is affected by socioeconomic factors and in turn affects those factors. Some health surveys attempt to address all aspects of health; others focus in greater depth on only one aspect. The universes from which the samples are drawn, the methods used to collect the information, and the health and health-related information obtained will vary depending on the specific objectives of the survey.

Content of Health Surveys The information collected on health surveys can be divided into three general types: (1) health status; (2) determinants or correlates of health and risks to health, including health behaviors; and (3) health-care utilization. In addition, information is also collected on demographic and socioeconomic factors that affect health. Each of these subjects is complex and multidimensional. Health status has many components, which range from physiologic structure and function to the ability to participate in a range of social activities (sometimes referred to as health related quality of life or well being). Risk factors also are varied and include exposure to environmental contaminants, economic and social characteristics, and individual behaviors. Health care can affect the incidence, development, and impact of health conditions. To obtain information on all of these topics, a range of survey mechanisms is used, but each mechanism is subject to known, and often uncontrollable,

International Encyclopedia of Public Health, 2nd edition, Volume 3

measurement error. It is usually necessary to piece together information from different sources to get a full picture of health.

Conditions and Diseases Health status is sometimes equated with whether or not one or more physical, psychological, or mental diseases or conditions is present. A variety of approaches can be used to measure disease incidence and prevalence, including reporting of a diagnosis by a health-care provider, reporting of symptoms (if an appropriate symptom battery exists), medication use, and direct diagnostic testing. Additional information of interest related to conditions includes date of onset, the use of health-care services, and the impact of the condition on the individual’s ability to function. Condition severity is often inferred from the type of medications or health-care services used or the nature of the functional impact of the condition. Information on conditions that is obtained through interviews reflects an individual’s knowledge of his or her health status, which in turn is a function of the receipt of appropriate health care and adequate communication between a health-care professional and a patient. This is particularly true when condition prevalence is based on having received a diagnosis from a health-care professional. Surveys that include direct physical exams, however, have the advantage of allowing for the measurement of previously undiagnosed conditions. Interview surveys provide a major source of information on conditions and disease. One issue that must be addressed is the number of conditions to be included in the questionnaire. Condition checklists can be used to obtain information on a great number of conditions, but in most cases, only a minimal amount of information on any given condition is collected. In addition, long checklists are difficult to administer and may result in reporting errors. However, the use of comprehensive lists does allow for the ascertainment of comorbidities. An alternative is to obtain more detailed information on a select group of conditions. Criteria such as the prevalence of the condition or the potential impact on the individual or the health-care system are used to select target conditions such as heart disease, diabetes, cancer, pulmonary diseases, depression, and arthritis. Limiting the focus to more serious conditions which result in the receipt of medical care or in missing days of work or school, can result in improved data validity and reliability. However, this approach is more appropriate when ill health is primarily the result of acute conditions for which onset is clear and there is a closer association between the condition and the care-seeking behavior. As a result of the ‘epidemiologic transition,’ acute conditions have given way to chronic conditions as the major sources of morbidity. Chronic conditions are more difficult to diagnose, and longer periods are spent in the disease state both prior to and after diagnosis. This complicates the collection of self-

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reported condition information because respondents have difficulty recalling the onset of symptoms or diagnoses made many years prior to the survey. Requiring that health-care use or activity limitation be present when identifying conditions also makes it difficult to investigate social correlates of health status, since the definition incorporates a social dimension. Access to sick leave or affordable medical care may be limited by social or economic factors. Persons who do not demonstrate the required behaviors because of these social factors will not be considered as having a health condition. This can result in bias if the data are used to measure the condition’s prevalence or impact or to investigate disparities across subgroups. Examination surveys provide a complementary mechanism for obtaining information on conditions. The results of the physical exam, and of blood and other tests, can be used to objectively measure health status. For example, information on diagnosed hypertension or diabetes can be obtained from an interview, but information on undiagnosed conditions must be obtained from objective tests. However, if a condition is controlled by medication, the objective test will not provide information on diagnosed cases without accompanying interview or medical record data. Information on diagnosed and undiagnosed conditions is needed for a complete accounting of the health condition. Surveys of providers (hospitals, office-based private physicians, managed-care organizations, hospital outpatient departments, emergency departments, ambulatory surgery centers, and long-term care facilities) are generally used to obtain information on health-care utilization and the health-care system, but information in the administrative and medical record can be used to study conditions that are associated with medical care. Provider-based surveys are particularly important for obtaining information on rare conditions that would not be picked up in population-based surveys. Although information is collected on all conditions for which health care is obtained, the nature of the information available is limited to that which would routinely be obtained from medical records. Information on the condition can be abstracted from the record and then coded, or the codes can be taken from summaries or billing records. The amount of information available affects the accuracy with which codes can be assigned. Payment considerations can affect what is entered into the record and the coding process. These constraints need to be considered when analyzing this type of data. In addition, the event (e.g., the discharge), rather than the person, is the unit of analysis. For example, although it is possible to estimate the number of hospital stays associated with heart attack from a survey of hospital stays, it is not possible to estimate the number of persons having had a heart attack even if one could assume that all persons with a heart attack were admitted to the hospital. An enhancement to health-care surveys would be to follow patients after the health-care encounter. The development and adoption of electronic health records has the potential of changing how provider-based surveys are conducted. Currently, information is usually obtained from discharge summaries or billing records. If more detailed information is needed, it is necessary to abstract information from

the medical record, a method that is costly and subject to bias, as information is not entered into records in a structured and standardized way. Electronic health records have the potential not only to facilitate the retrieval of information but also to standardize the information made available, thus improving the quality of that information. Cause of death statistics obtained from vital registration systems also provide essential information on medical conditions. Although not error free, a great deal of effort is put forth to standardize the collection and coding of cause of death. International standards (WHO, 2004) have been developed which provide coding rules and specifications, and these are updated periodically to reflect advances in medical science.

Measuring Functioning and Disability Physical, cognitive, emotional, and social functioning are important components of health status. Although disease states are more closely related to the biologic aspects of health, functioning is dependent on both the biologic and social realms. Information on functional status can be ascertained through objective tests but is most often obtained through direct reporting by the individual or a proxy. Information on functional status encompasses a wide range of activities from the very basic such as raising an arm to the more complex such as working and going to school. Obtaining information on functioning is complicated by the fact that performance is affected not only by physiologic abilities but also by the environment (which includes the physical environment, the use of assistive devices and governmental policies). A person’s ability to walk may be impaired by a condition that leads to weakened muscles, but with the use of braces or a wheelchair, along with appropriate accommodations in the physical environment (e.g., ramps), that individual is mobile and able to carry out appropriate social roles. For some purposes, information is needed on functional ability without the use of assistance of any type. In other cases, functioning ability as measured by usual performance is important. Although functional limitations in a given domain can result from a range of impairments and conditions and it is not necessary to know the specific causes to evaluate functional status, information on the conditions causing the limitation is often collected. This information is needed to fully understand causal processes and to plan targeted interventions focused on prevention and accommodation. Age at onset and changes in functioning ability over time are also often used to characterize functional status. Although the concept of functioning is central to health, the measurement of functioning presents complex problems for data collecting. Since functioning involves all aspects of life, obtaining complete information on functioning would require an extensive effort to collect data. In addition, since functioning results from the interaction between abilities and the environment, a full evaluation would require independent documentation of the component parts. Following good survey practices, specific questions would be needed to assure standardized responses. However, no health survey is comprehensive enough to obtain all the necessary

Health Surveys information. As a result, information is usually collected on a limited number of functional domains using questions that are general rather than specific in nature and that use unstated rather than explicit standards against which respondents compare their own functioning. The less explicit the standard, the more likely the response will be affected by external factors and the less likely that the data will be comparable across population groups. For example, no explicit standard is provided by a question that asks subjects if they are limited in the kind or amount of work they can do. Responses to this question will be affected by the kind of work that the individual thinks he or she should be doing as defined by his or her own expectations and by the requirements set by government agencies such as disability programs as well as by more objective states of health. This is less of a problem if one is interested in monitoring the impact of health on work. However, it is much more of a problem if the aim is to understand and monitor a more standardized measure of functioning. As a result of these complexities, a large number of questionnaire batteries have been developed to measure functioning. Some use only a few questions, focus on the more complex social roles, and do not differentiate between different aspects of functioning (physical, cognitive, emotional, or behavioral). Others are quite lengthy and obtain detailed information on a wide range of activities both with and without assistance. Survey data on functioning are used to study disability from a policy and programmatic perspective. Disability is an umbrella term that encompasses physiological impairments; limitations in physical, cognitive, mental, and psychological functioning; and restrictions in the ability to participate in daily life. This requires information on characteristics of the individual but also on characteristics of the environment and the interaction between the two. Historically, statistics on disability have been a function of the specific conceptual definition used and the way the concepts were operationalized in the data collection process. As a result, disability statistics have not been comparable across time, place, or population subgroup or easily interpretable. Recent work has focused on clarifying the various aspects of disability (including aspects of functioning, as previously mentioned) and developing standard data collection methods that will produce a range of statistics that can be used for different purposes. Many health surveys are limited to the noninstitutionalized population and therefore do not include those segments of the population in poorest health or with the highest level of functional limitations: those in long-term care settings. Special studies of these populations can be carried out, and there should be some attempt to combine results from the noninstitutionalized and long-term care populations. Changes in the delivery of long-term care with the expansion of transitional establishments have made this an even more important issue for survey designers.

Overall Health Status and Summary Measures of Health As previously noted, health status is a multidimensional concept. This complex construct requires multiple indicators and methodologies for adequate measurement. However,

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there is a strong desire on the part of policymakers and researchers for an overall measure of health in order to more easily characterize and monitor the health status of a population and for use in cost–benefit and cost-effectiveness analyses. There is also increasing interest in developing basic health status indicators comparable to the economic indicators currently in use. These indicators would be used to monitor the effects of public policy and to identify areas in which interventions are needed. An overall health measure is very appealing in this context. Such a measure could take a variety of forms. A single question can be used to obtain information on overall health status. An example of such a question is the request for the respondent to rate his or her own health or the health of another person as excellent, very good, good, fair, or poor. Respondent-assessed general health status is a popular summary indicator of health. This measure has been shown to be highly correlated with other measures of health status and is predictive of mortality and admission to long-term care facilities. However, this measure also has limitations when used to monitor change over time, one of the primary uses of health status indicators. The means by which individuals evaluate the various aspects of health have been shown to be affected by contextual parameters. Implicit in selfperceived health status is the individual’s evaluation of his or her health status against some unstated standard. Societal norms act to define the standard, but the norms and the standards change in response to a variety of conditions and can change over time. For example, another measure of overall health, reported limitation of activity, has been shown to be affected by the criteria used by government agencies in determining eligibility for disability benefits, which influence how individuals evaluate their health. Thus, observed changes in the indicator may not reflect changes in underlying health status but rather reflect changes in broader societal trends that affect how individuals evaluate their health. Alternatively, summary measures can be constructed by using information on diagnosis of a disease or condition, symptoms such as pain or fatigue, and physical, cognitive, emotional, and social functioning. Health surveys that collect information on the widest possible range of health-related factors offer the opportunity to develop multiple summary measures that can be used for different purposes. Measures of health states can also be combined with measures of life expectancy to create measures of healthy life expectancy. Examples of this kind of measure include disability-free life years, disability adjusted life years, healthy life expectancy, and years of healthy life. Constructs such as these combine measures of the different aspects of health into a single number by using a conceptual model that views health as a continuum. The health states are assigned weights that represent the values that either society as a whole or individuals place on that health status. Various methods have been used to determine the values of the different health states. These measures are used to modify duration of life and may be multiplied by the number of years in that state.

Determinants of Health Health surveys generally include measures of risk factors, health behaviors, and non-health determinants or correlates

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of health such as socioeconomic status. The range of measures that can be included is wide and varies by survey. Age, gender, and race/ethnicity are the basic demographic variables that are included in health surveys. Socioeconomic determinants of health include education, income, geographic region, and urbanicity of residence. Strong health differentials are found across these variables, and public programs are designed to eliminate these health disparities. However, the relationship between these measures and health is often complex. Social factors can act as causal agents or they can be affected by health. For example, low income can result in poorer health status, but poor health status can also affect earning capability and income. In order to identify causal relationships between determinants and outcomes, longitudinal designs are needed. The causal pathways are more easily teased apart if health surveys can include a broader array of potential determinants of health (biological, psychological, and social). Tobacco use, alcohol use, diet, and physical exercise are common health behaviors that are included in health surveys. As in the case of health status, these concepts present difficult measurement challenges. Obtaining valid information on behaviors such as diet, smoking, and exercise requires significant survey time. Diet is particularly difficult to capture in the survey context. Respondents have difficulty remembering what they ate and in what quantities. The information obtained would then be linked to external data bases that contain the nutritional content of foods. These databases are expensive and time consuming to develop. There is also a tendency for respondents to underreport negative behaviors such as smoking, and this is even more of a problem for surveys that obtain information on illegal activities such as drug use. Survey procedures have been developed to improve reporting of health behaviors such as maximizing privacy to encourage accurate reporting and developing aids to enhance memory.

Health Care Utilization The use of the health-care system is a major dimension of health. Information on utilization and related characteristics such as health insurance are collected from person-based surveys and through surveys of administrative records. In person-based surveys, respondents are asked to recall the number of contacts they have had with various health-care providers and the nature of the provider and the contact. Information on the receipt of particular services, such as immunizations or mammography, is also obtained. This is often difficult for respondents so the reporting of contacts with the health-care system drops off considerably when the recall period extends beyond 2 weeks. To address this recall problem, some surveys ask respondents to keep detailed diaries of their medical care contacts, obtain the name of the provider, and then contact the providers (with the subject’s permission) to verify the self-reported information. Information on utilization can also be obtained from surveys of providers. More accurate information on the nature of the contact, including the reason for the contact and the services provided, can be obtained in this way. Surveys of providers can also address the structure of the health-care system itself and how the characteristics of the system affect access to care and the cost of care.

The ability to assess quality of care is becoming more and more important. Utilization data can address this issue, but there are serious methodological challenges. Many data systems do not contain the needed information or enough specificity to be able to address quality issues. Moreover, there are many differing opinions on how best to measure quality. Work in this area is progressing and data systems are attempting to collect information that will address the issue of quality and appropriateness of care.

General Design Issues Sample Design Health surveys either can obtain information directly from individuals (the subject or an informant) or can rely on administrative records. A wide range of sampling methodologies, sampling frames, and data collection strategies are used depending on survey objectives and the characteristics of the area in which the survey is done. Countries that have universal health care with centralized administrative systems can use designs that would be inappropriate in countries with less well-developed or decentralized health-care systems. The simplest sampling scheme is a simple random sample of a population obtained from a complete and up-to-date list such as from a census of the population or a centralized health-care system. In the case of surveys of persons, if such lists do not exist, another way to identify members of the population of interest is needed. In order to be able to report information on subpopulations of interest as defined by geography and/ or demographic, socioeconomic, or health characteristics, designs often include oversampling of these groups to provide adequate sample size for analysis. It is often necessary to incorporate screening into designs to achieve this objective. Sample selection can be related to mode of data collection (see section Mode of Data Collection). If interviewing is to be done in-person, area sampling can be used with clustering to reduce costs. If interviewing is to be done by phone, sampling is often done through random-digit dialing. Sample for mail surveys, in-person surveys and to some extent for phone surveys use address listing to select a sample. Internet panels use a variety of methods to identify participants. Many health surveys limit their population of interest. For example, it is common for health surveys to only include the noninstitutionalized population. The dramatic differences in the living conditions of the institutionalized and noninstitutionalized populations make it difficult to design survey methodologies that would apply in all situations. The military population is also often excluded from general health surveys. The scope of the universe needs to be clearly defined, especially if populations that differ in their health status are omitted – such as persons residing in nursing homes. When obtaining information directly from the population is inefficient or would result in either poor data quality or high costs or both, an alternative is to sample from existing records that were created for other purposes. Information on health-care utilization for specific conditions is more easily obtained from hospital or provider records than from a population sample, given the relative rarity of the phenomena of interest. The vital statistics system can also be considered

Health Surveys a census of administrative/legal records for the purpose of describing the health of the population. Administrative systems, in addition to providing basic health information, are often used as sampling frames for population-based surveys. They are very attractive for this purpose, as they eliminate the need to identify members of the population who have the characteristics of interest.

Longitudinal Designs Most health surveys use cross-sectional designs which provide data for the calculation of population estimates and are most appropriate for monitoring changes in health over time. A cross-sectional design is not appropriate for investigating causal patterns or for documenting transition probabilities from one health state to another where change at the individual level needs to be measured. Longitudinal studies are expensive and more complicated to field but are needed to study causal patterns and transitions. A less expensive alternative is to transform cross-sectional studies into longitudinal studies by linking information from mortality or health-care-provider records to the survey data. Cross-sectional surveys also can form the baseline cohorts for future active longitudinal follow-ups. These longitudinal activities present extensive opportunities for understanding the relationship between risk factors and disease outcome, as well as the natural history of disease.

Mode of Data Collection Information can be obtained either by mail, phone, web, inperson interview, or by some combination of modes, depending on the ability of the researchers to contact the population using these means. The latter modes can also incorporate computer-assisted technologies. Computer-assisted telephone and personal interviewing have allowed for increasing levels of complexity of survey administration. Errors associated with keying and coding have been replaced by errors associated with programming. The use of these technologies has resulted in the need for longer lead times prior to fielding a study but has reduced the time from the end of data collection to the availability of results. Each mode of data collection has strengths and weaknesses. More complex questions can be used for intervieweradministered in-person interviewing, since the interviewer is available to provide standard explanations and can use the social interaction aspects of the interview to establish a relationship with the respondent. These surveys are the most expensive on a per case basis, and when the subject matter is sensitive, the presence of the interviewer can bias responses (although this can be alleviated by the use of computer-assisted techniques in which the respondent listens to the question on a headset and enters responses directly into the computer). Mail, random digit-dialing (RDD) phone and Internet surveys usually use simpler. A growing problem for RDD surveys is the increasing prevalence of households with only cell phones which increases the cost of the survey and has been associated with lower response rates. There are also concerns that respondents might be participating while driving. Combining different approaches to selecting the sample and to conducting

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interviews is becoming more common. Internet panels are also increasing in popularity but generally the samples are not probability based and even when they are, response rates are extremely low. Work is underway to improve the representativeness of web panels. One path is to combine web panels with more traditional methods or to benchmark the web panels to high quality surveys. This would require a more integrated approach to survey design.

Selection of Respondents In general, obtaining information directly from the survey subject provides more reliable and valid health data. However, this is not universally true and depends on the nature of the information sought and the characteristics of the subject. For example, although accurate information on risk behaviors among adolescents can probably only be obtained from the adolescent in a private environment, adolescents are not good reporters of health-care utilization or household income. Even more problematic is the situation in which a health condition does not permit a subject to respond for himself or herself. Eliminating the subject from the survey would seriously bias the results, so a proxy respondent is often used. Although necessary, the use of proxy respondents does introduce a source of error into health surveys, particularly longitudinal surveys. Obtaining information on the relationship of the proxy to the subject, as well as the conditions leading to the use of a proxy, can reduce this error. There are other areas in which the subject is not a good reporter of the needed information. For example, information on the characteristics of an insurance plan is usually better obtained from the insurer rather than the person holding the insurance. Finally, reliable assessment of specific types of morbidity, risk factors, and mortality requires direct measurement through physical examination or access to administrative records from health-care providers.

Question Development A major advancement has been the development and application of cognitive methods for questionnaire construction. Drawing from the field of cognitive psychology, cognitive research laboratories have been established and can investigate how respondents perceive and answer questions. Another fruitful area of research involves studying the behavior of both interviewers and respondents within the social context of the interview situation. A more structured approach to the errors found in health surveys can enhance data quality. The results of such research will lead to improved design that reduces error but can also lead to ways to adjust for known errors in the analysis and interpretation of results.

Data Linkage The increase in electronic as opposed to paper files has greatly expanded the opportunities for linking data from various sources. Ecological or contextual information about the geographic area in which survey respondents reside can now be linked to the survey data. This has the advantage of allowing researchers to incorporate variables defined for different units of analysis into their investigations of

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complex problems. Survey data can also be augmented with administrative data from mortality files and from health-care providers. In addition to enhancing the amount of information available for analysis and reducing survey costs, this often leads to data of improved quality. When survey data are linked to other sources of information on the respondent, permission to do the link must be obtained from the sample person. This is often required by research ethics review boards and by the organization responsible for the data to be linked, especially if it is considered private data (e.g., medical records). Concerns about privacy and confidentiality have made some respondents unwilling to allow this linkage and to provide the information to facilitate the link. Persons who do not allow the linkage become nonrespondents on the linkage information. It is possible to use standard techniques to adjust for nonresponse if the rates are not too high, but as rates increase, the linked data will be of limited usefulness.

‘Big Data’ and Health Surveys As health surveys become more expensive and response rates decline, alternative sources of information on health are sought. The growing use of web panels is one example of this trend. Just as the information obtained from web panels may not be generalizable to the population of interest, information obtained from ‘big data’ maybe not be representative. The definition of ‘big data’ is still evolving but in addition to involving very large numbers of records, ‘big data’ is usually characterized as unstructured. Whereas designers of health surveys have a lot of control over survey respondents and content and collect data in a standard way, web based ‘big data’ are collected for purposes other than to describe the characteristics of the population and little is known about how the ways in which the data are obtained could affect the quality and representativeness of the data. One way to take advantage of ‘big data’ is to combine it in some way, or benchmark it to, survey data that is more structured and about which more is known. Similar approaches are being undertaken for combining representative survey data with web based panels. Work in these areas if just beginning but could grow to be major sources of information on health in the future.

International Comparability There is great interest in comparing health status and healthcare systems across countries. Variation in disease rates across countries can be used to understand disease etiology. Policymakers and directors of health programs can use the experiences of other countries to devise strategies to improve health status. Perhaps most important, the health status of populations in other countries provides a standard by which domestic characteristics can be evaluated. However, there are many reasons for observed international variation in health, and many of them do not reflect true differences in health. As already discussed, health is a complex phenomenon with a large social component. International comparisons often reflect cultural differences rather than objective measures of health. These cultural differences can relate to social, economic,

or environmental factors but also relate to basic differences in how subjects respond to questions. Work is under way to identify ways to design data collections that minimize the influence of cultural factors that are unrelated to the intent of the data collection.

Informed Consent, Privacy, and Confidentiality For ethical reasons and in order to obtain high response rates and valid information, most health surveys closely guard the information provided by respondents. In some cases, the requirement to protect confidentiality is legislatively mandated. This is particularly important for health surveys, given the personal nature of the information collected. Confidentiality is protected by not releasing data that could identify a respondent. Most survey sponsors subject files that are to be released for public use to rigorous disclosure review, but the risk for inadvertent disclosure has increased in recent years. It is no longer necessary to have access to large mainframe computers to use survey data that are now provided on the Internet. In addition, databases that are not related to the survey data but can be used to identify individuals in the survey data files are more available and more easily accessible. It is the potential linking of survey data to these external databases that increases the risk of disclosure, and the risk increases with the amount of information that is available. The ability to link external data to survey responses presents an analytic breakthrough, as the utility of survey data can be greatly increased through the appropriate linkages; however, this ability also greatly increases the risk of disclosure, especially when the linkages are done in an uncontrolled and inappropriate way. The increased sensitivity to issues of privacy in many countries, especially as related to health care, is affecting how confidential data are being protected. There has been a decrease in the amount of data that can be released as public use files, especially data that are collected by national statistical offices under strong promises of confidentiality. Other mechanisms are being developed so that access to data can be maximized while protecting confidentiality. The use of special use agreements, licensing, and research data centers are examples of these approaches.

See also: Biostatistics; Children and Adolescents, Measuring the Quality of Life of; International Classification Systems for Health; Systematic Reviews in Public Health.

References World Health Organization, 2004. International Statistical Classification of Diseases and Related Health Problems, second ed. WHO, Geneva, Switzerland. 10th revision.

Further Reading Biemer, P.P., Groves, R.M., Hyberg, L., Mathiowetz, N., Sudman, S., 1991. Measurement Errors in Surveys. Wiley, New York. Bradburn, N.M., Sudman, S., 1979. Improving Interview Method and Questionnaire Design. Jossey-Bass, San Francisco, CA.

Health Surveys Cannel, C.F., Monquis, K.H., Launent, A., 1977. A Summary of Studies of Interviewing Methodology. Vital and Health Statistics, Washington, DC (Series 1, No. 69). Fowler, F.J., 1995. Improving Survey Questions. Sage, Thousand Oaks, CA. Groves, R.M., Couper, M.P., 1998. Nonresponse in Household Interview Surveys. Wiley, New York. Groves, R.M., Fowler, F.J., Couper, M.P., Singer, E., Tourangeau, R., 2004. Survey Methodology. Wiley, New York. Korn, E.L., Graubard, B.I., 1999. Analysis of Health Surveys. Wiley, New York. Lessler, J.T., Kalsbeek, W.T., 1992. Nonsampling Error in Surveys. Wiley, New York. Madans, J.H., Webster, K., 2015. Health surveys. In: Wright, J. (Ed.), International Encyclopedia of the Social and Behavioral Sciences, second ed. Elsevier, Amsterdam, The Netherlands. Madans, J.H., Cohen, S., 2005. Health surveys. In: Health Statistics in the 21st Century: Implications for Health Policy and Practice. Oxford University Press, London/New York.

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Madans, J.H., Miller, K., Maitland, A., Willis, G. (Eds.), 2011. Question Evaluation Methods: Contributing to the Science of Data Quality. John Wiley & Sons, Hoboken, NJ. Sirken, M.D., Herrmann, D.J., Schecter, S., Tourangeau, R., 1999. Cognition and Survey Research. Wiley, New York.

Relevant Website http://www.cdc.gov/nchs/ – National Center for Health Statistics (last accessed 07.06.16.).

Health Systems of Australia and New Zealand Diana MS Hetzel, John D Glover, and Sarah K McDonald, Public Health Information Development Unit (PHIDU), Torrens University Australia, Adelaide, SA, Australia Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by John D. Glover, Diana M.S. Hetzel, Sarah K. Tennant, volume 1, pp. 255–267, Ó 2008, Elsevier Inc.

Australia Introduction Geography

Australia is the world’s largest island and smallest continent. Geographically, it lies in the southern hemisphere surrounded by the Pacific, Indian, and Southern oceans and is separated from the Asian continent by the Arafura and Timor seas (Figure 1). Australia’s landmass stretches over 7 700 000 km2 and is contained by 25 760 km of coastline. Australia is the driest inhabited continent and features a wide range of climatic zones, from tropical regions in the north, through its arid interior, to the temperate areas of the south. The majority of people live along the southeastern coastline.

Demography

Aboriginal and Torres Strait Islander peoples have been the original inhabitants for over 40 000 years. There are no

accurate data regarding the size of their populations before European settlement in the late 1700s, although a plausible estimate is of 750 000–800 000 people, divided into about 500 different cultural groups (Madden and Jackson Pulver, 2009). However, following colonization, the size of the Indigenous population decreased rapidly as a result of introduced diseases, violent dispossession of land, and repressive disruption of culture and communities; and this decline continued well into the twentieth century (Australian Bureau of Statistics (ABS), 2007). Today, Australia is home to an estimated 23.2 million people (ABS, 2013a). The population represents a great diversity of ethnic backgrounds, resulting from waves of migration from many countries over the last two centuries. In 2013, people born overseas made up over one-quarter (27.7%) of the total population (ABS, 2013b). In 2011, Australia’s Indigenous population was estimated to be 3.0% of the total population.

Indian Ocean Northern Territory Pacific Ocean Queensland Western Australia South Australia

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Australian Capital Territory

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Map of Australia.

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Health Systems of Australia and New Zealand The population is contained in six states, two major mainland territories, and other minor offshore territories. The states are New South Wales, Victoria, Queensland, South Australia, Western Australia, and Tasmania. The two mainland territories are the Northern Territory and the Australian Capital Territory. About 64% of the total population lives in the capital cities of the states and territories. Remarkably, 86.1% of the total land area is occupied by only 2.9% of the population (Figure 2). Remote areas of Australia are disproportionately populated by Indigenous Australians, with almost half (45%) of all people in very remote areas and 16% in remote areas being Indigenous compared with 3.0% Indigenous representation in the total population (ABS, 2013c). This distribution presents challenges in ensuring appropriate access for nonmetropolitan communities to preventive and treatment-based health services. Australia’s population is aging because of continued low fertility, and increased life expectancy, leading to proportionally more older people in the population. However, the Indigenous population is relatively young, with a median age of 22 years, compared with 36 years for the non-Indigenous population (Figure 3; ABS, 2014). It is predicted that the number of people living into older age will increase, together with the average age of the population. As life expectancy rises, the chance of living long enough to suffer from age-related diseases and disability also increases; and aging and population growth are estimated to account for 23% and 21%, respectively, of the projected increase in total expenditure on health and residential aged care over the period 2003–2033 (Goss, 2008).

Economy and Government

Australia is a prosperous nation with an established capitalist economy. It has an internationally high standard of living and a gross domestic product (GDP) per capita above the average for the Organisation for Economic Co-operation and Development (OECD). However, significant socioeconomic inequalities remain across the population, particularly for Indigenous peoples and other disadvantaged Australians. The Commonwealth of Australia is a constitutional monarchy with a federal system of government, within which there are four divisions: Commonwealth (federal), state, territory, and local. As such, the formal powers of the Commonwealth Parliament are limited to areas of national importance such as trade and commerce, taxation, foreign relations, defense, immigration, and quarantine. However, constitutional amendments, commonwealth-state agreements, and the use of grants to the states and territories have seen the Commonwealth gain influence in regard to other areas including industrial relations, financial regulation, health, and education (ABS, 2007). The overlapping of certain fiscal and functional responsibilities results in regular disagreement between the Commonwealth and the states and territories, especially in the funding and administration of the health-care sector (Healy et al., 2006).

Health of Australians Historical Trends

A substantial decline in mortality in Australia occurred during the twentieth century, with a major improvement in life

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Population density, Australia, 2001.

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Indigenous females - AUSTRALIA

20

Figure 3 Age structures for the Indigenous and non-Indigenous populations, Australia, 2011. Source: Public Health Information development unit, University of Adelaide.

Deaths per 100 000 population 700 600 500 400 Circulatory diseases 300 Respiratory diseases 200 Cancer 100 Injury 0 1900

Infectious diseases 1910

1920

1930

1940

1950

1960

1970

1980

1990

2000

Year Note: Age-standardized to the population at 30 June 1991. Source: AIHW National Mortality Database.

Figure 4

Death rates by major causes, Australia, 1907–98.

expectancy. A ‘health transition’ occurred, from a pattern of high mortality from infectious diseases to one of lower overall mortality from noncommunicable diseases and injury (Figure 4). From 1951, trends in death rates from major causes were evident, with the rise and partial fall of two ‘epidemics,’

coronary heart disease and stroke, and lung cancer (Hetzel, 2001). However, for Indigenous peoples, the picture was significantly worse. In the late 1990s, the life expectancy at birth of Indigenous Australians reflected life expectancies that were

Health Systems of Australia and New Zealand

473

a 100 years behind those for non-Indigenous people (Hetzel, 2001).

and injury for the Australian population as a whole (about 80%) and for particular subgroups (Mathers et al., 2000).

Current Health Status

The System to Address Indigenous Health in Australia

Today, the overall Australian population is one of the healthiest when compared internationally using indicators such as life expectancy, birth and death rates, incidence of disease, and self-perceptions of health status. Australian life expectancy at birth, for example, is among the highest worldwide; and the infant mortality rate was 3.3 deaths per 1000 live births in 2012, a decrease on the rate in 2011 (3.8 infant deaths per 1000 live births) (ABS, 2013e). Infant mortality rates in the Indigenous population are higher than the equivalent rates in the non-Indigenous population, although there has been a significant closing of this gap in recent years (Australian Institute of Health and Welfare (AIHW), 2014a). In 2009, the overall mortality rate in Australia was among the lowest of all OECD countries, at 687 deaths per 100 000 population, second only to Japan (613 deaths per 100 000 population) (AIHW, 2014). In the two decades since 1990, Australia has seen its ranking among OECD countries also improve greatly for colon cancer deaths (from 23rd to 7th) and chronic obstructive pulmonary disease deaths (from 27th to 16th) (AIHW, 2012). Australia’s change in ranking from 1990 to 2009 also improved for deaths due to lung cancer (16th to 10th), coronary heart disease (23rd to 18th), stroke (13th to 8th), breast cancer (15th to 12th), and suicide (14th to 11th) (AIHW, 2014a). Smoking rates have continued to fall, with the ranking improving from middle third to best third (AIHW, 2012). However, obesity rates (based on measured data) are among the highest in the world, with about one in four Australian adults classified as obese (AIHW, 2012). Self-assessed health status provides an indication of a person’s perception of his/her overall health. In 2011–12, the majority of Australians aged 15 years and over considered themselves to be in good health, with 85% reporting their health status as good, very good, or excellent (AIHW, 2014a). However, 25% of Indigenous Australians reported their health as fair or poor – nearly double the rate of non-Indigenous Australians (ABS, 2013d). Regardless of how health is measured, good health is not shared equally by all Australians. There are significant differences in health depending on sex, age, area of residence, ethnic background, employment, income, and level of education. Many of these differences are avoidable. As indicated, Aboriginal and Torres Strait Islander peoples generally have much poorer health than the population as a whole; other vulnerable groups include disadvantaged children and young people, people with mental illness, those living with disabilities, jobless families, refugees, and the frail aged (Table 1(a)). Socioeconomic disparities in health are evident in the prevalence of chronic diseases (e.g., heart disease and diabetes) and their associated biomedical risk factors (such as obesity and overweight, high blood pressure, smoking, physical inactivity), which are an increasing social and economic burden in Australia (Table 1(b)). These diseases are major contributors to the extent of illness, disability, and premature mortality in the population and are estimated to make up the greatest proportion of the burden of disease, mental health problems,

One of the recommendations of the United Nations Working Group on Indigenous Health is the right to respect Indigenous peoples’ traditional medicines and health practices (United Nations Working Group on Indigenous Health, 1994). For Australia’s many Aboriginal and Torres Strait Islander peoples, colonization resulted in significant erosion of culture, languages, customary health practices, and ownership of spiritual lands. Unlike the individualistic biomedical model, the Indigenous concept of health is broad, encompassing the wellbeing of the whole community and linked to the health and spirit of their sacred lands. However, neither the term ‘health’ nor the term ‘well-being’ fully captures the Aboriginal concept of living a life of value (Carey, 2013). The National Aboriginal Health Strategy definition indicates that achieving health and well-being is an attribute of communities as well as of the individuals within a community, and it identifies cultural wellbeing – along with physical, social, and emotional well-being – as equally important (National Aboriginal Health Strategy Working Party, 1989). Culture and identity are central to Aboriginal perceptions of health and ill-health; and an ongoing and active relationship with ‘country’ means that the health of community land plays an important role in determining the health of the people themselves (Green, 2008). Today, inequalities exist for Aboriginal and Torres Strait Islander peoples at all ages and in all settings, the result of detrimental events experienced throughout a lifetime. The legacy of colonization produced pervasive social and cultural change and led to complex effects on health and well-being, many of which have been cumulative over generations. The resulting trauma, loss, and disempowerment contributed to the further erosion of culture and community and undermined the holistic nature of Indigenous health and well-being, and it is difficult to determine the extent to which traditional approaches to healing are still practiced in some form by Aboriginal communities. Aboriginal and non-Aboriginal practitioners and scholars have long identified social inequality, racism, and oppression as the key issues affecting Indigenous well-being (Daniel et al., 1999; Paradies, 2006; Awofeso, 2011). Over the last three decades, the Indigenous population has advocated for greater funding and control of culturally responsive health services to address their health needs. Today, the state and territory governments provide funding primarily through mainstream hospitals, community clinics, and Aboriginal Community Controlled Health Services (ACCHS). The ACCHS approach to service delivery is broad and encompasses an Indigenous model of health. The federal government provides funding for a range of Indigenous-specific primary health care and substance misuse services, which are largely delivered in community-based settings. However, most secondary and all tertiary medical services are provided by the mainstream health system, which remains largely insensitive to the specific cultural needs of Aboriginal and Torres Strait Islander peoples. There are increasing numbers of trained

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Health Systems of Australia and New Zealand Table 1a

Key demographic and health indicators, Australia, various time periods from 2008 to 2013a

Indicator Outcome indicators Life expectancy (years) At birth Males Females At 65 years Males Females Infant mortality (rate) Avoidable mortality (rate) Mortality (rate) Health status Self-rated health: % rating health as fair or poor Chronic diseases Diabetes mellitus (%) Males Females Heart, stroke, and vascular disease (%) Males Females Risk factors Current smokers, 18þ years (%) Males Females Obese, 18þ (%) Males Females

Australia

Indigenous cf. total populationb

Lowest cf. highest socioeconomic statusc

79.7 83.1


10.6 years
9.4 years

n.a.d n.a.

19.1 22.0 3.7 135.9 573.0

n.a. n.a. 1.7 timese 3.7 times 2.0 times

n.a. n.a. n.a. n.a. n.a.

14.6

1.7 times

n.a.

5.1 4.2

2.6 times 4.3 times

1.5 times

5.5 4.5

1.6 times 1.8 times

2.0 times

18.3 14.1

2.0 times 2.5 times

n.a. n.a.

27.5 27.5

1.4 times 1.7 times

n.a. n.a.

Note – Rates are as follows: for infants, deaths under 12 months of age per 1000 live births; for mortality, age-standardized rate per 100 000 population; for avoidable mortality, potentially avoidable deaths before age 75 years per 100 000 population, indirectly age-standardized. a Data are for various time periods: life expectancy, 2010–12; infant mortality, 2008–12; mortality, 2012; avoidable mortality, 2010; chronic diseases, risk factors, and self-rated health, 2011–13. b ‘Indigenous cf. total population’ shows the variation between the rate for the Indigenous population and the rate for the total Australian population. For mortality rates, the comparison is between Indigenous deaths in selected states and the Northern Territory and the total population for Australia. c Socioeconomic status is based on the area of residence: comparison is between the most disadvantaged areas and least disadvantaged areas, each comprised of approximately 20% of the population. d n.a., no recent data available. e Shows infant mortality rate from selected Australian states. Source: Public Health Information Development Unit, University of Adelaide.

Aboriginal and Torres Strait health workers and Indigenous medical and nursing practitioners, but still far fewer than are required, given the perilous state of Indigenous health. Indigenous Australians are still more likely to live in conditions considered to be unacceptable by general Australian standards and detrimental to health: overcrowding, poorly maintained buildings, high housing costs relative to income, and, in some remote areas, a lack of basic environmental health infrastructure, such as reliable power supply, adequate sanitation, fresh and nutritious food, and appropriate shelter. In the period 2010–12, life expectancy at birth for Indigenous Australians was estimated to be 69.1 years for males and 73.7 years for females. This was a gap to non-Indigenous life expectancy of 10.6 years for men and 9.5 years for women (Council of Australian Governments Reform Council, 2014). This situation is overtly inequitable, and there is an urgent need to remedy the profound disadvantage in health and well-being experienced by Indigenous Australians.

The Mainstream Australian Health System Although Australia consistently ranks in the best-performing group of countries for healthy life expectancy and health expenditure per person, its dominant health system is complex, largely biomedical in focus, and characterized by a wide variety of service providers and funding and regulatory mechanisms (AIHW, 2014a). Health service providers include general and specialist medical and nursing practitioners, other health practitioners, hospital staff, community health workers, pharmacists, and Aboriginal health workers.

Funding and Expenditure

In 2012–13, health expenditure in Australia was AU$147.4 billion, 1.5% higher than in 2011–12 and the lowest growth since the mid-1980s (AIHW, 2014b). Almost 70% of total health expenditure during 2011–12 was funded by governments, with the Australian Government contributing 42.4% and state

Health Systems of Australia and New Zealand Table 1b Key demographic and health indicators, Australia, earlier time periods from 1997 to 2005a Indicator Outcome indicators Life expectancy (years) At birth Males Females At 65 years Males Females Infant mortality (rate) Avoidable mortality (rate) Mortality (rate) Ischemic heart disease Males Females Lung cancer Males Females Female breast cancer Health status Self-rated health: % rating health as fair or poor Chronic diseases Diabetes (%) Males Females Heart disease (%) Males Females Risk factors Current smokers, 18þ years (%) Males Females Overweight (preobese), 15þ (%) Males Females Obese, 15þ (%) Males Females Health determinants Educational participation (%) Unemployment (%)

Australia

Lowest cf. highest socioeconomic status b

78.5 83.3


3.8 years
2.2 years

18.1 21.4 4.8 176.6 674.8


1.5 years
0.9 years 2.0 times 1.8 times 1.3 times

70.5 58.7

1.3 times 1.3 times

54.5 23.7 26.8

1.5 times 1.3 times No difference

15.8

1.7 timesc

4.0 3.2

2.3 times

4.0 3.7

2.0 times

26.2 20.4

2.0 times 2.0 times

40.5 24.9

0.9 times 0.9 times

17.8 15.1

1.4 times 1.7 times

78.6 5.0

0.8 times 2.5 times

Note – Rates are as follows: for infants, deaths under 12 months of age per 1000 live births; for avoidable mortality, potentially avoidable deaths before age 75 years per 100 000 population, indirectly age-standardized. Educational participation is proportion of 16-year-olds in full-time education; unemployment is the proportion of the labor force who are unemployed. a Data are for various time periods: life expectancy, 2003–05; infant mortality, 2003; avoidable mortality, 1997–2000; chronic diseases, risk factors, and self-rated health, 2004–05; education participation, 2001; unemployment, 2003. b Socioeconomic status is based on the area of residence: comparison is between the most disadvantaged areas and least disadvantaged areas, each comprised of approximately 20% of the population. c Based upon data from South Australia. Source: Public Health Information Development Unit, University of Adelaide.

and territory governments, 27.3% (AIHW, 2014a). The remaining 30.3% ($42.4 billion) was paid for by patients (17%), private health insurers (8%), and accident compensation schemes (5%). Hospitals represented the largest area of health expenditure (with a proportion of 40.4%), and public hospitals accounted

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for AU$53.5 billion (AIHW, 2014a). The overall health expenditure estimates mainly represent health spending on health goods and services, such as pharmaceuticals, services by medical practitioners, and hospital care, as well as related activities, such as research and administration. It excludes areas such as the training of health practitioners and the ‘insurance component’ of private health insurance premiums; the former is regarded as expenditure on education and the latter as expenditure on insurance (AIHW, 2006). The Australian health system is largely funded through taxation and a small personal income tax–based health insurance levy (Healy and Hall, 2011). The federal government’s contribution is made primarily via two national subsidy schemes: Medicare and the Pharmaceutical Benefits Scheme (PBS). These schemes subsidize payments for services provided by doctors, optometrists, and psychologists, and for a high proportion of prescription medications. Medicare has operated since 1984, and its three objectives are to make health care affordable for all Australians, to give all Australians access to health-care services, and to provide high-quality health care. In its present form, the scheme guarantees all residents of Australia free public hospital care, subsidized access to their doctor of choice for out-of-hospital care, and subsidized medications (Healy and Hall, 2011). Medicare and the PBS also provide larger rebates for those who are eligible for income-support payments (such as for unemployment or disability), and there are additional health-care provisions for members of the defense forces, and war veterans and their dependents (AIHW, 2006). The PBS subsidizes the cost of a broad range of prescription medications and is an integral part of Australia’s health-care system. Before a medicine is subsidized by the PBS, it is assessed by the Pharmaceutical Benefits Advisory Committee for its clinical effectiveness, safety, and cost-effectiveness compared with other treatments. Once recommended, a price is negotiated between the manufacturer and the federal government and the medicine is listed (Healy and Hall, 2011). In 2010–11, 201 million pharmacy services were subsidized, which included 188.1 million PBS prescriptions claimed at a cost of AU$8.8 billion (AIHW, 2012). Until about a decade ago, the PBS was widely recognized as a world leader in controlling government expenditure on pharmaceuticals, while providing consumers with equitable access to affordable medicines. However, using a comparison across 13 countries, Australia is now 40% more expensive than the United Kingdom across the board for all its top pharmaceuticals and the third highest country after the United States and Germany (Clarke, 2013; Clarke and Fitzgerald, 2011). Australians can also purchase insurance from private health insurers to cover services in private hospitals, as well as those provided in public hospitals for private patients and associated medical services. Additional schemes cover other allied health and other professional services, including some complementary health services. In response to a decline in private health insurance membership, the federal government introduced a 30% rebate on membership fees in 1999 and a policy of lifetime cover in 2000. In March 2014, 47% of the Australian population had some form of private hospital cover and 55% had some form of general treatment cover (Private Health Insurance

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Health Systems of Australia and New Zealand

Administration Council, 2013). On 1 July 2014, the Australian Government Medicare levy temporarily increased from 1.5% to 2%, to fund a new National Disability Insurance Scheme.

Regulation

The federal government’s regulatory roles include overseeing the safety and quality of pharmaceutical and therapeutic goods and appliances, managing international quarantine and pandemic outbreaks, ensuring the safe supply of blood products, and regulating the private health insurance industry (AIHW, 2014a). State and territory governments are responsible for licensing private hospitals (including freestanding day hospital facilities), and each state and territory has legislation relevant to the operation of public hospitals and to public health. There is also a role for governments in the regulation of food safety and product labeling, safe handling and disposal of hazardous substances, sale of alcohol and tobacco products, air quality, and other relevant regulations. Local governments within states and territories deliver most environmental health programs (AIHW, 2014a).

Hospital and Health Service Operations

State and territory governments have principal responsibility for the operation of the hospital and health-care system. They receive substantial funding through the Medicare agreements that exist between each state and the federal government and also apply state revenue to the operation of recognized hospitals (AIHW, 2014a). These funds are also applied to public health and preventive and community health services, including mental health and dental services, health promotion, immunization, injury prevention, and screening programs for diseases such as breast and cervical cancers (AIHW, 2014a). The private hospital system accounts for approximately 30% of total hospital expenditure, and private hospitals receive their revenue from charges that are largely reimbursed through private health insurance funds. The private hospitals are a mixture of private, for-profit, and taxable hospitals; charitable not-for-profit hospitals; and community not-for-profit hospitals.

Health Workforce

In 2012, there were almost 600 000 people working in health occupations (Health Workforce Australia, 2014), with the largest group being nurses and midwives. There were 1124 full-time equivalent nurses and midwives employed for every 100 000 people, 374 medical practitioners, 85 psychologists, and 15 podiatrists (AIHW, 2014a). The health workforce has been undergoing considerable growth in recent years, partially in response to shortages of certain personnel (such as doctors, dentists, pharmacists, and nurses) because of an aging workforce, changing work practices, and demand in areas such as Indigenous health, rural health, and general practice. In 2010, the Council of Australian Governments (COAG) brought about a major reform of health practitioner regulation: a nationally consistent law was passed establishing a National Registration and Accreditation Scheme (the National Scheme) and the Australian Health Practitioner Regulation Agency (AHPRA), responsible for implementing the National Scheme across the nation.

Australia is currently dependent on overseas-trained practitioners to fill vacancies in public hospitals and private practice, particularly in rural and outer suburban areas where locally trained professionals are reluctant to work. In 2009, onequarter (18 458) of working doctors in Australia obtained their first medical qualification overseas. The number of temporaryresident overseas-trained doctors arriving in Australia to work in ‘areas of need,’ such as rural and remote areas, increased significantly from 2003. Some specialties are highly reliant on international medical graduates, particularly general practice, psychiatry, and obstetrics/gynecology; for example, one-third (35% or 9191) of general practitioners were overseas-trained in 2009–10 (Health Workforce Australia, 2012).

Health-Care Reform Reform moves slowly in Australia as both tiers of government must concur on any proposed changes (Healy et al., 2006). In recent years, initiatives have included reform of the Australian Health Care Agreements; efforts to address national priorities by way of the Australian Health Ministers’ Conference and the Council of Australian Governments; national funding for the prevention of chronic and complex conditions, electronic health records, and improved safety and quality of hospital care; and better national health information. In 2011, the Australian Government established Medicare Locals to plan and fund extra health services in communities across Australia (AIHW, 2014a). They were created as local organizations, to coordinate and deliver services to meet particular local needs (AIHW, 2014a). On 13 May 2014, the Australian Government announced that the 61 Medicare Locals would be replaced with a smaller number of Primary Health Networks, to be operational from 1 July 2015. Local Hospital Networks (LHNs) are also being established across the country to improve delivery, coordination, and access to health services (AIHW, 2014a). LHNs are small groups of local hospitals, or an individual hospital, linking services within a region or through specialist networks across a state or territory. Ongoing areas of concern are Indigenous health, rural and remote health, socioeconomic disparities in health, cost containment, an aging workforce, and the increasing burden of chronic conditions. The challenge for the Australian health system will be in managing the relationship between these demands, the health workforce mix, and the levels, types, and quality of services supplied in response.

New Zealand Introduction Geography

New Zealand or Aotearoa (in Maori – the land of the long white cloud) is an archipelago with over 700 offshore islands, which lies in the southwest Pacific Ocean to the east of Australia (Figure 5). Its three main islands, the North and South Islands and Stewart Island, are spread over 1600 km and have 18 000 km of coastline, and an area of 268 000 km2. The northern outlying islands are subtropical in climate, while those in the south are subantarctic; between these extremes, the climate is cool to temperate.

Health Systems of Australia and New Zealand

North Island Tasman Sea

Pacific Ocean South Island

Figure 5

Map of Aotearoa – New Zealand.

Demography

New Zealand was the last habitable landmass in the world to be discovered, by the ancestors of Maori, over 1000 years ago. In 1840, the country became a British colony when more than 500 Maori chiefs and representatives of the British

Figure 6

Population density, New Zealand, 2001.

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monarch signed Te Tiriti o Waitangi, the Treaty of Waitangi. The Treaty still governs the relationship between the Crown and Maori and has been interpreted in the health system through the principles of ‘partnership, protection, and participation’ (Ministry of Health, 2003). Today, about one in seven New Zealanders identify themselves ethnically as Maori. As the country’s original inhabitants, Maori culture is a key element of the New Zealand identity, and the Maori language (Te Reo) is spoken fluently by more than 160 000 people. Maori are disadvantaged compared to most other groups, with lower life expectancy, living and housing standards, and educational attainments, and poorer health. They share these characteristics with Pacific Islander (Pasifika) peoples in New Zealand. The Pacific population consists of at least 13 distinct languages and cultural groups, with the Samoan community the largest (49%), followed by Cook Islanders (22%), Tongans (19%), Niueans (8%), Fijians (4%), Tokelaueans (3%), and Tuvaluans and others (3%) (the totals add to more than 100 because multiple ethnic identities can be given) (Cumming et al., 2014). New Zealand has an estimated 4.51 million people, predominantly of New Zealand European ethnicity (74.0%), with significant Maori (14.9%), Pacific (7.4%), Asian (11.8%), and Middle Eastern/Latin American/African (1.2%) populations. The majority of the population resides in urban areas (87%), and approximately three quarters (76%) live in the North Island (Figure 6). The population of New Zealand is aging, although the Maori and Pacific populations are younger than the New Zealand population as a whole. The median age of the Maori ethnic group was 23.9 years on 5 March 2013, 14.1 years younger

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Health Systems of Australia and New Zealand

than that of the total population. Only 5.4% of Maori are aged 65 years and over, compared to 14.3% overall. The Pacific peoples are also a younger population.

New Zealand has an established capitalist economy, with a relatively high standard of living and a GDP per capita below the OECD average in 2011. Its economic performance improved significantly over the 1990s following a sustained period of low economic growth during the 1980s, although a major imbalance has been built up in the economy over the past four decades, in the form of persistent current account deficits producing a net external liabilities position equal to 85% of GDP. Significant socioeconomic inequalities exist across the population: Maori and Pacific peoples are more disadvantaged across all socioeconomic indicators than New Zealanders of European backgrounds. New Zealand is a parliamentary democracy and a constitutional monarchy. In 1996, the electoral system was changed to a mixed member proportional representation system, which has increased the representation of smaller parties in the Parliament and government. There is a single chamber in the Parliament, whose powers are the approval of government revenue raising and expenditure, and the enactment of legislation. Maori have had separate representation in the Parliament since 1867. More than 3000 crown entities, funded by the state, perform a variety of functions and include the 20 district health boards (DHBs) which operate the country’s hospitals, and nine crown research institutes (Cumming et al., 2014).

Other health disparities are also evident. The overall infant mortality rate was 4.2 infant deaths per 1000 live births in 2012, with a rate of 4.7 for the Maori population, which had improved significantly from a rate of 7.0 in 2011. In the National Health Survey 2012/13, non-Maori adults generally rated their health higher than Maori adults (Ministry of Health, 2013). Maori adults have higher rates of most health conditions, with differences most notable for some cancers, asthma, chronic obstructive pulmonary disease, ischemic heart disease, stroke, and diabetes (Ministry of Health, 2013). Since the 1990s, improvements in New Zealanders’ health have been most evident for ischemic heart disease, cervical cancer, road traffic injuries, alcohol-related diseases, and control over HIV/AIDS. Other conditions have continued to increase, however, such as diabetes (French et al., 2001). Cancer has been the leading cause of death since 1993; and other major causes are ischemic heart and cerebrovascular diseases. Some key health indicators and disparities in health indicators are in Table 2. In 2013, the prevalence of daily smoking among European New Zealanders aged 15 years or above was 13.9%, but Maori smoking rates (32.7%) were twice those of non-Maori, with elevated rates also apparent for Pacific peoples (23.2%) (Health Promotion Agency n.d.). Proportionally more Maori people die from heart disease, lung cancer, and chronic respiratory diseases than non-Maori. Despite the continued disparities in health, there have been some gains for Maori health over the last decade, with an improvement in areas such as asthma and other respiratory problems, immunization, and mental health (Cumming et al., 2014).

Health of New Zealanders

The System to Address Maori Health in New Zealand

Historical Trends

Prior to European settlement, Maori customs, similar to those of other Polynesian peoples of the Pacific islands, recognized land as the sacred trust and asset of the people as a whole community. After colonization, the loss of ancestral land undermined Maori identity and well-being and the social links between families and within tribes; and, with the loss of the resources necessary to sustain well-being, the health of the people also deteriorated (Durie, 2001). The Maori philosophy toward health, Te Whare Tapa Wha, is based on a wellness or holistic health model – a four-sided concept representing four basic beliefs of life: Te Taha Hinengaro (psychological health), Te Taha Wairua (spiritual health), Te Taha Tinana (physical health), and Te Taha Whanau (family health). Knowledge of whakapapa (one’s ancestry) and whenua (land) are also important. It was not until 1983 that the Department of Health allowed awhina (healers) to work alongside doctors in hospitals. There has been a growing awareness that the key to Maori wellness lies in a more holistic approach and that rongoa Maori (traditional Maori healing) practitioners and practices need to be combined with Western health methods to give people the best of both healing systems. Today, health policy for Maori people is governed by He Korowai Oranga, the Maori Health Strategy. The original He Korowai Oranga has been updated to ensure it continues to provide a strong platform for Maori health for the future and expands the aim of He Korowai Oranga from whanau ora

Economy and Government

Over the last 130 years, there has been a shift from the predominance of infectious diseases and from significant levels of infant and childhood mortality, to that of chronic and degenerative diseases of late adulthood as the main causes of death (Statistics New Zealand (NZ), 2006). A major contributor to the decline in the size of the Maori population until the 1890s was deaths in the New Zealand Wars and associated dislocation, susceptibility to disease, and reduced population in the reproductive ages (Statistics NZ, 2006). This decline eased partly because of improved health as Maori developed immunity to diseases introduced by the non-Maori population. For a small country, the impact of the two World Wars and the 1918 influenza pandemic on death rates of all young adults, especially males, was substantial.

Current Health Status

The New Zealand population is one of the healthiest when compared internationally; for example, its life expectancy is above that of the USA and the UK, but slightly below that of Australia. Life expectancy at birth for the years 2010–12 was 79.3 years for males and 83.0 years for females. However, there were marked ethnic differences in life expectancy over this time period: for example, life expectancy at birth was 76.5 years for Maori females and 72.8 years for Maori males, compared with 83.7 years for non-Maori females and 80.2 years for non-Maori males.

Health Systems of Australia and New Zealand Table 2 Key demographic and health indicators, New Zealand, various time periods from 2004 to 2013a Indicator

New Zealand

Outcome indicators Life expectancy (years) At Birth Males 80.2 Females 83.7 Infant mortality (rate) 4.2 Avoidable mortality (rate) 68.1(non-Maori) Mortality (rate) Ischemic heart disease Males 85.9 Females 47.3 Lung cancer Males 28.0 Females 21.2 Female breast cancer 18.3 Chronic diseases, 15D years Diabetes (%) Males 6.4 Females 5.1 Ischemic heart disease (%) Males 6.0 Females 3.9 Stroke (%) Males 2.2 Females 1.7 Asthma (%) Males 8.9 Females 13.0 Risk factors Current smokers (% age 15 years) Males 18.7 Females 16.4 Overweight (not obese) (%) Males 38.4 Females 30.0 Obese (%) Males 30.3 Females 32.2 Health determinants School retention (%) 82.6 Unemployment (%) 6.2

Maori cf. total populationb


7.4 years
7.2 years 1.1 times 2.6 times 1.6 times 2.0 times 2.2 times 3.4 times 1.5 times 1.2 times 1.3 times 0.9 times 1.2 times 0.5 times 1.2 times 1.3 times 1.5 times 1.9 times 2.6 times 0.8 times 0.8 times 1.5 times 1.6 times 0.8 times 2.0 times

Note – Rates are as follows: for infants, deaths under 12 months of age per 1000 live births; for avoidable mortality, potentially avoidable deaths before age 75 years per 100 000 population, age-standardized; for mortality by cause, deaths per 100 000 population, age-standardized. Risk factor expressed as percentage (crude) and comparison with Maori based on percentage (standardized). School retention is the proportion of young people staying at school to their 17th birthday; unemployment is the proportion of the labor force who are unemployed. a Data are for various time periods: life expectancy, 2010–12; infant mortality rate, 2012; avoidable mortality rate, 2004–06; mortality, 2011; chronic diseases and risk factors, 2012/13; school retention, 2013; unemployment, 2013. b ‘Indigenous compared with total population’ shows the variation between the rate for the Indigenous population and the rate for the total New Zealand population. Sources: NZ Ministry of Health; Statistics New Zealand; NZ Ministry of Education.

(healthy families) to pae ora (healthy futures). All Primary Health Organizations (PHOs) are required to develop a Maori Health Action Plan appropriate to the needs of their enrolled population, to contribute toward reducing health inequalities. In addition, Maori-led programs designed to improve healthcare access are aimed at developing Maori provider services

479

and supporting self-sufficiency, and enhancing mainstream services through provision of culturally safe care.

The System to Address Pacific Health in New Zealand On a population basis, Pacific communities also experience poorer health outcomes in New Zealand. For example, Pacific male life expectancy is 6.7 years less than the total male population of New Zealand and Pacific female life expectancy is 6.1 years less than the total female population. Pacific health status remains unequal with non-Pacific, across almost all chronic and infectious diseases. Like Maori, poor health outcomes are related to social determinants, such as income, employment, housing quality, and education. ’Ala Mo’ui is a combination of a number of Pacific languages meaning ‘pathways to the essence of life force.’ It represents the holistic view of health and well-being, encompassing the physical, mental, cultural, and spiritual dimensions that are important to Pacific people: Tongan (’Ala Mo’ui), Niuean (Ala Moui), Samoan (Ala), Cook Island Maori (Ara), Tokelauan (Ala), and Tuvaluan (Ala). ’Ala Mo’ui: Pathways to Pacific Health and Wellbeing, 2014–2018 sets out the priority outcomes and actions for all Pacific and non-Pacific health, disability, and other relevant agencies that contribute to achieving better health outcomes for Pacific peoples, families, and communities (Ministry of Health, 2014). There is a shortage of health practitioners with an understanding of Maori and Pacific health perspectives and cultures. To this end, the government adopted the Raranga Tupuake Maori Workforce Development Plan 2006, with the aims of removing barriers to Maori and Pacific people entering the health workforce, actively attracting Maori and Pacific people into the sector, and implementing measures to retain existing workers (Health Workforce Advisory Committee, 2006). The Hauora Maori Training Fund helps DHBs develop Maori staff in the nonregulated health and disability workforce and provides access to training programs to develop formal competencies in their current roles and improve potential to move into other roles. Continuing inequalities in health between Maori, Pacific, and other New Zealanders indicate that more remains to be done. The achievement of good health for Maori and Pacific peoples necessitates an approach that goes beyond building their capacity to manage their own health needs and the provision of culturally specific health services. It also requires access to culture and heritage, amelioration of existing socioeconomic and other inequities, and greater opportunities for cultural expression within society’s institutions (Durie, 1999).

The Mainstream New Zealand Health System New Zealand has a predominantly publicly funded, universal coverage health system with services provided by public, private, and nongovernmental sectors. The Minister of Health has overall responsibility for the health and disability system, and the Ministry of Health (MOH) is the main advisory body to the government on policy issues. The organization of these health services in New Zealand has undergone considerable change in the last two decades, from a ‘purchaser/provider,’ market-oriented model

480

Health Systems of Australia and New Zealand

introduced in 1993, to a more community-oriented model in 2013. In 2000, the purchase and provision of services were brought back together into the same organizations, and decision making was devolved to 21, now 20 community-focused DHBs (Cumming et al., 2014). The Minister works through the MOH to enter into accountability arrangements with DHBs via the National Health Board, determines the health strategy, and agrees with government colleagues how much public money will be spent on the delivery of services. DHBs are Crown entities responsible to the Minister of Health (administration is through the MOH). Each board has up to eleven members, seven of which are elected by the community, a minority are appointed by the Minister, and at least two must be Maori. The role of DHBs includes planning, funding, and ensuring the provision of health and disability services to a geographically defined population, in keeping with national priorities and Ministry guidelines on essential service provision (Ministry of Health, 2005). Services are delivered by a range of providers including public hospitals, nonprofit health agencies, iwi (tribal) groups, or private organizations. Funding is allocated to DHBs using a weighted population-based funding formula.

Funding and Expenditure

The New Zealand health-care system is largely a publicly financed system, with the government funding 82.7% of national health-care expenditures in 2012, with the remaining 17.3% paid by individuals – a level well below the OECD average of 27.7% (WHO, 2014). In 2012, New Zealand’s public expenditure on health care was equivalent to 10.3% of GDP, just above the OECD average of 9.3%; and total health expenditure was around NZ$14.5 billion (New Zealand Treasury, 2013). Private health insurance payments account for only 4.9% of national health expenditure (Cumming et al., 2014). Although the private health insurance share of national health expenditures is modest, about 38% of New Zealand adults held private health insurance in 2013.

Regulation and Operation of the Health System

Government funding of health services means that all New Zealand residents receive free inpatient and outpatient public hospital services, and subsidized prescription medications. The New Zealand Public Health and Disability Act 2000 gives DHBs overall responsibility for assessing the health and disability needs of communities in their regions, and for managing resources and service delivery to best meet those needs. Although capitation funding replaced fee-for-service funding of general practice, patients continue to pay additional fees, though these have generally reduced. Most prescriptions have a co-payment of NZ$5 per item (Cumming et al., 2014). Basic dental services are free for children; adult dental care and optometry are paid for privately. Long-term care is funded through both public and private mechanisms (Cumming et al., 2014). In July 2002, not-for-profit PHOs began operating to promote a population focus to health service delivery, with particular emphasis on reducing the cost of access to services. This represented a new direction for primary health care, with a greater emphasis on population health and the role of the community, health promotion, and preventive care.

The New Zealand Health Strategy (2013) provides an overall framework for the health sector. To support this direction, the 32 PHOs are funded on a population basis through a needs-based capitation formula. This aims to reduce inequalities by directing resources to communities in greatest need. PHOs involve a team of health practitioners offering public health and health-promotion initiatives, and primary care for their enrolled populations. Community participation in the PHO governing process allows people a voice in the planning and delivery of services in their communities. Following the November 2011 election, the government shifted the focus of the public sector from outputs to results that benefit families and communities (Cumming et al., 2014). In 2012, the Prime Minister announced 10 high-level targets across the public sector. The MOH is leading the delivery of those in the areas of increasing immunization and reducing rheumatic fever cases among children (Cumming et al., 2014). A new Health Quality and Safety Commission replaced the government’s Quality Improvement Committee in mid-2010 and is intended to increase the focus on quality, while better coordinating the varied approaches to quality improvement across DHBs (Gauld, 2011). New Zealanders have had access to subsidized pharmaceutical drugs since the 1930s. Since 1993, the Pharmaceutical Management Agency of New Zealand (PHARMAC) has managed around 2600 prescription medicines and related products subsidized by the government. Many drugs are purchased in bulk by PHARMAC via a tendering system, which helps contain the cost of drugs. Those on low incomes or who are high health-care users receive subsidies for medical and pharmaceutical costs. In 2012–13, the community pharmaceutical budget was NZ$784 million (PHARMAC, 2014). In 2012, the management of the national immunization schedule, assessment of new vaccines, and purchasing of medical devices for hospitals transferred to PHARMAC from the MOH. PHARMAC has been successful in controlling New Zealand’s expenditure on pharmaceuticals and is a key reason for the nation’s low pharmaceutical prices (Cumming et al., 2010). Not surprisingly, PHARMAC has been a regular point of contention in debates around potential free-trade agreements, particularly the Trans-Pacific Strategic Economic Partnership, which may affect its ability to operate (Gleeson et al., 2013).

Health Workforce

In 2010, there were 12 867 registered medical practitioners in New Zealand: one-third were general practitioners, just over one-third were specialists, and just under one-third were junior doctors in hospitals (NZ Government, n.d.). However, as a small country, New Zealand has difficulty retaining its medical and other health graduates, losing many practitioners to other countries able to offer better remuneration and working conditions (Health Workforce Advisory Committee, 2006). New Zealand is the developed country identified by OECD with the highest level of inflow and outflow of health professionals (Zurn and Dumont, 2009). It recruits from many countries but also loses many doctors and nurses, including recent international recruits, to Australia. In part, the high level of international recruitment to New Zealand is an attempt to compensate for the high level of outflow of doctors to Australia (Buchan et al., 2011). Consequently,

Health Systems of Australia and New Zealand New Zealand has one of the highest proportions of overseastrained doctors (approximately 40% of its medical workforce) of any western country (OECD, 2009). The patterns defined above are largely replicated in relation to nurses (Hawthorne, 2012). By 2005–06, New Zealand had among the highest proportion of foreign-born (29%) and foreign-trained nurses (24%) in the OECD, plus the second highest OECD expatriation rate for nurses (23%) (Zurn and Dumont, 2009). There is also evidence that the situation will worsen. The aging population, greater incidence of key chronic diseases, and changing expectations of practitioners and consumers are likely to further increase pressure on the existing New Zealand health workforce (New Zealand Institute of Economic Research, 2004).

Health-Care Reform The New Zealand health-care system has undergone numerous waves of change since the early 1990s. A move away from a competitive, market-driven model, to one that focuses more on improved population health and greater consultation with health-care providers and communities regarding the strategic directions of the health system, has improved waning public confidence (Cumming et al., 2014). Issues of equity of health outcomes across the population remain an ongoing challenge, particularly for Maori and Pacific Islander peoples and others who are socioeconomically disadvantaged.

References Australian Bureau of Statistics (ABS), 2007. Year Book Australia, 2007. ABS, Canberra. Australian Bureau of Statistics (ABS), 2013a. Australian Demographic Statistics, June 2013 (ABS cat. no. 3101.0). ABS, Canberra. Australian Bureau of Statistics (ABS), 2013b. Migration, Australia, 2011–12 and 2012–13 (ABS cat. no. 3412.0). ABS, Canberra. Australian Bureau of Statistics (ABS), 2013c. Estimates of Aboriginal and Torres Strait Islander Australians, June 2011 (ABS cat. no. 3238.0.55.001). ABS, Canberra. Australian Bureau of Statistics (ABS), 2013d. Australian Aboriginal and Torres Strait Islander Health Survey: First Results, Australia, 2012–2013. ABS, Canberra. Australian Bureau of Statistics (ABS), 2013e. Deaths, Australia, 2012 (ABS cat. no. 3302.0). ABS, Canberra. Australian Bureau of Statistics (ABS), 2014. Estimates and Projections, Aboriginal and Torres Strait Islander Australians, 2001 to 2026 (ABS cat. no. 3238.0). ABS, Canberra. Australian Institute of Health and Welfare (AIHW), 2006. Australia’s Health 2006. AIHW, Canberra. Australian Institute of Health and Welfare (AIHW), 2012. Australia’s Health 2012. AIHW, Canberra. Australian Institute of Health and Welfare (AIHW), 2014a. Australia’s Health 2014. AIHW, Canberra. Australian Institute of Health and Welfare (AIHW), 2014b. Health Expenditure Australia 2012–13. AIHW, Canberra. Awofeso, N., 2011. Racism: a major impediment to optimal Indigenous health and health care in Australia. Aust. Indigenous Health Bull. 11 (3). Buchan, J.M., Naccarella, L., Brooks, P.M., 2011. Is health workforce sustainability in Australia and New Zealand a realistic policy goal? Aust. Health Rev. 35, 152–155. Carey, T.A., 2013. Defining Australian Indigenous wellbeing: do we really want the answer? Implications for policy and practice. Psychother. Polit. Int. 11 (3), 182–194. Clarke, P.M., 2013. The pricing of statins and implications for Pharmaceutical Benefits Scheme expenditure. Med. J. Aust. 198 (5), 260. Clarke, P.M., Fitzgerald, E.M., 2011. Expiry of patent protection on statins: effects on pharmaceutical expenditure in Australia. Med. J. Aust. 194 (1), 52–54.

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Council of Australian Governments (COAG) Reform Council, 2014. Report on the National Indigenous Reform Agreement. COAG, Canberra. Cumming, J., Mays, N., Daubé, J., 2010. How New Zealand has contained expenditure on drugs. Br. Med. J. 340, c2441. Cumming, J., McDonald, J., Barr, C., et al., 2014. New Zealand health system review. Health Syst. Transition 4 (2), 1–244. Daniel, M., O’Dea, K., Rowley, K., McDermott, R., Kelly, S., 1999. Social environmental stress in Indigenous populations: potential biopsychosocial mechanisms. Ann. N.Y. Acad. Sci. 96, 420–423. Durie, M., December 1999. Te pae mahutonga: a model for Maori health promotion. Health Promot. Forum N.Z. Newsl. 49, 2–5. Durie, M., 2001. Mauri Ora: The Dynamics of Maori Health. Oxford University Press, Auckland. French, S., Old, A., Healy, J., 2001. Health care systems in transition - New Zealand. Health Syst. Transition 3, 1–128. Gauld, R., 2011. The New Zealand health care system. In: Thomson, S., et al. (Eds.), International Profiles of Health Care Systems. The Commonwealth Fund, New York. Gleeson, D., Lopert, R., Reid, P., 2013. How the Trans Pacific Partnership Agreement could undermine PHARMAC and threaten access to affordable medicines and health equity in New Zealand. Health Policy 112 (3), 227–233. Goss, J., 2008. Projection on Australian Health Care Expenditure by Disease, 2003 to 2033 (AIHW cat. no. HWE 43). AIHW, Canberra. Green, D., 2008. Climate impacts on the health of remote northern Australian Indigenous communities. In: Garnaut, R. (Ed.), Garnaut Climate Change Review. Australian Government Department of Climate Change, Canberra. Hawthorne, L., 2012. Health Workforce Migration to Australia: Policy Trends and Outcomes, 2004–2010. University of Melbourne, Melbourne. Health Promotion Agency (HPA), n.d. Tobacco Control Data Repository. (Online). At: http:// www.tcdata.org.nz/TobaccoSectorOverview.aspx (retrieved 12 September 2014). Health Workforce Advisory Committee (NZ), 2006. Report of the Health Workforce Advisory Committee on Encouraging Maori to Work in the Health Professions. Health Workforce Advisory Committee, Wellington. Health Workforce Australia, 2012. Australia’s Heath Workforce Series - Doctors in Focus. Health Workforce Australia, Adelaide. Health Workforce Australia, 2014. Health Workforce by Numbers - Issue 3. Health Workforce Australia, Adelaide. Healy, J., Sharman, E., Lokuge, B., 2006. Australia: health system review. Health Syst. Transition 8, 1–158. Healy, J., Hall, J., 2011. The Australian health care system. In: Thomson, S., et al. (Eds.), International Profiles of Health Care Systems. The Commonwealth Fund, New York. Hetzel, D.M.S., 2001. Death, disease and diversity in Australia, 1951 to 2000. Med. J. Aust. 174, 21–24. Madden, R.C., Jackson Pulver, L.R., 2009. Aboriginal and Torres Strait Islander population: more than reported. Aust. Actuarial J. 15 (2), 181–208. Mathers, C.D., Vos, E.T., Stevenson, C.E., et al., 2000. The Australian burden of disease study: measuring the loss of health from diseases, injuries and risk factors. Med. J. Aust. 172, 592–596. Medical Reference Group, Health Workforce Advisory Committee (NZ), 2006. Fit for Purpose and for Practice: Advice to the Minister of Health on the Issues Concerning the Medical Workforce in New Zealand. Health Workforce Advisory Committee, Wellington. Ministry of Health (New Zealand), 2003. New Zealand health and Disability Sector Overview. Ministry of Health, Wellington. Ministry of Health (New Zealand), 2005. PHO Yearbook: 2004. Ministry of Health, in Association with District Health Boards, Wellington. Ministry of Health (New Zealand), 2013. New Zealand Health Survey: Annual Update of Key Findings 2012/13. Ministry of Health, Wellington. Ministry of Health (New Zealand), 2014. ’Ala Mo’ui: Pathways to Pacific Health and Wellbeing, 2014–2018. Ministry of Health, Wellington. National Aboriginal Health Strategy Working Party (NAHSWP), 1989. A National Aboriginal Health Strategy. NAHSWP, Canberra. New Zealand Government, n.d. Te Ara: Medical Practitioners. (Online). At: http://www. teara.govt.nz/en/health-practitioners/page-2 (retrieved 30 September 2014). New Zealand Institute of Economic Research (NZIER), 2004. Ageing New Zealand and Health and Disability Services: Demand Projections and Workforce Implications, 2001–2021. Ministry of Health, Wellington. New Zealand Treasury, 2013. Financial Statements of the Government of New Zealand for the Year Ended 30 June 2013 (Online). http://www.treasury.govt.nz/ government/financialstatements/yearend/jun13 (retrieved 26 August 2014). Organisation for Economic Co-operation and Development (OECD), 2009. OECD at a Glance 2009. OECD, Paris.

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Paradies, Y.C., 2006. Race, Racism, Stress and Indigenous Health (PhD thesis). The University of Melbourne, Melbourne. Pharmaceutical Management Agency (PHARMAC), 2013. Annual Review 2013 (Online). http://www.pharmac.health.nz/assets/annual-review-2013.pdf (retrieved 22 June 2014). Private Health Insurance Administration Council, 2013. Private Health Insurance Administration Council, Quarterly Statistics March 2014. Private Health Insurance Administration Council, Canberra. Productivity Commission, 2005. Australia’s Health Workforce. Productivity Commission, Canberra. Scott, M.L., Whelan, A., Dewdney, J., et al., 2004. “Brain drain” or ethical recruitment? Solving health workforce shortages with professionals from developing countries. Med. J. Aust. 180, 174–176. Statistics New Zealand, 2006. A History of Survival in New Zealand: Cohort Life Tables 1876–2004. Statistics New Zealand, Wellington. United Nations Working Group on Indigenous Populations, 1994. 1994/45 Draft United Nations Declaration on the Rights of Indigenous Peoples (36th Meeting, 26 August 1994-E/CN.4/Sub.2/1994/56). United Nations, Geneva. World Health Organization, 2014. Global Health Observatory Data Repository: New Zealand, Statistics Summary, 2002-present (Online). http://www.apps.who.int/gho/ data/node.country.country-NZL?lang¼en (retrieved 2 September 2014). Zurn, P., Dumont, J.-C., 2009. Health Workforce and International Migration: Can New Zealand Compete? (OECD Health Working Papers, DELSA/HEA/WD/HWP3) World Health Organization and OECD, Paris.

Australian Institute of Health and Welfare (AIHW), 2014. Australia’s Health 2014. AIHW, Canberra. Australian Institute of Health and Welfare (AIHW), 2016. Australia’s Health 2016. AIHW, Canberra. Cumming, J., McDonald, J., Barr, C., et al., 2014. New Zealand health system review. Health Syst. Transition 4 (2), 1–244. Hall, J., 2015. Australian health care – the challenge of reform in a fragmented system. N. Engl. J. Med 373, 493–497. Harris, R., Cormack, D., Stanley, J., Rameka, R., 2015. Investigating the relationship between ethnic consciousness, racial discrimination and self-rated health in New Zealand. PLoS One 10 (2) e0117343. http://dx.doi.org/10.1371/journal.pone. 0117343. Health Quality and Safety Commission New Zealand (HQSC), 2015. A window on the quality of New Zealand’s Health Care. HQSC, Wellington. Healy, J., Sharman, E., Lokuge, B., 2006. Australia: health system review. Health Syst. Transition 8, 1–158. Organisation for Economic Co-operation and Development (OECD), 2015. OECD Reviews of Health Care Quality: Australia 2015: Raising Standards. OECD Publishing, Paris. Robson, B., Ellison-Loschmann, L., 2016. Maori and cancer care in Aotearoa/New Zealand – responses to disparities. Eur. J. Cancer Care 25 (2), 214–218. University of Otago, 2015. District Health Board – Maori Health Profiles 2015. (Online). http://www.otago.ac.nz/wellington/departments/publichealth/research/erupomare/ research/otago147631.html.

Further Reading

Relevant Websites

Atmore, C., 2015. The role of medical generalism in the New Zealand health system into the future – future challenges. N. Z. Med. J. 128 (1419), 50–55. Australian Bureau of Statistics (ABS), 2007. Year Book Australia, 2007. ABS, Canberra. Australian Bureau of Statistics (ABS) and Australian Institute of Health and Welfare (AIHW), 2011. The Health and Welfare of Australia’s Aboriginal and Torres Strait Islander Peoples. ABS, Canberra. Australian Commission on Safety and Quality in Health Care (ACSQHC), 2015. Vital signs 2015: The State of Safety and Quality in Australian Health Care. ACSQHC, Sydney. Australian Government, Department of the Prime Minister and Cabinet, December 2014. Reform of the federation white paper: roles and responsibilities in health. Issues Paper 3. (Online). https://www.federation.dpmc.gov.au/sites/default/files/ issues-paper/Health_Issues_Paper.pdf. Australian National Preventive Health Agency (ANPHA), 2013. State of Preventive Health 2013: Report to the Australian Government Minister for Health. ANPHA, Canberra. Australian Institute of Health and Welfare (AIHW), 2000. Changes in Australia’s disease profile: a view of the twentieth century. In: Australian Institute of Health and Welfare, Australia’s Health 2000. AIHW, Canberra, pp. 340–364.

Australia http://www.abs.gov.au/ – Australian Bureau of Statistics. http://www.aihw.gov.au/ – Australian Institute of Health and Welfare. http://www.health.gov.au/ – Australian Government Department of Health. http://www.healthinfonet.ecu.edu.au/ – Australian Indigenous HealthInfoNet. http://www.naccho.org.au/ – National Aboriginal Community Controlled Health Organisation. http://www.publichealth.gov.au/ – Public Health Information Development Unit, The University of Adelaide. New Zealand http://www.maorihealth.govt.nz/ – Maori Health. http://www.moh.govt.nz/ – New Zealand Ministry of Health. http://www.moh.govt.nz/pacific – Pacific health. http://www.stats.govt.nz/ – Statistics New Zealand.

Health Systems of Mexico, Central America and the Caribbean Miguel A Gonzalez Block, Centro de Investigacion en Sistemas de Salud, Cuernavaca, Morelos, Mexico Sebastian Gonza´lez McQuire, Wyeth Pharmaceuticals Mexico and Central America, Mexico City, Mexico Ó 2017 Elsevier Inc. All rights reserved.

across countries or subregions, with Haiti having only $1742, Central America reaching $4696, ESC with $6268, Mexico with $9168, and Costa Rica with $9605 (Pan American Health Organization (PAHO), 2007). Although the region performs relatively well in terms of international GDP, it still has an average of 12% of people living below the poverty line (PAHO, 2007). The large economic and demographic variations within the region are reflected in health characteristics. Cuba and Costa Rica perform the best, having an average life expectancy of 78 years at birth, while Haiti’s life expectancy reaches only 52.7 years. Infant mortality for every 1000 births has a regional average of 22 deaths, a figure that rises to nearly 60 in Haiti and is as low as 5.6 for Cuba. Countries in the region present stark contrasts in the road toward achieving the Millennium Development Goals (eradicate extreme poverty and hunger, reduce child mortality, improve maternal health, combat HIV/AIDS, malaria and other diseases, ensure environmental sustainability, develop a global partnership for development). Central America and Mexico account for 4% of the world’s maternal deaths and in the reduction of child mortality the region performs relatively well compared to countries in Africa and Asia (World Health Organization (WHO), 2000). However, countries in Central America still have some way to go, as it is this subregion that has nearly 14 more deaths per 1000 than the ESC. Regarding the fight against HIV/AIDS, there is a prevalence of HIV/AIDS infections in the regions (Table 2). The country with the most worrying statistics is Haiti, given that it underperforms in all indicators both relative to the regional countries as well as to the rest of the world. Total per capita health expenditure for the region is $415 and corresponds to 6% of GDP (Table 3). Public health expenditure for the region averages 46% of the total. Costa Rica has the highest total spending with $797, as well as the highest public share of the total, with 59%. Haiti is at the other

Introduction The health systems of Mexico, Central America, and the Caribbean are changing rapidly due to epidemiological transition and political pressure toward universal access to and financial protection of care. Health systems in this region have important differences and commonalities; unified public systems predominate in the English-speaking Caribbean countries (ESC) due to the heritage of British colonial institutions. Mexico and Central America share corporatist roots reflected in multiple public providers. Most health systems have achieved a high level of coverage in basic health services, however, they also share problems of inequity and risk of financial instability as a result of ineffective and inequitable financing methods. They differ in terms of potential health achievements and health risks facing the population, both regarding the current health system and the potential effects of future reforms. This article identifies first the trends in health, demographic, and health service indicators. A framework is then presented to understand trends in national health systems and in health sector reforms. On this basis the health systems of Mexico, Costa Rica, and Haiti are then analyzed in greater detail.

Economic, Demographic, and Health Situations The region of Mexico, Central America, and the Caribbean has a population of over 184 million people, with Mexico being the largest at 107 million. The level of urbanization is high, with 69% of the total (and rising) in Mexico and 76% in Cuba. Haiti is the most rural with only 38.8%. The fertility rate is 2.4 births per 1000 for the region, with Haiti reaching 3.8 births per 1000 and Cuba as low as 1.6 births per 1000 (Table 1). The region has an average gross domestic product (GDP) per capita of (international) US$7414 per year, characterizing the region as middle income. This figure varies greatly

Table 1

Demographic characteristics per selected countries and region

Population (thousands) Proportion of urban population (%) Proportion of population less than 15 years (%) Proportion of population 60 or over (%) Life expectancy at birth (years) Total fertility rate (children/women) Infant mortality rate (per 1000) (estimated children less than 1 year) Reported maternal mortality rate (per 100 000) Total mortality rate adjusted by age (per 100 000 hab)

Dominican Republic

Haiti

Cuba

Costa Rica

Mexico

ESC

CA

All region

69 72.7 18.57 10.44 74.7 2 14.8

8528 38.8 34.67 6.01 52.7 3.8 59.6

11 269 76 17.86 15.26 78 1.6 5.6

4327 61.7 26.54 8.29 78.5 2.2 10.2

107 029 76 28.96 7.81 75.7 2.2 19

4141 57 27 10 72 2 14

40 001 53 35 7 71 3 28

184 671 69 30 8 73 2 22

N/A 813.4

523 1252.6

38.5 738.7

30.5 461.1

65.2 627.4

N/A 561

N/A 708

128 685

Reproduced from Organización Panamericana de la Salud, 2005. Área de Análisis de Salud y Sistemas de Información Sanitaria. Iniciativa Regional de Datos Básicos en Salud; Sistema de Información Técnica en Salud. Washington, DC.

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Health Systems of Mexico, Central America and the Caribbean

Table 2

HIV/AIDS prevalence and deaths in selected countries

Country

People living with HIV/AIDS

Adults aged 15 to 49 HIV prevalence rate

Adults aged 15 and over living with HIV

Women aged 15 and over living with HIV

Deaths due to AIDS

Costa Rica Cuba Haiti Mexico Dominican Republic

7400 (3600–24 000) 4800 (2300–15 000) 190 000 (120 000–270 000) 180 000 (99 000–440 000) 66 000 (56 000–77 000)

0.3 (0.1–3.6%) 0.1 (0.0–0.2%) 3.8 (2.2–5.4%) 0.3 (0.2–0.7%) 1.1 (0.9–1.3%)

7300 (3500–24 000) 4700 (2300–15 000) 180 000 (100 000–250 000) 180 000 (97 000–440 000) 62 000 (53 000–73 000)

2000 (860–6700) 2600 (1100–8500) 96 000 (50 000–150 000) 42 000 (17 000–91 000) 31 000 (27 000–37 000)

50% >50%

Cortina (2001), Am. J. Cardiol. Devereux (2000), Am. J. Cardiol. Vasan (2000), Circulation Vasan (1999), JACC

50% 50%

As measured by Vital Statistics, the burden of heart failure and its societal cost are staggering, thereby constituting a public health problem as underscored in guidelines from the American Heart Association and American College of Cardiology (Hunt, 2005). Indeed, heart failure is the single most frequent cause of hospitalization in persons 65 years of age or older, and approximately 4.9 million Americans carry this diagnosis (American Heart Association, 1997). Contrasting with these administrative statistics, however, data on the prevalence and particularly the incidence of heart failure are relatively sparse and lack consistency, as shown in Table 3. Several observations can be made from the review of this table. First, several estimates are derived from hospital discharges. As these are event-based, not person-based, this allows multiple hospitalizations for the same individual to be counted without distinguishing between first and subsequent admission, such that incidence cannot be measured. Further, the diagnoses are not validated using standardized criteria, and

522

Heart Failure

Table 3

Incidence and prevalence of heart failure

Author, years

Incidence

Prevalence

Data source

Diagnostic criteria

Gibson (1962–64)

–

1%

No validation

Schocken (1971–75) Rodeheffer (1981)a Senni (1981, 1991) Ho (1980s)

– 1.1/1000 year 1 3/1000 year 1 1.4–2.3/1000 year

1–2% 0.3% – 0.8%

Croft (1986, 1993)a

22–26/1000 year

Remes (1986–88)

1.0–4.1/1000 year

Cowie (1995–96)

1.3/1000

Gottdiener (1990–96)

19/1000 year

Stewart (1990–96)a Mehjhert (1987–96) Davies M.K. (1995–99)

4.5/1000 year 1 1.5–10.2/1000 –

– – 2–3%

Rural US counties Survey of Physicians NHANES I – Survey, Self-report Olmsted County; age 2500ml1. There is no associated lymphatic pathology.

Immunology The host immune mechanism plays a major role in the pathogenesis of LF, along with parasite-induced pathology. Thus in asymptomatic microfilaremia, which is associated with lymphangiectasia, there is production of cytokines and antibodies that downregulate the immune system and contain the inflammatory reaction. This facilitates the persistence of the parasite in the host without its being destroyed by the immune system. The stage of clinical disease is associated with breakdown of this tolerance and is characterized by the proinflammatory response. The TPE syndrome is a hyperimmune response, associated with extremely high levels of IgE antibodies, markedly raised peripheral eosinophilia count, and absence of microfilaremia (WHO, 1992).

Clinical Management of Cases In LF, there usually are no obvious clinical signs/symptoms during the initial stage of active filarial infection. Similarly, when patients present with chronic lymphedema, there is no active filarial infection in most of them. This makes treatment of LF challenging.

Treatment of Active Filarial Infection

Evidence of active filarial infection is by demonstration of mf in blood, a positive test for circulating filarial antigen, or demonstration of adult worms in the lymphatic system by ultrasonography. The drug of choice is diethylcarbamazine (DEC) given orally, which is very effective in destroying the mf and to some extent the adult worms. The dose of DEC recommended by WHO for the treatment of filariasis is 6 mg kg1 daily for 12 days (Noroes et al., 1997). A single dose of 6 mg kg1 is as effective as the 12-day course, against

both microfilariae and adult worms (Freedman et al., 2002). Ultrasonography has shown that this single dose of DEC kills
50% of the adult worms. If they are insensitive to this single dose, repeated administrations of the drug do not kill the parasite. Treatment with DEC does not seem to reverse the lymphatic damage in adults once it is established (Addiss and Dreyer, 2000). The effective dose of the drug is shown to be 6 mg kg1 in single dose, which may be repeated once in 6 or 12 months, if evidence of active infection persists (Ismail et al., 2001). The adverse effects noticed with DEC are mostly in subjects who have microfilaremia, due to their rapid destruction. Characterized by fever, headache, myalgia, sore throat, or cough that lasts from 24 to 48 h, these symptoms are usually mild, self-limiting, and require only symptomatic treatment. Adverse effects directly related to the drug are very rare. The well-known anthelmintic drug albendazole is shown to destroy the adult filarial worms when given in doses of 400 mg orally twice daily for 2 weeks (Suma et al., 2002). This dosage results in severe scrotal inflammation, presumably due to adult worm death. The optimum dose of this drug for treatment of active filarial infection is yet to be determined. Ivermectin, even though a good microfilaricidal drug, has no proven action on the adult parasite. Drugs acting on the Wolbachia endosymbionts may have a role in treatment of active filarial infection when the parasite is not sensitive to DEC. It has been shown that administration of doxycycline 100 mg orally twice a day for 6 weeks destroys adult worms through its action on Wolbachia (Taylor et al., 2005).

Treatment and Prevention of ADLA Attacks

The most distressing aspect of LF is the acute attacks of ADLA. So their prompt treatment and prevention are of paramount importance. Bed rest and symptomatic treatment with simple drugs like paracetamol are enough to manage mild cases. Any local precipitating factor like injury and bacterial or fungal infection should be treated with local antibiotic or antifungal ointments. Moderate or severe attacks of ADLA should be treated with oral or parenteral administration of antibiotics, depending on the general condition of the patient. Since they result from secondary bacterial infections, systemic antibiotics like penicillin, amoxicillin, or cotrimoxazole may be given in adequate doses until the infection subsides. Bacteriological examination of swabs from the entry lesions may help in selecting the proper antibiotic in severe cases. Antifilarial drugs DEC, ivermectin, or albendazole have no role in the treatment of ADLA attacks, which are caused by bacterial infections (Ramaiah et al., 2000a). Presently there is a simple, effective, cheap, and sustainable method available for prevention of these attacks associated with filarial lymphedema. Many recent studies have shown that this can be achieved by proper ‘local hygiene’ of the affected limbs, carried out regularly (Shenoy et al., 1998). Foot care aimed at prevention of fungal and bacterial infections in order to avert ADLA is the mainstay for disability alleviation in LF elimination programs. This foot-care program consists of washing the affected limb,

Helminthic Diseases: Filariasis especially the webs of the toes and deep skin folds, with soap and water twice a day, or at least once before going to bed, and wiping dry with a clean and dry cloth. Other important components of foot care are clipping the nails at regular intervals and keeping them clean, preventing or promptly treating any local injuries or infections using antibiotic ointments, applying antifungal ointment to the webs of the toes, skin folds, and sides of the feet to prevent fungal infections, regular use of proper footwear, and keeping the affected limb elevated at night (WHO, 2005). In patients with late stages of edema, proper local care of the limb is not always possible due to deep skin folds or warty excrescences. To prevent ADLA attacks in such patients, long-term antibiotic therapy using oral penicillin or long-acting parenteral benzathine penicillin is indicated.

Treatment of Lymphedema and Elephantiasis

In early stages of the disease if the adult worms are sensitive to DEC, treatment with this drug might destroy them and thus logically prevent the later development of lymphedema. Once lymphedema is established, there is no permanent cure. The following treatment modalities offer relief and help to prevent further progression of the swelling: l l l l

l l l

Using elastocrepe bandages or tailor-made stockings while ambulant Keeping the limb elevated at night, after removing the bandage Regular exercise of the affected limb Regular light massage of the limb to stimulate the lymphatic system and to promote flow of lymph toward larger patent vessels. This is useful only in early stages of lymphedema Intermittent pneumatic compression of the affected limb using single or multicell jackets Heat therapy using either wet heat or hot ovens Various surgical options are available to offer relief of lymphedema, like lymph nodo-venous shunts, omentoplasty, and excision with skin grafting. Even after surgery, the local care of the limb should be continued for life, so that ADLA attacks and recurrence of the swelling are prevented.

Oral and topical benzopyrones and flavonoids are advocated for the treatment of lymphedema. These drugs are supposed to reduce high-protein edema by stimulating macrophages to remove the proteins from the tissues when administered for long periods. Further controlled trials are needed to substantiate this claim.

Treatment of Genitourinary Manifestations

Acute-onset hydrocele caused by the death of adult worms in the vicinity of tunica vaginalis is usually self-limiting and resolves in a few weeks. DEC is indicated when there is evidence of active filarial infection. Chronic hydrocele can be corrected by surgery, which is the treatment of choice. Chylocele is symptomatically managed by avoiding fat intake, but surgery is indicated in persistent cases. Attacks of acute epididymo-orchitis respond to rest and treatment with antibiotics. For the treatment of lymphorrhea and elephantiasis of scrotum and penis, corrective surgical

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procedures like excision and skin grafting are indicated. Local hygiene measures are important to prevent acute attacks.

Treatment of Tropical Pulmonary Eosinophilia

DEC is the mainstay of treatment of TPE, and it is given in the dose of 6 mg kg1 daily in three divided doses for a period of 3 weeks or more, depending on the response. In resistant cases, oral corticosteroids are useful.

Control/Elimination Strategy Currently in Operation against LF Control operation against LF has a long history, and many countries like China, Korea, the Maldives, and a few Pacific Islands are at the verge of elimination. Mainstay of control against LF has been chemotherapy and vector control, either alone or in combination. New tools and strategies have become available, largely as a result of TDR research, and the World Health Assembly has adopted a resolution on the global elimination of LF as a public health problem. A Global Programme for the Elimination of Lymphatic Filariasis (PELF) has been launched, and many country-level elimination activities have already taken off. The two principal components of the PELF are to interrupt transmission of infection and to alleviate and prevent the disability caused by the infection and disease. To interrupt transmission, the essential strategy is to treat the entire population ‘at risk’ annually for periods long enough to ensure that levels of microfilariae in the blood remain below those necessary to sustain transmission. For a yearly, single dose, this period has been estimated to be 4–6 years, corresponding to the reproductive lifespan of the parasite. Two drug regimens are being advocated: albendazole (400 mg) plus diethylcarbamazine (DEC; 6 mg kg1); or albendazole (400 mg) plus ivermectin (200 mg kg1). For a treatment regimen based on use of DEC-fortified salt, the period has been found empirically to be 6–12 months of daily fortified salt intake. To alleviate suffering and to decrease the disability caused by LF disease, the principal strategy focuses on avoiding secondary bacterial and fungal infection of limbs or genitals, where lymphatic function has already been compromised by filarial infection. Elimination of the disease will take a long time when the program aims at preventing any new case of filarial infection. This could be achieved only if the entire community at risk consumes the drug. The challenges faced for elimination have been highlighted by the latest Technical Advisory Group (WHO, 2005). It is hoped that LF, which is a cause and an effect of poverty, will get its due attention and focus. Poverty elimination is one of the key Millennium Development Goal, and elimination of filariaisis is one step toward achieving this.

See also: Disability and Rehabilitation; Global Health Law: International Law and Public Health Policy; Global Issues: Urban Health in Developing Countries; Helminthic Diseases: Dracunculiasis; Helminthic Diseases: Onchocerciasis and Loiasis; Parasitic Diseases, an Overview; Male Reproductive Function.

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References Aguinaldo, A.A., Turbeville, J.M., Linford, L.S., Rivera, M.C., Garey, J.R., Raff, R.A., Lake, J.A., 1997. Evidence for a clade of nematodes, arthropods and other moulting animals. Nature 387, 489–493. http://dx.doi.org/10.1038/387489a0. Addiss, D.G., Dreyer, G., 2000. Treatment of lymphatic filariasis. In: Nutman, T.B. (Ed.), Lymphatic Filariasis. Imperial College Press, London, pp. 151–199. Cavalier-Smith, T., 1983. A 6-kingdom classification and a unified phylogeny. In: Schwemmler, W., Schenk, H.E.A. (Eds.), Endocytobiology II. de Gruyter, Berlin, pp. 1027–1034. Cavalier-Smith, T., 1998. A revised six-kingdom system of life. Biol Rev Camb Philos Soc 73, 203–266. Dreyer, G., Medeiros, Z., Netto, M.J., et al., 1999. Acute attacks in the extremities of persons living in an area endemic for bancroftian filariasis: differentiation of two syndromes. Trans. R. Soc. Trop. Med. Hyg. 93, 413–417. Freedman, D.O., Plier, D.A., de Almeida, A.B., et al., 2002. Effect of aggressive prolonged diethylcarbamazine therapy on circulating antigen levels in bancroftian filariasis. Trop. Med. Int. Health 6, 37–41. Grobben, K., 1908. Die systematische Einteilung des Tierreichs. Verhandlungen der Kaiserlich-Königlichen Zoologisch-Botanischen Gesellschaft in Wien 58, 491–511. GlaxoSmithKline, 2006. Lymphatic Filariasis. FAQs. http://www.gsk.com/community/ filariasis/qanda.htm (accessed November 2007). Global Alliance to Eliminate Lymphatic Filariasis, n.d. http://www.filariasis.org/ resources/indepthinfo.htm. Global Alliance to Eliminate Lymphatic Filariasis, n.d. http://www.filariasis.org/index.pl? iid¼1768. Hatschek, B., 1888. Lehrbuch der Zoologie. Gustav Fischer, Jena, 1, Lieferung, p. 144. Hise, A.G., Gillette-Ferguson, I., Pearlman, E., 2004. The role of Endosymbiotic Wolbachia bacteria in filarial disease. Cell Microbiol. 6, 97–104. Ismail, M.M., Jayakody, R.L., Weil, G.J., et al., 2001. Trans. R. Soc. Trop. Med. Hyg. 95 (3), 332–335. Lankester, E.R., 1877. Notes on the embryology and classification of the animal kingdom: Comprising a revision of speculations relative to the origin and significance of germ layers Q. J. Microsc. Soc. 17, 399–454. Linnaeus, C., 1758. Tomus I. Syst. nat, ed. 10. Laurentii Salvii, Holmiae, pp. 1–4. 1-824. Manson-Bahr, P.E.C., Bell, D.R., 1987. Filariasis. Manson’s Tropical Diseases, nineteenth ed. Balliere Tindall, London, p. 353. Michael, E., Bundy, D.A., Grenfell, B.T., 1996. Reassessing the global prevalence and distribution of lymphatic filariasis. Parasitology 112, 409–428. Noroes, J., Addiss, D., Amaral, F., et al., 1996. Occurrence of adult Wuchereria bancrofti in the scrotal area of men with microfilaraemia. Trans. R. Soc. Trop. Med. Hyg. 90, 55–56. Noroes, J., Dreyer, G., Santos, A., et al., 1997. Assessment of efficacy of diethylcarbamazine on adult Wuchereria bancrofti in vivo. Trans. R. Soc. Trop. Med. Hyg. 91, 78–81. Olszeevski, W.L., Jamal, S., Manoharan, G., Lukomska, B., Kubicka, U., 1993. Skin changes in filarial and non-filarial lymphodema of the lower extremities. Trop. Med. Int. Health 44, 40–44. Ramaiah, K.D., Ramu, K., Guyatt, H., VijayaKumar, K.N., Pani, S.P., 1998. Direct and indirect costs of the acute form of lymphatic filariasis to households in rural areas of Tamil Nadu, south India. Trop. Med. Int. Health 3 (2), 108–115. Ramaiah, K.D., VijayaKumar, K.N., Ramu, K., Pani, S.P., Das, P.K., 1997. Functional impairment caused by lymphatic filariasis in rural areas of South India. Trop. Med. Int. Health (J. Trop. Med. Hyg.) 2 (9), 832–838. Ramaiah, K.D., Guyatt, H., Ramu, K., Vanamail, P., Pani, S.P., Das, P.K., 1999. Treatment cost and loss of work time to individuals with cronic lymphatic filariasis in rural communities in south India. Trop. Med. Int. Health 4, 19–25.

Ramaiah, K.D., Das, P.K., Michael, E., Guyatt, H., 2000a. The economic burden of lympahatic filariasis in India. Parasitol. Today 16 (6), 251–253. Ramaiah, K.D., Radhamani, M.P., John, K.R., et al., 2000b. The impact of lymphatic filariasison labour inputs in southern India: results of a multi-site study. Ann. Trop. Med. Parasitol. 94 (4), 353–364. Ramu, K., Ramaiah, K.D., Guyatt, H., Evans, D., 1996. Impact of lymphatic filariasis on the productivity of male weavers in a south Indian village. Trans. R. Soc. Trop. Med. Hyg. 90 (6), 669A–670A. Rudolphi, C. A. 1808–1809. Entozoorum sive Vermium Intesstinalium Historia Naturalis, Vol. 1þ2, 527 pp. & 457pp. (Resp.) Amstelaedami. Shenoy, R.K., Suma, T.K., Rajan, K., Kumaraswami, V., 1998. Prevention of acute adenolymphangitis in brugian filariasis: comparison of the efficacy of ivermectin and diethylcarbamazine, each combined with local treatment of the affected limb. Ann. Trop. Med. Parasitol. 92, 587–594. Suma, T.K., Shenoy, R.K., Kumaraswami, V., 2002. Efficacy and sustainability of foot-care programme in preventing acute attacks of adenolymphangitis (ADL) in brugian filariasis. Trop. Med. Int. Health 7, 763–766. Taylor, M., Makunde, W.H., McGary, F.M., et al., 2005. Macrofilaricidal activity after doxycycline treatment of Wuchereria bancrofti: a double-blind, randomized placebo-controlled trial. Lancet 365, 2116–2121. Taxonomicon, 2006. http://www.sn2000.taxonomy.nl/taxonomicon/ToxnTree.aspx. Vanamail, P., Subramanian, S., Das, P.K., Pani, S.P., Rajagopalan, P.K., 1990. Estimation of fecundic life span of Wuchereria bancrofti from longitudinal study of human infection in an endemic area of Pondicherry (south India). Indian J. Med. Res. 91, 293–297. WHO, 1992. Lymphatic Filariasis: The Disease and Its Control. World Health Organization, Geneva, Switzerland. Tech. Rep. Ser. 821. WHO, 1999. Removing Obstacles to Healthy Development. World Health Organization Report on Infectious Diseases. http://www.who.int/infectious-disease-report/pages/ textonly.html. WHO, 2000. Lymphatic Filariasis. Fact Sheet No.102. http://www.who.int/mediacentre/ factsheets/fs102/en/ (accessed November 2007). WHO, 2005. Sixth Meeting of the Technical Advisory Group on the Global Elimination of Lymphatic Filariasis. Weekly Epidemiological Record, Geneva, pp. 401–408. No. 46.

Further Reading Amaral, F., Dreyer, G., Figueredo-Silva, J., et al., 1994. Live adult worms detected by ultrasonography in human bancroftian filariasis. Am. J. Trop. Med. Hyg. 50, 735–757. Rahmah, N., Anuar, A.K., Shenoy, R.K., et al., 2001. A recombinant antigen-based IgG4 ELISA for the specific and sensitive detection of Brugia malayi infection. Trans. R. Soc. Trop. Med. Hyg. 95, 280–284. Weil, G., Lammie, P.J., Weiss, N., 1997. The ICT filariasis test: a rapid format antigen test for diagnosis of bancroftian filariasis. Parasitol. Today 13, 401–404.

Relevant Websites http://www.who.int/lymphatic_filariasis/resources – Lymphatic Filariasis Details on World Health Organization Website. http://www.filariasis.org.uk/resources/gaelf.htm – Lymphatic Filariasis Support Centre (Global Alliance to Eliminate Lymphatic Filariasis (GAELF)). http://www.pon.nic.in/vcrc – Vector Control Research Centre (Indian Council of Medical Research).

Helminthic Diseases: Foodborne Trematode Infections Bernard Fried, Lafayette College, Easton, PA, USA Jane E Huffman, East Stroudsburg University, East Stroudsburg, PA, USA Ó 2017 Elsevier Inc. All rights reserved.

Introduction to Foodborne Trematodiasis Foodborne trematodiases (FBT) represent a major group of the neglected tropical diseases (NTDs) (Utzinger et al., 2010) and a public health problem in many parts of the world, with a global burden of 665 000 disability adjusted life years (Furst et al., 2012; Hotez, 2013). FBT often coexist with soil-transmitted helminthiasis (Sayasone et al., 2009, 2011). In 2005, more than 56 million people worldwide were infected with foodborne trematodes, over 7000 people died and 750 million (>10% of the world’s population) others worldwide remain at risk of contracting FBTs. Cases of FBT have been reported from over 70 countries worldwide; however, South-East Asia and South America are the most affected areas. People become infected through the consumption of raw fish, crustaceans, or vegetables that harbor the trematode. In these regions, infections with FBT represent a significant public health problem (WHO, 2013). Within countries, transmission is often restricted to limited areas and reflects behavioral and ecological patterns, such as people’s food habits, methods of food production and preparation, and the distribution of the intermediate hosts. Over 100 species of FBT are known to infect humans, although only several are responsible for much of the FBT disease burden. Clonorchiasis, opisthorchiasis, fascioliasis, and paragonimiasis are the infections that pose the most significant public health and economic burden. Clonorchiasis and opisthorchiasis are confined to Asia, while paragonimiasis can be found in Africa, Asia, and Latin America. Fascioliasis is a global disease, affecting a significant number of countries throughout the world. As with the NTDs at large, most FBTs affect the poorest people in rural areas of the endemic countries. Many factors contribute to the high prevalence of these infections, including lack of education, poor recognition of the trematode infections because of their vague clinical presentation, poverty, malnutrition, lack of food inspection, and poor sanitation (Graczyk and Fried, 2007; Hotez et al., 2008; Keiser and Utzinger, 2009; Sripa et al., 2010). Keiser and Utzinger (2009) summarized the taxonomy and key characteristics of foodborne trematodes. The life cycle and contextual determinants were depicted, and estimates of the atrisk population and number of infections, geographic distribution, history, and ecological features of the major FBT were reviewed. Current means of diagnosis, treatment, and other control options and clinical manifestations were also highlighted. Fried and Abruzzi (2010) reviewed the literature on imported (allochthonous) and local (autochthonous) cases of FBT infections in the United States of America (USA) from 1890 to 2009. Most of the literature is concerned with imported cases of the opisthorchiids, Clonorchis sinensis, and Opisthorchis viverrini.

International Encyclopedia of Public Health, 2nd edition, Volume 3

We have compiled a list of more than 80 species of trematodes associated with FBT in humans (Table 1). Many of these species infect relatively few people and have minimal impact on health care. Most of the compiled species are intestinal trematodes in the families Echinostomatidae and Heterophyidae. Although some species of both families are significant contributors to FBT, most global concerns are associated with genera in the families Fasciolidae, Opisthorchiidae, and Paragonimidae. Because of the global health significance of FBT associated with fasciolids, opisthorchiids, and paragonimids, considerable coverage of these digeneans is made herein.

Major Groups of Trematodes The major species and families associated with FBT are summarized in Table 1.

Major Gastropod First Intermediate Hosts Gastropod mollusks (snails) are obligatory first intermediate hosts of foodborne trematodes. To initiate a life cycle, the correct snail species must either swallow an egg or be penetrated by the active larval stage that emerges from the egg, the miracidium. Within the correct snail species, a digenean will undergo intramolluskan development by asexual reproduction. Various developmental stages occur, and the miracidium usually gives rise to a sporocyst (amorphous sac) that then gives rise to rediae (active larval stages with a gut and ambulatory appendages). A daughter redia usually gives rise to cercariae, which emerge from the snails and infect a second intermediate animal or plant host and form cysts (encysted metacercariae). Most foodborne trematodes are vectored by freshwater pulmonates (snails with modified lungs), but some use freshwater prosobranchs (snails with gills) as hosts. Marine and land snails play a less significant role in the transmission of FBT. Vectors frequently associated with the more important foodborne trematodes are species of Lymnaea for fasciolids, Biomphalaria for echinostomatids, Pomatiopsis and Semisulcospira for paragonimids, Semisulcospira and Cerithidea for heterophyids, and species of Bulimus and Bithynia for the opisthorchiids.

Second Intermediate Hosts Fish are important second intermediate hosts of many foodborne trematodes. Freshwater fish are a major source of protein for people in Asia, in particular Thailand, China, Laos, and Vietnam. Among the naturally occurring freshwater fish,

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Table 1

The main species of human foodborne trematodes, their geographic locations, and sources of infection

Family

Main species

Geographic location

Source of human infection

Brachylaimidae Dicrocoeliidae

Brachylaima ruminate Dicrocoelium dendriticum Eurytrema pancreaticum Alaria americana Fibricola seoulensis Echinostoma hortense Echinostoma cinetorchis Echinostoma angustitestis Echinostoma ilocanum Echinostoma lindoense Echinostoma malayanum

Australia North America China, Japan USA, Canada Korea Korea, China, Indonesia Japan, Taiwan, Korea China Philippines Indonesia Singapore, Malaysia, Thailand, Philippines, Indonesia Japan Taiwan, China, Indonesia, Thailand Former USSR, China Thailand Hungary, Italy, former USSR, Romania, far East China and Korea China China China India Thailand New York East Asia East Asia East Asia India, Vietnam, Burma, Philippines, Thailand, China, Kazakhstan Korea Far East, Tunisia, Egypt, Turkey, Iran, India Korea, Japan Korea, Thailand Japan Korea China Egypt, Taiwan Taiwan, Thailand Japan Philippines, China, Taiwan, Egypt Thailand, Indonesia, Taiwan, Philippines, south China Egypt Bangladesh, Thailand, Laos, Philippines, Taiwan Japan Philippines Taiwan Taiwan Hawaii, Philippines Philippines, Korea, Japan, China Korea Far East Taiwan Korea Philippines, Hawaii, Japan, Thailand, Korea Korea Japan Philippines, China, Africa Japan, Korea Brazil USA Greenland

Helicid snails Ants Grasshoppers Frogs Frogs Fish (loach) Snails Fish Snails Clams Freshwater snails

Diplostomidae Echinostomatidae

Echinostoma macrorchis Echinostoma revolutum Echinoparyphium paraulum Episthmium caninum Echinochasmus perfoliatus

Fasciolidae Gastrodiscidae Gymnophallidae Heterophyidae

Echinochasmus japonicus Echinochasmus iiliputanus Echinochasmus jiufoensis Echinochasmus fujianensis Artyfechinostomum mehrail Hypoderaeum conoideum Himasthla muehlensi Fasciolopsis buski Fasciola hepatica Fasciola gigantica Gastrodiscoides hominis Gymnophalloides seoi Heterophyes heterophyes Heterophyes nocens Heterophyes dispar Heterophyes katsuradai Centrocestus armatus Centrocestus formosanus Centrocestus cuspidatus Centrocestus caninus Centrocestus kurokawai Haplorchis pumilio Haplorchis yokogawai Haplorchis pleurolophocerca Haplorchis taichui Haplorchis microrchis Haplorchis vanissimus Diorchitrema formosanum Diorchitrema amplicaecale Diorchitrema pseudocirratum Heterophyopsis continua Metagonimus takahashii Metagonimus yokogawai Metagonimus minutus Metagonimus miyatai Stellantchasmus falcatus Stictodora fuscatum Procerovum varium Procerovum calderoni Pygidiopsis summa Phagicola sp. Appophalus donicus Cryptocotyle lingua

Freshwater snails Mollusks, tadpoles, and clams Freshwater fish Fish Fish Fish Fish Fish Snails Snails Clams Watercress Aquatic plants Aquatic plants Aquatic plants, frogs, tadpoles, and crayfish Oysters Fish (mullet, Tilapia) Fish (mullet) Fish (mullet and Tilapia) Fish Fish Freshwater fish, frogs Freshwater fish Fish, frogs Freshwater fish Freshwater fish Shrimp, mullet Fish Freshwater fish Fish Fish Mullet Mullet Mullet Mullet, carp, and goldfish Carp and goldfish Freshwater fish Mullet Fish Mullet Minnows Fish Mullet Mullet Mullet Fish Fish (gobies) (Continued)

Helminthic Diseases: Foodborne Trematode Infections Table 1

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The main species of human foodborne trematodes, their geographic locations, and sources of infectiondcont'd

Family

Main species

Geographic location

Source of human infection

Lecithodendriidae

Phaneropsolus bonnie Phaneropsolus spinicirrus Prosthodendrium molenkampi Spelotrema brevicaeca Clonorchis sinensis Opisthorchis viverrini Amphimerus pseudofelineus Metochis conjunctus Opisthorcis felinus Paragonimus westermani Paragonimus uterobilateralis Paragonimus africanus Paragonimus mexicanus Paragonimus ecuadoriensis Paragonimus kellicotti

Indonesia Thailand Indonesia Thailand, Philippines Japan, China, Korea Thailand, Laos Ecuador North America Ukraine Asia Nigeria, West Africa West and Central Africa Central and South America Ecuador Canada, North and Central America, South America West Africa China Philippines Japan, Korea Thailand Indonesia Russia, Western USA China

Unknown Unknown Fish contaminated with infected naiads Shrimp Fish Fish Fish Fish (common sucker) Fish Crabs, crayfish Unknown Unknown Crabs Crabs Crabs

Microphallidae Opisthorchiidae

Paragonimidae

Paramphistomidae Plagiorchiidae

Troglotrematidae Strigeidae

Watsonius watsoni Fischoederius elongates Plagiorchis philippinensis Plagiorchis muris Plagiorchis harinasutai Plagiorchis javensis Nanophyetus salminocola Cotylurus japonicus

cyprinids are major species that breed in natural water reservoirs, streams, or rivers and are caught daily. The availability of these fish is an essential factor that influences the rate of infection of people with foodborne trematodes such as Clonorchis, Opisthorchis, and some echinostomids. Mollusks are important second intermediate hosts for many foodborne trematodes. Infection with some species of Echinostoma occurs by eating uncooked bivalves that contain metacercariae. Other species of Echinostoma may be transmitted to humans who eat raw or improperly cooked fish, tadpoles, frogs, and snakes. Species of Heterophyidae infect fish, which serve as a source of human infection. Freshwater crustaceans are important second intermediate hosts for many. Sources of Paragonimus westermani infection in humans are freshwater crabs and crayfish. Aquatic vegetations serve as second intermediate hosts for numerous foodborne trematodes. The mode of transmission of Fasciolopsis buski is related to the nutritional customs (feeding habits) of people in East Asia who consume the fruit of water nuts, which are contaminated with metacercariae. Infection results from consumption of the raw pods, roots, stems, or bulbs of certain water plants, often water chestnuts, and is related to the habit of humans peeling metacercariae-contaminated hulls of these vegetables with their teeth before consumption. Nonaquatic plants such as lettuce, alfalfa, mint, and sugarcane, which may be eaten raw, have also been implicated in F. buski infections. Watercress is a major source of human Fasciola hepatica infection (WHO, 1995). Over 300 000 clinical cases of fascioliasis occurred in more than 55 countries in Africa, the Americas, Asia, Europe, and the western Pacific from 1970 to 1990. Large endemic areas have been reported recently in Bolivia, Egypt, Iran, and Peru.

Aquatic plants Aquatic plants Insects Insects Insects Insects Fish Unknown

Epidemiology Intestinal trematodes infecting humans can be considered in six groups: fishborne; snailborne; mollusk- and crustaceanborne; plantborne; amphibianborne; and insectborne (WHO, 1995). Geographical and age-related patterns of human infection overlap with dietary habits. The probability of trematode transmission from animals to humans is influenced by the length of time the animal is infective and the length of time the parasite is viable in the intermediate host. Population groups defined by a specific age, gender, or reported food habit (identified through questionnaire surveys) can in principle be considered as high-risk groups and therefore targeted by preventive chemotherapy interventions. An association has been found between clonorchiasis/ opisthorchiasis and the reported regular consumption of raw freshwater fish and fermented fish. There is also a link with reported alcohol consumption in countries where fish often accompanies drinks (e.g., Republic of Korea and Vietnam). The most affected population groups are typically adults (in some countries young adults and in others older adults); in some areas, males are more affected than females but this pattern is not consistent. An association has been found between fascioliasis and the reported regular consumption of raw aquatic plants or their derivatives, such as juices or infusions. In some areas, females are more affected than men, but this pattern is not consistent. An association has been found between paragonimiasis and the reported regular consumption of raw freshwater crabs and crustaceans. In some areas, raw freshwater crabs and crustaceans are mostly eaten by children and consumption decreases with age, but this pattern is not consistent.

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The stability of the parasite in direct transmission, where the trematode is exposed to environmental changes, is also important. The population density of the reservoir animals in the endemic area contributes to the prevalence of infection. Husbandry practices and dose and virulence of the parasite are important factors in transmission. Extensive economic losses have been attributed to FBT in terms of lost productivity, absenteeism, direct health-care costs, and the costs associated with animal infections. The epidemiology of FBT has changed in recent years. In some settings, the prevalence of FBT has decreased significantly, which can be explained by factors such as social and economic development, urbanization, adequate food inspections, health education campaigns, use of chemical fertilizers, and water pollution. In many other areas, however, higher frequencies and transmission dynamics have been observed, which are probably the result of expansion of aquaculture for production of freshwater fish and crustaceans and improved transportation and distribution systems to bring these aquatic foods to local and international markets. Considering the focal nature of FBT infections, identification of endemic areas is crucial. Once this has been done, an operational decision on the most appropriate intervention can be taken, based on the level of endemicity and therefore on the magnitude of the public health problem represented by such infections in the target area. If universal treatment – mass drug administration (MDA) – is chosen, the entire population in the selected area is treated. If targeted treatment or selective chemotherapy is chosen, the population groups or the individuals at highest risk of infection or already infected individuals need to be identified. The identification of both the geographical areas to be targeted by the disease control intervention and the population groups – or the individuals – to be treated requires appropriate diagnostic tools. A number of different tools can be used – medical case reports, demographic characteristics, behavior and habits, signs and symptoms, parasitological examination, immunodiagnosis, and molecular methods.

Symptoms The symptoms attributable to FBT are predominantly due to morbidity rather than mortality. Early and light infections often pass unnoticed, as they are asymptomatic or only scarcely symptomatic. Conversely, if the worm load is high, general malaise is common and severe pain can occur, especially in the abdominal region, and most frequently in the case of fascioliasis. Chronic infections are invariably associated with severe morbidity. Symptoms are mainly organ specific and reflect the final location of the adult worms in the body. In clonorchiasis and opisthorchiasis, the adult worms lodge in the smaller bile ducts of the liver, causing inflammation and fibrosis of the adjacent tissues and eventually cholangiocarcinoma, a severe and fatal form of bile cancer. Both C. sinensis and O. viverrini, and not O. felineus, are classified as carcinogenic agents. In fascioliasis, the adult worms lodge in the larger bile ducts and the gallbladder, where they cause inflammation, fibrosis, blockage, colic pain, and jaundice. Liver fibrosis and anemia are also frequent. In paragonimiasis, the final location of the worms

is the lung tissue. Migration of the worms is possible: cerebral locations are the most severe (WHO, 2013).

Diagnosis of Foodborne Trematodiases The importance of accurate diagnosis cannot be overemphasized for adequate patient management and for monitoring of community-based helminth control programs (Keiser and Utzinger, 2009). Parasitological diagnosis of clonorchiasis and opisthorchiasis) can be accomplished by demonstration of eggs in feces, bile, or duodenal fluid. Although the KatoKatz thick smear is the most commonly used technique, other methods such as Stoll’s dilution or quantitative formalin ethyl acetate concentration can be used (Hong et al., 2003; Berguist et al., 2009). Particular problems arise in parasitological diagnosis of zoonotic trematodes in South-East Asia due to the very similar appearances of trematode eggs, including those of Clonorchis, Opisthorchis, and other less common minute intestinal flukes (Chai et al., 2005). Definitive species diagnosis requires morphological identification of the adult flukes following expulsion, surgical resection, or at autopsy. The issue of multiple species has largely been ignored in the literature, resulting in a likely overestimation of C. sinensis prevalence, and underestimation of the prevalence of other species, including minute intestinal flukes (Utzinger et al., 2010). Parasitological methods are insensitive in light infection of other intestinal helminth infections; for example, in an autopsy study, fecal eggs were not detected in individuals harboring less than 20 worms in the liver (Sithithaworn et al., 1991). Excellent results have been reported with the recently developed FLOTAC technique, a multivalent fecal egg count technique (Cringoli, 2006), for F. hepatica in sheep (Keiser et al., 2008). Studies are under way in different epidemiological settings to further validate the FLOTAC technique for human foodborne trematode diagnosis. Serodiagnostic tests have been developed for Clonorchis and Opisthorchis infections. As occurs in the filariases, these tests are relatively nonspecific, and an antibody response can be detected long after curative treatment. Serological tests using recombinant antigens and those detecting isotypespecific antibodies (Wongratanacheewin et al., 2003) may be more specific. Assays using specific recombinant antigens for the diagnosis of C. sinensis or O. viverrini indicate that they are more sensitive and specific than tests using native parasite antigens (Ruangsittichai et al., 2006; Hu et al., 2007; Ma et al., 2007). Regardless of the antigen target, such tests do not enable differentiation between past and current infection. Coproantigen diagnostic testing by ELISA with monoclonal antibodies raised against secretory antigens of intestinal and liver flukes have been developed. These showed a diagnostic sensitivity of 31–57% and a specificity of 70–100%. A monoclonal antibody-based copro-ELISA was found to be more sensitive than conventional fecal examination, particularly in light infections (100 cells/ml is highly efficient in preventing most cases of CMV end-organ disease. Primary prophylaxis with valganciclovir is not recommended. Clinical response to therapy cannot be predicted, although delays in the initiation can significantly jeopardize a positive outcome. Despite substantial toxicity, severe CMV encephalitis is best treated with intravenous ganciclovir, whereas in some cases a combination of intravenous ganciclovir and foscarnet has been used in order to maximize response. Treatment should

Cytomegalovirus Encephalitis Introduction

Figure 7 Coronal MRI images of a patient with CMV encephalitis. Note the thin rim of contrast enhancement lining cerebral ventricles in T1 image with gadolinium (a), with more extensive bright signal visible in cerebral tissues adjacent to ventricles on FLAIR image, indicating inflammation of ependymal surfaces (b). Adapted from Spudich, S.S. HIV/AIDS of the Central Nervous System. Elsevier, 2008.

44

HIV/AIDS of the Central Nervous System

be continued until clinical response is achieved, usually several weeks or even months after therapy onset. Since the role of oral valganciclovir has not been fully elucidated yet, HAART initiation should target for optimal immune recovery. Due to scarce reports on fatal cases of IRIS related to CMV encephalitis, introduction of antiretrovirals can be deferred until clinical improvement is noticed (IDSA guidelines for OIs).

CNS Cryptococcal Infection Introduction The majority of HIV-associated cryptococcal infections are caused by the ubiquitously found encapsulated yeast Cryptococcus neoformans. In some cases Cryptococcus gattii may be the etiologic agent, mostly in Australia and similar subtropical regions. Following introduction of HAART the incidence of the disease has declined substantially and new infections are mostly related to recently diagnosed HIV infection with profound immunosuppression and CD4 count below 100 cells/ml. Cryptococci are spread through inhalation of the encapsulated yeast found in the soil and may virtually affect all systems, although cryptococcal meningitis is the most common and most severe manifestation of the disease. There are limited data suggesting that exposure to bird droppings may increase the risk of cryptococcal infection (Gullo et al., 2013).

positive (95% sensitivity) in both meningeal and nonmeningeal cryptococcosis, and its presence may precede symptom onset by weeks or months. A positive result should be followed by lumbar puncture in order to rule out CNS involvement even in the absence of neurologic symptoms and signs. CrAg in CSF is also a useful marker positive in more than 70% of cases. The immense burden of organisms associated with the disease may disrupt CSF drainage thus resulting in elevated intracranial pressure and hydrocephalus. CSF opening pressure may be > 25 cm H2O in 60–80% of patients on initial diagnostic evaluation and is predictive of increased diseaserelated mortality. Indeed, communicating hydrocephalus in the context of cryptococcal meningoencephalitis is a significant cause of irreversible neurological damage and death. Neuroimaging with MRI scanning reveals the presence of hydrocephalus often accompanied by meningeal enhancement (Thurnher and Donovan Post, 2008). In some patients, contrast-enhanced focal lesions may be present within the basal ganglia and cerebellum indicative of focal cerebritis (Figure 8).

Therapy In the United States primary prophylaxis in the absence of positive serum CrAg is not recommended, even though prospective controlled trials showed that prophylactic fluconazole in patients with CD4 count below 100 cc mm 3 can reduce the frequency of primary cryptococcal disease. Recommendation

Clinical Presentation and Diagnosis Cryptococcal CNS infection in patients with AIDS usually presents as subacute meningitis or meningoencephalitis with a wide spectrum of symptoms ranging from headache alone to rapidly progressive confusion that ultimately may lead to coma and death. Classic signs and symptoms of meningeal irritation such as neck stiffness occur only in 25–35% of cases. Fungal infiltration of the optic and auditory cranial nerve may lead to visual and hearing loss, sometimes with minimal accompanying symptoms such as drowsiness or lethargy. Cryptococcal encephalopathy is the result of increased intracranial pressure manifested as altered mental status, personality changes, memory loss, and lethargy. When diagnosed in a patient with advanced HIV infection, cryptococcosis is usually disseminated with a variety of systems concomitantly affected such as the skin, lungs, bone marrow, and others. The absence of typical meningeal signs is the result of profound immunosuppression associated with AIDS that ultimately limits inflammatory response to the presence of Cryptococcus. This is subsequently reflected in CSF analysis which in most cases reveals mild lymphocytic pleocytosis with slightly elevated protein levels and low-to-normal glucose. Despite minimal findings in the CSF, especially in the setting of advanced HIV infection, India ink preparation for identification of the fungal capsule reveals numerous yeast forms in 60–80% of cases. Blood and CSF cultures are usually positive within 7 days in 55% and 95% of cases, respectively. Testing for cryptococcal antigen (CrAg) in serum is a useful screening test for diagnosing cryptococcosis in HIV-positive patients whose CD4 counts are below 100 cells/ml, and especially in those with CD4 less than 50 cells/ml. Serum CrAg is usually

Figure 8 MRI scan of a patient with cerebral cryptococcosis. Although patients with cerebral cryptococcosis may have normalappearing neuroimaging or scans that solely indicate communicating hydrocephalus, in some cases patients develop focal lesions in the cerebellum and occipital lobes that enhance with gadolinium and may represent focal cerebritis adjacent to collections of infected cerebrospinal fluid, as is evident in this case. Adapted from Spudich, S.S. HIV/AIDS of the Central Nervous System. Elsevier, 2008.

HIV/AIDS of the Central Nervous System against such prophylaxis is based on the low frequency of the disease, lack of evidence showing beneficial effect in terms of survival, and possible resistance development. Treatment of cryptococcal meningitis consists of induction, consolidation, and maintenance therapy. Induction therapy consists of an amphotericin B formulation combined with oral flucytosine for at least 2 weeks. In cases where renal dysfunction is expected or established, liposomal amphotericin should be the preferred agent over other amphotericin B formulations. Flucytosine levels should be monitored (suggested peak and trough levels 70–80 mg L 1 and 30–40 mg L 1, respectively) and dose adjusted accordingly in the context of renal impairment. Higher levels are associated with adverse bone marrow effects. Addition of flucytosine is linked to improved survival outcomes and faster CSF sterilization. Although less preferable as an alternative, amphotericin combined with fluconazole may be given in the presence of flucytosine side effects or contraindications. Fluconazole plus flucytosine may be used and is preferable to monotherapy with fluconazole, which should be reserved only for patients unable to tolerate currently recommended schemes. Following at least 2 weeks of induction therapy, amphotericin B and flucytosine can be discontinued in the context of clinical improvement and negative CSF culture. Consolidation therapy for 10 weeks is then initiated consisting of fluconazole at 400–800 mg daily. After consolidation completion the dose is halved to 200 mg daily until CD4 counts are >200 cc mm 3 for 6 months. The role of posaconazole or voriconazole in treating cryptococcosis in HIV patients has not been extensively studied, and when used either as primary or maintenance therapy should be done with caution. Optimal time for initiation of HAART is not clearly defined. Some studies evaluating initiation of antiretrovirals in patients with cryptococcal meningitis showed increased mortality in the early treated HAART group compared to the deferred ART initiation. This increase was mostly notable during the first month of treatment particularly in patients with minimal CSF findings upon diagnosis, thus indicating a possible role for IRIS-related mortality. It is therefore advised to delay HAART initiation at least until induction therapy is completed especially for those patients presenting with elevated intracranial pressure and minimal CSF pleocytosis. In a recent study deferring HAART to allow for 5 weeks of antifungal treatment was suggested, since initiating HAART within 1–2 weeks of onset of antifungal therapy was associated with increased mortality. IRIS associated with CNS cryptococcal disease may have a striking clinical picture and present with high fever, intense headache accompanied by vomiting, and fulminant signs of meningismus. Excessive inflammatory response associated with immune reconstitution is mirrored in CSF analysis findings which may reveal lymphocytic pleocytosis usually above 50 cells mm 3. IRIS is expected approximately 6 weeks after HAART initiation most commonly in patients with profound immunosuppression and CD4 < 50 cells/ml. Differentiating between treatment failure and IRIS can be daunting based only on clinical criteria. Guidance is provided through microbiology since in most cases IRIS presents with negative CSF cultures in contrast to treatment failure which is associated with persistent positive cultures.

45

When present, IRIS should be treated as indicated with lumbar punctures to reduce intracranial pressure and corticosteroids, although official guidelines are not available (IDSA guidelines for the management of cryptococcal disease, 2010).

Neurosyphilis Introduction Infection with Treponema pallidum has been well documented to increase the risk for both acquisition and transmission of HIV infection. There have been conflicting reports on whether coinfection with HIV modifies the protean manifestations of syphilis; it seems, however, that advanced immunosuppression may accelerate syphilis progression and halt serologic response to treatment. In addition, neurologic manifestations associated with early secondary syphilis such as meningitis and strokes appear more frequently in this specific population group. In recent years, syphilis has emerged as an important coinfection among patients living with HIV; thus, clinicians should be alert in identifying atypical symptoms that might be associated with treponemal infection.

Clinical Presentation and Diagnosis Neurosyphilis refers to CNS infection caused by T. pallidum and can occur during all syphilis stages with different clinical presentation. HIV-infected individuals are more prone to developing CNS involvement. Early stage neurosyphilis may be completely asymptomatic or present with symptoms and signs of meningitis such as headache, confusion with delirium, and signs of meningeal inflammatory irritation. Cranial neuropathies in most cases are seen as facial and auditory cranial nerve palsies. Recent reports highlight the increased incidence of ocular disease during the early stage of neurosyphilis. This may involve cases of posterior uveitis, chorioretinitis, and optic neuritis. Finally, meningovascular disease may also be present in the form of ischemic stroke in a young person caused by thrombotic infarction of cerebral vessels. During early stages CSF abnormalities are common and consist of pleocytosis (6–600 cells) of mononuclear predominance, mildly elevated protein concentration, or a reactive CSF VDRL. It is well documented that in persons with syphilis and HIV infection, positive CSF findings are commonly found and associated with CD4 count of less than 350 cells/ml or in combination with RPR titer higher or equal to 1:32. The above is of unknown significance in the absence of clinical signs and symptoms. Presentation of latestage syphilis is expected years or even decades after the initial infection. Brain parenchyma involvement results in paresis characterized by dementia and severe personality changes. Neuroimaging may be positive for cerebral atrophy, while CSF findings are less striking when compared to early stage disease with mild lymphocytic pleocytosis ( ; : and S0 ðt; aÞ ¼ expð  t=sa La Þ$

ð1=s a Þ1 X

. tj j!

[34]

j¼0

The exponential distribution is a special case of the gamma distribution, gamma(k,q), where k ¼ 1 and q ¼ 1/m. Recall that under the reparameterization, sa ¼ 1/ka and qa ¼ saLa, therefore, sa ¼ 1/sa ¼ 1 and t/saLa ¼ tma. Thus, the survival function shown in eqn [34] simplifies to: S0(t;a) ¼ exp(tma). Excess hazard due to disease is modeled by a mixture of exponential distributions. This allows the effect of disease to be heterogeneous among different groups of patients: SD ðtÞ ¼

n X i¼1

pi $expðmi tÞ

[35]

where p1 þ p2 þ . þ pn ¼ 1 represents the proportion of the diseased cohort that belongs to each group. Note that the overall hazard starts as a composite of the hazards in the n groups but decreases toward that in the group with the smallest hazard as time passes and the members of the higher risk groups make up a smaller proportion of the survivors. Van Den Hout describes two methods for estimating the pi and mi parameters from observed survival curves for the disease. In the first method, one assumes that there are two groups, one of which has no excess mortality. From the observed disease-specific survival curve, one picks an arbitrary time, x and another time halfway between 0 and x, then:  2 v 1b S D ðx=2Þ b2 ¼ 1  p b1 b1 ¼  p   ; p S D ðx=2Þ  b S D ðxÞ 1b S D ðx=2Þ  b ! 2 v1  b S D ðx=2Þ m b 1 ¼ In ;m b2 ¼ 0 b x S D ðxÞ S D ðx=2Þ  b [36] In the second method, the parameters for any arbitrary number of groups can be found using a spreadsheet with a optimization procedure by minimizing an error function. The method is described in detail in the paper by Van Den Hout and in a worked example in a spreadsheet that is available on his website (Van Den Hout, 2004). Finally, the survival functions for healthy and diseased individuals are assumed to be independent and therefore the overall survival function is their product. The GAME estimate of LE is then the area under the combined survival curve for individuals at age a: ðN SD ðtÞ$S0 ðt; aÞdt [37] Ld ðaÞ ¼ 0

Using a complex derivation, Van Den Hout shows that the combined LE estimate for a patient at age ‘a’ is: ( 1=Sa )  n X pi v1 1 [38] Ld ðaÞ ¼ 1 þ mi ðSa La Þ m i¼1 i Note that if a particular disease group has no excess mortality, then the expression above involves division by zero. In that case, the summand for that group should be replaced with piLa. Van Den Hout validated the GAME approach using LE tables for Dutch women with ages from 0 to 100 years and with a range of constant disease-specific hazards, m, from 0 to 1. The GAME and DEALE methods were compared to a gold standard model: Ld ðaÞ ¼ ½pa pd $ð1 þ Ld ða þ 1ÞÞ þ ½ð1  pa pd Þ$ð1=2Þ

[39]

where pd is equal to exp(m). Once again, LE estimates for the gold standard are computed starting with the oldest age and working backward. The DEALE underestimated the gold standard LE to a much greater degree (a maximum of 10 years) than did the GAME approach (a maximum of 2 months). However, a better validation might have been achieved if the two methods were compared to an LE estimate produced with a Markov process (see the section Parametric LE Estimation Using Markov Processes below) implementing a Gompertz– Makeham hazard. For validation of the GAME method in a scenario where disease-specific hazard decreases with time, survival curves and LE estimates for both the DEALE and GAME approaches were calculated for breast cancer survival data from the National Cancer Institute. The GAME method more closely approximated the observed data.

Conclusions Regarding the Closed-Form Approaches The advantage of the closed-form approaches is that, despite the complex derivation for some of them, they all result in formulas that are relatively easy to implement with a hand-held calculator or a spreadsheet. There are, however, a few unresolved issues. First, the clinical studies that one might hope to use for LE estimation are often heterogeneous. This complicates the choice of the particular Lasr value to use in the estimation formulas. Furthermore, in order to use these methods – except for the GAME approach – one must make the assumption that the disease-specific hazard estimated from the clinical data is constant across age, sex, race, and other factors. The GAME method has the advantage that a single observed survival curve from a heterogeneous diseased population can be decomposed into a set of subgroups, each with its own constant disease-specific hazard rate. Alternatively, if one has the luxury of having disease-specific mortality data for the subgroups of a cohort then the other methods could be used to estimate an LE for each in turn. Indeed, Benbassat et al. (1993) showed that substantially different LE results were obtained for cancer patients if cancer-specific hazard was modeled to be constant, a function of age at diagnosis, or a function of both age at diagnosis and time since diagnosis. Second, the natural hazards computed from LE tables for the general population represent the composite risk from all causes of death including the disease of interest. Thus methods

Life Expectancy Measurements that combine natural hazards in the general population and disease-specific hazards are actually counting the effect of the disease twice. For rare causes of death, this issue is negligible, but for studies of mortality due to cardiovascular disease, common cancers, and diabetes, the error would be expected to be more substantial.

Parametric LE Estimation Using Markov Processes If one is willing to forego a closed-form approach and engage in numerical approximation, then discrete, Markov process-based calculation of LE has advantages. A two-state (alive and dead) Markov process can be set up and allowed to run until the proportion of the theoretical cohort left in the alive state reaches some negligible value. The resulting output of the Markov process is the LE estimate (see Life Expectancy as the Output of a Markov Process). Note that commonly used decision-analytic software accounts for alive state membership in discrete Markov processes at the end of each time increment or cycle and therefore underestimates the true LE value. This is particularly true when the Markov process is coarse – i.e., when the length of each cycle is a significant proportion of the time horizon (see above). This can be remedied by shortening the cycle length and by adding a value equivalent to a half-cycle length to the LE estimate produced by the Markov process. As an example of the Markov-based approach, Tsevat et al. (1991) used a more complex Markov model to estimate the gain in LE associated with population-wide cardiovascular risk-reduction strategies. Because the Markov process is discrete, the incorporation of annual age-, sex-, and race-specific natural hazards becomes straightforward. It is also straightforward to incorporate disease hazards that have either a multiplicative or an additive effect on natural hazards. For example, a feature of the DEALE method and its extensions is the assumption that the disease-specific and natural hazards are additive. Kuntz and Weinstein (1995) have used a Markov-based approach to examine the differences in calculated LE values when additive and multiplicative models are used. The effect of these different disease-specific effects on the calculated gain in LE associated with treatment was also examined. They use a step function to represent survival without disease: ! t X mASR ðiÞ [40] S0 ðtÞ ¼ exp  i¼1

where mASR(i) is the age-, sex-, and race-specific annual hazard rate for the general population in the ith year after some arbitrary starting age. Then LE at the starting age without disease is: Lasr ¼

n 1 X þ S0 ðtÞ 2 t¼1

[41]

where n is chosen so that S0(n) is negligible. Equation [41] is representative of a two-state Markov process that is allowed to run for n cycles. Under the model where hazard due to disease is additive: ! t X ðmASR ðiÞ þ mD Þ [42] SD ðtÞ ¼ exp  i¼1

429

and the survival function for a cohort of diseased individuals who are treated is: ! t X ðmASR ðiÞ þ mD la Þ [43] SR ðtÞ ¼ exp  i¼1

where la has the value 0 for a perfectly effective treatment and the value 1 for a completely ineffective one. LEs for diseased individuals with and without treatment were computed using Markov processes, as represented in eqn [41], by replacing S0(t) with estimates of SD(t) and SR(t). Estimates for mD and la were obtained by using RCT data and rearranging eqns [42] and [43], respectively: t P   v mASR ðiÞ v  In b S D ðtÞ  i¼1 m bD ¼ t t

[44]

and ba ¼ g

t   P S R ðtÞ  v v  In b mASR ðiÞ

tbm D

i¼1

[45]

Under the model where hazard due to disease is multiplicative: ! t X ðmASR ðiÞ$bD Þ [46] SD ðtÞ ¼ exp  i¼1

and the survival function for a cohort of diseased individuals who are treated is: ! t X ðmASR ðiÞ$bD lm Þ [47] SR ðtÞ ¼ exp  i¼1

where lm has the value ‘1/bD’ for a perfectly effective treatment and the value 1 for a completely ineffective one. Estimates for bD and lm were obtained by using RCT data and rearranging eqns [46] and [47], respectively:   S D ðtÞ In b b bD ¼ In½S0 ðtÞ and bm g

  In b S R ðtÞ ¼ In½S0 ðtÞ$ b bD

[48]

[49]

Kuntz et al. derived these parameter estimates for three large RCTs comparing medical and surgical therapy for coronary artery disease. In general, the multiplicative model produced lower LE estimates and smaller gains in LE for surgery over medical therapy than did the additive model. The difference in DLE between the two approaches ranged from 0.42 to 0.98 years for LE estimates that averaged 21.3 and 14.1 years, respectively, across treatment arms and types of disease-specific effect. When the parameter estimates derived from patients as old as the enrollees in the cardiovascular RCTs were extrapolated to other ages, predictable behavior of the DLE occurred. Under the additive model, the gain in LE associated with surgery declined monotonically with age and was always lower for men. Kuntz et al. show that this is due to the fact that, in the additive model, constant disease-specific hazard has a smaller relative

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Life Expectancy Measurements

magnitude (and therefore treatment is less efficacious in absolute terms) as age increases. Furthermore, since men have a larger burden of death from natural causes at any given age, if disease-specific hazard is the same for men and women, then men have a smaller relative effect of disease-specific hazard and therefore less absolute benefit from treatment. In the multiplicative case, the DLE rises with age and then falls. Men have larger DLE values at younger ages and then lower values at older ages compared to women. Kuntz et al. show that this effect is due to the fact that two factors are in tension: While the relative magnitude of a multiplicative disease effect remains constant, its absolute size increases. Thus treatment efficacy increases with age, while at the same time the LE and therefore the number of years over which the treatment can have an effect decreases with age. For young people who have large LEs, the higher natural hazard experienced by men produces a larger absolute treatment effect compared to women. For older people, shorter LEs become the limiting factor so that women, who have longer LEs than men, experience a larger treatment effect. These effects are artifacts and result from extrapolation of LE estimates from RCT data to other age groups. Kuntz and Weinstein recommend that, wherever possible, parameter estimates for the disease-specific effects should be obtained from RCTs that break survival estimates down by age. Furthermore, the relative proportion of disease-specific to natural deaths across age groups can give a clue as to which model, additive or multiplicative, is operating. If disease-specific deaths fall as a proportion of total mortality in older patients, then an additive effect is likely. Conversely, if the proportion of disease-specific deaths remains constant with age, then a multiplicative model should be used.

Nonparametric LE Estimation It is possible to estimate LE from clinical studies that report Kaplan–Meier (KM) survival curves without resorting to estimating parameters. One must be cautious because a curve derived from heavily censored data is likely to be biased unless the censoring is purely random. Furthermore, the estimated cumulative survival probability of the right-hand tail of the KM curve tends to be unstable because it is based on the data from fewer patients. Also, a true LE estimate cannot be made unless the KM curve extends down to zero probability of survival. Otherwise, the method described below will provide an estimate of the number of life-months accrued by the cohort during the period of observation. In that case, a true LE estimate will require an extrapolation of the KM curve. In order to produce an LE estimate, one must have access to the life table upon which the Kaplan–Meier curve was based. Suppose that there are n observed subjects, and that the ith subject has an associated observation time, ti, and an estimated cumulative survival probability, S(ti), at that time. Estimates of the number of life units associated with the ith individual and the LE are: ( ti ; i ¼ 1 bI i ¼ b Sðti1 Þ$ðti  ti1 Þ; i > 1 [50] n X b bI i LD ¼ i¼1

LE estimates are also possible to derive from Cox regression models if one has access to the original data. The Cox proportional hazard model is:  !   !  ! S t; X ¼ exp  H t; X H t; X   [51] ¼ H0 ðtÞ$exp b1 X 1 þ b2 X 2 þ . þ bp X p Statistical software is readily available for estimating the beta coefficients of a Cox model for right-censored, time-toevent data. If the statistical program reports a value of the survival function for each case in the data set, then it is possible to arrange these estimates and observation times into a table, order them in an ascending fashion by observation time and apply eqn [50] in order to calculate an LE estimate for the cohort. However, one may wish to calculate the LE of a person with particular values for the X variables or the DLE associated with a change in the value of one or more of them. In that case, an estimate of the baseline hazard function, H0(t), is required. Unfortunately, H0(t) is not often reported by statistical programs. However, in the course of estimating the Cox model, if the statistical package offers the option of calculating a logminus-log (lml) and x-beta statistic for each case in the data set, then it is possible to reconstruct the estimated baseline hazard function. Rearranging eqn [51] for the ith case in the data set yields: _ n   !  !o b 0 ðti Þ ¼ exp In  In s ti ; ! Xi H  b $Xi [52] b 0 ðti Þ ¼ expðImli  xbetai Þ H Here, lmli represents the log of the minus log of the estimated survival function for the ith case at ti and xbetai represents the linear combination of the estimated Cox regression coefficients with the ith case’s particular vector of values for the predictor variables, Xi. One calculates an estimate of the baseline hazard function value for each case in the data set. These values, when ordered by ti, can then be used as a lookup table which is set up for interpolation. Then 

 T X _ ! ! c L Dz [53] exp 0 ðjÞ  exp b $ X new j¼1

where the LE value is estimated over T units of time, such that the value of the summand at T is negligible, H0(j) is the interpolated value of the baseline hazard function obtained from the lookup table and Xnew is the new vector of values for the predictor variables. In order to calculate the effect on LE of a difference in one or more of the predictor variables, eqn [53] can be implemented twice using the different values of the vector Xnew and subtracting the resulting LD estimates. An expression for the variance of the LE estimate using this method has not been developed, nor has the magnitude of the bias in the estimate of the baseline hazard function been determined. As discussed in section Closed-Form, Parametric LE Estimation above, this bias may exist because H0(j) is a nonlinear function of the survival estimate. As for nonparametric LE estimation from KM curves, this method will only provide true LE estimates if the survival function extends down to a value close to zero. Otherwise the method provides the number of life-months (or years) accrued by a cohort – or the difference in life-months between two cohorts – during the observation time.

Life Expectancy Measurements

Conclusion Life expectancy can be understood to be equal to the area under a survival curve regardless of its shape. A gain in life expectancy associated with adopting one health strategy over another (or of being in one exposure group vs another) is the area between the respective survival curves. In order to put a given gain into proper perspective, it is necessary to understand the baseline risk in the control group and the proportion of people who are likely to benefit from the intervention. It is certainly a misconception to view gains in life expectancy as increments of time tacked onto the end of a fixed life span. Life expectancy can be estimated from empirical data by a variety of methods that each have strengths and weaknesses.

See also: Cancer Mortality; Cancer Survival; Clinical Epidemiology; Comparative Risk Assessment; Cost-Influenced Treatment Decisions and Cost-Effectiveness Analysis; Decision Analytic Modeling; Longevity of Specific Populations; Measurement and Valuation of Health for Economic Evaluation; Quality Adjusted Life Years.

References Beck, J.R., Kassirer, J.P., Pauker, S.G., 1982a. A convenient approximation of life expectancy (the DEALE): 1. Validation of the method. Am. J. Med. 73, 883–888. Beck, J.R., Pauker, S.G., Gottlieb, J.E., Klein, K., Kassirer, J.P., 1982b. A convenient approximation of life expectancy (the DEALE): 2. Use in medical decision making. Am. J. Med. 73, 889–897. Benbassat, J., Zajicek, G., Van Oortmarssen, G.J., Ben-Dov, I., Eckman, M.H., 1993. Inaccuracies in estimates of life expectancies of patients with bronchial cancer in clinical decision making. Med. Decis. Making 13, 237–244. Keeler, E., Bell, R., 1992. New DEALES: other approximations of life expectancy. Med. Decis. Making 12, 307–311.

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Kuntz, K.M., Weinstein, M.C., 1995. Life expectancy biases in clinical decision making. Med. Decis. Making 15, 158–169. Tsevat, J., Weinstein, M.C., Williams, L.W., et al., 1991. Expected gains in life expectancy from various coronary heart disease risk factor modifications. Circulation 83, 1194–1201. Van Den Hout, W.B., 2004a. The GAME estimate of reduced life expectancy. Med. Decis. Making 24, 80–88. Van Den Hout, W.B., 2004b. The GAME Estimate of Reduced Life Expectancy: Worked-Out Example. Wright, J.C., Weinstein, M.C., 1998. Gains in life expectancy from medical interventions – standardizing data on outcomes. N. Engl. J. Med. 339, 380–386.

Further Reading Cox, D.R., 1972. Regression models and life tables. J. R. Stat. Soc. B 34, 187–220. Gompertz, B., 1825. On the Nature of the Function Expressive of the Law of Human Mortality, vol. 115. Philosophical Transcripts of the Royal Society, London, pp. 513–585. Kaplan, E.L., Meier, P., 1958. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53, 457–481. Laupacis, A., Sackett, D.L., Roberts, R.S., 1988. An assessment of clinically useful measures of the consequences of treatment. N. Engl. J. Med. 318, 1728–1733. Naglie, G., Krahn, M., Naimark, D., Redelmeier, D.A., Detsky, A.S., 1997. Primer on medical decision analysis. Part 3. Estimating probabilities and utilities. Med. Decis. Making 17, 136–141. Naimark, D., Naglie, G., Detsky, A.S., 1994. The meaning of life expectancy: what is a clinically significant gain? J. Gen. Intern. Med. 9, 702–707. Naimark, D., Krahn, M., Naglie, G., Redelmeier, D.A., Detsky, A.S., 1997. Primer on medical decision analysis. Part 5. Working with Markov processes. Med. Decis. Making 17, 152–159. Olshansky, S.J., Carnes, B.A., Cassel, C., 1990. In search of Methuselah: estimating the upper limits to human longevity. Science 250, 634–640. Sonnenberg, F.A., Beck, J.R., 1993. Markov models in medical decision making: a practical guide. Med. Decis. Making 13, 322–338. Tsai, S.P., Lee, E.S., Hardy, R.J., 1978. The effect of a reduction in leading causes of death: potential gains in life expectancy. Am. J. Public Health 68, 966–971.

Literacy and Public Health Michael S Wolf, Northwestern University, Chicago, IL, USA Ruth M Parker, Emory University, Atlanta, GA, USA Scott C Ratzan, Johnson & Johnson, St. Stevens-Woluwe, Belgium Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 4, pp. 98–104, Ó 2008, Elsevier Inc.

Efforts to promote self-efficacy and empowerment in health care are changing how the role of the patient is viewed, from passive participant to informed and activated consumer. Health information has become increasingly accessible to consumers of health-care services as a result of the Internet and mass media. In this new era, greater attention on how information is accessed, understood, and used is warranted. The definition of health literacy accepted by the Institute of Medicine (IOM) and National Library of Medicine (NLM) in the United States is the “degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.” It is a multifaceted concept, of which reading ability is a fundamental component. An individual’s ability to read, comprehend, and take action based on health-related material may be closely related to the ability to read, comprehend, and take action based on other types of materials (general literacy). The prerequisite health literacy skill set ultimately is determined by the level of complexity of tasks imparted to individuals by a particular health-care system, and include more than one’s ability to read text in print materials. Rather, health literacy skills encompass a broad range of cognitive and social processes that are involved in the act of comprehending and responding to both oral and print communication. Individuals therefore need to have adequate listening and speaking skills, numeracy ability, and conceptual knowledge to engage in routine self-care activities and to navigate complex healthcare systems (see Figure 1). Within the IOM model, determinants of individual health literacy skills include culture and society and the educational system, as well as the health-care system (see Figure 2). This, perhaps, was the most groundbreaking achievement of the IOM report: the acknowledgment of limited health literacy as a problem mostly situated in the way essential health information is communicated to consumers of health care. As such, the IOM report recommends that the responsibility for

improvement must be shared by these various sectors and that the health-care system carries significant, but not complete, responsibility for improvement.

Beyond the U.S. IOM Model While the accepted definition of health literacy is the same in the United States and the United Kingdom, the definition of health literacy in continental Europe has been expanded to not only include basic health, patient, and consumer competencies (e.g., self-care, navigation, making healthy decisions in the selection and use of goods and services) but citizen competencies as well. This means individuals must share in the responsibility of promoting and protecting health in a society by being informed on health matters, advocating on behalf of health issues, and being proactive instead of only responding to health problems at the time when decisions need to be made. Thus, health literacy in this definition refers to being an empowered consumer of health care. Both the U.S. and European definitions reflect a broad conceptual understanding of health literacy, although it should be noted that the related body of research literature that has led to the eventual creation of this field of study has operationalized the term in a very limited manner. This is explained in part due to the difficulty in measuring certain aspects of the conceptual definitions, and by the early beginnings of research in this area that focused on health associations with patients’ reading ability.

Background The term ‘health literacy’ formally arrived and became part of the U.S. public health lexicon during the 1990s, although investigations of whether patients possess the necessary skills to read,

Literacy

Cultural and conceptual knowledge

Listening

Speaking

Oral literacy

Writing

Reading

Numeracy

Print literacy

Figure 1 Components of health literacy. Reproduced with permission from Nielsen-Bohlman, L., Panzer, A., Kindig, D.A. (Eds.), 2004. Health Literacy: A Prescription to End Confusion. National Academies Press, Washington, DC.

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Ireland, and the United Kingdom. Awareness of the issue and its potential impact on health care and costs has made health literacy a priority for an increasing number of governments around the world.

Potential intervention points 2 Health system

1 Culture and society

Health outcomes and costs

Health literacy

Epidemiology

Education system 3 Figure 2 The Institute of Medicine (IOM) model for health literacy. Reproduced with permission from Nielsen-Bohlman, L., Panzer, A., Kindig, D.A. (Eds.), 2004. Health Literacy: A Prescription to End Confusion. National Academies Press, Washington, DC.

understand, and act on available health information had been conducted for some time before then. What began as a handful of studies evaluating associations between poor reading ability and health knowledge and behaviors since has expanded to an independent field of study. Currently, there are approximately 1000 health literacy-related publications; a large proportion of these address the readability of health materials. Texts, annual conferences, and numerous available funding opportunities are further indication of the rapidly growing awareness of the health literacy agenda. In the United States, where the term was conceived and the clear majority of research performed, the federal government has identified improving the health literacy of Americans as a priority for national public health efforts. As a result of the increased recognition of the importance of literacy skills in health care, the U.S. Department of Education conducted the first national assessment of adult health literacy in 2003, and is expecting to track the progress of Americans at 5-year intervals. From a global perspective, other countries have also begun to individually address the problem of limited health literacy. Both Switzerland and the United Kingdom have recently completed national health literacy surveys, the first of their kind in Europe. Likewise, formative responses to health literacy have been implemented and are now underway within many different national health-care systems, including Canada,

In the United States, estimates of health literacy were first derived from general adult literacy statistics that measured an individual’s functional literacy skills within a variety of daily living situations (including health), as defined by the National Adult Literacy Act of 1991 (see Figure 3). According to the U.S. National Assessment of Adult Literacy (NAAL) of 2003, approximately 14% of U.S. adults possess skills in the lowest level of prose and document literacy, which is termed ‘below basic,’ and 22% are at the lowest level for quantitative literacy. In practical terms, adults at the below-basic level have difficulty reading and understanding information, even in short and common texts (prose, document literacy), and locating easily identifiable numerical information (quantitative literacy). At best, they can perform only the most simple and concrete literacy tasks. However, those with only ‘basic’ literacy proficiency also have limited abilities and are likely to be hindered in routine daily activities. When considering individuals with basic and below-basic skills combined, as many as one-third to one-half of adults in the United States have limited literacy skills. Estimates are significantly higher among the elderly; nearly two-thirds of Americans over the age of 65 have limited levels of prose and document literacy. Those who are socioeconomically disadvantaged, belong to racial/ethnic minority groups, and are from rural locations are also disproportionately afflicted by limited literacy skills. These estimates, however, may not give the full picture for health literacy. For instance, reading fluency and the full range of literacy skills is likely to vary with an individual’s familiarity with the content of the text. Health materials and encounters may be more likely to use difficult and often-unclarified medical terms that are not familiar to many individuals. Therefore, the estimates of limited health literacy using the NAAL general literacy assessment may underestimate the problem. As a response to this concern, the NAAL 2003 included a health literacy assessment that evaluated health literacy proficiency

Prose (reference literature)

Functional literacy

Document (brochures, tables)

Figure 3

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Constellation of skills comprising functional literacy.

Quantitative (calculation, basic math)

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Example of skills needed for health

Health-related goal

Sample tasks and skills needed

Promote and protect health and prevent disease

Read and follow guidelines for physical activity Read, comprehend, and make decisions based on food and product labels Make sense of air quality reports and modify behavior as needed Find health information on the Internet or in periodicals and books Analyze risk factors in advertisements for prescription medicines Determine health implications of a newspaper article on air quality Determine which health websites contain accurate information and which do not Understand the implications of health-related initiatives in order to vote Determine and adopt guidelines for increased physical activity at an older age Read and apply health information regarding child care or elder care Read and interpret safety precautions at work; choose a health-care plan Fill out health insurance enrollment or reimbursement forms Understand printed patient rights and responsibilities Find one’s way in a complicated environment such as a busy hospital or clinical center Ask for clarification Ask questions Make appropriate decisions based on information received Work as a partner with care providers to discuss and develop an appropriate regimen to manage a chronic disease Comprehend required informed consent documents before procedures or for involvement in research studies Advocate for safety equipment based on worker right-to-know information Request access to information based on patient rights documents Determine use of medical records based on the privacy Act Advocate on behalf of others such as the elderly or mentally ill to obtain needed care and services

Understand, interpret, and analyze health information

Apply health information over a variety of life events and situations Navigate the health-care system

Actively participate in encounters with health-care professionals and workers

Understand and give consent Understand and advocate for rights

Reproduced with permission from Nielsen-Bohlman, L., Panzer, A., Kindig, D.A. (Eds.), 2004. Health Literacy: A Prescription to End Confusion. National Academies Press, Washington, DC.

among U.S. adults. However, this and other assessments have all limited the measure of literacy to the ability to use print health information, and not the full list of activities that may fall under capabilities to perform health tasks (see Table 1). The report showed the average health literacy scores of Americans to be lower than average general literacy scores of adults. Those over 65 years of age had the lowest levels of health literacy, placing them on average at the threshold between below-basic and basic proficiency. Adults between the ages of 25–39 reported the highest levels of health literacy, yet still only placing them on average in the basic health literacy proficiency category. Evidence from this first health literacy assessment also confirms the persistence of disparities in health literacy skills as reported with general literacy skills. AfricanAmerican and Latino/Hispanic men and women tested at lower levels of health literacy compared to Whites. In all, the conclusion appears to remain the same: Large numbers of U.S. adults lack the basic competencies enabling them to effectively use various health materials and to accomplish health-related activities.

Considering Culture The racial/ethnic divide in literacy and health literacy skills highlights the significance of limited health literacy as a likely contributing factor to noted health disparities in the United

States. These differences may be deeply rooted in access and quality of opportunities in education and other needed socioeconomic resources. Educational attainment alone has been strongly linked to poorer health in numerous studies. But health disparities may also reflect less experience with the terminology used by physicians and other health-care providers. For people of all ethnicities, ages, and other variations in experience, cultural factors can strongly influence beliefs, communication, and behaviors related to health. Culture is defined as the shared ideas, meanings, and values acquired by individuals as members of society; this is not entirely separate from the idea of health literacy. Acquiring cultural ideas, meanings and values continues throughout one’s lifetime, as ‘lived experiences’ build for individuals. The World Health Organization has acknowledged health literacy within its own definition of the concept as a set of active, adaptable, and dynamic skills that evolve as does our cultural experience. For health, culture includes not only language and vocabulary but also the definitions and meanings attached to health and illness concepts, expectations regarding interactions with health professionals, and proper utilization of health-care services. It is the context that influences notions of how people interface with various health services, and this is the ‘lens’ through which an individual interprets and gives meaning to health information, and eventually to what choices are made. Embedded in culture are many individual, family, and societal

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factors that determine health behaviors and related communication, much of which precede and shape the gradual development of health literacy proficiency.

is needed to examine the impact and usefulness of literacy feedback to clinicians before promoting the use of literacy measures in a clinical role.

Measurement

Why Limited Literacy or ‘Health Literacy’ Affects Health Outcomes

In earlier health literacy studies, general literacy tests from educational research, such as the Wide Reading Achievement Test (WRAT) and the Slosson Oral Reading Test (SORT) were used. Since then, the assessment of health literacy skills in clinical research settings has been predominantly performed with one of two instruments: the Rapid Estimate of Adult Literacy in Medicine (REALM) and/or the Test of Functional Health Literacy in Adults (TOFHLA) or short form (S-TOFHLA). The REALM tests an individual’s ability to recognize and pronounce words, while the TOFHLA measures the ability to read and comprehend text and perform computations involving health-related activities (e.g., reading a prescription label and calculating dosing intervals). Both the REALM and TOFHLA were modeled after general functional literacy measures and provide estimates of literacy ability as applied to health-care contexts. The limitations of these instruments have often dictated which one would be used in a particular research study. For instance, the REALM can be administered quickly (approximately 2 min), but it does not measure comprehension and it is only available in English. The TOFHLA, on the other hand, measures comprehension and is available in both English and Spanish, but its length (20 min or more) has been an obstacle to use when research is performed in clinical settings. A shortened version of the TOFHLA (S-TOFHLA) has been developed, but it still requires about 8 min, precluding its use in many busy clinical settings. A new screening instrument for limited literacy, the Newest Vital Sign (NVS), is a six-item literacy assessment structured around the activity of reading and demonstrating an understanding of information included on a nutrition label. The NVS is short enough (3 min) to use in clinical settings, and it is available in both English and Spanish. Shortened versions of the REALM have also been developed, but are not widely used at this time. Others have also proposed single-item questions to ascertain likelihood of health literacy problems, as well as using years of school completed as a proxy measure for limited literacy ability. Both of these screening strategies have been criticized, though, and may misclassify many patients as having adequate literacy skills when they actually may not. Authors of these tests recommend only aggregate testing to provide profiles of the reading ability of groups of patients in clinics or health systems. They currently do not recommend testing individual patients unless health education interventions are being specifically tailored for the patient. In addition, these experts recommend attending to privacy issues in recording literacy levels in medical records. If providers test patient’s literacy skills, they need to be sensitive to patient’s concerns and potential embarrassment, and ensure that testing results will be confidential. As an additional word of caution, it should be acknowledged that there is no evidence to date that suggests literacy testing results in improved delivery of health care or improved health outcomes. Clearly, additional research

There is a significant amount of research literature demonstrating that individuals with less education, in terms of years of school completed, have worse health outcomes. In most of these studies, educational attainment appears to have a direct effect on health after adjusting for socioeconomic indicators. However, the causal pathways between education and poorer health, including mortality, have not been extensively articulated. While the relationship between health literacy and health outcomes also is not entirely clear, there are plausible mechanisms by which literacy could directly affect health behaviors, compliance with medications, and other pathways to health. Empirical data collected over the past two decades support these links. Limited health literacy has been associated with less health knowledge, worse self-management skills, higher hospitalization rates, worse health, greater mortality risk, and higher health-care costs. In the few studies that have demonstrated associations between limited literacy and health outcomes, literacy has been a more dominant indicator of outcomes than years of education. In order to have a general understanding of the projected pathway through which limited health literacy impacts health outcomes, we have broken down the definition of health literacy to describe in more detail its three requisite functions: (1) obtaining health information and services; (2) processing and understanding health information; and (3) making appropriate health decisions.

Obtaining Health Information and Services Prior studies have shown that individuals with limited oral, written, and quantitative literacy skills face considerable difficulty in accessing print health information materials, and are often challenged when engaging in dialogue with health-care providers. This is likely attributed to the high reading difficulty found among consumer health information materials, which have been reported upon in numerous contexts. Yet low literacy may impair access to health information and subsequent recommended health services in ways other than the ability to read existing printed health materials and to communicate effectively with health services providers. Lower-literate adults have previously been found to be more likely to report their physician to be their only source of health information compared to more functionally literate patients, who may often access multiple informational sources. This is problematic, considering many physicians and other health services providers do not communicate health information and instructions in a manner that is understandable to lower-literate patients, in particular, and to patients without clinical training in general. Many adults, regardless of education and background, find it difficult to navigate the health-care system and decipher the complex health information required to successfully manage

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personal and family health care. This highlights an important point: An individual’s health literacy skills may be closely related to his or her ability to read, comprehend, and take action based on other types of materials (i.e., general literacy). Yet reading comprehension varies with an individual’s familiarity with the content of the text. Therefore, accessing health information that uses difficult medical terms or conversing with a health-care provider may be problematic for an even larger proportion of adults in the United States than previously suggested.

Processing and Understanding Health Information

As a result of problems accessing health materials, persons with limited health literacy skills are at greater risk of having difficulty comprehending health information and medical instructions. Consequentially, several research studies conducted among individuals living with a chronic disease have reported poorer knowledge among lower-literate patients of concepts that are central to having a proper understanding of both disease and treatment. For instance, lower-literate persons with HIV were less able to have a working definition of a CD4 count or viral load. Other studies have cited examples of poor understanding of self-care activities among patients with limited literacy skills, including improper use of metered-dose inhalers for adults with asthma and inadequate knowledge of dietary restrictions among hypertensive patients. This association has also been found for understanding of basic terms commonly used to describe recommended preventive services and medication label instructions. In many of these cases, however, a sizable percentage of functionally literate adults had difficulty understanding basic medical terms associated with the care of their chronic condition or information presented on a medication label. This is further evidence of the inadequacies that persist throughout health-care systems and their ability to provide services to those with limited health literacy skills.

Making Appropriate Health Decisions

The impact of limited health literacy has a cumulative effect. Limitations in access to comprehensible health information leads to poor knowledge and understanding, affecting decision making and health behaviors, and ultimately health outcomes. Patients and families are increasingly asked to participate and to be held responsible in health-care decisions. Yet those with limited health literacy skills will likely face problems during information exchange and deliberation on health decisions due to a lack of information and/or miscommunication and a desire to appear knowledgeable. The consequences of less-informed health decisions are reflected in outcomes. Patients defined as having inadequate health literacy according to the TOFHLA have been previously reported as having poorer physical and mental functioning, higher rates of hospitalization, and, among diabetic patients, poorer glycemic control. Recently, studies found that literacy (as measured by both the REALM and S-TOFHLA) was associated with a greater mortality risk among the elderly. Health literacy may be intrinsically linked to several socioeconomic and cultural factors within an ecological

model, and the combined effect could be predicting these health outcomes.

Responding to Limited Health Literacy At present, little information is available on how best to overcome health literacy barriers. Simplifying written health information has been previously recommended to improve comprehension of health information; however, these ‘enhanced print’ strategies support only minimal improvement in knowledge outcomes among lower-literate individuals. The inclusion of visual aids (i.e., graphics) has been proposed as a better way to improve patient comprehension, recall, and compliance with recommended health behaviors. Multimedia tools have also been promoted as a more sophisticated means for health education that might best respond to the special health learning needs of adults with limited literacy. However, findings have been mixed concerning the efficacy of either graphics in print materials or the use of multimedia tools to improve knowledge transfer among patients with limited health literacy. Other system-based interventions have been developed and tested with more robust results. Clinician-directed training to improve provider–patient communication has led to sizable increases in preventive screening utilization among patients with low literacy. Intensive care-management strategies have been proven to be effective at reducing health literacy barriers among patients with certain chronic conditions, such as heart failure and diabetes, and at a fairly low cost. More research is needed to provide more conclusive evidence as to best practices for overcoming the problem of health literacy, in terms of health promotion, disease prevention, chronic disease management, and health-care navigation.

The Challenge of a Health-Literate Society The 55-year-old World Health Organization preamble states that “informed opinion and active cooperation on the part of the public are of utmost importance in promoting health.” Yet many countries have restrictive policies on health information provision, limiting the opportunity for attaining our goal of a health-literate society. In the United States, poor health literacy has been described as a silent epidemic, with almost half of the adult population lacking the literacy skills to understand and use health information. There are increasing demands on people to be informed and activated consumers, able to make good choices about their health plan, which include picking a good provider and hospital for services and choosing the drug benefit program that best serves their needs and is most cost-effective. Health insurers in the United States promote consumerism in health care through the use of high-deductible health plans with savings accounts and health reimbursement arrangements. They promise consumers choice among health plans, providers, and even treatments; however, this all requires well-informed consumers. In reality, most patients in the United States usually depend on their doctors to act in their best interests.

Literacy and Public Health The challenges of addressing the magnitude of the problems of health literacy are heightened by growing diversity in many countries, as culture gives meaning to health information. An evidence-based review of health literacy research by the Agency for Healthcare Quality and Research in 2004 found that numerous interventions had been shown to improve knowledge in mixed populations that included substantial numbers of people with low literacy. However, the field of research is not currently advanced enough to determine whether certain interventions actually reduce literacy-related disparities in health, and more research is needed to better identify approaches for improving health communication for culturally diverse populations. Informed, activated consumers and patients with better outcomes define a health-literate public. They are more concordant with the people who provide health services; seek care earlier because they recognize and understand warning signs; read and comprehend instructions; understand what their doctors advise them; and are not afraid to ask questions when they do not understand. Health-literate people can seek new and reliable information on the Internet, critically hear and read the news, and place new health studies in context. In articulating a vision for a health-literate America, the IOM report described a society in which everyone has the skills to obtain, understand, and use health information effectively. Importantly, health institutions and systems in the society are responsible for facilitating this by providing clear communication and necessary support to promote health. Those working in public health – private and public funders, professionals from the academic sector, health-care providers, policy makers, researchers, marketers, publishers, information technology professionals, and others – must educate those on the front lines delivering health to embrace and address health literacy. Perhaps it is time for a multisector-driven ‘manifesto’ or ‘convention’ on health information provision to advance the knowledge base and practice to enhance a health-literate public. Improving health literacy is both a process and an outcome for improving health and health care in the United States and elsewhere. To reach the goal of a health-literate public requires prioritization by leadership and worldwide professional communities to raise awareness of the issue and to develop meaningful solutions.

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See also: Health Literacy; Risk Communication.

Further Reading Baker, D.W., 2006. The meaning and the measure of health literacy. J. General Intern. Med. 21, 878–883. Davis, T.C., Long, S.W., Jackson, R.H., et al., 1993. Rapid estimate of adult literacy in medicine: a shortened screening instrument. Fam. Med. 25, 391–395. Dewalt, D.A., Berkman, N.D., Sheridan, S., Lohr, K.N., Pignone, M.P., 2004. Literacy and health outcomes: a systematic review of the literature. J. General Intern. Med. 19, 1228–1239. Gazmararian, J.A., Williams, M.V., Peel, J., Baker, D.W., 2003. Health literacy and knowledge of chronic disease. Patient Educ. Couns. 51, 267–275. Howard, D.H., Gazmararian, J., Parker, R.M., 2005. The impact of low health literacy on the medical costs of Medicare managed care enrollees. Am. J. Med. 118, 371–377. Human Resources and Social Development Canada, 1997. Literacy Skills for the Knowledge Society: Second Report of the International Adult Literacy Survey. Human Resources and Social Development Canada, Ottawa, Canada. Kickbusch, I., 2002. Health literacy: a search for new categories. Health Promot. Int. 15 (3), 183–184. Kickbusch, I., Wait, S., Maag, D., 2006. Navigating Health: The Role of Health Literacy. Alliance for Health and the Future, London. Kutner, M., Greenberg, E., Baer, J., 2005. A First Look at the Literacy of America’s Adults in the 21st Century (NCES 2006–470). U.S. Department of Education. National Center for Education Statistics, Washington, DC. Nielsen-Bohlman, L., Panzer, A., Kindig, D.A. (Eds.), 2004. Health Literacy: A Prescription to End Confusion. National, Washington, DC. Press, A., Parker, R.M., Baker, D.W., Williams, M.V., Nurss, J.R., 1995. The test of functional health literacy in adults: a new instrument for measuring patients’ literacy skills. J. General Intern. Med. 10, 537–541. Parker, R.M., Ratzan, S.C., Lurie, N., 2002. Health literacy: a policy challenge for advancing high-quality health care. Health Aff. 22, 147–153. Pignone, M., DeWalt, D.A., Sheridan, S., Berkman, N., Lohr, K.N., 2005. Interventions to improve health outcomes for patients with low literacy. A systematic review. J. General Intern. Med. 20, 185–192. Ratzan, S., Nov/Dec 2003. From passive patient to health-competent consumer. Consumer Policy, Review 13 (6), 205–211. Rudd, R.E., Kirsch, I., Yamamoto, K., 2004. Literacy and Health in America. Educational Testing Service, Princeton, NJ. Schillinger, D., Grumbach, K., Piette, J., et al., 2002. Association of health literacy with diabetes outcomes. J. Am. Med. Assoc. 288, 475–482. Schwartzberg, J.G., VanGeest, J.B., Wang, C.C. (Eds.), 2004. Understanding Health Literacy: Implications for Medicine, Public Health. AMA Press, Chicago, IL. Wolf, M.S., Gazmararian, J.A., Baker, D.W., 2005. Health literacy and functional health status among older adults. Archiv. Intern. Med. 165, 1946–1952. Wolf, M.S., Knight, S.J., Durazo-Arvizu, R., et al., 2006. Associations of race, literacy, and income with PSA level among men with newly diagnosed prostate cancer. Urology 68, 89–93.

Liver Cancer Michael C Kew, University of the Witwatersrand, Johannesburg, South Africa Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 4, pp. 104–113, Ó 2008, Elsevier Inc.

Glossary Angiography Visualization of arteries using radiographic contrast material. Anorexia Loss of appetite. Ascites Accumulation of fluid within the peritoneal (abdominal) cavity. Bruit A rough sound heard with a stethoscope during the phase of cardiac contraction. Budd-Chiari syndrome A condition caused by blockage of the hepatic veins (which drain blood from the liver) by clotted blood. Canaliculus Little channels through which bile drains from the liver. Cavernous hemangioma Large benign tumor of blood vessels. Chemoembolization To inject an anti-cancer agent into a tumor at the same time as embolizing the tumor. Cirrhotic Cirrhosis is a liver disease characterized by fibrosis and nodular regeneration of the liver. Constitutive Uncontrolled. Crescentic outline The diaphragms normally have a crescentic outline or shape on X-ray of the chest. Cytotoxic Drugs that kill cells; used in treatment of cancers. Doppler A type of ultrasonography. Dysplastic Abnormal-looking preneoplastic cell or nodule. Edema Swelling caused by accumulation of water in the subcutaneous tissue. Embolization To cut off the blood supply to a tumor by introducing a clot into the feeding artery. Eosinophilic Staining red with a particular stain. Fibrolamellar Specific clinical and histologic type of liver cancer. Fibrous septa Sheets of fibrous tissue. Fibrous stroma Tissue between cancer cells that is fibrous. Gadopentetate dimeglumine A radiographic contrast medium. Hemangioendothelioma Type of tumor of blood vessels seen in children. Hemoperitoneum Bleeding into the peritoneal (abdominal) cavity. Hepatocytes The main cells in the liver. Hepatomegaly Enlargement of the liver. Hilar The hilum of the liver is the point where the hepatic artery enters and the bile duct leaves the liver.

Introduction Hepatic tumors may either originate in the liver – from hepatocytes, bile duct epithelium, or mesenchymal tissue – or spread to

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Hypercalcemia Increased calcium level in blood. Hypercitrullinemia Inherited disease of citrulline metabolism. Hypertriglyceridemia Too high a level of triglycerides in the blood. Hypoglycemia Low blood sugar level. Impissated Clotted. Intrahepatic cholelithiasis Formation of gallstones within the bile ducts in the liver. Ischemic necrosis Cell death caused by insufficient supply of blood. Mediastinum Name given to the central portion of the chest. The aorta and superior vena cava run through the mediastinum and the latter may be obstructed by a mass lesion in the mediastinum giving rise to a clinical syndrome. Nonseminomatous A subgroup of tumors of the gonads. Opacify To show vessels during radiography by injecting a radiographic contrast material into the vessel. Paraneoplastic An unusual phenomenon attributable to a tumor. Patency State of openness (if something is patent it is open). Polycythemia An increased amount of hemoglobin in the blood. Porphyria Disease of porphyrin metabolism. Portography Specialized visualization of vessels using radiographic contrast material. Percutaneous Via the skin. Pleomorphic Very abnormal-looking cells. Right hemidiaphragm Right side of the diaphragm. Scirrhous Type of tumor containing a lot of fibrous tissue. Sclerosing cholangitis Disease characterized by fibrous narrowing or occlusion of the bile ducts. Steatohepatitis Liver condition characterized by excessive amounts of fat in the liver and also inflammation of the liver. Thrombi Clots formed by blood or tumor tissue. Tomogram A special form of X-ray which allows a structure to be visualized at a number of depths. Trabecular Pattern of liver cells seen under microscope (columns of cells separated by narrow spaces). Tyrosinemia Inherited disease of tyrosine metabolism.

the liver from primary malignant tumors in distant or adjacent organs. Tumors originating in the liver are either malignant or benign. Of the primary malignant tumors, the most common is hepatocellular carcinoma, with cholangiocarcinoma being

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Liver Cancer the only other tumor that occurs with any frequency. Rare but important primary malignant tumors are hepatoblastoma and angiosarcoma. Benign hepatic tumors, with the exception of hemangiomas, are rare. They include hepatocellular adenoma, hemangioepithelioma, and the tumor-like lesion, focal nodular hyperplasia. In most parts of the world, secondary spread of cancers to the liver (hepatic metastases) is more common than primary malignant tumors.

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The incidence of hepatocellular carcinoma increases progressively with advancing age in all populations, although it tends to level off in the oldest age groups. However, in Chinese and even more in Black African populations, the age distribution is skewed toward a younger age. This phenomenon is most striking in Mozambique, where more than 50% of Shangaan men with the tumor are younger than 30 years of age. Hepatocellular carcinoma is rare in children.

presents with typical symptoms and physical signs, and diagnosis is then relatively easy. Before this late stage is reached, however, clinical recognition is often difficult. The tumor frequently coexists with longstanding cirrhosis, more so in industrialized countries. In these countries, the cirrhosis is usually symptomatic and when hepatocellular carcinoma supervenes the patient has few, if any, symptoms attributable to the tumor. If, in addition, the tumor is small (as it often is in the presence of cirrhosis), it may not be obvious on physical examination. One circumstance that should alert the clinician to the possibility that hepatocellular carcinoma has developed is a sudden and unexplained change in the patient’s condition: He or she may complain of abdominal pain or weight loss; ascites may worsen or become blood-stained or intractable; the liver may enlarge rapidly or develop a bruit or hepatic failure may supervene. In contrast, in Chinese and Black African populations at high risk of hepatocellular carcinoma, the symptoms, if any, of the coexisting cirrhosis are overshadowed by those of the tumor. Hepatocellular carcinomas are generally considerably larger in these populations and the patient’s symptoms and signs are accordingly more florid, and this facilitates clinical diagnosis. The most common symptom is upper abdominal pain, which is usually a dull ache but may become intense in the later stages of the illness. Pain is usually accompanied by weakness, anorexia, and loss of weight. Jaundice is infrequent. Physical findings depend upon the stage of the disease at the time the patient is first seen. Early on there may be no abnormal findings or only evidence of cirrhosis. More often the tumor is advanced at the first visit. The liver is then almost always enlarged, sometimes massively so, especially in Black African and Chinese patients, and may be tender. The surface may be smooth or obviously nodular, and the texture is stony-hard or firm. An arterial bruit (or rarely a friction rub) may be heard over the liver. Ascites may be present and increases in severity with progression of the tumor and the spleen is sometimes slightly enlarged. Slight or moderate wasting may be evident at the time of the first visit. Thereafter, progressive wasting is the rule. Jaundice is unusual and mild early on but may appear or deepen with progression of the disease. Physical evidence of cirrhosis is common in patients in industrialized countries. Atypical presentations of hepatocellular carcinoma are with obstructive jaundice; an acute abdominal crisis when the tumor ruptures causing acute hemoperitoneum; Budd-Chiari syndrome when it invades the hepatic veins and severe pitting edema of the lower limbs when the inferior venal cava is blocked by tumor; superior mediastinal syndrome when the superior vena cava is compressed by malignant lymph nodes in the mediastinum; bone pain in the presence of bony metastases; and respiratory symptoms when the right hemidiaphragm is markedly elevated or pulmonary metastases or a large pleural effusion are present. Hepatocellular carcinoma may also present with one or more of a number of paraneoplastic syndromes, including most often hypoglycemia, polycythemia, or hypercalcemia.

Clinical Presentation

Diagnosis

Primary Malignant Tumors of the Liver Hepatocellular Carcinoma Incidence and Geographic Distribution

Hepatocellular carcinoma is the fifth most common malignant tumor in men and the eighth in women, but is among the three most common tumors in many of the most populous regions of the world. Approximately 550 000 new cases of hepatocellular carcinoma occur globally each year, constituting 5.6% of all new cancers. Hepatocellular carcinoma ranks third in annual cancer mortality rates. High incidences of the tumor occur in eastern and southeastern Asia, some of the western Pacific Islands, and subSaharan Africa, but the tumor is rare or uncommon in most industrialized countries. Intermediate incidences occur in some European and South American countries. Hepatocellular carcinoma is increasing in incidence in a number of industrialized countries, especially in Japan but to a lesser extent in parts of North America and Europe.

Gender Distribution

Men are generally more susceptible to hepatocellular carcinoma. Male predominance is, however, more obvious in populations at high risk for the tumor (mean ratio 3.7:1.0) than in those at low or intermediate risk (2.4:1.0). The main determinant of this difference is the higher rate of chronic hepatitis B virus infection (the most important cause of hepatocellular carcinoma in countries with a high incidence of the tumor) and exposure to the fungal toxin, aflatoxin (another important cause of the tumor in countries with a high incidence of hepatocellular carcinoma) in males than females in populations at high risk for hepatocellular carcinoma. In industrialized countries, patients with hepatocellular carcinoma in the absence of cirrhosis have an approximately equal sex distribution.

Age Distribution

Patients with hepatocellular carcinoma are often unaware of its presence until the tumor has reached an advanced stage. Black Africans, in particular, usually seek treatment late in the illness. When far advanced, hepatocellular carcinoma generally

Conventional tests of hepatic function do not distinguish hepatocellular carcinoma from other hepatic masses or from cirrhosis. Accordingly, they contribute little to the diagnosis of the tumor.

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a-Fetoprotein is an a1-globulin that is normally present in high concentration in fetal serum but in only minute amounts thereafter. Reappearance of high concentrations of the globulin in the serum strongly suggests the diagnosis of hepatocellular carcinoma (or hepatoblastoma). This finding is especially true in populations with a high incidence of hepatocellular carcinoma: Approximately 90% of Chinese and Black African patients have raised serum levels and roughly 75% have diagnostically raised levels (greater than 500 ng ml 1). These percentages are appreciably lower in populations with low or intermediate incidences of the tumor, and a-fetoprotein is consequently a less useful tumor marker in these populations. Raised serum levels range over six orders of magnitude, although figures of greater than 1 million are rare. Synthesis of a-fetoprotein by a tumor is permanent and age-related: The younger the patient, the more likely the serum value is to be raised and the higher the level attained. There is no gender difference in a-fetoprotein production provided the patients are matched for age. No obvious correlation exists between the serum concentration of a-fetoprotein and any of the clinical or biochemical features of the tumor or the survival time of the patient. Small, asymptomatic tumors are accompanied by appreciably lower serum levels of a-fetoprotein than are symptomatic tumors. The reason why 500 ng ml 1 is taken as a diagnostic level of a-fetoprotein is that serum concentrations up to this level may be found in patients with acute and chronic hepatitis and cirrhosis. False-positive results may also occur in patients with tumors of endodermal origin and nonseminomatous tumors of the ovary or testis. Pulmonary metastases may be seen on plain chest radiography, particularly often in Black African and Chinese patients. They are almost always multiple. The right hemidiaphragm may be abnormally raised and may lose its normally crescentic outline. Ultrasonography detects the majority of hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver. Its advantages include safety, availability, and cost-effectiveness, although it has the drawbacks of being nonstandardized and observer-dependent. Approximately two-thirds of hepatocellular carcinomas are uniformly hyperechoic, with the remainder being partly hyperechoic and partly hypoechoic; small, early tumors are hypoechoic. Tumors located immediately under the right hemidiaphragm may be difficult to visualize. Ultrasonography with Doppler is useful for assessing the patency of the inferior vena cava, portal vein and its larger branches, and hepatic veins. Dynamic contrast-enhanced Doppler ultrasonography with intraarterial infusion of carbon dioxide microbubbles and intravenousenhanced color Doppler ultrasonography, by characterizing hepatic arterial and portal venous flow in hepatic nodules, facilitates the differentiation between malignant and benign hepatic nodules. Spiral (helical) computerized tomography and computerized tomography during arterial portography have greatly improved imaging of hepatocellular carcinoma. The images obtained are, however, not specific. Computerized tomography is particularly useful in defining the extent of the tumor within and beyond the liver, and showing the course, caliber, and patency of blood vessels. Because iodized poppy seed oil (Lipiodol) is concentrated and retained in hepatocellular

carcinoma tissue, injection of this material at the end of hepatic arteriography can be used in conjunction with computerized tomography, performed after a suitable delay, to detect very small tumors. Magnetic resonance imaging provides another means of distinguishing hepatocellular carcinoma from normal liver tissue. Many tumors have a low signal intensity on T1-weighted images and a high signal intensity on T2-weighted images. Gradient echo sequences and turbo spin-echo sequences have greatly reduced the time needed for magnetic resonance imaging. Furthermore, use of a contrast agent, such as gadopentetate dimeglumine and superparamagnetic iron oxide, increases the accuracy of magnetic resonance imaging, especially in detecting small hepatocellular carcinomas in cirrhotic livers and distinguishing small hepatocellular carcinomas from hemangiomas or dysplastic nodules uncovered in surveillance programs. Hepatic digital subtraction angiography is helpful in recognizing small hypervascular hepatocellular carcinomas, but may miss early well-differentiated hypovascular tumors. Angiography is also essential in delineating the hepatic arterial anatomy when planning surgical resection, transplantation, bland or chemoembolization of the tumor, or infusion of cytotoxic drugs into the hepatic artery or its branches. Angiography with recirculation will also determine the patency of the hepatic veins. Laparoscopy can be used to detect peritoneal and other extrahepatic spread, ascertain whether the nontumorous part of the liver is cirrhotic, and obtain a biopsy of the liver under direct vision.

Pathology

Definitive diagnosis of hepatocellular carcinoma depends upon demonstrating the typical histological features of the tumor. Samples suitable for diagnosis can usually be obtained by either percutaneous needle biopsy or fine-needle aspiration. Because there is a risk of local, regional, or systemic dissemination of the tumor cells by needling the liver, these procedures should be avoided as long as the tumor is thought to be operable.

Gross Appearance

Hepatocellular carcinoma may take three forms: nodular, massive, or diffuse. The nodular variety accounts for 75% of tumors and usually coexists with cirrhosis. It is characterized by numerous round or irregular nodules scattered throughout the liver, many of which are confluent. The massive type is more common in younger patients without cirrhosis. It is the type most likely to rupture. The diffusely infiltrating variety is rare: A large part of the liver is infiltrated homogeneously by indistinct tumor nodules, which may be difficult to distinguish from the cirrhotic nodules that are almost invariably present. The portal vein and its branches are infiltrated by tumor in approximately 70% of cases seen at necropsy. The hepatic veins and bile ducts are invaded less often.

Microscopic Appearance

Hepatocellular carcinoma is classified histologically into welldifferentiated, moderately differentiated, and undifferentiated (pleomorphic) varieties.

Liver Cancer Well-differentiated: Despite the aggressive nature and poor prognosis of the great majority of hepatocellular carcinomas, most tumors are well differentiated. Trabecular and acinar (pseudoglandular) varieties occur. In the trabecular variety the malignant hepatocytes grow in irregular anastomosing plates separated by sinusoids lined by flat epithelial cells. The trabeculae resemble those of normal adult liver, although they are often thicker and are composed of several layers of cells. The malignant hepatocytes are polygonal with abundant slightly granular cytoplasm that is less eosinophilic than that of normal hepatocytes. The nuclei are large and hyperchromatic with prominent nucleoli. Bile production is the hallmark of hepatocellular carcinoma, regardless of the pattern. A variety of gland-like structures are present in the acinar variety. They are composed of layers of malignant hepatocytes surrounding the lumen of a bile canaliculus, which may contain impissated bile. The individual cells may be more elongated and cylindrical than in the trabecular variety. Moderately differentiated: Solid, scirrhous and clear-cell varieties occur. In the solid type, the cells are usually small. Pleomorphic multinucleated giant cells are occasionally present. The tumor grows in solid masses or cell nests. Central ischemic necrosis is common in the larger tumors. In the scirrhous type, the malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma. Duct-like structures are occasionally present. In most tumors, the cells resemble hepatocytes, although occasionally the cells are clear cells. Undifferentiated: The cells are pleomorphic, varying greatly in size and shape. The nuclei are also extremely variable. Large numbers of bizarre-looking giant cells are present. Occasionally, the cells may be spindle-shaped, resembling sarcoma cells. Extrahepatic metastases are present at necropsy in 40–57% of patients with hepatocellular carcinoma. They are more common (roughly 70%) in patients without coexisting cirrhosis than in those with cirrhosis (approximately 30%). The most frequent sites are the lungs (up to 50%) and regional lymph nodes (approximately 20%). Fibrolamellar hepatocellular carcinoma typically occurs in young patients, has an approximately equal sex distribution, does not produce a-fetoprotein, is not caused by chronic hepatitis B or C viruses, and almost always arises in a noncirrhotic liver. It is more often amenable to surgical treatment and therefore generally has a better prognosis than typical hepatocellular carcinoma. It does not, however, respond to chemotherapy any better than other forms of the tumor. The hepatocytes are characteristically plump and deeply eosinophilic and are encompassed by abundant fibrous stroma composed of thin parallel fibrous strands that separate the cells into trabeculae or nodules. The cytoplasm is packed with swollen mitochondria, and in approximately half of the tumors contains pale or hyaline bodies. Nuclei are prominent and mitoses are rare.

Etiology and Pathogenesis

Hepatocellular carcinoma is multifactorial in etiology and complex in pathogenesis. A number of risk factors for the tumor have been identified. Chronic necroinflammatory hepatic disease, especially cirrhosis, is the most common causal association, especially in industrialized countries. All forms of cirrhosis may be complicated by tumor formation, although not with the same frequency. Constitutive proliferation of

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hepatocytes triggered by continuous cycles of hepatocyte necrosis and regeneration and DNA damage resulting from the generation of oxidative stress by the chronic necroinflammation are the main pathogenetic mechanisms. The most common environmental risk factor for hepatocellular carcinoma is chronic hepatitis B virus infection. It is implicated in about 80% of the hepatocellular carcinoma that occurs at high frequency in eastern and southeastern Asia, the Pacific islands, and subSaharan Africa. Approximately 54% of patients with the tumor globally are infected with the virus. Chronic carriers of the virus are infected very early in life, either by perinatal or horizontal infection, and they are at very high risk of developing the tumor later in life. The virus is thought to be both directly and indirectly hepatocarcinogenic. Many of the patients who develop hepatocellular carcinoma have cirrhosis and this contributes to the carcinogenic process. However, hepatitis B virus DNA becomes integrated into host DNA and is thought to be directly oncogenic. The hepatitis B virus x gene appears to play a central role in the direct hepatocarcinogenicity of this virus. Possible mechanisms include direct disruption of cellular DNA, generation of chromosomal instability, suppression of the function of tumor suppressor genes, and increased transactivation of protooncogenes. Chronic hepatitis C virus infection is an important risk factor in industrialized countries. Together with hepatitis B virus, it is estimated to be responsible for more than 80% of global hepatocellular carcinoma. Virtually every patient with hepatitis C virus-induced hepatocellular carcinoma has cirrhosis and this is thought to be the major contributor to hepatocarcinogenesis. However, evidence is accumulating that the core and NS5A proteins of the virus may be directly carcinogenic. Hepatitis B and C viruses have synergistic hepatocarcinogenic effects. A fungal toxin, aflatoxin B1, is an important cause of the tumor in sub-Saharan Africa, China, and Taiwan. It contaminates certain staple foodstuffs, such as maize and ground nuts. High levels of dietary intake result in the accumulation of an electrophilic metabolite, aflatoxin B1-8,9-exo-epoxide that, together with its metabolite, forms adducts with host DNA that result in the inactivation of the p53 tumor suppressor gene and other genotoxic effects. Aflatoxin B1 and chronic hepatitis B virus infection have synergistic hepatocarcinogenic effects. Iron overload of the liver is a cause of hepatocellular carcinoma in patients with one of two diseases. The first is an inherited disease, known as hereditary hemochromatosis, in which the iron overload results from an inherited predisposition to absorb too much iron from a diet with a normal iron content. The second disease, dietary iron overload in the African, results from the consumption of large quantities of a traditional beer, which is homebrewed in cast iron drums or pots and which therefore contains a high iron content. Excess hepatic iron in these conditions causes cirrhosis, but is also directly hepatocarcinogenic by producing oxygen reactive species and oxidative damage to cellular DNA and other organelles. Recently, it has been realized that nonalcoholic steatohepatitis with its associated metabolic abnormalities of hyperglycemia, insulin resistance, hypertriglyceridemia as well as

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obesity and arterial hypertension, is a risk factor for hepatocellular carcinoma. The resulting cirrhosis contributes to the carcinogenic process, but in addition oxidative damage and other changes are incriminated. A number of rare inherited abnormalities may be complicated by hepatocellular carcinoma. These are a1-;antitrypsin deficiency, glycogen storage disease, hereditary tyrosinemia, hereditary hypercitrullinemia, and acute intermittent porphyria.

Natural History and Prognosis

Symptomatic hepatocellular carcinoma carries a grave prognosis. The main reasons for this are the advanced stage of the disease when the patient is first seen and the presence of coexisting cirrhosis. The natural history of hepatocellular carcinoma in its florid form is one of rapid progression with increasing hepatomegaly, abdominal pain, wasting, and deepening jaundice. In Black African and Chinese populations, death often ensues within 4 months, although in industrialized countries the tumor generally runs a more indolent course with longer survival times.

Treatment

The treatment of hepatocellular carcinoma depends on the burden of disease, the presence or absence of cirrhosis, and the degree of hepatic dysfunction.

Surgical Resection

Surgical intervention offers the only chance of cure. For resection to be considered, the tumor must be confined to one hepatic lobe and be favorably located in that lobe, and ideally the nontumorous tissue should not be cirrhotic. Resection can, however, be considered if the cirrhosis is not severe and the tumor is either confined to the left lobe or, if present in both lobes, allows the surgeon to perform a segmentectomy or limited nonanatomic resection. The number of patients with resectable tumors is small in countries with a high incidence of hepatocellular carcinoma. Even after successful resection, there is a high recurrence rate of the tumor.

Transplantation

Transplantation can be performed in patients in whom the tumor is not resectable but is confined to the liver, or in whom advanced cirrhosis and poor liver function preclude resection. Even patients with reasonably good liver function may be better served by transplantation. Because of undetected spread before surgery, the rate of tumor recurrence is high.

Chemotherapy

A large number of anticancer drugs, including alkylating agents, antitumor antibiotics, antimetabolites, plant alkaloids, platinum derivatives, and procarbazine, have been tried alone and in various combinations, and by different routes of administration, in the treatment of hepatocellular carcinoma, but response rates have invariably been less than 20%. Because single agents have limited value in treating hepatocellular carcinoma, it is not surprising that combinations of these agents are also disappointing. Multidrug resistance is an important factor in the poor outcomes, and the development and testing of drugs that reverse this resistance is in progress. Biologic response modifiers tested to date have not proved to be of value.

Screening for Small Presymptomatic Tumors

Because symptomatic hepatocellular carcinoma is seldom amenable to surgical intervention and responds poorly to conservative modalities of treatment, there is a pressing need either to prevent the tumor or to diagnose it at a presymptomatic stage when surgical intervention is still possible. Mass screening of populations at high risk for the tumor is a daunting and expensive task with a relatively low yield. Long-term surveillance of individuals known to be at high risk (particularly those chronically infected with hepatitis B or C viruses) is more effective and can be cost-effective. Ultrasound examination is used as the initial imaging screen in association with measurement of serum a-fetoprotein levels, usually performed at 6-month intervals.

Prevention

The only very effective means of preventing hepatocellular carcinoma at present is the use of hepatitis B virus vaccination. Universal incorporation of this vaccine into the Expanded Program of Immunization in countries in which infection with this virus is endemic and hepatocellular carcinoma common has already resulted in a more than tenfold decrease in viral carrier rates and a more than 70% reduction in the occurrence of hepatitis B-virus-induced hepatocellular carcinoma in the age cohorts that have received the vaccine.

Cholangiocarcinoma Cholangiocarcinomas may originate from small intrahepatic bile ducts (peripheral cholangiocarcinoma), larger or hilar intrahepatic ducts (hilar cholangiocarcinoma) (when located at the bifurcation of the right and left main intrahepatic bile ducts, referred to as Klatskin tumor), or extrahepatic bile ducts (bile duct carcinoma).

Nonoperative Treatments

Small tumors not amenable to resection because they are multiple or inaccessible or because of severe liver dysfunction have been treated with a variety of intralesional techniques. Alcohol injection was used initially, but more recently radiofrequency ablation has been preferred. Arterial embolization or chemoembolization are additional palliative methods in selected patients. They are also used to reduce the size of the tumor in an attempt to make resection possible or to allow a more conservative resection.

Epidemiology and Etiology

The occurrence of peripheral cholangiocarcinomas shows geographical variation, although not to the same extent as hepatocellular carcinoma. The tumor occurs most often in Hong Kong, Canton and, most notably in northeastern Thailand where it is causally related to chronic infestation with the liver flukes, Clonorchis sinensis and Opisthorchis viverrini. Occasionally, cholangiocarcinoma is a late complication of the use of thorium dioxide (Thorotrast) as

Liver Cancer a radiographic contrast medium. Hilar cholangiocarcinoma may complicate longstanding sclerosing cholangitis, biliary atresia, Caroli’s disease, von Meyenberg complexes, or intrahepatic cholestasis. Intrahepatic cholangiocarcinomas are more common in older age groups (average age at presentation, 50–60 years). The gender distribution is approximately equal.

Clinical Presentation

Peripheral cholangiocarcinomas seldom produce symptoms until the tumor is far advanced. The clinical features are then similar to those of hepatocellular carcinoma, except that jaundice may be more frequent, earlier, and deeper. In addition, the liver tends not to be as enlarged, a bruit is not heard, ascites is much less common, and fever and extrahepatic metastases are less frequent. The clinical picture of hilar cholangiocarcinoma is one of progressive obstructive jaundice, with or without weight loss.

Diagnosis

Apart from the higher serum bilirubin, alkaline phosphatase and g-glutamyl transpeptidase levels in peripheral cholangiocarcinoma, the results of liver biochemical tests are similar to those in hepatocellular carcinoma. a Fetoprotein levels are rarely raised in cholangiocarcinomas. The appearances of peripheral cholangiocarcinoma on ultrasonography and computerized tomography are similar to those of hepatocellular carcinoma. Larger hilar tumors and the resulting ductular dilatation can also be seen with these imaging modalities and endoscopic retrograde or transhepatic cholangiography localizes their site. In peripheral cholangiocarcinoma, the marked desmoplastic reaction characteristic of this tumor causes the branches of the hepatic artery to appear scanty, stretched, and attenuated on hepatic arteriography.

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Hepatoblastoma Epidemiology

Hepatoblastoma is the most common malignant hepatic tumor in children. It occurs almost exclusively in the first 3 years of life. Boys are affected twice as often as girls.

Clinical Presentation

The most common symptom is abdominal swelling, but others are failure to thrive, weight loss, and abdominal pain. The liver is almost always enlarged and firm with a smooth or nodular surface. Jaundice is uncommon. The tumor occasionally presents with isosexual precocity in boys.

Diagnosis

Serum a-fetoprotein levels are raised in 80–90% of patients. The tumor is seen as a nonspecific echogenic mass on ultrasonography or computerized tomography and an avascular mass on hepatic arteriography.

Pathology

Hepatoblastomas arise as malignant derivatives of incompletely differentiated hepatocyte precursors. They are classified into an epithelial type and a mixed epithelial and mesenchymal type. Two types of epithelial cells are present. The first resemble fetal hepatocytes and the second less differentiated embryonal cells. Mixed hepatoblastomas contain both types of cells.

Treatment and Prognosis

Hepatoblastoma is a rapidly progressive tumor, with the fetal variety carrying the worst prognosis. If solitary, the tumor may be resected or liver transplantation performed. Chemotherapy, with or without radiotherapy, may shrink the tumor to the point that it becomes operable. Neither chemotherapy nor radiotherapy is, however, curative.

Angiosarcoma Pathology

Cholangiocarcinomas are usually large and solitary tumors, but they may be multinodular. They arise in a noncirrhotic liver, although hilar tumors, when longstanding, can cause biliary cirrhosis. Hilar cholangiocarcinomas may take the form of a firm intramural tumor encircling the bile duct, a bulky mass centered on the duct and radiating into the surrounding hepatic tissue, or a spongy friable mass within the lumen of the duct. Microscopically, cholangiocarcinomas consist of acinar or tubular structures, resembling adenocarcinomas. Most are well differentiated. The tumor cells provoke a variable but often extensive desmoplastic reaction.

Treatment and Prognosis

Peripheral cholangiocarcinoma carries a poor prognosis. Resection is rarely possible and the results of radiation therapy and chemotherapy are disappointing. Liver transplantation offers the only chance of cure. Hilar cholangiocarcinoma may be resectable, depending on size, position, and spread. For inoperable tumors, bile drainage must be established for relief of symptoms of cholestasis.

Epidemiology

This rare tumor occurs almost exclusively in adults in the sixth and seventh decades. Men are affected four times more often than women.

Etiology

In early reports, this tumor often arose as a late complication of radiographic examination with thorium dioxide. More recently, it has usually followed many years of exposure to vinyl chloride monomers in industry.

Clinical Presentation

The most common presenting symptom is upper abdominal pain, but other frequent complaints are abdominal swelling, malaise, anorexia, weight loss, and rapidly progressing liver failure. The liver is almost always enlarged and is usually tender, with an irregular surface. The patient is often jaundiced. Splenomegaly and ascites may be present.

Diagnosis

Evidence of declining hepatic function is frequently present. Radiopaque deposits of thorium dioxide may be visible in

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the liver and spleen. One or more masses may be seen on ultrasonography, and hepatic arteriography shows a blush and puddling during the middle of the arterial phase, except in the central region, which may be hypovascular.

Complications and Prognosis

Angiosarcomas grow rapidly and the prognosis is very poor.

Pathology

Angiosarcomas are usually multicentric. Their hallmark is blood-filled cysts, although solid tumor growth is also evident. The earliest change is the presence of hypertrophic sinusoidal lining cells in ill-defined loci. With progression, sinusoidal dilatation and disruption of hepatic plates occur and malignant cells become supported by collagen tissue. Enlarging vascular spaces lined by malignant cells cause the lesion to become cavernous.

Treatment

Operative treatment is usually precluded by the advanced state of the tumor. Even when surgery is performed the results are poor. The results of radiotherapy and chemotherapy are poor.

all forms of progestogens contained in contraceptive steroids have been incriminated, especially in preparations with a high hormonal potency.

Clinical Presentation

Hepatocellular adenomas may produce no symptoms and are then usually discovered coincidentally during upper abdominal imaging for other reasons. They may produce upper abdominal pain, which is mild unless hemorrhage into or infarction of the lesion has occurred. The liver may be enlarged and slightly tender. The most alarming presentation is with an acute abdominal crisis resulting from rupture of the tumor with consequent acute hemoperitoneum. This is most likely to occur during pregnancy.

Diagnosis

Hepatic angiography is the most useful aid to diagnosis. Onehalf of the tumors are avascular with vessels seen to be draped over the tumor. Often nearly parallel vessels are seen entering the lesion from the periphery (spoke-wheel appearance).

Pathology Hepatic Metastases The liver is the organ most frequently targeted for metastatic spread of tumors. The reasons for this are the double blood supply to the liver and the presence of fenestrations in the sinusoidal endothelium that facilitate the penetration of malignant cells into the hepatic parenchyma.

Clinical Presentation

Hepatic metastases are often silent or their symptoms are overshadowed by those of the primary tumor. Likely symptoms are malaise, weight loss, or upper abdominal pain. The liver may be enlarged. The surface may be nodular and umbilication of nodules may be felt.

Pathology

Hepatic metastases are almost always multiple. They may be discrete or infiltrative. Subcapsular metastases are often umbilicated. The microscopic appearance duplicates that of the primary tumor.

Diagnosis, Treatment, and Outcome

The diagnosis is made by hepatic imaging, confirmed if necessary by needle biopsy or aspiration cytology. The extent of replacement of liver tissue determines the patient’s prognosis. Metastases from colorectal cancer may be successfully resected, but otherwise there is little that can be done therapeutically.

Hepatocellular adenomas are usually solitary and arise in a normal liver. They are usually 8–25 cm in diameter and are larger in women taking contraceptive steroids. Microscopically, hepatocellular adenomas may mimic normal liver tissue to an astonishing degree. They are composed of sheets or chords of normal-looking or slightly atypical hepatocytes. Kupffer cells are usually markedly reduced in number or are absent. There are few or no portal tracts or central veins.

Treatment and Prognosis

Because of the danger of rupture and the small risk of the adenoma undergoing malignant transformation, surgical resection is recommended. If the lesion is not resected, pregnancy, oral contraceptives, and estrogen-containing preparations should be avoided.

Cavernous Hemangioma Epidemiology

Cavernous hemangioma is the most common benign hepatic tumor and is present in as many as 7% of necropsies. It is thought to be a congenital malformation or hamartoma. Cavernous hemangiomas are present at all ages but most commonly in the third, fourth, and fifth decades. They increase in size during pregnancy and with the taking of estrogencontaining preparations.

Clinical Presentation

Benign Tumors of the Liver Hepatocellular Adenoma Epidemiology and Etiology

Hepatocellular adenoma is extremely rare in men, but is less rare in women taking oral contraceptive steroids, particularly with prolonged usage. Both types of synthetic estrogen and

The great majority are small and asymptomatic and are discovered by chance. Larger or multiple lesions produce symptoms. Upper abdominal pain is the most common complaint. Cavernous hemangiomas occasionally rupture. The only abnormal finding may be an enlarged liver. Cavernous hemangiomas in the liver are occasionally associated with hemangiomas in other organs.

Liver Cancer Diagnosis

Blood-pool radionuclide scanning, bolus-enhanced computerized tomography, magnetic resonance imaging, and hepatic arteriography can be used in the diagnosis of cavernous hemangiomas. Because of the risk of bleeding, percutaneous biopsy should not be performed.

Pathology

Cavernous hemangiomas are usually solitary, although multiple lesions occur in 10% of patients. They are well circumscribed but seldom encapsulated. Microscopically, they are composed of multiple vascular channels lined by a single layer of flat epithelium and supported by fibrous septa. The channels may contain thrombi.

Treatment

The great majority can safely be left alone. Large hemangiomas causing incapacitating pain should be resected.

Infantile Hemangioendothelioma Epidemiology and Clinical Presentation

The importance of this tumor lies in the high incidence of congestive cardiac failure that occurs in infants with the tumor and the resulting 70% mortality rate. The cardiac failure results from arteriovenous shunting of blood in the tumor. Infantile hemangioendothelioma almost invariably presents in the first 6 months of life and is twice as common in girls. It often coexists with hemangiomas in other organs, especially the skin. Small lesions are asymptomatic. The presence of a large tumor is recognized by the diagnostic triad of an enlarged liver, high-output cardiac failure, and multiple cutaneous hemangiomas. The size of the liver is disproportionate to the severity of cardiac failure.

Diagnosis

Hepatic arteriography is particularly helpful in diagnosis. Abnormal vessels arise from the hepatic artery and promptly opacify the liver, the characteristic picture of an arteriovenous shunt. Percutaneous biopsy is contraindicated because of the danger of bleeding.

Pathology

Infantile hemangioendotheliomas are characteristically multifocal and produce a nodular deformity of the whole liver. The nodules vary in size from a few millimeters to many centimeters. Microscopically the tumor is composed of layers of plump endothelial cells: a single layer is a type I pattern, multiple layers a type II pattern. Fibrous stroma may be prominent.

Treatment and Prognosis

The course of infantile hemangioendothelioma is characterized by growth during the early months, followed by gradual involution. If the child survives, the tumor involutes completely. Life-threatening aspects of the disorder are intractable congestive cardiac failure and, to a lesser extent, tumor rupture. The cardiac failure should be treated by conventional means. If this fails, embolization or ligation of the hepatic artery or surgical resection should be attempted.

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Focal Nodular Hyperplasia Focal nodular hyperplasia is a tumor-like lesion. It is a circumscribed, usually solitary lesion composed of nodules of benign hyperplastic hepatocytes surrounding a central stellate fibrous scar.

Epidemiology and Pathogenesis

Focal nodular hyperplasia occurs at all ages, but most patients present in the third and fourth decades. It is hormonedependent and is seen more often in women. The cause is unknown, but an ischemic origin related to vascular malformation is possible.

Clinical Presentation and Diagnosis

Focal nodular hyperplasia is almost always asymptomatic. Mild pain may be felt, particularly with bleeding into or necrosis of the lesion. The mass lesion seen on ultrasonography and computerized tomography is not specific for focal nodular hyperplasia, although the central scar may be seen and is a useful diagnostic pointer. The picture obtained with dynamic contrast-enhanced Doppler ultrasonography with intraarterial infusion of CO2 microbubbles is characteristic.

Pathology

Focal nodular hyperplasia presents as a firm, coarsely nodular light brown or yellowish gray mass of variable size with a dense central stellate scar and radiating fibrous septa that divide the lesion into lobules. The nodule may be small or extremely large. Microscopically, focal nodular hyperplasia closely resembles inactive cirrhosis.

Treatment

Large symptomatic or complicated lesions should be resected, usually by segmental resection or enucleation. Otherwise, focal nodular hyperplasia should be left alone. If the lesion is not resected, contraceptive steroids should be discontinued and pregnancy avoided. There is no convincing evidence that focal nodular hyperplasia is a premalignant condition.

See also: Cancer: Global Burden, Trends, and Projections; Cancer Mortality; Future Organization of Cancer Care.

Further Reading Bannasch, P., Keppler, D., Weber, G. (Eds.), 1989. Liver Cell Carcinoma. Kluwer Academic, Dordrecht, the Netherlands. Bosch, F.X., Ribes, J., Borras, J., 1999. Epidemiology of primary liver cancer. Semin. Liver Dis. 13, 271–285. Clavien, P.A. (Ed.), 2004. Malignant Liver Tumors: Current and Emerging Therapies. Jones and Bartlett Publishers International, London. Craig, J.R., Peters, R.L., Edmondson, H.A., 1988. Tumors of the Liver and Intrahepatic Bile Ducts. Armed Forces Institute of Pathology, Washington, DC. Exelby, P.R., Filler, R.M., Grosfeld, J.M., 1975. Liver tumors in children with particular reference to hepatoblastom and hepatocellular carcinoma. J. Pediatr. Surg. 10, 329–337. Kew, M.C., 1989. Tumor markers of hepatocellular carcinoma. J. Gastroenterol. Hepatol. 4, 373–384.

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Kew, M.C., 1991. The detection and treatment of small hepatocellular carcinoma. In: Hollinger, F.B., Lemon, S.M., Margolis, H. (Eds.), Viral Hepatitis and Liver Disease. Williams and Wilkins, Baltimore, MD. Kew, M.C., Paterson, A.C., 1985. Unusual clinical presentations of hepatocellular carcinoma. J. Trop. Gastroenterol. 6, 10–22. Okuda, K., Tabor, E. (Eds.), 1997. Liver Cancer. Churchill Livingstone, New York. Okuda, K., Ishak, K.G. (Eds.), 1987. Neoplasms of the Liver. Springer Verlag, Tokyo. Tabor, E. (Ed.), 2002. Viruses and Liver Cancer. Elsevier, Amsterdam, the Netherlands.

Tabor, E., DiBisceglie, A.M., Purcell, R.H. (Eds.), 1991. Etiology, Pathology, and Treatment of Hepatocellular Carcinoma in North America. Gulf Publishing Co, Houston, TX. Tang, Z.-Y., 2000. Surgery of hepatocellular carcinoma – current status and future prospects. J. Gastroenterol. Hepatol. 15 (Suppl.), 11, G1–G7. Terblanche, J. (Ed.), 1994. Hepatobiliary Malignancy: Its Multidisciplinary Management. Edward Arnold, London. Weiss, L., Gilbert, H.A. (Eds.), 1982. Liver Metastases, vol. 19. CK Hall, Boston, MA, p. 323. Seminars in Liver Disease.

Long Term Care for Aging Populations Eric Stallard, Duke University, Durham, NC, USA Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 4, pp. 114–126, Ó 2008, Elsevier Inc.

Long-term care (LTC) encompasses a wide range of health and social services including skilled and intermediate nursing care, assisted living, custodial or personal care, adult day care, respite care, home health care, and hospice care; LTC generally does not include care in short-stay hospitals (Actuarial Standards Board, 1999). The primary use of LTC is among people with limitations in one or more activities of daily living (ADLs) or instrumental activities of daily living (IADLs), and people with cognitive impairment (CI), where the expected duration of the limitation or impairment is at least 3 months. Some people use LTC throughout their lives; more generally, the use of LTC increases exponentially with age, making it a significant health and financial risk for the elderly. Use of LTC is associated with developmental disabilities and mental illnesses, chronic diseases, injuries, disabling conditions, physiological frailty, and dementia. LTC use rates are high in the period preceding death. Recovery from conditions requiring LTC declines with age; higher recovery rates among the elderly occur at ages 65–74 and lower rates at ages 85þ. LTC financing varies substantially between and within countries, and according to the LTC user’s income, assets, and social support networks. This article focuses on LTC in the United States.

IADL limitations, of whom 3.5 million were younger than age 65 and 6.0 million were aged 65þ. Manton and Gu (2001) used the 1999 NLTCS to estimate that 7.0 million persons aged 65þ had ADL or IADL limitations. The 1.0 million person difference at age 65þ was the difference between the estimates of the size of the noninstitutionalized LTC population: 4.5 million in the NHIS versus 5.5 million in the NLTCS. Kinosian (2006) performed detailed comparisons of ADL limitations in the NHIS and NLTCS and found that the 1999 NHIS estimate for noninstitutionalized persons was 72.4% of that in the 1999 NLTCS; in contrast, the 1999 NNHS estimate for institutionalized persons was 99.6% of that in the 1999 NLTCS. Blackwell and Tonthat (2003) reported estimates for noninstitutionalized persons in the 1999 NHIS that were 82.8% of the 1999 NLTCS estimates. The above comparisons indicate that the estimates of the size of the population using LTC will depend on the source of the data used in making the estimates, even when using data that are judged to be of high quality and reliability. Time differences in the relative sizes of the NHIS and NLTCS estimates can produce trend differences in the rates of change of the sizes of the population using LTC.

NLTCS LTC Surveys The population using LTC can be defined narrowly based on ADL limitations and more broadly using IADL limitations and/or CI. Variations in operational implementations of each definition can yield vastly different estimates of the size of the population using LTC and its change over time. Wiener et al. (1990) reviewed the measurement of ADL status in 11 national surveys and found that the prevalence of ADL limitations among noninstitutionalized persons in the 1984 National Health Interview Survey Supplement on Aging (NHIS-SOA) was 62% of that in the 1987 National Medical Expenditure Survey (NMES) and 56% of that in the 1984 National Long-Term Care Survey (NLTCS). Freedman et al. (2002) reviewed the quality and consistency of disability trends in seven national surveys and assigned the best ratings to the NLTCS and to a combination of the National Health Interview Survey (NHIS) and the National Nursing Home Survey (NNHS). The NLTCS used a nationally representative stratified list sample of elderly Medicare enrollees aged 65þ years; the NHIS used a complex area-probability sample of the civilian noninstitutionalized population, covering all ages; the NNHS used a stratified two-stage list sample of nursing homes, covering all ages. The combined NHIS-NNHS sample, in theory, overlaps and extends to all ages the elderly sample of the NLTCS. Rogers and Komisar (2003) used the combined 2000 NHIS-NNHS to estimate that 9.5 million persons had ADL or

International Encyclopedia of Public Health, 2nd edition, Volume 4

The best source for details on the use of LTC in the US is the NLTCS. Its purpose was to measure LTC disability and the use of LTC services among the U.S. elderly aged 65þ at multiple points in time. It included six closely related surveys conducted in 1982, 1984, 1989, 1994, 1999, and 2004. LTC disability included ADL and IADL limitations, cognitive impairment (CI), and institutionalization. The six waves constituted a nationally representative longitudinal sample of 49 274 Medicare enrollees aged 65þ. Beginning in 1984, each wave added a replenishment sample of approximately 5000 persons who had passed their 65th birthday since the closing date of the sample drawn for the prior wave. The replenishment sample ensured that each wave contained a representative cross-sectional sample of approximately 20 000 elderly Medicare enrollees. The response rates were generally 95% or higher, except for 2004, which dropped to 91%. The NLTCS employed a two-stage sampling of Medicare enrollment files. The first stage consisted of a short screener interview to assess the inability of a community resident to perform nine ADLs and seven IADLs without help or to determine that the respondent was a resident of a nursing home or a similar LTC institution. Help meant assistance from another person or special equipment needed to perform the activity. The IADLs were recognized as being limited only when the inability to perform the activity was the result of a disability or health problem. A community resident screened in if the duration of the ADL and/or IADL limitation was expected to

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be at least 3 months. Institutionalized persons screened in without any additional conditions. The second stage consisted of a detailed in-person assessment that was given to new and prior screened-in persons, institutionalized persons, and certain supplemental samples of persons who screened out at the first-stage assessment. The ADLs and IADLs were modified in the second stage to facilitate the detailed assessment of the nature of the limitations. One ADL was dropped and one was moved to the IADL list, where it was separated into two component activities. These changes yielded seven ADLs and nine IADLs. The nine IADLs were light housework, laundry, meal preparation, grocery shopping, outside mobility, travel, managing money, taking medication, and making telephone calls. An IADL limitation was recognized only when caused by a disability or health problem. A tenth IADL, heavy housework, was also assessed but was not part of the screener criteria. The seven ADLs were eating, inside mobility, transferring, dressing, bathing, toileting, and continence. The NLTCS questions allowed the ADL limitations to be classified according to the following hierarchy: 1. 2. 3. 4. 5.

needs, but does not receive, help with ADL; performs ADL with special equipment; uses standby help with/without special equipment; uses active help with/without special equipment; unable to perform ADL.

Questions were also asked about the elapsed (but not expected) duration of the ADL limitations and the frequency of help. Beginning in 1994, questions were asked about whether the help actually received on specific ADLs was enough to meet the respondent’s needs, and if not, the frequency at which such insufficiencies occurred. Continence was included in the first-stage screener interview and as part of the toileting module in the second-stage detailed interview; however, it did not trigger the toileting ADL nor was it included as part of the standard set of six flap-item ADLs designed to identify disabled persons in the NLTCS. The NLTCS did not screen for CI in the first-stage assessment. The second-stage detailed interviews employed the Short Portable Mental Status Questionnaire (SPMSQ; Pfeiffer, 1975) in 1982–94 and 2004, and the Mini Mental State Exam (MMSE; Folstein et al., 1975) in 1999. In addition, CI can be inferred when a proxy interview was listed as resulting from senility or Alzheimer’s disease.

Health Insurance Portability and Accountability Act Clarification of the tax treatment of LTC expenses (including LTC insurance) was included in the Health Insurance Portability and Accountability Act of 1996 (HIPAA). HIPAA introduced rules under which LTC expenses could qualify as income-tax-deductible medical expenses. HIPAA required that a licensed health-care practitioner certify that the LTC care recipient is a chronically ill individual on account of one or more of three possible triggering criteria (Internal Revenue Service, 1977): 1. ADL Trigger: The individual is unable to perform without substantial assistance from another individual at least two

out of six ADLs (bathing, dressing, toileting, transferring, continence, and eating) for at least 90 days due to a loss of functional capacity. Substantial assistance means hands-on or standby assistance. Hands-on assistance means the physical assistance of another person without which the individual would be unable to perform the ADL. Standby assistance means the presence of another person within arm’s reach that is necessary to prevent injury to the individual while the individual is performing the ADL. 2. Cognitive Impairment (CI) Trigger: The individual requires substantial supervision to protect him or her from threats to health and safety due to severe cognitive impairment. Severe cognitive impairment means a loss or deterioration in intellectual capacity comparable to Alzheimer’s disease or similar irreversible dementia with a measurable impact on memory, orientation, or reasoning. Substantial supervision means continual supervision (including cueing) that is necessary for the individual’s health/safety. 3. Similar Level Trigger: The individual has a level of disability similar to that described in the ADL Trigger, as determined under regulations developed in consultation with the Department of Health and Human Services (DHHS). This trigger is currently inactive, but may at some future date be activated using, for example, some combination of ADLs and IADLs. By 2002, 90% of all LTC insurance policies sold in the US complied with the HIPAA requirements for tax qualification (Coronel, 2004). These rules are the de jure criteria for classifying LTC expenses as medical expenses, making it reasonable to consider their use in public health and public policy research.

LTC Disability Estimates Table 1 displays the population distribution of the HIPAA ADL and CI Triggers by ADL and IADL disability levels among the U.S. elderly in 1999, based on data from the 1999 NLTCS. The cumulative totals at the bottom of the table indicate that 4.75 million elderly met at least one of the two HIPAA triggering criteria: 2.96 million met the ADL Trigger, 3.44 million met the CI Trigger, and 1.65 million met both triggers. The implementation of the HIPAA ADL Trigger in this article followed the standard NLTCS protocol in accepting as ADL-disabled all cases that met the personal assistance criterion for ADL limitations in the detailed questionnaire without further considering whether the expected disability duration would be at least 3 months. Expected 3-month duration was queried on the screener questionnaire, but only for newly screened-in cases; for previously screened-in cases, expected 3-month duration was queried, if at all, at the time they screened in. Thus, the determination that the expected duration was at least 3 months was incomplete in the NLTCS detailed interview; some cases (e.g., institutionalized persons; the healthy subsamples) were automatically screened in or were otherwise designated for detailed interview without explicitly meeting the expected 3-month duration criterion (Wolf et al., 2005).

Long Term Care for Aging Populations Table 1

449

Distribution of HIPAA triggers by ADL/IADL disability level, United States 1999, age 65 and above, in 000s HIPAA trigger

ADL/IADL disability level

None

CI trigger only

Nondisabled IADL only or inside-mobility 1 ADL 2 ADLs 3 ADLs 4 ADLs 5 ADLs 6 ADLs Total Right cumulative total

27 861 2001 598

564 895 327

30 461 35 211

1786 4750

ADL trigger only

324 237 205 318 229 1313 2963

ADL & CI trigger

214 190 231 415 601 1651 1651

Total

Right cumulative total

28 426 2897 925 539 427 435 733 830 35 211

35 211 6785 3888 2963 2425 1998 1563 830

CI trigger is defined as a score in the range 0–23 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

The standard NLTCS protocol may have a small bias when used to estimate HIPAA ADL prevalence rates. Among the reasons for this opinion are the following: 1. The HIPAA ADL prevalence rate based on two or more ADL impairments in the NLTCS detailed questionnaire would be approximately 15% lower if one eliminated all cases whose disability duration was less than 3 months (Stallard and Yee, 2000). Multiple decrement analysis of these same cases showed that the relative risks of ending the disability episode with institutionalization or death versus recovery or improvement were 1.3 at ages 68 and 70, 2.3 at age 75, 2.9 at age 80, 4.8 at age 85, and 6.3 or higher at ages 90 and over. With the highest absolute numbers of cases that met the two or more ADL impairment criteria occurring at age 81, these relative risks imply that roughly one-quarter of the 15% reduction in prevalence that would result from the elimination of cases with less than 3 months’ duration of disability would be due to recovery or improvement. Hence, the bias induced by failing to screen for expected 3-month duration could be as large as 3.75%. 2. The 3-month minimum duration in the HIPAA ADL Trigger is neither a waiting period nor a qualification period; it is an expectation that may or may not be realized. HIPAA certifiers might assume that the age-specific average durations

Table 2

for two or more ADL disability episodes (in the range 36– 26 months at ages 65–90) (Stallard and Yee, 2000) applied to each individual case, implying that the bias associated with the standard NLTCS protocol could be zero. 3. Alternatively, HIPAA certifiers might rely on model-based (or expert-opinion-based) estimates of the expected individual durations, in which case the bias would be non-zero only if the durations from initial disability to recovery/ improvement were predictable and the model (or expert) yielded at least some predicted durations below 3 months; the bias would reach the upper limit of 3.75% only if the model reproduced the distribution of durations without error. Under these conditions, the bias associated with the use of the standard NLTCS protocol is likely to be substantially less than the upper limit of 3.75%. The estimates for the CI Trigger depend on the scoring range selected for the MMSE. An individual with an MMSE score in the range of 0–23 of a possible 30 points was classified as cognitively impaired in Table 1. An alternative classification would use the range 0–15. The upper bounds of 23 and 15 correspond to the midpoints of the ranges for mild (21–25) and moderate (11–20) dementia identified by Perneczky et al. (2006) using the Clinical Dementia Rating instrument. The impact of the alternative classification rule can be seen in Table 2.

Distribution of modified HIPAA triggers by ADL/IADL disability level, United States 1999, age 65 and above, in 000s Modified HIPAA trigger

ADL/IADL disability level

None

CI trigger only

Nondisabled IADL only or inside-mobility 1 ADL 2 ADLs 3 ADLs 4 ADLs 5 ADLs 6 ADLs Total Right cumulative total

28 317 2583 776

108 313 149

31 677 35 211

571 3534

ADL trigger only

402 296 273 389 249 1608 2963

CI trigger is defined as a score in the range 0–15 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

ADL & CI trigger

137 131 163 344 581 1355 1355

Total

Right cumulative total

28 426 2897 925 539 427 435 733 830 35 211

35 211 6785 3888 2963 2425 1998 1563 830

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Long Term Care for Aging Populations

The number of persons meeting only the CI Trigger declined from 1.79 million to 571 000 million. The total number meeting the CI Trigger declined from 3.44 million to 1.93 million. The number meeting the ADL Trigger was unchanged at 2.96 million. The number meeting at least one of the triggers declined from 4.75 million to 3.53 million. Although the HIPAA CI Trigger uses the terms severe cognitive impairment with a measurable impact, HIPAA did not provide guidance as to the specific cut-points one should use for standard tests such as the MMSE. As a consequence, there may be substantial variation in estimates of the size of the LTC population when different tests of cognitive functioning or different cut-points on the same tests are employed. The remainder of this article employs the criteria in Table 1. The cumulative totals at the right side of Table 1 show the distribution of the 2.96 million persons who met the HIPAA ADL Trigger. Of these, 2.00 million had four or more ADL limitations and 830 000 had six ADL limitations; and, of these, 62% and 72%, respectively, were also cognitively impaired. The number of persons with any ADL or IADL limitation, including limitations in inside mobility, was estimated as 6.79 million. The number of nondisabled persons meeting the CI Trigger was 564 000 (108 000 in Table 2). Since the NLTCS did not screen for CI, this may be an underestimate of the true number. Thus the total number with any CI, ADL, or IADL limitation was at least 7.35 million. Table 3

An area of potential discrepancy in estimating the LTC population involves differences between the list of ADLs in HIPAA and the list used in the NLTCS flap items, which forms the set traditionally used in published reports based on the NLTCS (Manton and Gu, 2001). Five of the six HIPAA ADLs are the same as the traditional six flap-item ADLs in the NLTCS. HIPAA’s ADLs include continence, but not inside mobility. The flap-item ADLs include inside mobility, but not continence. Because continence was measured in the NLTCS, the NLTCS can be used to generate estimates of the population meeting the HIPAA LTC criteria in addition to estimates of the population meeting the traditional NLTCS disability criteria. The former are shown in Tables 1 and 2; the latter are shown in Table 3. The flap-item ADLs in the NLTCS are triggered by the use of special equipment in addition to the use of personal assistance. The largest difference occurs under the column heading None, where 1.14 million persons having two or more flap-item ADLs are classified as not disabled by the HIPAA LTC triggers. The total number of 7.08 million with any ADL or IADL limitations is only 4.3% higher than the corresponding number (6.79 million) in Table 1. The 4.61 million with two or more ADLs in Table 3 is 56% larger than the corresponding number (2.96 million) in Table 1. Table 4 provides a direct comparison between the two sets of classification rules. The 16 000 with one HIPAA ADL that

Distribution of HIPAA triggers by traditional NLTCS ADL/IADL disability level, United States 1999, age 65 and above, in 000s HIPAA trigger

NLTCS ADL/IADL disability level

None

CI trigger only

Nondisabled IADL only 1 ADL 2 ADLs 3 ADLs 4 ADLs 5 ADLs 6 ADLs Total Right cumulative total

27 600 714 1006 564 373 183 20 1 30 461 35 211

530 382 358 294 156 66

ADL trigger only

9 54 181 271 359 438 1313 2963

1786 4750

ADL & CI trigger

2 90 123 200 433 802 1651 1651

Total

Right cumulative total

28 131 1096 1375 1003 834 720 812 1241 35 211

35 211 7080 5984 4609 3606 2773 2053 1241

CI trigger is defined as a score in the range 0–23 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

Table 4

Distribution of HIPAA ADL/IADL disability level by traditional NLTCS ADL/IADL disability level, United States 1999, age 65 and above, in 000s HIPAA ADL/IADL disability level

NLTCS ADL/IADL disability level

Nondisabled

Nondisabled IADL only 1 ADL 2 ADLs 3 ADLs 4 ADLs 5 ADLs 6 ADLs Total Right cumulative total

28 115

IADL only or inside-mobility

255 49 5 3

1090 800 565 314 121 6

28 426 35 211

2897 6785

1 ADL 16 5 309 244 211 125 14 1 925 3888

Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

2 ADLs

11 130 203 150 44 539 2963

3 ADLs

14 84 233 86 9 427 2425

4 ADLs

17 71 329 19 435 1998

5 ADLs

18 304 411 733 1563

6 ADLs

29 801 830 830

Total 28 131 1096 1375 1003 834 720 812 1241 35 211

Right cumulative total 35 211 7080 5984 4609 3606 2773 2053 1241

Long Term Care for Aging Populations Table 5

451

Distribution of HIPAA triggers by sex and age, United States 1999, age 65 and above, in 000s HIPAA trigger

Sex

Age

None

CI trigger only

ADL trigger only

ADL & CI trigger

Total

Right cumulative total

Male

65–74 75–84 85þ Total 65–74 75–84 85þ Total

7700 4456 918 13 074 9342 6306 1739 17 387 30 461 35 211

206 286 139 631 248 529 378 1156 1786 4750

140 184 132 456 221 294 341 857 1313 2963

101 191 142 434 120 426 671 1216 1651 1651

8147 5117 1331 14 594 9931 7556 3129 20 616 35 211

14 594 6447 1331

Female

Total Right cumulative total

20 616 10 685 3129

CI trigger is defined as a score in the range 0–23 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

were nondisabled on the traditional flap-item ADLs and IADLs were all due to incontinence.

LTC Demographics Table 5 displays the distribution of the HIPAA LTC triggers by age and sex among the U.S. elderly population. Among males, 434 000 met both the ADL and CI Triggers, with the largest number of those aged 75–84. Among females, 1.22 million met both the ADL and CI Triggers, with the largest number of those aged 85þ. Among the 6.1% of males who met the ADL Trigger, 49% simultaneously met the CI Trigger; among the 10% of females who met the ADL Trigger, 59% simultaneously met the CI Trigger. Certain patterns of change over age can be more readily assessed using the percentage distributions shown in Table 6. For example, the relative frequency of ADL Trigger cases meeting the CI Trigger increased with age for both sexes, but the increase was larger for females. Moreover, the percentage of females meeting any HIPAA trigger was larger at all ages for females and the relative excess increased with age from 8.1% at age 65–74 to 43% at age 85þ. This latter

Table 6

increase was attributable to the absolute excess of 10.7% of females at age 85þ meeting both the ADL and CI Triggers. Table 7 and Table 8 stratify the population counts and percentage distributions in Tables 5 and 6 by community residence versus residence in an LTC institution, where an LTC institution was a nursing facility or similar setting having a health professional (e.g., registered nurse, licensed practical nurse, licensed vocational nurse, psychiatrist, etc.) on duty for 24 h each day (including weekends). The age–sex group with the largest number of institutional residents was females aged 85þ with 656 000 of the total 1.44 million. The next largest group was females aged 75–84, followed by males aged 75–84. Among institutional residents, 92% met at least one HIPAA LTC trigger, the only notable discrepancy occurring among males aged 65–74, where 80% met at least one trigger. For females aged 65–74, the corresponding value was 89%. For both sexes, the value increased with age, reaching 97% for males aged 85þ and 93% for females aged 85þ. These results indicate that the HIPAA LTC triggers were reasonably successful (i.e., their overall sensitivity was 92%) in meeting their goal of identifying severely disabled elderly persons,

Percent distribution of HIPAA triggers by sex and age, United States 1999, age 65 and above HIPAA trigger

Sex

Age

None

CI trigger only

ADL trigger only

ADL & CI trigger

Any trigger

Total (in 000s)

Male

65–74 75–84 85þ Total 65–74 75–84 85þ Total

94.5 87.1 69.0 89.6 94.1 83.5 55.6 84.3 86.5 100.0

2.5 5.6 10.4 4.3 2.5 7.0 12.1 5.6 5.1 13.5

1.7 3.6 9.9 3.1 2.2 3.9 10.9 4.2 3.7 8.4

1.2 3.7 10.7 3.0 1.2 5.6 21.4 5.9 4.7 4.7

5.5 12.9 31.0 10.4 5.9 16.5 44.4 15.7 13.5

8147 5117 1331 14 594 9931 7556 3129 20 616 35 211

Female

Total Right cumulative total

CI trigger is defined as a score in the range 0–23 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

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Table 7

Distribution of HIPAA triggers by institutional status, sex, and age, United States 1999, age 65 and above, in 000s HIPAA trigger

Institutional status

Sex

Age

None

CI trigger only

ADL trigger only

ADL & CI trigger

Total

Right cumulative total

Community

Male

65–74 75–84 85þ Total 65–74 75–84 85þ Total

7687 4441 913 13 041 9332 6280 1695 17 307 30 349 13 15 4 32 10 26 43 80 112 30 461 35 211

200 272 127 599 238 514 351 1103 1701 6 14 12 32 10 16 27 53 85 1786 4750

128 143 88 359 176 210 178 563 922 12 41 44 96 46 84 164 294 390 1313 2963

71 100 73 244 93 217 249 559 803 31 91 69 190 27 209 421 658 848 1651 1651

8085 4956 1201 14 243 9839 7220 2473 19 532 33 775 61 160 129 351 93 336 656 1085 1436 35 211

14 243 6158 1201

Female

LTC institution

Total Male

Female

Total Right cumulative total

Total

65–74 75–84 85þ Total 65–74 75–84 85þ Total

19 532 9693 2473 351 290 129 1085 992 656

CI trigger is defined as a score in the range 0–23 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

Table 8

Percent distribution of HIPAA triggers by institutional status, sex, and age, United States 1999, age 65 and above HIPAA trigger

Institutional status

Sex

Age

None

CI trigger only

ADL trigger only

ADL & CI trigger

Any trigger

Total (in 000s)

Community

Male

65–74 75–84 85þ Total 65–74 75–84 85þ Total

95.1 89.6 76.0 91.6 94.9 87.0 68.6 88.6 89.9 20.5 9.6 3.4 9.2 10.9 7.9 6.6 7.4 7.8 86.5 100.0

2.5 5.5 10.6 4.2 2.4 7.1 14.2 5.6 5.0 10.1 8.7 9.2 9.1 10.7 4.7 4.2 4.9 5.9 5.1 13.5

1.6 2.9 7.3 2.5 1.8 2.9 7.2 2.9 2.7 19.0 25.3 34.2 27.5 49.3 25.1 25.0 27.1 27.2 3.7 8.4

0.9 2.0 6.1 1.7 0.9 3.0 10.1 2.9 2.4 50.3 56.4 53.2 54.2 29.1 62.3 64.2 60.6 59.1 4.7 4.7

4.9 10.4 24.0 8.4 5.1 13.0 31.4 11.4 10.1 79.5 90.4 96.6 90.8 89.1 92.1 93.4 92.6 92.2 13.5

8085 4956 1201 14 243 9839 7220 2473 19 532 33 775 61 160 129 351 93 336 656 1085 1436 35 211

Female

LTC institution

Total Male

Female

Total Right cumulative total

Total

65–74 75–84 85þ Total 65–74 75–84 85þ Total

CI trigger is defined as a score in the range 0–23 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

assuming that residence in an LTC institution was a valid indicator of severe disability. Meeting a HIPPA LTC trigger, however, does not necessarily imply institutional residency. Table 9 displays the age, sex, and HIPAA LTC-Trigger-specific institutionalization rates for the data displayed in Table 7.

Among those meeting any HIPAA LTC trigger, 31% of females and 21% of males (28% combined) were institutionalized. The institutionalization rates varied significantly depending on the specific triggers that were met. Among those meeting both the ADL and CI Triggers, 54% of females and 44% of

Long Term Care for Aging Populations

453

Percent institutionalized by HIPAA triggers by sex and age, United States 1999, age 65 and above

Table 9

HIPAA trigger Sex

Age

None

CI trigger only

ADL trigger only

ADL & CI trigger

Any trigger

Total

Male

65–74 75–84 85þ Total 65–74 75–84 85þ Total

0.2 0.3 0.5 0.2 0.1 0.4 2.5 0.5 0.4

3.0 4.9 8.5 5.1 4.0 3.0 7.2 4.6 4.8

8.3 22.0 33.5 21.2 20.7 28.7 48.0 34.3 29.7

30.4 47.4 48.5 43.8 22.6 49.1 62.8 54.1 51.4

10.9 21.9 30.3 21.0 14.0 24.7 44.1 31.1 27.9

0.8 3.1 9.7 2.4 0.9 4.4 21.0 5.3 4.1

Female

Total

CI trigger is defined as a score in the range 0–23 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

males (51% combined) were institutionalized; among those meeting only the ADL Trigger, 34% of females and 21% of males (30% combined) were institutionalized; and among those meeting only the CI Trigger, 4.6% of females and 5.1% of males (4.8% combined) were institutionalized. The overall institutionalization rates were 5.3% for females and 2.4% for males (4.1% combined); these rates increased significantly across the three age groups, from 0.8% to 9.7% for males and 0.9% to 21% for females. Within the HIPAA LTC triggered groups, the highest institutionalization rate (63%) was for females aged 85þ meeting both the ADL and CI Triggers; the next highest rate (49%) was for females aged 75–84 meeting the same triggers. Table 10 stratifies the institutionalization rates in Table 9 by marital status. Among those meeting any HIPAA LTC trigger, 15% of married females and 12% of married males (13%

Table 10

combined) were institutionalized. For the same conditions, 35% of unmarried females and 34% of unmarried males (35% combined) were institutionalized. Among those meeting both the ADL and CI Triggers, 35% of married females and 26% of married males (30% combined) were institutionalized. For the same conditions, 57% of unmarried females and 67% of unmarried males (59% combined) were institutionalized. The highest rates of institutionalization were among unmarried males aged 75–84 (75%) and 85þ (74%) meeting both the ADL and CI Triggers.

Home and Community-Based LTC Table 11 displays the usage rates among community residents of personal assistance within the week prior to the NLTCS

Percent institutionalized by HIPAA triggers by marital status, sex, and age, United States 1999, age 65 and above HIPAA trigger

Married

Sex

Age

None

CI trigger only

ADL trigger only

ADL & CI trigger

Any trigger

Total

Yes

Male

65–74 75–84 85þ Total 65–74 75–84 85þ Total

0.0 0.0 0.2 0.0 0.0 0.1 0.9 0.1 0.0 0.8 1.3 0.9 1.0 0.2 0.6 2.7 0.7 0.8 0.4

0.0 2.6 1.6 1.6 4.8 3.4 8.9 4.5 2.7 6.9 8.6 13.4 9.5 3.5 2.9 7.1 4.6 5.7 4.8

4.6 13.3 30.7 13.6 6.5 10.4 15.7 9.2 11.9 40.4 41.2 36.4 38.8 30.6 38.0 50.0 42.5 41.8 29.7

11.1 32.6 24.3 25.9 19.4 42.2 39.9 35.4 29.8 47.7 75.0 73.6 66.8 24.7 51.0 63.9 57.1 58.6 51.4

3.9 14.4 19.9 12.3 8.4 18.1 23.8 14.9 13.3 23.8 35.9 39.7 34.1 17.8 26.8 45.1 34.8 34.7 27.9

0.2 1.7 5.7 1.1 0.4 2.2 5.9 1.2 1.1 2.9 7.3 14.2 6.4 1.5 5.5 22.6 7.9 7.5 4.1

Female

No

Total Male

Female

Total

Total

65–74 75–84 85þ Total 65–74 75–84 85þ Total

CI trigger is defined as a score in the range 0–23 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

454

Long Term Care for Aging Populations Table 11 Percent of community residents reporting personal assistance within the prior week due to a disability or health problem; by HIPAA triggers by marital status, sex, and age, United States 1999, age 65 and above HIPAA trigger Married

Sex

Age

None

CI trigger only

ADL trigger only

ADL & CI trigger

Any trigger

Total

Yes

Male

65–74 75–84 85þ Total 65–74 75–84 85þ Total

1.4 4.3 9.6 2.8 3.8 7.4 10.4 5.1 3.8 1.7 5.7 17.8 5.3 3.2 7.0 17.6 6.9 6.5 4.9

36.5 45.5 37.1 41.1 38.1 44.7 69.2 43.9 42.2 48.2 45.0 73.3 54.0 36.0 44.4 59.3 48.6 49.8 47.3

94.3 91.2 85.9 91.7 84.3 96.3 100.0 91.2 91.5 100.0 91.5 97.1 95.2 93.7 92.0 92.1 92.4 92.9 92.2

100.0 99.0 94.8 98.0 81.9 97.0 100.0 92.2 95.8 91.1 78.2 86.5 86.3 82.3 89.7 95.9 92.0 91.3 92.9

71.1 71.3 71.6 71.3 64.1 75.7 89.2 72.1 71.6 61.9 59.4 82.7 67.7 62.5 63.1 78.3 69.4 69.1 70.1

4.4 10.9 24.3 7.9 6.3 14.2 24.3 9.4 8.5 6.1 12.1 33.5 12.5 6.9 15.2 37.8 16.1 15.3 11.5

Female

No

Total Male

Female

Total

Total

65–74 75–84 85þ Total 65–74 75–84 85þ Total

CI trigger is defined as a score in the range 0–23 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

detailed interview, where the assistance stemmed from a disability or health problem and details of the nature and amount of the assistance were provided. The personal assistance rates were very low for persons who met neither HIPAA LTC trigger: 3.8% of married persons and 6.5% of unmarried persons (4.9% combined) had such assistance; unmarried females had the highest rates of assistance (6.9%) and married males the lowest (2.8%). The specificity of the HIPAA LTC triggers can be estimated as the percentage of persons among the estimated 29.88 million community residents meeting neither HIPAA LTC trigger who had no personal assistance due to a disability or health problem within the prior week, assuming that the lack of such assistance was a valid indicator of the absence of severe disability. The number of such persons was 28.85 million, implying a specificity of 97%. In contrast, personal assistance rates were substantial for persons meeting any HIPAA LTC trigger: 72% of married persons and 69% of unmarried persons (70% combined) had such assistance; married females had the highest rates of assistance (72%) and unmarried males the lowest (68%). The highest personal assistance rates were for persons meeting both the ADL and CI Triggers: 96% of married persons and 91% of unmarried persons (93% combined) had such assistance; married males had the highest rates of assistance (98%) and unmarried males the lowest (86%). The assistance rates for females meeting both the ADL and CI Triggers were the same (92%) for married and unmarried women. The personal assistance rates were almost as high for persons meeting only the ADL Trigger: 92% of married persons and 93% of unmarried persons (92% combined) had such assistance; unmarried males had the highest rates of assistance (95%) and married females the lowest (91%).

The personal assistance rates were substantially lower for persons meeting only the CI Trigger: 42% of married persons and 50% of unmarried persons (47% combined) had such assistance; unmarried males had the highest rates of assistance (54%) and married males the lowest (41%). These declines suggest that the current implementation of the CI Trigger may overestimate the number of cases that meet the HIPAA certification requirements. However, because the modified CI Trigger used in Table 2 would only raise the marginal percentage in Table 11 from 47% to 55%, it follows that the use of more stringent MMSE scoring criteria would not resolve the overestimation. The relatively low frequency of personal assistance among those meeting only the basic or modified CI Triggers was attributable to subgroups of persons identified in Tables 1 and 2 as CI Trigger Only who were free from IADL and ADL limitations and whose marginal rates of personal assistance were only 8.4% and 6.6%, respectively, for the two forms of the CI Triggers. Among married persons meeting these same criteria, the rates of personal assistance were similarly low at 6.3% and 6.6%, respectively. These calculations suggest that some forms of assistance provided to persons meeting only the CI Trigger may not be captured by the NLTCS survey instruments. Eliminating the CI Trigger Only persons who were free from IADL and ADL limitations would raise the marginal percentages among those meeting only the basic or modified CI Triggers to 67% and 68%, respectively. The marginal percentages would increase further to 79% and 80%, respectively, if the IADL-only groups were eliminated (leaving a residual group with exactly 1 ADL limitation). These calculations indicate that ADL and IADL assistance provided to persons meeting only the CI Trigger is captured by the survey instruments.

455

Long Term Care for Aging Populations Table 12 Percent of community residents reporting paid personal assistance among those with any personal assistance within the prior week due to a disability or health problem; by HIPAA triggers by marital status, sex, and age, United States 1999, age 65 and above HIPAA trigger Married

Sex

Age

None

CI trigger only

ADL trigger only

ADL & CI trigger

Any trigger

Total

Yes

Male

65–74 75–84 85þ Total 65–74 75–84 85þ Total

0.0 5.1 47.6 10.9 9.3 19.7 13.6 14.0 12.7 9.5 36.0 47.8 36.9 27.1 40.2 29.9 33.7 34.3 24.9

12.0 9.3 11.7 10.5 9.0 10.7 22.0 11.6 10.9 48.9 63.1 26.6 45.0 19.8 28.4 32.2 29.1 32.8 26.5

8.9 28.3 31.1 20.1 38.4 13.7 44.1 26.8 22.9 21.9 52.0 56.6 51.0 44.1 48.7 37.9 42.9 44.4 33.6

13.0 40.7 32.2 31.6 20.0 44.5 49.8 37.7 33.8 41.9 22.7 61.6 43.0 37.2 47.6 57.9 52.0 50.9 44.6

10.4 26.5 28.0 21.2 26.8 21.8 40.2 26.0 23.1 43.4 53.1 42.9 46.4 35.4 39.8 43.7 41.0 42.0 34.6

7.3 18.9 33.9 17.9 16.7 20.8 30.8 19.9 18.8 34.3 46.1 44.9 42.8 31.8 40.0 39.4 38.4 39.2 30.9

Female

No

Total Male

Female

Total

Total

65–74 75–84 85þ Total 65–74 75–84 85þ Total

CI trigger is defined as a score in the range 0–23 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

Table 12 displays the percentages using paid personal assistance among community residents with any personal assistance within the week prior to the NLTCS detailed interview. The numerators of the percentages in Table 11 were the denominators of the percentages in Table 12. The use of paid personal assistance was substantial for persons who met neither HIPAA LTC trigger but who had personal assistance: 13% of married persons and 34% of unmarried persons (25% combined) had paid assistance; unmarried males had the highest rates of paid assistance (37%) and married males the lowest (11%). Of course, these percentages would be reduced substantially if one multiplied them by the corresponding values in Table 11 to produce the marginal usage rate of paid personal assistance among all persons who met neither HIPAA LTC trigger. The use of paid personal assistance was 8–10% higher, absolutely, for persons who met any HIPAA LTC trigger: 23% of married persons and 42% of unmarried persons (35% combined) had paid assistance; unmarried males had the highest rates of paid assistance (46%) and married males the lowest (21%). The use of paid personal assistance was an additional 9–11% higher for persons who met both the ADL and CI Triggers: 34% of married persons and 51% of unmarried persons (45% combined) had paid assistance; unmarried females had the highest rates of paid assistance (52%) and married males the lowest (32%). The use of paid personal assistance for persons who met only the ADL Trigger was similar to the use for those who met any HIPAA LTC trigger: 23% of married persons and 44% of unmarried persons (34% combined) had paid assistance; unmarried males had the highest rates of paid assistance (51%) and married males the lowest (20%).

The use of paid personal assistance for persons who met only the CI Trigger was substantially lower than for persons who met the HIPAA ADL trigger, and was close to the use for persons who met neither HIPAA LTC trigger: 11% of married persons and 33% of unmarried persons (27% combined) had paid assistance; unmarried males had the highest rates of paid assistance (45%) and married males the lowest (11%). Table 13 displays the average number of hours of help per week among community residents reporting personal assistance within the week prior to the NLTCS detailed interview. The numerators of the percentages in Table 11 were the denominators of the averages in Table 13. Hours of help were missing for about 8% of the respondents in the numerators of Table 13; these missing values were assumed to be equal to the cell-specific means for the nonmissing values. The weekly hours of help were substantial for persons who met neither HIPAA LTC trigger but who had personal assistance: Married persons had an average of 20 h and unmarried persons an average of 13 h (combined average was 15 h); married males had the highest average (25 h) and unmarried females the lowest (12 h). These averages would be reduced substantially if one multiplied them by the corresponding values in Table 11 to produce the marginal hours of help among all persons who met neither HIPAA LTC trigger. The weekly hours of help were substantially higher for persons who met any HIPAA LTC trigger: Married persons had an average of 49 h and unmarried persons an average of 46 h (combined average was 47 h); married males had the highest average (52 h) and unmarried males the lowest (44 h). The weekly hours of help were highest for persons who met both the ADL and CI Triggers: Married persons had an average of 63 h and unmarried persons an average of 68 h (combined average was 66 h).

456

Long Term Care for Aging Populations Table 13 Average hours of help per week among community residents reporting personal assistance within the prior week due to a disability or health problem; by HIPAA triggers by marital status, sex, and age, United States 1999, age 65 and above HIPAA trigger Married

Sex

Age

None

CI trigger only

ADL trigger only

ADL & CI trigger

Any trigger

Total

Yes

Male

65–74 75–84 85þ Total 65–74 75–84 85þ Total

23.8 23.9 28.0 24.7 14.5 14.6 28.2 15.8 19.8 6.2 16.6 13.6 13.7 8.6 11.9 13.7 12.2 12.5 15.1

23.7 26.4 44.9 28.4 33.4 14.4 20.2 20.0 25.4 11.6 18.3 20.6 17.6 7.7 17.0 15.8 15.9 16.3 18.8

61.9 55.4 53.0 56.9 41.7 40.9 47.6 41.9 50.1 19.8 69.8 57.0 58.1 39.6 43.4 54.4 48.3 50.2 50.1

51.8 72.8 42.8 60.4 50.6 78.8 58.0 67.3 63.1 105.4 44.6 56.4 68.2 29.7 64.3 73.7 67.7 67.7 66.1

53.6 53.1 47.2 52.0 42.9 46.3 44.7 45.1 49.1 41.0 46.3 44.3 44.4 30.8 41.8 52.1 46.2 45.9 47.1

43.7 42.9 40.8 42.7 28.3 31.5 38.3 31.2 37.3 27.6 32.5 30.9 31.0 19.6 28.0 38.7 32.1 31.9 33.9

Female

No

Total Male

Female

Total

Total

65–74 75–84 85þ Total 65–74 75–84 85þ Total

CI trigger is defined as a score in the range 0–23 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long-Term Care Survey.

Among those meeting only the ADL Trigger, married and unmarried persons both had an average of 50 h. Among those meeting only the CI Trigger, married persons had an average of 25 h and unmarried persons an average of 16 h (combined average was 19 h).

Table 14 displays the average number of paid hours of help per week among community residents reporting paid personal assistance within the week prior to the NLTCS detailed interview. The numerators of the percentages in Table 12 were the denominators of the averages in Table 14.

Table 14 Average hours of paid help per week among community residents reporting paid personal assistance within the prior week due to a disability or health problem; by HIPAA triggers by marital status, sex, and age, United States 1999, age 65 and above HIPAA trigger Married

Sex

Age

None

CI trigger only

ADL trigger only

ADL & CI trigger

Any trigger

Total

Yes

Male

65–74 75–84 85þ Total 65–74 75–84 85þ Total

– 6.3 10.7 8.7 3.6 8.7 15.5 8.2 8.4 5.8 8.3 7.2 7.5 6.5 9.7 11.4 10.0 9.5 9.3

6.5 7.4 40.0 11.3 3.0 7.7 2.0 5.6 9.1 12.2 15.3 8.8 13.1 14.7 8.3 8.2 8.6 9.9 9.8

31.8 25.9 30.0 28.0 12.1 20.0 10.8 15.0 21.7 40.5 54.1 43.1 47.8 21.2 24.5 48.3 35.3 38.1 33.4

2.5 16.0 10.4 12.9 7.7 23.5 36.0 23.6 17.7 67.0 2.5 19.0 34.9 25.8 63.3 55.0 56.4 54.7 45.3

20.9 19.6 20.8 20.1 10.7 20.2 20.0 17.2 18.8 37.3 33.8 32.4 33.9 21.4 34.5 44.5 38.9 37.9 33.2

20.9 17.1 16.9 17.5 9.0 15.3 19.3 14.2 15.9 27.4 24.2 21.2 23.4 15.4 23.4 35.5 28.5 27.5 24.9

Female

No

Total Male

Female

Total

Total

65–74 75–84 85þ Total 65–74 75–84 85þ Total

CI trigger is defined as a score in the range 0–23 on the MMSE, senility, or Alzheimer’s disease. Source: Author’s calculations based on the 1999 National Long Term Care Survey.

Long Term Care for Aging Populations Hours of help were missing for about 4% of the respondents in the numerators of Table 14; these missing values were assumed to be equal to the cell-specific means for the nonmissing values. The weekly hours of paid help were lowest for persons who met neither HIPAA LTC trigger but who had paid personal assistance: Married persons had an average of 8 h and unmarried persons an average of 10 h (combined average was 9 h); unmarried females had the highest average (10 h) and married females the lowest (8 h). The weekly hours of paid help were substantially higher for persons who met any HIPAA LTC trigger: Married persons had an average of 19 h and unmarried persons an average of 38 h (combined average was 33 h); unmarried females had the highest average (39 h) and married females the lowest (17 h). The weekly hours of paid help were similar or higher for persons who met both the ADL and CI Triggers: Married persons had a similar average of 18 paid h and unmarried persons a higher average of 55 paid h (combined average was 45 paid h). Among those meeting only the ADL Trigger, married persons had an average of 22 paid h and unmarried persons an average of 38 paid h (combined average was 33 paid h). Among those meeting only the CI Trigger, married persons had an average of 9 paid h and unmarried persons an average of 10 paid h (combined average was 10 paid h).

Disability Declines One of the most significant findings from the NLTCS was the discovery (Manton et al., 1993, 1997) and confirmation (Manton and Gu, 2001; Freedman et al., 2002; Freedman et al., 2004) that LTC disability rates among the U.S. elderly were declining at a rate faster than the 0.6% per year expected based on the century-long trends established by Fogel and Costa (1997), Costa (2000) and Costa (2002). Stallard et al. (2004) used longitudinal weights to establish that the general decline in disability also applied to the more severe form represented by the HIPAA ADL Trigger. Longitudinal weights were used because concerns had been raised about the reliability of the standard cross-sectional weighting procedures in the NLTCS (Freedman et al., 2004). The standard cross-sectional weighting procedures used the CDS Screener Cross-Sectional Weights for each indicated year, with adjustment for noncomplete institutional interviews. The longitudinal weights were defined as the cross-sectional weights assigned to the NLTCS respondents in 1984 or, if not then, the first cross-sectional weights assigned to the respondents as they aged in at some later date. The longitudinal weights did not include adjustments for non-response, in part because the response rates to the survey were very high (about 95%), and in part to minimize the number of assumptions used in their construction. However, the longitudinal weights included a one-time adjustment for deletions of certain persons aged 70–74 at their second survey, which reverted to the original longitudinal weights when these persons were reinstated beginning at their third survey. All of these deleted persons screened out at their first survey when they were aged 65–69. The surveys affected by these deletions were conducted

457

in 1989, 1994, and 1999. The deletions were made because the vast majority of these persons were free of disabilities and the limited resources had to be directed toward the disabled. Table 15 and 16 display separately by sex the age-specific and age-standardized disability prevalence rates and their changes based on the HIPAA ADL Trigger using the standard cross-sectional weights for 1984 and 1999 and the longitudinal weights for 1999. For both sets of weights, for all ages, and for both sexes, the prevalence rates for persons meeting the HIPAA ADL Trigger declined at rates faster than the expected rate of 0.6% per year. The age-standardized rates declined at a rate of 2.2% per year for males (for both sets of weights) and 1.4% or 1.5% per year for females (longitudinal vs. cross-sectional weights).

Table 15 Percent of population meeting HIPAA ADL trigger under cross-sectional and longitudinal weighting, United States 1984, and 1999, age 65 and above, males Cross-sectional weights

Longitudinal weights

Year

Year

Age

1984

1999

Annual rate of decline; 15 year

65–69 70–74 75–79 80–84 85–89 90–94 95–99 Age standardized rate

3.12 5.50 8.57 13.48 21.88 37.31 53.20 7.48

2.17 3.76 5.29 10.73 18.40 23.87 35.56 5.32

2.39% 2.51% 3.16% 1.51% 1.15% 2.93% 2.65% 2.24%

1999

Annual rate of decline; 15 year

2.17 3.76 5.24 11.21 17.87 25.10 31.61 5.35

2.39% 2.50% 3.22% 1.22% 1.34% 2.61% 3.41% 2.21%

Results were age-standardized to the 1984 NLTCS weighted male population. Source: Author’s calculations based on the 1984 and 1999 NLTCS.

Table 16 Percent of population meeting HIPAA ADL trigger under cross-sectional and longitudinal weighting, United States 1984, and 1999, age 65 and above, females Cross-sectional weights

Longitudinal weights

Year

Year

Age

1984

1999

Annual rate of decline; 15 year

65–69 70–74 75–79 80–84 85–89 90–94 95–99 Age standardized rate

3.49 4.91 9.00 17.25 30.15 49.78 69.32 10.95

2.56 4.28 7.07 13.08 24.09 42.05 54.31 8.74

2.04% 0.91% 1.59% 1.83% 1.49% 1.12% 1.61% 1.49%

1999

Annual rate of decline; 15 year

2.56 4.41 7.05 13.42 24.69 43.52 56.75 8.94

2.04% 0.71% 1.62% 1.66% 1.32% 0.89% 1.33% 1.35%

Results were age-standardized to the 1984 NLTCS weighted female population. Source: Author’s calculations based on the 1984 and 1999 NLTCS.

458

Long Term Care for Aging Populations

Significant areas of research involve the development and fielding of improved instruments for measurement of LTC disability and the analysis of existing data to enhance our understanding of the causes and public health implications of the declines.

Acknowledgment The research in this article was supported by grants from the National Institute on Aging (Grants No. P01-AG17937 and U01-AG07198).

See also: Aging, Physical Activity, and Health; Demography of Aging; Long Term Care in Health Services; Long-Term Care Organization and Financing.

References Actuarial Standards Board, 1999. Long-Term Care Insurance. Actuarial Standard of Practice No. 18. Actuarial Standards Board, Washington DC. Blackwell, D.L., Tonthat, L., 2003. Summary Health Statistics for the US Population: National Health Interview Survey, 1999. Vital and Health Statistics Series 10, No. 211. National Center for Health Statistics, Hyattsville, MD. Coronel, S., 2004. Long-Term Care Insurance in 2002. America’s Health Insurance Plans, Washington DC. Costa, D.L., 2000. Understanding the twentieth-century decline in chronic conditions among older men. Demography 37 (1), 53–72. Costa, D.L., 2002. Changing chronic disease rates and long-term declines in functional limitations among older men. Demography 39 (1), 119–137. Fogel, R.W., Costa, D.L., 1997. A theory of technophysio evolution, with some implications for forecasting population, health care costs, and pension costs. Demography 34 (1), 49–66. Folstein, M.F., Folstein, S.E., McHugh, P.R., 1975. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, 189–198.

Freedman, V.A., Martin, L.G., Schoeni, R.F., 2002. Recent trends in disability and functioning among older adults in the United States. J. Am. Med. Assoc. 288 (24), 3137–3146. Freedman, V.A., Crimmins, E., Schoeni, R.F., et al., 2004. Resolving inconsistencies in old-age disability trends: report from a technical working group. Demography 41 (3), 417–441. Internal Revenue Service, May 27, 1977. IRS Notice 97–31, Bulletin No. 1997–21. Internal Revenue Service, pp. 5–8. Kinosian, B., 2006. The Department of Veterans Affairs Long-Term Care Planning Model and the National Long-Term Care Survey. Department of Veterans Affairs, Philadelphia, PA. Manton, K.G., Gu, X., 2001. Changes in the prevalence of chronic disability in the United States black and nonblack population above age 65 from 1982 to 1999. Proc. Natl. Acad. Sci. U.S.A. 98 (11), 6354–6359. Manton, K.G., Corder, L.S., Stallard, E., 1993. Estimates of change in chronic disability and institutional incidence and prevalence rates in the US elderly population from the 1982, 1984, and 1989 National Long Term Care Survey. J. Gerontol. Soc. Sci. 48 (4), S153–S166. Manton, K.G., Corder, L.S., Stallard, E., 1997. Chronic disability trends in elderly United States populations 1982–1994. Proc. Natl. Acad. Sci. U.S.A. 94, 2593–2598. Perneczky, R., Wagenpfeil, S., Komossa, T., Grimmer, T., Diehl, J., Kurz, A., 2006. Mapping scores onto stages: mini-mental state examination and clinical dementia rating. Am. J. Geriatr. Psychiatry 14 (2), 139–144. Pfeiffer, E., 1975. A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients. J. Am. Geriatr. Soc. 23, 433–441. Rogers, S., Komisar, H., 2003. Who Needs Long-Term Care. Georgetown University Long-Term Care Financing Project. Georgetown University, Washington DC. Stallard, E., Yee, R.K., 2000. Non-Insured Home and Community-Based Long-Term Care Incidence and Continuance Tables. Actuarial Report. Long-Term Care Experience Committee Society of Actuaries, Schaumburg, IL. Stallard, E., Wolf, R.M., Weltz, S.A., 2004. Morbidity improvement and its impact on LTC insurance pricing and valuation. Record 30 (1). Session #107PD, Society of Actuaries. Wiener, J.M., Hanley, R.J., Clark, R.J., Van Nostrand, J.F., 1990. Measuring the activities of daily living: comparisons across national surveys. J. Gerontol. Soc. Sci. 45 (6), 229–237. Wolf, D.A., Hunt, K., Knickman, J., 2005. Perspectives on the recent decline in disability at older ages. Milbank Q. 83 (3), 365–395.

Long Term Care in Health Services Jenny Brodsky, Myers-JDC-Brookdale Institute, Jerusalem, Israel A Mark Clarfield, Ben-Gurion University, Beersheba, Israel Ó 2017 Elsevier Inc. All rights reserved. This article is reproduced from the previous edition, volume 4, pp. 127–132, Ó 2008, Elsevier Inc.

For the most part long-term care (LTC) has not been among the main concerns of health policy makers. Cost-containment issues, perhaps an excessive focus on specialized medical care, and the fact that families have always been and remain the major providers of LTC have contributed to a slow development of public long-term care services (WHO, 2000). However, demographic transitions are resulting in dramatic changes in health needs around the world. Care for the chronically ill and for those with disabilities and a steep rise in the numbers of elderly are a growing challenge in practically all societies.

government, nongovernmental organizations (NGOs) and the private (for-profit) sectors in service provision, informal care has remained the dominant form of care (Wiener, 2003). However, the increasing proportion of women in the labor market and the declining ratio between those needing care and those who are potential caregivers are raising questions of whether informal care will maintain its predominant role.

Definition and the Target Population in Need of LTC

All developed countries have established LTC programs under the auspices of health and welfare services, and many developing countries are in the initial stages of some development. Programs usually include some combination of health, social, housing, transportation, and support services for people with physical, mental, or cognitive limitations. However, there is no single paradigm and there are a number of different approaches in the organization and provision of LTC. An understanding of the nature of the variance among countries is important to provide insight for development of care policies. Countries differ in the way they have resolved basic design issues. Among the most central issues are the nature of entitlements, targeting and finance; service delivery strategies; and issues of integration between LTC and health and social services.

LTC includes activities undertaken for persons who are not fully capable of self-care on a long-term basis by informal caregivers (family and friends), formal caregivers, and volunteers. The target population includes those who suffer from any kind of physical or mental disability requiring assistance with the activities of daily living. LTC encompasses a broad array of services such as personal care and assistive devices that are designed to minimize, restore, or compensate for the loss of independent physical or mental functioning. Disability also results in difficulties in accessing health care and in complying with health-care regimes, and it affects the ability of the individual to maintain a healthy lifestyle to prevent deterioration in functional status. Therefore, LTC includes efforts to ensure access to acute, chronic care and rehabilitation services and to prevent deterioration of the functional capacity of the disabled (such as, e.g., preventing bedsores and preventing depression). The central role of the family in providing LTC requires significant efforts to inform and guide the families (WHO, 2002).

The Uniqueness of Long-Term Care Whereas more traditional health care is concerned with cure and recovery, LTC attempts mainly to contribute to alleviating suffering, maintaining the best possible quality of life, reducing discomfort, improving the limitations caused by diseases and disability, and maintaining the best possible levels of functioning (Larizgoitia, 2003). An additional significant difference between LTC and the acute sector is that the provision of LTC is heavily based on unspecialized, labor-intensive, and relatively unskilled providers. Professionals (physicians, nurses, social workers, and others) are involved to a degree that is significantly less than that in acute care. LTC allows lay volunteers, in particular the family, to take part in its implementation. Indeed, in most countries, care is still predominantly a family task – mainly performed by women. Despite the increasing role of the

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Issues in the Organization and Provision of LTC Services

Nature of Entitlements, Targeting and Finance Among the most significant key policy design issues are the principles of eligibility for publicly subsidized LTC services and the nature of entitlements. Underlying these issues are two fundamental decisions: 1. Who does a country decide to support – everyone or only the poor? 2. Should access to services be based on an entitlement (insurance principle) or subject to budget constraints (taxfunded principle)? Such questions also arise in the provision of acute care. What is unique, however, to LTC is the additional possibility that the family might at least in part meet these needs for many individuals. Thus, underlying this determination is society’s view of the appropriate and expected roles of the people with disabilities and their families. The choice among different options is often between selective (or means-tested) and universal approaches to service provision. Support for the poor is obviously based on a concern for their inability to purchase these services and can lead to an exclusive focus on this group. Even if such is one’s primary goal, this can lead to a strategy that supports the nonpoor, if it is

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believed that including them in a more universal program is the best way to mobilize support for the poor and to avoid the problems associated with programs for the poor, such as low quality. Support for the broader population can have several rationales, including: The catastrophic potential nature of LTC costs when broad segments of the population may find it difficult to pay; when resources are depleted, they become a burden on public programs; l Concern with the broader social costs of care provision and an interest in easing the burden on families (particularly women); l Reducing utilization of more costly acute care (particularly hospitalization) services by substituting LTC and in part by medicalizing it. l

A second key question is whether access to LTC services should be based on an entitlement or subject to budget constraints. An entitlement program means that, irrespective of available budgets, everyone who fulfills the eligibility criteria must be granted benefits. Entitlement programs are generally financed through insurance-type prepayments, whereas nonentitlement programs are usually financed through general taxation. A prepayment is generally viewed as granting a right to a service. It should be kept in mind that an entitlement approach can influence the targeting of services. With contributory entitlement, strict income testing is unlikely to be adopted so as to prevent exclusion from benefits for the many who contribute to financing the program. Nonentitlement programs, focused primarily on the poor, will usually have a relatively strict means test. The decision to adopt an entitlement approach and a contributory finance system has implications for additional eligibility criteria. The nature of family availability and support will not typically be taken into account in an insurance framework. A third implication is that under an entitlement system, benefit levels are set relatively lower because family support is not a criterion, and benefits will be provided to many who might already be receiving significant family support. Setting low benefit levels also reflects concern with cost control. In an entitlement system, cost is not easily predictable or defined because it is determined by the number of eligible applicants. We can illustrate the variation in these fundamental design issues by using a couple of examples. On the one hand, in the UK, provision of LTC is normally income tested and provided on a budget-restricted basis. On the other hand, Scandinavian countries (e.g., Sweden) have a policy commitment to maintaining high levels of services to the entire population and not only for the poor, even though services are financed through general taxation. There are user charges related to income, but given the high level of pensions, this has not been a significant barrier for those who need LTC services. Most Canadian provinces are somewhere in between countries like the UK and the Scandinavian countries with respect to targeting the poor (UK Royal Commission on Long-Term Care, 1999). The Medicaid program in the United States is an interesting example of a system that while focusing on the poor and

financed by general tax revenues provides an entitlement subject to a strict means test. In recent years, a number of countries have adopted a broader insurance-based approach and a full entitlement. This model includes Germany, Austria, Holland, Israel, and more recently Japan (Brodsky et al., 2000).

Service Delivery Strategies: Balancing Care in the Home, in the Community, and in Institutions Another element of variation among countries is reflected in the actual package of services offered to people with disabilities. There is no universally agreed-upon package of LTC services. For one thing, countries are in different stages of economic development, and some can afford a more comprehensive package than others. In addition, countries have different sociodemographic and epidemiological patterns, cultures, and values, which can all play an important role in defining the needs and priorities. For example, in Sweden most families do not feel obligated to look after older parents, believing that this is just as much the role of government. In contrast, in Israel much more is expected of family members (and less by government). One of the most important distinguishing dimensions among services is the location in which these services are to be provided, collectively referred to as a continuum of care: home-based, in ambulatory settings in the community, or in an LTC institutional setting.

Home-Based Programs

Such programs may include Home health services – include skilled medical/nursing care, health promotion, prevention of functional deterioration, training and education, facilitation of self-care, and palliative care; l Personal care – care related with activities of daily living (ADL) (e.g., bathing, dressing, eating, and toileting); l Homemaking – assistance with instrumental activities of daily living (IADL) (e.g., meal preparation, cleaning, and shopping); l Assistive devices, physical adaptations of the home, and special technologies (alarm systems). l

Ambulatory Settings

Ambulatory settings in the community can provide a different package of services, which may be more health related or more social related. For example, some models of day-care provision focus on health-related services such as monitoring of health status and rehabilitation, whereas others focus on providing the disabled person opportunities for recreation and socialization.

Institutional Services

This model includes a wide range of institutions which provide various levels of maintenance and personal or nursing care. There are LTC institutions aimed mainly at addressing housing needs and providing opportunities for recreation and socialization, whereas others (usually referred to as nursing homes or skilled nursing homes) address health-related needs. The first

Long Term Care in Health Services type serves the moderately disabled, whereas the second type the more severely disabled.

Assistive Living, Service-Enriched Housing, and Sheltered Housing

This model includes special housing units that offer independent living but also services and care to an extent, which, in some cases, comes close to a modern, noncustodial institution. These kinds of sheltered accommodations are now substituting the traditional residential homes, and to some extent also nursing homes. Whereas almost all industrialized countries offer a broad package of services, the absolute level and the relative importance of the service mix vary. There is also noticeable convergence. In most industrialized countries, the share of the older population (over 65) in institutions varies between 5 and 7%. This percentage does not appear to have grown dramatically in recent years despite continued aging of older populations, and in some countries such as Canada and Holland, it has even declined. Partly because of the rising cost of institutional care, a focus on community care has taken place in many industrialized countries. ‘Aging in place’ is perceived as preferred by the elderly and, in the majority of cases, as a less expensive alternative to institutional care. One of the hopes of those planning various LTC programs was that their broader availability would reduce costs by reducing acute care hospital utilization and the demand for long-term institutional care. In Japan and Canada, for example, there is an overuse of acute beds by those needing LTC. As a result, reforms have been introduced in Quebec. The Netherlands is one of the countries in which the level of institutional care has been particularly high. The Dutch government has actively implemented experimental programs aimed at reducing institutionalization. Although the infrastructure of supportive services has grown, the expectation of diverting a significant number of disabled elderly people from nursing homes has been somewhat scaled down in many countries. The extent to which the various LTC programs have influenced patterns of referral to institutions has depended in part on the extent and type of community care available. When such services are limited, they are less likely to offer an alternative to institutionalization, particularly for the more severely disabled elderly. More recently, some countries have highlighted the potential of health services such as post-acute care and rehabilitation in delaying or preventing long-term institutionalization. Over and above the availability of community services, other factors may affect an elderly client’s ability to choose between community and institutional services, including the supply of beds and the level of copayments for institutional care. In Germany, for example, a copayment of 25% is levied on people entering LTC to keep such care from becoming financially preferable to home care. Japan has made similar efforts to damp down institutional demand. There is a wide variation in the provision of home care. For example, home help (nursing and assistance in activities of daily living) has been estimated to be provided to between 5% and 17% of the population, depending on the country (OECD, 1999).

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In some countries, greater individual flexibility in choice of care delivery has been considered, for example, the provision of cash benefits in addition to or instead of services in-kind. There are three basic forms of provision: services in kind (e.g., Israel); cash allowances without restrictions which enables a client to use the funds as he or she sees fit (e.g., Germany and Austria); and cash allowances with a restriction to purchase services (e.g., experimental programs in Holland and the United States).

Long-Term Care Assessment Assessment in LTC serves multiple purposes: to determine eligibility for services, develop the most appropriate care plan according to clients’ needs, monitor clients’ status over time, and assess services’ outcomes in relation to functional needs or maintaining maximum function and enhancing the quality of life of people with disabilities and of their families. At a health-service level, measures may be used to monitor quality of care, allocate resources based on case mix, and even to plan for the development of appropriate resources (Berg and Mor, 2001). The desired characteristics of an assessment instrument will vary relative to the objective of the assessment, but the same instruments can sometimes be used for multiple purposes. Comprehensive assessment should address different domains of impairment (e.g., cognitive status, strength, sensory and perceptual deficits), disability (e.g., measures of activities of daily living), and health related quality of life (e.g., mental health and emotional well-being). For each domain, there is no single best measure. There is general agreement as to the types of domains and indicators that should be included in assessment for long-term care, although the relative weights to be placed on these various domains are more debatable. There are numerous available assessment instruments that focus on particular aspects of LTC. Table 1 gives selective examples of some of the most established instruments developed in the United States and Europe. Some of these instruments are quite culturally specific and would need to be adapted not only to other languages but also to other cultures and worldviews. In the United States, Medicare and Medicaid authorities, along with the development of managed care, have given a tremendous push to research in this area (Shaughnessy et al., 1994). One of the best-known LTC assessment tools is the Minimal Data Set (MDS). Its main aim is to provide a reliable, uniform, and universal set of data across settings and for different purposes, which are used to inform care planning to provide a basis for external quality surveys and internal continuous quality improvement and in the case mix adjusted reimbursement systems. Although MDS began in institutions in the United States, it has since been expanded for home care and other settings, and has been used in both English and non-English-speaking countries.

Issues of Integration between LTC and Health and Social Services A major concern involves the continuum of care between the acute and LTC systems, and between the health and social service systems. However, one of the major problems in

462 Table 1

Long Term Care in Health Services Long-term care: examples of assessment instruments

Assessment domain

Examples of indicators

Examples of standardized measures

Activities of daily living (ADL)

Ambulation; toileting; continence; personal hygiene; dressing; mobility; locomotion Meal preparation; housekeeping; shopping; laundry; management of oral medications; use of transportation; basic finances Skin condition; pain interfering with activity; nutritional status and significant weight loss; pressure ulcers; falls Cognitive functioning: Memory; decision making; language; orientation Anxiety level; level of social interaction; level of social participation; behavioral problems; depression

Katz index; Barthel index; functional independence measure (FIM); mobility assessment PSG scale

Instrumental activities of daily living (IADL) Health status Cognitive status Emotional/behavioral status (affect) General quality of life measures and measures of well-being Family/caregiver strain

Multidimensional indicators including health, mental, emotional, social status Caregiver burden (physical, emotional, economic, social); effect of caregiving on the relationship between caregiver and care receiver; abuse

many countries is fragmentation of such services (Clarfield et al., 2001). The interest in integration arises out of a number of concerns for the quality and efficiency of care. These include the ability to provide for coordinated care packages, consider alternative services in the most optimal way, and ease the access to services by offering one easily identified source of provision. Nevertheless, it is by no means simple to provide integrated LTC because services are the responsibility of many jurisdictions, and the various components tend to work in parallel with separate funding streams and budgets. Links between LTC and acute health systems can encourage continuity of care. These connections may reduce acute hospital stays and create an incentive to provide adequate home health care and rehabilitation, especially if the healthcare providers can enjoy the benefits of reduced institutional long-term care. At the same time, there are concerns about linking LTC with primary health care that generate interest in independent models of LTC. The impact of integration on incentives to provide adequate LTC are neither certain nor easily predictable. Within health systems, there is concern for a preference toward addressing acute care needs over those that are more chronic or function related. A related concern is for the overmedicalization of LTC services if provided in a medically oriented system and the consequences of higher costs as a result. In addition, in the United States, for example, the integration of acute and LTC has depended on integrating medical and social care funding streams. There is a belief that such integrated funding is the basis for program integration. However, although such linkage is necessary, it is insufficient. Successful integration requires a major reorganization of the programmatic infrastructure, which can then be reinforced with funding approaches (Kane, 2003). In general, most developed countries have not fully integrated LTC within the acute system. Some countries have made an effort to partially integrate components of LTC (e.g., Germany), where it is administratively but not financially integrated. Other countries have implemented demonstration

Minimum data set (MDS); the mini nutritional assessment (MNA) Mini-mental state (MMSE); the CERAD assessment packet Geriatric depression scale (GDS); neuropsychiatric inventory (NPI); the CERAD behavior rating scale for dementia (BRSD) SF-36; general health questionnaire (GHQ); Philadelphia geriatric center morale scale (PGCMS) Burden interview (BI); caregiver social impact scale; caregiving appraisal scale (CAS); cost of care index (CCI)

projects that fully integrate acute and LTC such as the PACE program in the United States and the SIPA program in Quebec (Béland et al., 2006). The PACE – program for all-inclusive care of the elderly – was implemented experimentally in one neighborhood in San Francisco in the 1970s and has been expanded to some 36 locations throughout the United States. The model enables the resources for acute and long-term care to be pooled. Disabled elderly who join the program receive a variety of services under one roof. Those eligible for the program are disabled elderly who are eligible to enter long-term care facilities from Medicaid, but who remain in their homes. The program is funded on a capitation basis by Medicare and Medicaid. SIPA – French acronym for system of integrated care for older persons – is an integrated system of social, medical, and short and long-term hospital services offered in both the community and institutions to vulnerable elderly persons. It has been implemented in Canada. Its distinguishing features are community-based multidisciplinary teams with full clinical responsibility for delivering integrated care through the provision of community health and social services and the coordination of hospital and nursing home care; all within a publicly managed and funded system. In the absence of integrated systems, many countries have been experimenting with various coordinating mechanisms such as care management.

Conclusions Care for people with disabilities is a major challenge in industrialized as well as in developing countries. We have shown that although almost all industrialized countries offer a broad package of services, their level and mix vary among countries. In some areas there seems to be more convergence, whereas in others, policies have taken a different route and differ on principles of targeting, entitlement, and finance. There is

Long Term Care in Health Services much to be learned from the experience of industrialized countries in defining the range of options and in learning from some of the disadvantages and advantages of these systems. Unfortunately, the ability to learn from the experience is limited by the lack of adequate systems for monitoring outcomes and evaluating implementation, as well as in difficulty in ‘comparing apples and oranges.’ As LTC programs continue to develop, it is hoped that more attention will be given to systematic and comparative evaluations.

See also: Comparative Health Systems; Home Care; Hospice and Palliative Care.

References Béland, F., Bergman, H., Lebel, L., et al., 2006. Integrated services for frail elders (SIPA): a trial of a model for Canada. Can. J. Aging 25 (1), 25–42. Berg, K., Mor, V., 2001. Long term care assessment. In: Maddox (Ed.), The Encyclopedia of Aging, third ed. Springer, New York, pp. 631–633. Brodsky, J., Habib, J., Mizrahi, I., 2000. Long-Term Care Laws in Five Developed Countries. World Health Organization, Geneva. Switzerland. WHO/NMH/ CCL/00.2. Clarfield, A.M., Bergman, H., Kane, R., 2001. Fragmentation of care for frail older people – an international problem. Experience from three countries: Israel, Canada and the United States. J. Am. Geriatr. Assoc. 49 (12), 1714–1721. Kane, R., 2003. The interface of LTC and other components of the health and social services systems in North America. In: Brodsky, J., Habib, J., Hirschfeld, M. (Eds.), Key Policy Issues in Long-Term Care. World Health Organization, Geneva, Switzerland, pp. 63–90. Larizgoitia, I., 2003. Approaches to evaluating LTC systems. In: Brodsky, J., Habib, J., Hirschfeld, M. (Eds.), Key Policy Issues in Long-Term Care. World Health Organization, Geneva, Switzerland, ISBN 92 4 156225 0, pp. 227–242. OECD, 1999. A Caring World. Organization for Economic Cooperation and Development, Paris, France. Royal Commission on Long-Term Care, 1999. With Respect to Old Age: Long-Term Care – Rights and Responsibilities. The Stationery Office, United Kingdom. Shaughnessy, P.W., Crisler, K.S., Schlenker, R.E., et al., 1994. Measuring and assuring the quality of home health care. Health Care Financ. Rev. 16 (1), 35–67. WHO, 2000. WHO Study Group on Home-based Long-Term Care. World Health Organization, Geneva, Switzerland. Technical Report Series, No. 898. WHO, 2002. Lessons for Long-Term Care Policy. World Health Organization, Geneva, Switzerland. WHO/NMH7CCL/02.1. Wiener, J., 2003. The role of informal support in long-term care. In: Brodsky, J., Habib, J., Hirschfeld, M. (Eds.), Key Policy Issues in Long-Term Care. World Health Organization, Geneva, Switzerland, pp. 3–24. Zarit, S.H., Reever, K.E., Bach-Peterson, J., 1980. Relatives of the elderly: correlates of feelings of burden. Gerontologist 20, 649–655.

Further Reading Brodsky, J., Habib, J., Hirschfeld, M., Siegel, B., 2002. Care of the frail elderly in developed and developing countries: the experience and the challenges. Aging Clin. Exp. Res. 14 (4), 279–286. Brodsky, J., Habib, J., Hirschfeld, M. (Eds.), 2003. Long-Term Care in Developing Countries: Ten Case Studies. World Health Organization, Geneva, Switzerland. Cummings, J.L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D.A., Gornbein, P.H., 1994. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 44, 2308–2314. Feldman, P.H., Kane, R.L., 2003. Strengthening research to improve the practice and management of long-term care. Milbank Q. 81 (2), 179–220. Folstein, M.F., Folstein, S.E., McHugh, P.R., 1975. Mini mental state: a practical method for grading the conginitive state of patients for the clinician. J. Psychiatric Res. 12, 189–198. Golberg, D.P., Hillier, V.F., 1989. A scaled version of the general health questionnaire. Psychol. Med. 9, 139–145.

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Consortium to establish a registry for Alzheimer’s disease: the CERA experience. In: Heyman, A., Fillenbaum, G., Nash, F. (Eds.), 1997. Neurology, vol. 49. Suppl. 3, (whole issue). Ikegami, N., Campbell, J.C., 2002. Choices, policy logics and problems in the design of long-term care systems. Soc. Policy Adm. 36 (7), 719–734. James, L.M., Mack, J., Patterson, M., Tariot, P., 1999. Behavior rating scale for dementia: development of test scales and presentation of data for 555 individuals with Alzheimer’s disease. J. Geriatr. Psychiatry Neurol. 12 (4), 211–223. Jacobzone, S., 1999. Ageing and Care for Frail Elderly Persons: An Overview of International Perspectives. Organization for Economic Cooperation and Development (OECD), Paris. Labour Market and Social Policy– Occasional Papers, No. 38. Kane, R.A., Kane, R.L., Ladd, R., 1998. The Heart of Long-Term Care. Oxford University Press, New York. Katz, S., Ford, A.B., Moskowitz, R.W., Jackson, B.A., Jaffe, M.W., 1963. The index of ADL: a standardized measure of biological psychosocial function. J. Am. Med. Assoc. 185, 914–919. Keith, R.A., Granger, C.V., Hamilton, B.B., et al., 1987. The functional independence measure (FIM): a new tool for rehabilitation. Adv. Clin. Rehabil. 1, 6–18. Kodner, D.L., 2004. Following the logic of long term care: toward an independent but integrated sector. Int. J. Integr. Care 4. http://www.ijic.org (accessed November 2007). Kosberg, J.I., Cairl, R.E., 1986. The cost of care index: a case management tool for screening informal care providers. Gerontologist 26 (3), 273–278. Lawton, M.P., 1975. The Philadelphia Geriatric center morale scale: a revision. J. Gerontol. 30 (1), 85–89. Lawton, M.P., Brody, E.M., 1969. Assessment of older people: selfmaintaining and instrumental activities of daily living. Gerontologist 9, 179–186. Lawton, M.P., Kleban, M.H., Moss, M., et al., 1989. Measuring caregiving appraisal. J. Gerontol. 44 (3), 61–71. Mahoney, F.J., Barthel, D.W., 1965. Functional evaluation: the barthel index. Med. J. Rehabil. 14, 61–65. Morris, J.N., Fries, B.E., Steel, K., et al., 1997. Comprehensive clinical assessment in community settings: applicability of the MDS-HC. J. Am. Geriatr. Soc. 45 (8), 1017–1024. OECD, 1996. Caring for Frail Older People, Policies in Evolution. Organization for Economic Cooperation and Development, Paris, France. Social Policies Studies No. 19. Pacolet, J., Bouten, R., Lanoye, H., Vesieck, K., 1999. Social Protection for Dependency in Old Age in the 15 EU Member States and Norway. Luxemburg: Employment & Social Affairs – Social Security and Social Integration, European Commission. Office for Official Publications of the European Communities. Poulschock, S.W., Deimling, G.T., 1984. Families caring for elders in residence: issues in the measurement of burden. J. Gerontol. 39 (2), 230–239. Sheikh, J.I., Yesavage, J.A., 1986. Geriatric Depression Scale (GDS): Recent Evidence and Development of a Shorter Version. Clinical Gerontology: A Guide to Assessment and Intervention. The Haworth Press, New York, pp. 165–173. Stone, R., 2000. Long-term Care for the Elderly with Disabilities: Current Policy, Emerging Trends, and Implications for the Twenty-first Century. Milbank Memorial Fund, New York. Tinetti, M.E., 1986. Performance-oriented assessment of mobility problems in elderly patients. J. Am. Geriatr. Soc. 34 (2), 119–126. Vellas, B., Guigoz, Y., Garry, P.J., et al., 1999. The mini nutritional assessment (MNA) and its use in grading the nutritional state of elderly patients. Nutrition 15 (2), 116–122. Ware Jr., J.E., Sherbourne, C.D., 1992. The MOS 36-item short-form health survey (SF-36). Med. Care 30 (6), 473–483.

Relevant Websites http://www.cdc.gov/ – Centers for Disease Control and Prevention (last accessed 18.04.16.). http://www.medicare.gov/ – Medicare, U.S. Department of Health and Human Services (last accessed 18.04.16.). http://www.nia.nih.gov/ – National Institute on Aging, U.S. National Institutes of Health (last accessed 18.04.16.). http://www.archive.official-documents.co.uk/ – Official-Documents.co.uk (last accessed 18.04.16.). http://www.oecd.org/document/ – Organisation for Economic Cooperation and Development (last accessed 18.04.16.). http://www.who.int/topics/longterm_care/en/ – World Health Organization, health topics, long-term care (last accessed 18.04.16.).

Longevity of Specific Populations Thomas Theodore Samaras, Reventropy Associates, San Diego, CA, USA Ó 2017 Elsevier Inc. All rights reserved.

Introduction Human longevity can be defined in three ways. The first and most common approach is average life expectancy for a particular age and the second is age-specific all-cause mortality rate (deaths/100 000 people), which is the inverse of longevity. A third but unconventional definition deals with the percentage of centenarians in a population that indirectly reflects the longevity of the adult population. Note that the maximum life span (MLS) of humans appears to be fixed at
120 years. Unlike life expectancy that has increased substantially since ancient Rome, MLS has not changed over thousands of years. The following material focuses on the longevity of various populations.

Factors Affecting Longevity It is well established that environment is a key factor affecting the longevity of individuals and entire populations. This includes socioeconomic status (SES), sanitation, the quality of medical care, educational facilities, and exposure to various diseases. Nutrition also has a critical role because malnutrition can cause susceptibility to infections and premature death (Samaras, 2006). While many populations suffer from food deprivation, many developing and developed populations experience excessive food intake, and obesity is now a worldwide health problem leading to premature mortality (Elrick et al., 2002). In view of the increasing weight trend, the body mass index (BMI) has become an important guideline for predicting mortality/longevity. Generally, a BMI (weight/height2) of 19–23 kg m2 with good nutrition predicts greater longevity. Other factors that affect longevity are heredity, smoking, stress levels, traumatic events, regular physical activity; toxins in the environment, food, and water; and exposure to disease-producing bacteria, viruses, and parasites. Although climate and elevation of a population’s habitat may play a role in longevity, long-living people are found in semitropical, cold, and temperate climates. The same is true for sea level and mountainous elevations. However, longevity appears to favor relatively small populations, such as Andorra (
80 000) and Sweden (
9 million) as shown in Table 1.

Worldwide Variations in Life Expectancy Life expectancy is the median age at death for a particular population group. For example, if a group of people have a life expectancy at birth of 70 years, half died before 70 and half survived beyond this age. Note that life expectancies are also determined for each age group, usually in 10-year increments. Life expectancies are available for over 200 populations ranging from China to the tiny sovereign states of Andorra and San Marino. As shown in Table 1, life expectancy

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at birth for males and females combined range from 33.22 years for Swaziland to 83.51 years for Andorra (Wikipedia, 2006). Consistent with findings that a good environment and SES promote longevity, most of the longest living populations are found in highly developed populations with superior sanitation, education, and health care. The worst life expectancies are found in Africa with its lower economic development and very high rate of mortality from HIV/AIDS infection. The top 10 populations in terms of descending life expectancy (83.51–80.42 years) are Andorra, Macau, San Marino, Singapore, Hong Kong, Japan, Sweden, Switzerland, Australia, and Guernsey (UK). (Depending on the year, the ranking varies somewhat, but has essentially remained unchanged over the last 15 years). The low life expectancy of developing versus developed populations does not mean that elderly people are absent from developing populations. Since poor countries tend to have much higher infant death rates, this situation lowers the average life expectancy. In addition, early deaths of children and young adults due to malnutrition and infections reduce the average life expectancy. However, if early death is avoided, adults often reach advanced ages (Walker, 1974; Samaras, 2007, 2013). A common misconception in comparing today’s life expectancy to that of earlier times, such as the 1900s, is the belief that individuals can expect to live 25–30 years longer. However, if we look at the life expectancy of elderly people, the picture is quite different; e.g., 60-year-old white males could expect to live 6.6 years longer in 2004 versus 1900, and 80-year-olds could live 3 years longer. This is a small increase in view of the exceptional health and medical developments over the last century. Our workweek has also declined from about 60 to 40 h per week with increased worker safety and benefits. Table 1

Life expectancies for various populations

Rank

Population (both sexes)

Life expectancy at birth in years

1 2 3 4 5 6 7 11 20 30 34 50 107 163 204 225

Andorra Macau San Marino Singapore Hong Kong Japan Sweden Iceland Norway The Netherlands Germany Denmark China India Kenya Swaziland

83.51 82.19 81.71 81.71 81.59 81.25 80.51 80.31 79.54 78.96 78.80 77.79 72.27 64.35 47.99 33.22

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Gender and Life Expectancy

Longevity and Body Height

Females commonly have greater longevity compared to men throughout their lives. Exceptions exist, such as in Martinique and Afghanistan. However, there is a substantial difference of 10 years in longevity between the sexes, depending on the populations involved. Generally, the greatest differences are found in developed populations. Several reasons for this difference in longevity between the sexes have been proposed, such as hormonal protection, more robust physiology, better health-care habits, and lower high-risk activities. These factors no doubt have an impact, but animal and human research indicates that differences in body size may play a major role (Samaras et al., 2002). For example, one study reported that the average height for males in 21 European nations was 7.7% taller than females, and males had an 8.0% lower life expectancy (Samaras, 2009). Another study by Miller, based on about 1700 men and women in Ohio, found that when men and women of the same height were compared, there was essentially no difference in average life span (Samaras, 1996). Rollo also found that when he compared male and female mice of the same body weight, the usual difference in average life span disappeared (Samaras, 2007). Brown-Borg and Bartke also reported that dwarf male mice lived substantially longer than normal-size female siblings (Samaras, 2007).

If we look at the countries with the greatest life expectancies, developed countries lead the world. Based on this fact, it would appear that the tallest and heaviest (and sometimes the fattest) populations in the world live the longest. However, a number of factors contradict this hypothesis. In fact, if the top six populations in terms of life expectancy are examined for height, it appears that most of them are relatively short. For example, the populations of Andorra (mostly Catalans and Spaniards), Macau (mostly Chinese), San Marino (similar to Italians), Singapore (mostly Chinese), Hong Kong (mostly Chinese), and Japan are shorter than those of Northern Europe. In contrast, although Sweden ranks 7th from the top, other equally tall populations, such as Iceland, Norway, the Netherlands, Germany, and Denmark, collectively average 29th from the top ranking (vs 3rd for the top six populations) (Samaras, 2009). Note that the Dutch are the tallest people in the world and rank 30th in longevity. The negative impact of excess weight on longevity is widely accepted in the medical community (Samaras, 2006, 2007). However, the role of height is controversial, and the following material will highlight conflicting findings on longevity based on height differences among several populations.

Studies Showing Taller People Have Greater Longevity Centenarians Centenarians are another population of interest. Gerontologists have studied people who live to be 100 or more years in an attempt to define the qualities or conditions that characterize centenarians as a special population. They have identified a variety of positive attributes, such as not smoking, small body size, diet, regular exercise, avoidance of stress, lifestyle, family connectedness, avoidance of worry, and a positive attitude toward life. The greatest concentration of centenarians has been found in Okinawa, Japan, with 500/million, Bulgaria with 199/ million, and Sardinia with 136/million. The Okinawans have been studied for many years and researchers have attributed their longevity to good nutrition and low caloric intake. Okinawan children in the recent past consumed about 40% fewer calories than children in mainland Japan (Samaras, 1996). Other factors were a simple life and lifelong physical activity. It should be noted that centenarians tend to be relatively short and light. This could be an artifact due to the trend toward greater height and body size in the world during the last 150–200 years. In addition, people tend to shrink with age due to postural changes and compression of the discs in the spine. However, the Okinawan male centenarians average 148.3 cm and the females 138.8 cm. Even accounting for shrinkage and secular growth, these are small people. In addition, a centenarian study provided data on 14 European countries (The Italian Multicentric Study on Centenarians, 1997). Samaras separated 14 European and UK countries into two equal groups of taller and shorter populations (based on national height averages for the populations) and found that the shorter countries as a group had a 60% higher percentage of centenarians compared to the taller countries.

A review of life expectancy data shows that the tallest countries (and most developed) have on average the greatest longevity. Although not as great as the six top ranking populations, Western and Southern Europe, Australia, Canada, New Zealand, the UK, and the US have substantially longer life expectancies compared to shorter nations in the Middle East, Asia, South America, and Africa. Many studies found taller people have lower all-cause or cardiovascular disease mortality (CVD) (Samaras et al., 2004; Samaras, 2012). Since CVD is a major factor in reducing longevity, it indirectly supports the hypothesis that taller people live longer. However, a review of height and CVD worldwide found that it is the shorter people who have the lowest CVD. In fact, several populations of short people (e.g., 2 cm from main carina Invasion of visceral pleura Atelectasis/obstructive pneumonitis extending to hilum but not entire lung T3 Invasion of chest wall, diaphragm, mediastinal pleura, parietal pericardium Mainstem bronchus 48 h) by an infected tick. The rash may be asymptomatic or associated with vague, systemic symptoms including myalgias, arthralgias, headache, stiff neck, and fever, in 80% of cases (Steere, 2001). Within 3–4 weeks, the EM usually resolves. The EM rash is pathognomonic for LD; this coupled with exposure in an endemic area is sufficient for diagnosis. However, with extracutaneous manifestations of LD, laboratory diagnostic testing is necessary.

Early Disseminated Disease: Stage II The second stage, early disseminated disease, may occur days to weeks after transmission of Borrelia, even in the absence of an EM lesion. Hematogenous dissemination is a common and important feature of early LD. Symptoms may involve

Asia LD is seen in a wide belt reaching from western Russia to Japan across northern Asia, including Russia, northern China, Mongolia, Korea, and Japan. LD is not present in south Asian countries, except perhaps in travelers returning from endemic areas.

Clinical Presentation of Lyme Disease Case Definition The CDC surveillance case definition, updated in 2011 (see Relevant Websites), was developed for national reporting of LD and is not intended for clinical diagnosis. For surveillance purposes, a case of LD is defined as a physician-diagnosed EM lesion >5 cm in diameter or at least one manifestation of late LD (i.e.,: musculoskeletal, cardiovascular, or neurologic) with laboratory confirmation. We will discuss, in detail, clinical findings and laboratory diagnosis of LD in upcoming sections.

Figure 3 Erythema migrans rash. Photo courtesy: Cheleste Thorpe MD, Lucas Wolfe MD, and Linden T. Hu MD.

Lyme Disease the skin (multiple EM lesions may appear over the entire body), joints, muscles, peripheral, or CNS; joint involvement occurs in 60% of untreated patients. The central or peripheral nervous system may become involved at this stage and present as meningitis, cranial nerve VII palsy (Bell’s palsy), or sharp or tingling pains in the extremities (neuropathy). When the cardiovascular system is involved, carditis may lead to conduction delays including complete heart block.

Late Lyme Disease: Stage III The third stage, late LD, is a diagnosis of exclusion and generally affects the CNS and joints. In Europe, it may involve the skin as well, particularly with B. afzelii infection. This stage is characterized by inflammatory arthritis of large joints, most commonly the knee. Cognitive dysfunction of late LD can appear as nonspecific depression, anxiety, fatigue, and sleep disturbances. In the United States, arthritis is the most common late sequela, but in Europe radiculopathy, peripheral neuropathy, and late skin findings are associated with B. garinii infection.

Manifestations of Lyme Disease Skin

Three cutaneous manifestations of LD involve the skin: the prototypical EM, Borrelia lymphocytoma (BL), and acrodermatitis chronica atrophicans, more commonly seen in older patients infected with B. afzelii, particularly on extremities with higher sun exposure. After an incubation period of 7–14 days (range of 3– 32 days), an expanding skin lesion may be seen at the site of the tick bite. The EM rash is typically present in 70–90% of the patients, but may be undetected or forgotten. The EM lesion is often found near the axilla, inguinal region, behind the knee, or at belt lines, as the tick has a predilection to attach at warm, moist areas. It is often roughly circular but may also be irregular in shape and may demonstrate central clearing, with a ‘bull’seye’ appearance; however this is seen in only a minority of cases. The rash may progress at a rate of 1–2 cm per day and is unique in terms of the size it can reach, with >5 cm diameter being a hallmark of EM. A local allergic reaction may occur at the site of tick attachment and can appear as an erythematous macular expanding lesion; differentiation is important. Hypersensitivity reactions may occur while the tick is still attached, but generally disappear by 24–48 h and are less than 5 cm. Approximately 10% of patients with EM have multiple skin lesions, which represent dissemination of the organism. If EM goes unrecognized and untreated, patients may progress to early or late disseminated disease. Borrelia lymphocytoma is a bluish purple rash seen in early LD, which resembles dermal lymphoma. Histopathology demonstrates infiltration with polyclonal lymphocytes. BL is rare, with a prevalence of 0.6–1.3%. During late infection, an erythematous, atrophic plaque (acrodermatitis chronicum atrophicans) may develop; this is most commonly seen in Europe with B. afzelii infection. It presents as a localized edema and bluish-red discoloration on extensor surfaces of the hands, feet, elbows, and knees.

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Musculoskeletal

In North America, arthritis is the most common manifestation, usually with mono or oligoarticular infection affecting the knee, ankle, and elbow. Approximately 50% of untreated patients develop migratory polyarthritis and 10% develop monoarthritis. Sacroiliac or spinal involvement is not seen with LD and therefore favors an alternative diagnosis. Monoarthritis from LD may mimic septic arthritis particularly in the pediatric population. However, unlike septic arthritis, Lyme arthritis generally does not present with fever, or peripheral leukocytosis, and synovial fluid white blood cell counts are typically lower in Lyme arthritis (Milewski et al., 2011).

Neurological

The neurologic manifestations of LD were first described in France by Garin-Bujadoux in the 1920s, and later by Bannwarth in 1941, associating neurologic symptoms with the preceeding EM rash. The first systematic study of chronic neuropathy in LD was reported by Hopf in 1966 in 201 German patients with acrodermatitis chronicum atrophicans and a concomitant 10year asymmetric sensory neuropathy in 40% of the affected patients. Early disseminated disease may produce neurological symptoms such as meningitis (inflammation of the meninges resulting in headaches, photophobia, or stiff neck), neuropathy (inflammation of peripheral nerves), or radiculoneuritis, resulting in pain or numbness or tingling sensation or weakness. Cerebrospinal fluid (CSF) findings in Lyme meningitis are typically a lymphocytic pleocytosis with moderately elevated protein and normal-to-low glucose (Halperin, 2015). Neuropathy may affect both cranial and peripheral nerves. In the United States, cranial neuropathy is the most common symptom of early LD and typically affects cranial nerve (CN) VII, the facial nerve, presenting as a unilateral Bell’s palsy. Occasionally, LD may present as a bilateral Bell’s CN VII palsy, which helps differentiate it from idiopathic Bell’s palsy. The most prominent clinical symptom is pain caused by inflammation of a spinal nerve, or radiculoneuritis, seen more often in Europe than in the United States, and more frequent and severe in adults than in children. Chronic Lyme neuropathy, as compared with acute neuropathy, is generally less severe with mild sensory and rare motor or autonomic involvement and is associated with a reversible, mild axonal sensorimotor polyradiculoneuropathy or polyradiculopathy.

Cardiac

Lyme carditis occurs in
1% of patients in the United States. Inflammation in the myocardium results in acute seconddegree or third-degree atrioventricular conduction block. This presents with symptoms such as palpitations, lightheadedness, dizziness, or syncope (fainting). Case reports of sudden cardiac death associated with LD in young patients without prior cardiac history have been reported in the United States (Centers for Disease and Prevention, 2013; Forrester et al., 2014). For patients with advanced heart block, a temporary pacemaker may be required. Conduction system involvement usually reverses rapidly with antibiotic treatment.

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Lyme Disease

Posttreatment Lyme Disease Syndrome

Some patients continue to experience symptoms of illness after appropriate treatment for LD. This also occurs in a number of other infectious diseases, and the symptoms are referred to as ‘postinfection sequelae.’ Controversy exists as to B. burgdorferi survival and ability to cause disease after antibiotic treatment. The results of a National Institutes of Allergy and Infectious Diseases–supported randomized, placebo-controlled, doubleblind study demonstrated that a 90-day course of oral or intravenous antibiotics was no better than placebo in improving the persistent musculoskeletal, neurologic, or cognitive problems reported after a full course of treatment for a documented case of LD (Klempner et al., 2001). Survival of the spirochete has been demonstrated in experimentally infected mice and monkeys after antibiotic therapy, and in a single human patient. However, many of these studies were revealing more in terms of study design than in quantity of interpretable data. For example, live, infectious spirochetes were obtained only once, but DNA and protein were found somewhat more readily (Bockenstedt et al., 2012; Marques et al., 2014; Pavia and Wormser, 2014). More studies are needed to evaluate the possibility of postantibiotic persistence of viable and pathogenic B. burgdorferi and to evaluate the risk–benefit ratio of multiple or prolonged antibiotic treatments. Additionally, reinfection is a concern for those in endemic areas.

Lyme Disease in Pregnancy

Individual case reports have suggested poor fetal outcome in women with LD during pregnancy; however, there is no specific pattern of teratogenicity, and large studies have failed to demonstrate a causal relationship between maternal LD and adverse neonatal outcomes. There have also been no reports of transmission through breast feeding. Evidencebased recommendations from reviews of published literature do not suggest altering treatment, except for the avoidance of doxycycline in pregnant or breast-feeding women. An alternative agent such as amoxicillin should be used; however, one should keep in mind that amoxicillin will not be effective in treating potential coinfections caused by other agents transmitted by the same tick.

Coinfection

Coinfection with Babesia and/or Anaplasma and/or Ehrlichia and/or the deer tick virus may occur in patients with LD. Ixodes scapularis is a vector for Anaplasma phagocytophilum, the bacterial agent of human granulocytic anaplasmosis (HGA), and Babesia microti, the parasitic agent of babesiosis. The deer tick may also transmit a newly identified Ehrlichia species in Wisconsin and Minnesota (Pritt et al., 2011; Castillo et al., 2015; Johnson et al., 2015), and Borrelia miyamotoi in the northeastern United States (Barbour et al., 2009; Telford et al., 2015). Interestingly, B. miyamotoi is genetically more closely related to the RF Borrelia than to the LD Borrelia, but does not apparently cause clinical RF. Powassan virus, also known as the deer tick virus, is also transmitted by the same tick (Caulfield and Pritt, 2015; Wormser and Pritt, 2015). A high index of suspicion is needed in endemic areas or in patients who present with a