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The PLoS Medicine Editors and partners from the Maternal Health Task Force at the Harvard School of Public Health announce their partnership and a call for papers on “quality of maternal health care.”

Background During the Coronavirus Disease 2019 (COVID-19) pandemic, the number of consultations and diagnoses in primary care and referrals to specialist care declined substantially compared to prepandemic levels. Beyond deferral of elective non-COVID-19 care by healthcare providers, it is unclear to what extent healthcare avoidance by community-dwelling individuals contributed to this decline in routine healthcare utilisation. Moreover, it is uncertain which specific symptoms were left unheeded by patients and which determinants predispose to healthcare avoidance in the general population. In this cross-sectional study, we assessed prevalence of healthcare avoidance during the pandemic from a patient perspective, including symptoms that were left unheeded, as well as determinants of healthcare avoidance. Methods and findings On April 20, 2020, a paper COVID-19 survey addressing healthcare utilisation, socioeconomic factors, mental and physical health, medication use, and COVID-19–specific symptoms was sent out to 8,732 participants from the population-based Rotterdam Study (response rate 73%). All questionnaires were returned before July 10, 2020. By hand, prevalence of healthcare avoidance was subsequently verified through free text analysis of medical records of general practitioners. Odds ratios (ORs) for avoidance were determined using logistic regression models, adjusted for age, sex, and history of chronic diseases. We found that 1,142 of 5,656 included participants (20.2%) reported having avoided healthcare. Of those, 414 participants (36.3%) reported symptoms that potentially warranted urgent evaluation, including limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). Determinants related to avoidance were older age (adjusted OR 1.14 [95% confidence interval (CI) 1.08 to 1.21]), female sex (1.58 [1.38 to 1.82]), low educational level (primary education versus higher vocational/university 1.21 [1.01 to 1.46), poor self-appreciated health (per level decrease 2.00 [1.80 to 2.22]), unemployment (versus employed 2.29 [1.54 to 3.39]), smoking (1.34 [1.08 to 1.65]), concern about contracting COVID-19 (per level increase 1.28 [1.19 to 1.38]) and symptoms of depression (per point increase 1.13 [1.11 to 1.14]) and anxiety (per point increase 1.16 [1.14 to 1.18]). Study limitations included uncertainty about (perceived) severity of the reported symptoms and potentially limited generalisability given the ethnically homogeneous study population. Conclusions In this population-based cross-sectional study, 1 in 5 individuals avoided healthcare during lockdown in the COVID-19 pandemic, often for potentially urgent symptoms. Healthcare avoidance was strongly associated with female sex, fragile self-appreciated health, and high levels of depression and anxiety. These results emphasise the need for targeted public education urging these vulnerable patients to timely seek medical care for their symptoms to mitigate major health consequences., Marije J. Splinter and colleagues assess the prevalence of healthcare avoidance during the COIVD-19 pandemic and investigate related determinants, Author summary Why was this study done? ➢ During the Coronavirus Disease 2019 (COVID-19) pandemic, consultation rates in both primary and specialist care declined compared to prepandemic levels, which can partially be attributed to the postponement or cancellation of elective and nonurgent medical care. ➢ It is unclear to what extent these declines in consultation rates could be related to healthcare avoidance by patients in the general population. ➢ To evaluate the collateral health damage of the COVID-19 pandemic, it is important to not only assess the prevalence of healthcare avoidance, but also for what symptoms healthcare was avoided and which determinants are associated with this behaviour. What did the researchers do and find? ➢ We sent out a paper questionnaire to 8,732 participants of the population-based Rotterdam Study containing several COVID-19–related subjects, such as healthcare utilisation, work status, mental and physical health, and concerns about contracting COVID-19. ➢ About 6,241 participants (73%) returned the questionnaire, of whom 5,656 participants (90.6%) were included in our analyses. We found that 1,142 of them (20.2%) avoided healthcare during the COVID-19 pandemic, often for symptoms that might have needed urgent medical evaluation, such as limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). ➢ Determinants that were most strongly associated with healthcare avoidance were female sex, poor self-appreciated health, and high levels of depression and anxiety. What do these findings mean? ➢ The results of this population-based study suggest that healthcare avoidance contributed to the decline in consultation rates during the COVID-19 pandemic. Importantly, our findings suggest that this behaviour may be associated with certain vulnerable groups within the population. ➢ These findings should be interpreted in light of the limitations of this study, which include that the actual severity of the symptoms that were reported by participants is unknown, since they were not medically evaluated when they experienced these symptoms. ➢ The findings of this study can be used to develop policy interventions targeted to vulnerable individuals who may be more likely to exhibit healthcare avoiding behaviours.

The benefits of having a continuous, piped supply of safe drinking water delivered to household premises are widely recognised. Piped supplies on premises not only reduce the time and effort required to collect water, and thereby increase the amount of water available for personal and domestic needs but also are more likely to provide water that meets required standards for drinking water quality. A recent systematic review of drinking water quality [1] confirmed that piped water supplies are less likely to be contaminated than other types of “improved” sources, such as hand pumps, protected wells, and springs. However, continuity of piped supplies—that is, the uninterrupted supply of water—and the associated health impacts, are under-studied. Two papers in this issue of PLOS Medicine each shed light on a particular aspect of continuity and are a very welcome addition to the literature. Jeandron and colleagues [2] show that in the city of Uvira, in the Democratic Republic of the Congo, there was a significant relationship between interruptions in the piped water supply and cases of suspected cholera. This association was seen even though many in the city used piped services indirectly (that is, they did not have household connections and used water from standposts and shared connections). The interruptions in the piped water supply thus represented a lost opportunity to protect a cholera-vulnerable population. In Hubli-Dharwad, in the state of Karnataka in India, Ercumen and colleagues [3] show that while upgrading the piped supply to provide continuous service for 10% of the population was associated with a notable reduction in typhoid among the poor in the beneficiary group, they did not find the expected decrease in diarrhoeal diseases. The paper suggests a number of possible reasons, including unhygienic storage of water due to the use of yard taps rather than taps in the house; the perceived threat of supply interruptions; heavy contamination of the immediate household environment due to widespread open defecation among children; and the continuing presence of open sewers. It is notable that the research in India found a strong relationship between the continuity of the supply and quality of the water delivered. Among water samples taken from households receiving a continuous supply, less than 1% did not comply with WHO guidelines for drinking water quality, compared with over one-third of samples in households that did not benefit from improvements and still had intermittent supply. The importance of continuous piped supply to households in order to protect health is clear. This link is not surprising given the engineering reality—that maintaining continuous positive pressure in a piped network and avoiding negative pressure at all costs prevents infiltration of contaminated soil water [4]. Continuous supply also removes the need to store water and makes water readily available for hygiene, such as handwashing. From a public health policy point of view, ideally, households should have continuous water supply, treated with chlorine, piped directly into the house, with accompanying improvements in the sanitary environment. For this reason, a new benchmark has been proposed to be included in the indicators used for monitoring progress towards the Sustainable Development Goals adopted by the United Nations (UN) General Assembly in September 2015. The new term “safely managed drinking water services” is proposed as the highest level of service countries should aspire to reach, and refers to a source of drinking water that is on premises, available when needed (that is, in the case of piped supplies, continuous), and free of faecal and priority chemical contamination. This represents a significant step up from the highest level of service used in monitoring during the period of the Millennium Development Goals: “improved drinking-water source,” which did not include measures of distance to the home, quality or continuity of water supplied, and included off-premises sources such as hand pumps, dug wells, and springs. Reaching this new benchmark at a global scale is undoubtedly ambitious. However, monitoring data [5] show it is not impossible. During the last 25 years, coverage of piped water on premises increased from 44% to 58% globally, so now well over half the world’s population benefits from this level of service. In those countries designated as developing countries by the UN, the use of piped water on premises has grown even faster, from 31% in 1990 to an estimated 49% in 2015, representing an additional 1.7 billion people with piped water connections. Progress in some regions has been even faster, and in Eastern Asia the number of people with piped water on premises skyrocketed from 30% to 74%, mostly as a result of rapid increases in China. Continuous, treated, piped supply to every household should be our ambition, even though achieving it may be many years in the future, and in many settings, interim arrangements with lower levels of service are going to be the reality. However, many countries have decided providing piped supply is worth the investment, and innovations are being rolled out in many places to find robust, inexpensive ways to provide this service in an affordable way. The studies in this issue of PLOS Medicine highlight the importance of continuous piped water supply, but also the pitfalls. Interruptions in the supply can negate the possible health benefits, and installing piped water without addressing other environmental concerns may not deliver the hoped-for health benefits. It must not be forgotten that piped water supplies require more than just infrastructure; good governance and competent management are needed to ensure continuous service.

Michel Guillot and colleagues did a systematic evaluation to assess what proportion of under-five mortality occurs below age one compared with at age one and above, to determine how much observed values deviate from so called “model age patterns” of under-five mortality, Background The under-five mortality rate (the probability of dying between birth and age 5 y, also denoted in the literature as U5MR and 5 q 0) is a key indicator of child health, but it conceals important information about how this mortality is distributed by age. One important distinction is what amount of the under-five mortality occurs below age 1 y (1 q 0) versus at age 1 y and above (4 q 1). However, in many country settings, this distinction is often difficult to establish because of various types of data errors. As a result, it is common practice to resort to model age patterns to estimate 1 q 0 and 4 q 1 on the basis of an observed value of 5 q 0. The most commonly used model age patterns for this purpose are the Coale and Demeny and the United Nations systems. Since the development of these models, many additional sources of data for under-five mortality have become available, making possible a general evaluation of age patterns of infant and child mortality. In this paper, we do a systematic comparison of empirical values of 1 q 0 and 4 q 1 against model age patterns, and discuss whether observed deviations are due to data errors, or whether they reflect true epidemiological patterns not addressed in existing model life tables. Methods and Findings We used vital registration data from the Human Mortality Database, sample survey data from the World Fertility Survey and Demographic and Health Surveys programs, and data from Demographic Surveillance Systems. For each of these data sources, we compared empirical combinations of 1 q 0 and 4 q 1 against combinations provided by Coale and Demeny and United Nations model age patterns. We found that, on the whole, empirical values fall relatively well within the range provided by these models, but we also found important exceptions. Sub-Saharan African countries have a tendency to exhibit high values of 4 q 1 relative to 1 q 0, a pattern that appears to arise for the most part from true epidemiological causes. While this pattern is well known in the case of western Africa, we observed that it is more widespread than commonly thought. We also found that the emergence of HIV/AIDS, while perhaps contributing to high relative values of 4 q 1, does not appear to have substantially modified preexisting patterns. We also identified a small number of countries scattered in different parts of the world that exhibit unusually low values of 4 q 1 relative to 1 q 0, a pattern that is not likely to arise merely from data errors. Finally, we illustrate that it is relatively common for populations to experience changes in age patterns of infant and child mortality as they experience a decline in mortality. Conclusions Existing models do not appear to cover the entire range of epidemiological situations and trajectories. Therefore, model life tables should be used with caution for estimating 1 q 0 and 4 q 1 on the basis of 5 q 0. Moreover, this model-based estimation procedure assumes that the input value of 5 q 0 is correct, which may not always be warranted, especially in the case of survey data. A systematic evaluation of data errors in sample surveys and their impact on age patterns of 1 q 0 and 4 q 1 is urgently needed, along with the development of model age patterns of under-five mortality that would cover a wider range of epidemiological situations and trajectories. Please see later in the article for the Editors' Summary., Editors' Summary Background In 2000, world leaders agreed on eight Millennium Development Goals designed to end extreme poverty by 2015. The fourth of these goals—MDG 4—aims to reduce under-five mortality (the number of children who die before their fifth birthday) to a third of its 1990 level by 2015. A key indicator used to monitor progress towards this target is the under-five mortality rate (the probability of a child dying before his/her fifth birthday, also denoted as U5MR or 5 q 0). In developed countries, data collected through vital registration systems (which record all births and deaths) are used to calculate 5 q 0. However, developing countries, which are where most under-five deaths occur, rarely have vital registration systems, and 5 q 0 is estimated using data collected by programs such as the World Fertility Survey (WFS) and Demographic and Health Surveys (DHS), which conduct nationally representative surveys that ask a sample of women about their living and dead children. Why Was This Study Done? Although 5 q 0 is a key indicator of child health, it conceals important information about the age distribution of child deaths. Public health experts need to know the distribution of 5 q 0 with respect to 1 q 0 (the probability that an infant will die before age one) and 4 q 1 (the probability that a child reaching age one will die below age five) to help them reduce child mortality. At a given level of 5 q 0, high values of 1 q 0 indicate high levels of death from congenital (inherited) anomalies and conditions that occur around the time of birth; these deaths can be reduced by improving the care of women during pregnancy and childbirth and the care of newborn babies. By contrast, at a given level of 5 q 0, high values of 4 q 1 indicate high levels of death from infectious diseases; these deaths can be reduced by, for example, introducing immunization programs. 1 q 0 and 4 q 1 are usually estimated from observed (empirical) values of 5 q 0 using the Coale and Demeny or United Nations (UN) “model life tables” (mathematical models of the variation of mortality with age), which were constructed in 1966 and 1982, respectively, using the best data available. Since their construction, additional sources of data about under-five mortality have become available; in this study, the researchers systematically compare global empirical values of 1 q 0 and 4 q 1 with values obtained using model life tables. What Did the Researchers Do and Find? The researchers compared empirical combinations of 1 q 0 and 4 q 1 (estimated using vital registration data, WFS and DHS data, and data from Demographic Surveillance Sites in sub-Saharan Africa) with the combinations derived from 5 q 0 using the Coale and Demeny and UN model life tables. The empirical values mainly fell within the range provided by these tables, but there were important exceptions. For example, empirical values of 4 q 1 relative to 1 q 0 tended to be above the range provided by the model life tables for sub-Saharan African countries. This pattern was mainly because of epidemiological reasons (epidemiology is the study of disease patterns in populations), such as the occurrence of diseases such as malaria, measles, and diarrhea that generate excess mortality among children older than one year. Interestingly, the emergence of HIV does not seem to have substantially modified preexisting patterns of 1 q 0 versus 4 q 1. Importantly, the researchers also show that populations often experience changes in the age patterns of infant and child mortality as they experience an overall decline in mortality. What Do These Findings Mean? These findings suggest that the existing model life tables do not cover the entire global range of epidemiological situations and trajectories and must, therefore, be used with caution for estimating 1 q 0 and 4 q 1 on the basis of 5 q 0. The development of new model age patterns of under-five mortality that cover a wider range of epidemiological situations should improve this situation, but a systematic analysis of data errors in sample surveys and the impact of such errors on estimates of 1 q 0 and 4 q 1 is also urgently needed to ensure that public health experts have access to accurate information on child mortality. Importantly, this overview shows that a wide range of 1 q 0 and 4 q 1 combinations can occur at a given level of 5 q 0. Because the level of 4 q 1 relative to 1 q 0 provides important information about the disease processes occurring in a population, this finding highlights the importance of determining 1 q 0 and 4 q 1 as well as 5 q 0 whenever possible. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001299. This paper is part of a collection of papers on Child Mortality Estimation Methods published in PLOS Medicine The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on Millennium Development Goal 4, and its Childinfo website provides detailed statistics about child survival and health, including a description of the United Nations Inter-agency Group for Child Mortality Estimation; the 2011 UN IGME report Levels & Trends in Child Mortality is available The World Health Organization also has information about Millennium Development Goal 4 and provides estimates of child mortality rates (some information in several languages) Further information about the Millennium Development Goals is available Information is also available about the Human Mortality Database, which holds vital registration data; the World Fertility Survey program; the Demographic and Health Surveys program; and model life tables

In the first of two papers investigating surgical provision in eight district hospitals in Saharan African countries, Margaret Kruk and colleagues find low levels of surgical care provision suggesting unmet need for surgical services., Background Surgical conditions contribute significantly to the disease burden in sub-Saharan Africa. Yet there is an apparent neglect of surgical care as a public health intervention to counter this burden. There is increasing enthusiasm to reverse this trend, by promoting essential surgical services at the district hospital, the first point of contact for critical conditions for rural populations. This study investigated the scope of surgery conducted at district hospitals in three sub-Saharan African countries. Methods and Findings In a retrospective descriptive study, field data were collected from eight district hospitals in Uganda, Tanzania, and Mozambique using a standardized form and interviews with key informants. Overall, the scope of surgical procedures performed was narrow and included mainly essential and life-saving emergency procedures. Surgical output varied across hospitals from five to 45 major procedures/10,000 people. Obstetric operations were most common and included cesarean sections and uterine evacuations. Hernia repair and wound care accounted for 65% of general surgical procedures. The number of beds in the studied hospitals ranged from 0.2 to 1.0 per 1,000 population. Conclusion The findings of this study clearly indicate low levels of surgical care provision at the district level for the hospitals studied. The extent to which this translates into unmet need remains unknown although the very low proportions of live births in the catchment areas of these eight hospitals that are born by cesarean section suggest that there is a substantial unmet need for surgical services. The district hospital in the current health system in sub-Saharan Africa lends itself to feasible integration of essential surgery into the spectrum of comprehensive primary care services. It is therefore critical that the surgical capacity of the district hospital is significantly expanded; this will result in sustainable preventable morbidity and mortality. Please see later in the article for the Editors' Summary, Editors' Summary Background Every year, about 234 million major surgical procedures take place globally. Of these procedures, only a quarter are performed in low- and middle-income countries where nearly three-quarters of the world's population lives. Put another way, in high-income countries, 10,110 people out of every 100,000 have surgery each year on average compared to only 295 people out of every 100,000 in low- and middle-income countries. Yet conditions that need surgery (including complications of childbirth and traumatic injuries) are common in developing countries and contribute significantly to the burden of disease in these countries. Various organizations are working to reduce this burden by improving emergency and essential surgical care in developing countries. For example, the Bellagio Essential Surgery Group (BESG), which includes experts in surgery, anesthesia, obstetrics (the branch of medicine that cares for women during pregnancy and childbirth), and health policy from several African countries, the World Health Organization (WHO), and the US, aims to increase access to surgical services in sub-Saharan Africa. Why Was This Study Done? One way to improve access to surgical services in sub-Saharan Africa would be to promote the provision of essential surgical services at district hospitals. These hospitals are the first referral facilities for people living in rural areas. Traditionally, patients receive much of their primary health care at these facilities but are referred to secondary and tertiary health care facilities (regional and national referral hospitals, respectively) for more specialized care. However, many surgical conditions—in particular, obstetric emergencies—need to be treated at district hospitals if lives are to be saved. Unfortunately, very little is known about the range and volume of surgical procedures currently undertaken in district hospitals in sub-Saharan Africa and such information is needed before programs can be developed to increase access to surgical services at these facilities. In this retrospective, descriptive study, the researchers (some of whom are part of the BESG) investigate the scope of surgery undertaken in district hospitals in three sub-Saharan African countries. What Did the Researchers Do and Find? The researchers obtained recent data on the surgical procedures done at two representative district hospitals each in Tanzania and in Mozambique and four representative district hospitals in Uganda by examining hospital records and by interviewing administrators. The observed range of surgical procedures performed in these hospitals was narrow, they report, consisting mainly of essential and life-saving emergency procedures such as cesarean sections for the delivery of babies and wound-related procedures. Obstetric procedures accounted for around half of all surgical procedures in all the hospitals except one Ugandan hospital. Hernia repair and wound care accounted for nearly two-thirds of general surgical procedures. The surgical output across the hospitals varied from five to 45 major procedures per 10,000 people in the population (average 25 operations per 10,000 people). Across the hospitals, between one and 17 cesarean sections and between 0.5 and seven hernia repairs were performed per 10,000 people in the population. Finally, the researchers used their data and WHO estimates of the population need for cesarean sections to estimate that in the two Tanzanian district hospitals, between half and two-thirds of women that needed a cesarean section did not have access to this life-saving procedure. What Do These Findings Mean? These findings suggest that there are low levels of provision of surgical care in district hospitals in Tanzania, Mozambique, and Uganda. Further studies are needed to confirm that these findings are generalizable to district hospitals elsewhere in sub-Saharan Africa and to quantify the extent to which this low level of surgical care translates into unmet needs. Limitations of the study include a lack of information on outcomes, on referral of patients to higher-level facilities, and on how many of the surgical procedures undertaken at these hospitals dealt with traumatic injuries. Nevertheless, the information collected in this study, together with that in a separate paper that investigates the availability of health workers and funding for the provision of essential surgery in district hospitals in these three countries, suggests that the surgical capacity of district hospitals in sub-Saharan Africa needs to be improved. If this goal can be achieved, suggest the researchers, it should avert many illnesses and deaths in this poor region of the world. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000243. The availability of health workers and funding for surgery in the same hospitals is investigated in a PLoS Medicine Research Article by Margaret E. Kruk et al. Information on the Bellagio Essential Surgery Group is available WHO's Global initiative for Emergency and Essential Surgical Care plans to take essential emergency, basic surgery and anesthesia skills to health care staff in low- and middle-income countries around the world; WHO also has a page describing the importance of emergency and essential surgery in primary health care

In 2002, a clinical trial designed to evaluate optimal ventilation practice [1],[2] for patients with acute respiratory distress syndrome (ARDS) sparked a major controversy. Critics charged that management of ARDS in the different arms of the study did not adequately reflect usual medical care, and alleged that it was essential for scientific and ethical reasons to have a usual care comparison arm in the study. The controversy over trial design enmeshed the National Institutes of Health (NIH), the Office for Human Research Protections (OHRP) and the critical care research community. The trial was put on hold and reviewed by two independent expert panels. Experts pointed to the need for further analysis of the scientific and ethical issues involved in choosing trial designs when there is no consensus on standard of care. In November 2005, NIH and a number of other federal agencies sponsored a meeting (see Text S1) to discuss clinical trial design challenges involving selection of usual care comparison groups (Text S1). The meeting was informed by a background paper (Text S1) outlining types of challenges involved in selecting usual care arms, prepared by a working group with expertise in clinical trial design, ethics, evidence-based medicine, statistics, and science policy. We present here the background framework and case studies used in this paper (Text S1). We enumerate five factors that make consensus on these issues particularly difficult, and recommend specific criteria for assessing proposed study designs. Terminology Terms such as “standard of care,” “control arm,” “usual care,” and “community care” have all been used to describe arms reflecting conventional therapy. We use the term “usual care” to describe the care commonly given by practitioners in a community to avoid any legal or normative implications of the term “standard of care.”

Louise Howard and colleagues conduct a systematic review and meta-analysis to estimate the prevalence and odds of experience of domestic violence experience among women with antenatal and postnatal mental health disorders. Please see later in the article for the Editors' Summary, Background Domestic violence in the perinatal period is associated with adverse obstetric outcomes, but evidence is limited on its association with perinatal mental disorders. We aimed to estimate the prevalence and odds of having experienced domestic violence among women with antenatal and postnatal mental disorders (depression and anxiety disorders including post-traumatic stress disorder [PTSD], eating disorders, and psychoses). Methods and Findings We conducted a systematic review and meta-analysis (PROSPERO reference CRD42012002048). Data sources included searches of electronic databases (to 15 February 2013), hand searches, citation tracking, update of a review on victimisation and mental disorder, and expert recommendations. Included studies were peer-reviewed experimental or observational studies that reported on women aged 16 y or older, that assessed the prevalence and/or odds of having experienced domestic violence, and that assessed symptoms of perinatal mental disorder using a validated instrument. Two reviewers screened 1,125 full-text papers, extracted data, and independently appraised study quality. Odds ratios were pooled using meta-analysis. Sixty-seven papers were included. Pooled estimates from longitudinal studies suggest a 3-fold increase in the odds of high levels of depressive symptoms in the postnatal period after having experienced partner violence during pregnancy (odds ratio 3.1, 95% CI 2.7–3.6). Increased odds of having experienced domestic violence among women with high levels of depressive, anxiety, and PTSD symptoms in the antenatal and postnatal periods were consistently reported in cross-sectional studies. No studies were identified on eating disorders or puerperal psychosis. Analyses were limited because of study heterogeneity and lack of data on baseline symptoms, preventing clear findings on causal directionality. Conclusions High levels of symptoms of perinatal depression, anxiety, and PTSD are significantly associated with having experienced domestic violence. High-quality evidence is now needed on how maternity and mental health services should address domestic violence and improve health outcomes for women and their infants in the perinatal period. Please see later in the article for the Editors' Summary, Editors' Summary Background Domestic violence—physical, sexual, or emotional abuse by an intimate partner or family member—is a major public health problem and although more common in women, can also affect men. Due to the nature of the problem, it is difficult to collect accurate figures on the scale of domestic violence, but a study by the World Health Organization in ten countries found that 15%–71% of women aged 15–49 years reported physical and/or sexual violence by an intimate partner at some point in their lives. Women experiencing domestic violence have significant short- and long-term health problems, particularly regarding their mental health: experience of domestic violence can lead to a range of mental health disorders such as depression, psychosis, eating disorders, and even suicide attempts. Why Was This Study Done? As perinatal mental health disorders are among the commonest health problems in pregnancy and the postpartum period, and given the rate of domestic violence during pregnancy (previous studies have suggested a domestic violence prevalence of 4%–8% during pregnancy and the postnatal period), it is plausible that there may be a link between perinatal mental health disorders and having experienced domestic violence. Indeed, previous reviews have suggested the existence of such an association but were limited by the small number of included studies and focused on depression only, rather than the full range of antenatal and postnatal mental health disorders. So in this study the researchers systematically reviewed published studies to provide more robust estimates of the prevalence of having experienced domestic violence among women with antenatal and postnatal mental health disorders; the researchers also used a meta-analysis to estimate the odds (chance) of having experienced domestic violence among women with antenatal and postnatal mental health disorders. What Did the Researchers Do and Find? The researchers searched multiple databases and hand searched three relevant journals using key search terms to identify all types of relevant studies. Using specific criteria, the researchers retrieved and assessed over 1,000 full papers, of which 67 met the criteria for their systematic review. The researchers assessed the quality of each selected study and included only those studies that used validated diagnostic instruments and screening tools to assess mental health disorders in their calculations of the pooled (combined) odds ratio (OR) through meta-analysis. Using these methods, in cross-sectional studies (studies conducted at one point in time), the researchers found that women with probable depression in the antenatal period reported a high prevalence and increased odds of having experienced partner violence during their lifetime (OR = 3), during the past year (OR = 2.8), and during pregnancy (OR = 5). The results were similar for the postnatal period. The evidence was less robust for anxiety disorders: among women with probable anxiety in the antenatal period, the researchers found an OR of 2.9 of having experienced lifetime partner violence. The odds were less in the postnatal period (OR = 1.4) In their analysis of longitudinal studies (follow-up studies over a period of time), the researchers found an increased odds of probable postnatal depression both among women who reported having ever experienced partner violence in their lifetime (OR = 2.9) and among women who reported having experienced partner violence during pregnancy (OR = 3.1). The researchers also found a combined prevalence estimate of 12.7% for probable depression during the postnatal period following experiences of partner violence during pregnancy. Because of limited data, the researchers could not calculate an OR of the association between probable antenatal depression and later experiences of partner violence. What Do These Findings Mean? These findings suggest that women with high levels of symptoms of perinatal mental health disorders—antenatal and postnatal anxiety, depression, and post-traumatic stress disorder—have a high prevalence and increased odds of having experienced domestic violence both over their lifetime and during pregnancy. However, these findings cannot prove causality, they fail to show a two-way association (that is, perinatal mental health disorders leading to subsequent domestic violence), and no information on other perinatal mental disorders, such as eating disorders and puerperal psychosis, was available. The variation of the quality of the included studies also limits the results, highlighting the need for high-quality data to suggest how maternity and mental health services could address domestic violence and improve health outcomes for women and their infants in the future. Nevertheless, this study emphasizes the importance of identifying and responding to possible domestic violence among women attending antenatal and mental health services. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001452. The World Health Organization provides information and statistics about violence against women and also about mental health disorders during pregnancy The UK Royal College of Psychiatrists has information for professionals and patients about mental health disorders during pregnancy

Romesh Silva assesses and analyzes differences in direct and indirect methods of estimating under-five mortality rates using data collected from full and summary birth histories in Demographic and Health Surveys from West Africa, East Africa, Latin America, and South/Southeast Asia., Background Given the lack of complete vital registration data in most developing countries, for many countries it is not possible to accurately estimate under-five mortality rates from vital registration systems. Heavy reliance is often placed on direct and indirect methods for analyzing data collected from birth histories to estimate under-five mortality rates. Yet few systematic comparisons of these methods have been undertaken. This paper investigates whether analysts should use both direct and indirect estimates from full birth histories, and under what circumstances indirect estimates derived from summary birth histories should be used. Methods and Findings Usings Demographic and Health Surveys data from West Africa, East Africa, Latin America, and South/Southeast Asia, I quantify the differences between direct and indirect estimates of under-five mortality rates, analyze data quality issues, note the relative effects of these issues, and test whether these issues explain the observed differences. I find that indirect estimates are generally consistent with direct estimates, after adjustment for fertility change and birth transference, but don't add substantial additional insight beyond direct estimates. However, choice of direct or indirect method was found to be important in terms of both the adjustment for data errors and the assumptions made about fertility. Conclusions Although adjusted indirect estimates are generally consistent with adjusted direct estimates, some notable inconsistencies were observed for countries that had experienced either a political or economic crisis or stalled health transition in their recent past. This result suggests that when a population has experienced a smooth mortality decline or only short periods of excess mortality, both adjusted methods perform equally well. However, the observed inconsistencies identified suggest that the indirect method is particularly prone to bias resulting from violations of its strong assumptions about recent mortality and fertility. Hence, indirect estimates of under-five mortality rates from summary birth histories should be used only for populations that have experienced either smooth mortality declines or only short periods of excess mortality in their recent past. Please see later in the article for the Editors' Summary., Editors' Summary Background In 1990, 12 million children died before they reached their fifth birthday. Faced with this largely avoidable loss of young lives, in 2000, world leaders set a target of reducing under-five mortality (death) to one-third of its 1990 level by 2015 as Millennium Development Goal 4 (MDG 4); this goal, together with seven others, aims to eradicate extreme poverty globally. To track progress towards MDG 4, experts need accurate estimates of the global and country-specific under-five mortality rate (U5MR, the probability of a child dying before age five). The most reliable sources of data for U5MR estimation are vital registration systems—national records of all births and deaths. Unfortunately, developing countries, which are where most childhood deaths occur, rarely have such records, so full or summary birth histories provide the data for U5MR estimation instead. In full birth histories (FBHs), which are collected through household surveys such as those conducted by Demographic and Health Surveys (DHS), women are asked for the date of birth of all their children and the age at death of any children who have died. In summary birth histories (SBHs), which are collected through household surveys and censuses, women are asked how many children they have had and how many are alive at the time of the survey. Why Was This Study Done? “Direct” estimates of U5MRs can be obtained from FBHs because FBHs provide detailed information about the date of death and the exposure of children to the risk of dying. By contrast, because SBHs do not contain information on children's exposure to the risk of dying, “indirect” estimates of U5MR are obtained from SBHs using model life tables (mathematical models of the variation of mortality with age). Indirect estimates are often also derived from FBHs, but few systematic comparisons of direct and indirect methods for U5MR estimation have been undertaken. In this study, Romesh Silva investigates whether direct and indirect methods provide consistent U5MR estimates from FBHs and whether there are any circumstances under which indirect methods provide more reliable U5MR estimates than direct methods. What Did the Researcher Do and Find? The researcher used DHS data from West Africa, East Africa, Latin America, and South/Southeast Asia to quantify the differences between direct and indirect estimates of U5MR calculated from the same data and analyzed possible reasons for these differences. Estimates obtained using a version of the “Brass” indirect estimation method were uniformly higher than those obtained using direct estimation. Indirect and direct estimates generally agreed, however, after adjustment for changes in fertility—the Brass method assumes that country-specific fertility (the number of children born to a woman during her reproductive life) remains constant—and for birth transference, an important source of data error in FBHs that arises because DHS field staff can lessen their workload by recording births as occurring before a preset cutoff date rather than after that date. Notably, though, for countries that had experienced political or economic crises, periods of excess mortality due to conflicts, or periods during which the health transition had stalled (as countries become more affluent, overall mortality rates decline and noncommunicable diseases replace infectious diseases as the major causes of death), marked differences between indirect and direct estimates of U5MR remained, even after these adjustments. What Do These Findings Mean? Because the countries included in this study do not have vital registration systems, these findings provide no information about the validity of either direct or indirect estimation methods for U5MR estimation. They suggest, however, that for countries where there has been a smooth decline in mortality or only short periods of excess mortality, both direct and indirect methods of U5MR estimation work equally well, after adjustment for changes in fertility and for birth transference, and that indirect estimates add little to the insights provided into childhood mortality by direct estimates. Importantly, the inconsistencies observed between the two methods that remain after adjustment suggest that indirect U5MR estimation is more susceptible to bias (systematic errors that arise because of the assumptions used to estimate U5MR) than direct estimation. Thus, indirect estimates of U5MR from SBHs should be used only for populations that have experienced either smooth mortality declines or only short periods of excess mortality in their recent past. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001296. This paper is part of a collection of papers on Child Mortality Estimation Methods published in PLOS Medicine The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on Millennium Development Goal 4, and its Childinfo website provides detailed statistics about child survival and health, including a description of the United Nations Inter-agency Group for Child Mortality Estimation; the 2011 UN IGME report Levels & Trends in Child Mortality is available The World Health Organization has information about Millennium Development Goal 4 and provides estimates of child mortality rates (some information in several languages) Further information about the Millennium Development Goals is available Information is available about infant and child mortality data collected by Demographic and Health Surveys

Jon Pedersen and Jing Liu examine the feasibility and potential advantages of using one-year rather than five-year time periods along with calendar year-based estimation when deriving estimates of child mortality., Background Child mortality estimates from complete birth histories from Demographic and Health Surveys (DHS) surveys and similar surveys are a chief source of data used to track Millennium Development Goal 4, which aims for a reduction of under-five mortality by two-thirds between 1990 and 2015. Based on the expected sample sizes when the DHS program commenced, the estimates are usually based on 5-y time periods. Recent surveys have had larger sample sizes than early surveys, and here we aimed to explore the benefits of using shorter time periods than 5 y for estimation. We also explore the benefit of changing the estimation procedure from being based on years before the survey, i.e., measured with reference to the date of the interview for each woman, to being based on calendar years. Methods and Findings Jackknife variance estimation was used to calculate standard errors for 207 DHS surveys in order to explore to what extent the large samples in recent surveys can be used to produce estimates based on 1-, 2-, 3-, 4-, and 5-y periods. We also recalculated the estimates for the surveys into calendar-year-based estimates. We demonstrate that estimation for 1-y periods is indeed possible for many recent surveys. Conclusions The reduction in bias achieved using 1-y periods and calendar-year-based estimation is worthwhile in some cases. In particular, it allows tracking of the effects of particular events such as droughts, epidemics, or conflict on child mortality in a way not possible with previous estimation procedures. Recommendations to use estimation for short time periods when possible and to use calendar-year-based estimation were adopted in the United Nations 2011 estimates of child mortality., Editors' Summary Background In 2000, world leaders set, as Millennium Development Goal 4 (MDG 4), a target of reducing global under-five mortality (the number of children who die before their fifth birthday to a third of its 1990 level (12 million deaths per year) by 2015. (The MDGs are designed to alleviate extreme poverty by 2015.) To track progress towards MDG 4, the under-five mortality rate (also shown as 5 q 0) needs to be estimated both “precisely” and “accurately.” A “precise” estimate has a small random error (a quality indicated by a statistical measurement called the coefficient of variance), and an “accurate” estimate is one that is close to the true value because it lacks bias (systematic errors). In an ideal world, under-five mortality estimates would be based on official records of births and deaths. However, developing countries, which are where most under-five deaths occur, rarely have such records, and under-five mortality estimation relies on “complete birth histories” provided by women via surveys. These are collected by Demographic and Health Surveys (DHS, a project that helps developing countries collect data on health and population trends) and record all the births that a surveyed woman has had and the age at death of any of her children who have died. Why Was This Study Done? Because the DHS originally surveyed samples of 5,000–6,000 women, estimates of under-five mortality are traditionally calculated using data from five-year time periods. Over shorter periods with this sample size, the random errors in under-five mortality estimates become unacceptably large. Nowadays, the average DHS survey sample size is more than 10,000 women, so it should be possible to estimate under-five mortality over shorter time periods. Such estimates should be able to track the effects on under-five mortality of events such as droughts and conflicts better than estimates made over five years. In this study, the researchers determine appropriate time periods for child mortality estimates based on full birth histories, given different sample sizes. Specifically, they ask whether, with the bigger sample sizes that are now available, details about trends in under-five mortality rates are being missed by using the estimation procedures that were developed for smaller samples. They also ask whether calendar-year-based estimates can be calculated; mortality is usually estimated in “years before the survey,” a process that blurs the reference period for the estimate. What Did the Researchers Do and Find? The researchers used a statistical method called “jackknife variance estimation” to determine coefficients of variance for child mortality estimates calculated over different time periods using complete birth histories from 207 DHS surveys. Regardless of the estimation period, half of the estimates had a coefficient of variance of less than 10%, a level of random variation that is generally considered acceptable. However, within each time period, some estimates had very high coefficients of variance. These estimates were derived from surveys where there was a small sample size, low fertility (the women surveyed had relatively few babies), or low child mortality. Other analyses show that although the five-year period estimates had lower standard errors than the one-year period estimates, the latter were affected less by bias than the five-year period estimates. Finally, estimates fixed to calendar years rather than to years before the survey were more directly comparable across surveys and brought out variations in child mortality caused by specific events such as conflicts more clearly. What Do These Findings Mean? These findings show that although under-five mortality rate estimates based on five-year periods of data have been the norm, the sample sizes currently employed in DHS surveys make it feasible to estimate mortality for shorter periods. The findings also show that using shorter periods of data in estimations of the under-five mortality rate, and using calendar-year-based estimation, reduces bias (makes the estimations more accurate) and allows the effects of events such as droughts, epidemics, or conflict on under-five mortality rates to be tracked in a way that is impossible when using five-year periods of data. Given these findings, the researchers recommend that time periods shorter than five years should be adopted for the estimation of under-five mortality and that estimations should be pegged to calendar years rather than to years before the survey. Both recommendations have already been adopted by the United Nations Inter-agency Group for Child Mortality Estimation (IGME) and were used in their 2011 analysis of under-five mortality. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001289. This paper is part of a collection of papers on Child Mortality Estimation Methods published in PLOS Medicine The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on Millennium Development Goal 4, and its Childinfo website provides detailed statistics about child survival and health, including a description of the United Nations Inter-agency Group for Child Mortality Estimation; the 2011 IGME report on Levels and Trends in Child Mortality is available The World Health Organization also has information about Millennium Development Goal 4 and provides estimates of child mortality rates (some information in several languages) Further information about the Millennium Development Goals is available Information is also available about Demographic and Health Surveys of infant and child mortality

The authors do not consider these competing interests, but in the interest of full transparency declare the following: Dr. Glantz holds two research grants related to tobacco from the National Cancer Institute, an endowed chair as American Legacy Distinguished Professor in Tobacco Control, and a grant from the Robert Wood Johns Foundation to assist Ms. Eubanks, who led the US Department of Justice in its successful RICO case against the tobacco industry (United States v. Philip Morris USA, et al.) in writing a book about the case. Dr. Glantz also administers an endowment from the American Legacy Foundation, which supports the UCSF Center for Tobacco Control Research and Education, which Dr. Glantz directs, and the Legacy Tobacco Documents Library. He also has the William Cahan Endowment provided by the Flight Attendant Medical Research Institute. Mr. Barnes is an attorney in Dr. Glantz' research group, who is supported in part by Dr. Glantz' National Cancer Institute grants. Ms. Eubanks retired from the Department of Justice on December 1, 2005 and is now a lawyer in private practice in Washington, D. C. None of these organizations played any role in the preparation of this paper or the decision to submit it for publication. This paper was not prepared as part of any extramurally funded project. Provenance: Not commissioned; externally

Health (GCGH) initiative, discussed in the fi rst article in this series [3], we are exploring a range of ESC issues identifi ed by the GCGH investigators and developing world key informants, discussed in the second article in this series [4]. The investigators and key informants placed particular emphasis upon the importance of community engagement, and therefore we prepared a conceptual paper on this topic, which we distributed as a working paper to GCGH investigators and program staff at the 2nd Annual GCGH Meeting. In this article, we summarize this conceptual paper. We fi rst examine the concept of CE in research in developing countries, then we describe published models of CE, and fi nally we discuss two relevant examples of CE in research from Africa. What Is a Community?

Medecins Sans Frontieres is a respectable organisation which helps people in jeopardy and provides medical relief in difficult situations all over the world. Despite this recognition I must confess I found the last paper of G. Ooms in PLoS Medicine [1] to develop highly debatable concepts about health, development, and even sustainability. Ooms postulates that sustainable intervention creates a bias for development agencies to maintain the status quo. On the other hand, it could very easily be argued that conventional emergency “humanitarian aid” has failed to improve health on even a medium-term basis in the last four decades. Common sense indicates that populations benefit more from improvements in wealth, water supply, and agriculture than from consuming free goods from international aid. Several studies provide a basis for this conclusion [2]. On the contrary, a persistent status quo could result from an exclusive humanitarian approach, precluding the necessary changes to develop health care. International agencies say that, based on numerous studies, improving health on a medium- or long-term basis is a matter of “sustainable” programmes. But what is meant by “sustainability”? It seems that Dr. Ooms interprets sustainability as durability, a confusion which is obvious when one reads the French version of his paper. Durability is a plain matter of time; pollution, totalitarian regimes, or poverty could as well, unfortunately, meet a single durability criterion. This is the main point, if one wants to assess the criticism which Ooms aims at development agencies. Their main objective is to assess the sustainability of the health programmes which means (in French the supportabilite and not the durabilite) whether these programs exceed the economic, organisational, and ecological possibilities of the country and its population. And I recognize that I am in keeping with that! To give rice to people who usually consume rice is helpful, but next time it will be even more helpful to give them the means to grow their own! Yet the reality is far more complex, something which requires that agencies carefully assess the different programmes [3]. I must add that such an approach does not preclude an increase in annual governments outlays. But before increasing expenditure, it is wise to assess whether the programmes is working, and for whom. I don't miss the point that sustainable aid is for certain governments synonymous with conditional aid, and such difficulties must not be hidden, but every one of us is able to make the distinction between the principle and some penny-pinching, restrictive policies which can be amended and reversed. Indeed, the two approaches are complementary. When an emergency situation arises, it is obvious that some of the critical health issues of the local populations could be addressed by emergency international aid. But after a few weeks, only structural and political changes (that is, peace, convenient water supply, agriculture revival, affordable energy, information, free trade, free enterprise through microrenting...) are crucial for maintaining health and eventually improving it. As a matter of fact it could be a more dangerous illusion for these endangered populations to give credit to the ideas that Dr. Ooms develops in order to justify the spending of more public funds to extend emergency humanitarian aid indefinitely.

Background Strengthening Evidence base on scHool-based intErventions for pRomoting adolescent health (SEHER) is a multicomponent, whole-school health promotion intervention delivered by a lay counsellor or a teacher in government-run secondary schools in Bihar, India. The objective of this study is to examine the effects of the intervention after two years of follow-up and to evaluate the consistency of the findings observed over time. Methods and findings We conducted a cluster randomised trial in which 75 schools were randomised (1:1:1) to receive the SEHER intervention delivered by a lay counsellor (SEHER Mitra [SM]) or a teacher (Teacher as SEHER Mitra [TSM]), respectively, alongside a standardised, classroom-based life skills Adolescence Education Program (AEP), compared to AEP alone (control group). The trial design was a repeat cross-sectional study. Students enrolled in grade 9 (aged 13–15 years) in the 2015–2016 academic year were exposed to the intervention for two years and the outcome assessment was conducted at three time points─at baseline in June 2015; 8-months follow-up in March 2016, when the students were still in grade 9; and endpoint at 17-months follow-up in December 2016 (when the students were in grade 10), the results of which are presented in this paper. The primary outcome, school climate, was measured with the Beyond Blue School Climate Questionnaire (BBSCQ). Intervention effects were estimated using mixed-effects linear or logistic regression, including a random effect to adjust for within-school clustering, minimisation variables, baseline cluster-level score of the outcome, and sociodemographic characteristics. In total, 15,232 students participated in the 17-month survey. Compared with the control group, the participants in the SM intervention group reported improvements in school climate (adjusted mean difference [aMD] = 7.33; 95% CI: 6.60–8.06; p < 0.001) and most secondary outcomes (depression: aMD = −4.64; 95% CI: −5.83–3.45; p < 0.001; attitude towards gender equity: aMD = 1.02; 95% CI: 0.65–1.40; p < 0.001; frequency of bullying: aMD = −2.77; 95% CI: −3.40 to −2.14; p < 0.001; violence victimisation: odds ratio [OR] = 0.08; 95% CI: 0.04–0.14; p < 0.001; and violence perpetration: OR = 0.16; 95% CI: 0.09–0.29; p < 0.001). There was no evidence of an intervention effect in the TSM group compared with control group. The effects of the lay counsellor–delivered intervention were larger for most outcomes at 17-months follow-up compared with those at 8 months: school climate (effect size [ES; 95% CI] = 2.23 [1.97–2.50] versus 1.88 [1.44–2.32], p < 0.001); depression (ES [95% CI] = −1.19 [−1.56 to −0.82] versus −0.27 [−0.44 to −0.11], p < 0.001); attitude towards gender equity (ES [95% CI] = 0.53 [0.27–0.79] versus 0.23 [0.10–0.36], p < 0.001); bullying (ES [95% CI] = −2.22 [−2.84 to −1.60] versus −0.47 [−0.61 to −0.33], p < 0.001); violence victimisation (OR [95% CI] = 0.08 [0.04–0.14] versus 0.62 [0.46–0.84], p < 0.001); and violence perpetration (OR [95% CI] = 0.16 [0.09–0.29] versus 0.68 [0.48–0.96], p < 0.001), suggesting incremental benefits with an extended intervention. A limitation of the study is that 27% of baseline participants did not complete the 17-month outcome assessment. Conclusions The trial showed that the second-year outcomes were similar to the first-year outcomes, with no effect of the teacher-led intervention and larger benefits on school climate and adolescent health accruing from extending lay counsellor–delivered intervention. Trial registration ClinicalTrials.gov NCT02907125., In an extension of a cluster randomized trial, Sachin Shinde and colleagues investigate the effects of a second year of the SEHER school health promotion intervention on school climate and adolescent health outcomes in Bihar, India., Author summary Why was this study done? Schools are recognised as a critically important platform for promoting adolescent health literacy and healthy behaviours in India. We conducted this study to assess the effects of the SEHER multicomponent school health promotion intervention on adolescent health outcomes after two years of exposure. What did the researchers do and find? We conducted a three-arm cluster randomised controlled trial in 74 government-run secondary schools in the Nalanda district of the state of Bihar in India. The SEHER intervention was delivered either by a lay counsellor or by an existing teacher. The intervention included whole school–, class-, and individual-focused components. Students enrolled in grade 9 (aged 13–15 years) in the 2015–2016 academic year were exposed to the intervention for two years and three rounds of repeated cross-sectional surveys─at baseline in June 2015; 8-months follow-up in March 2016, when the students were still in grade 9; and at 17-months follow-up in December 2016 (when the students were in grade 10). We found that the lay counsellor–delivered intervention, compared with control group, reported improvements in school climate, depression, bullying, attitude towards gender equity, violence victimisation, and violence perpetration. The effect sizes for these outcomes at end of year 2 were larger than at the end of year 1. There was no evidence of an intervention effect of the teacher-delivered intervention at either follow-up. What do these findings mean? Our findings provide compelling evidence of the incremental benefits of a multicomponent school health promotion intervention, when delivered by lay counsellor, on school climate and a range of health and well-being outcomes of adolescents. No effects are seen when the same intervention is delivered by teachers.

Background In low-resource settings where disease burdens remain high and many health facilities lack essentials such as drugs or commodities, functional equipment, and trained personnel, poor quality of care often results and the impact can be profound. In this paper, we systematically quantify the potential gain of addressing quality of care globally using country-level data about antenatal, childbirth, and postnatal care interventions. Methods and findings In this study, we created deterministic models to project health outcomes if quality of care was addressed in a representative sample of 81 low- and middle-income countries (LMICs). First, available data from health facility surveys (e.g., Service Provision Assessment [SPA] and Service Availability and Readiness Assessment [SARA]) conducted 2007–2016 were linked to household surveys (e.g., Demographic and Health Surveys [DHS] and Multiple Indicator Cluster Surveys [MICS]) to estimate baseline coverage for a core subset of 19 maternal and newborn health interventions. Next, models were constructed with the Lives Saved Tool (LiST) using country-specific baseline levels in countries with a linked dataset (n = 17) and sample medians applied as a proxy in countries without linked data. Lastly, these 2016 starting baseline levels were raised to reach targets in 2020 as endline based upon country-specific utilization (e.g., proportion of women who attended 4+ antenatal visits, percentage of births delivered in a health facility) from the latest DHS or MICS population-based reports. Our findings indicate that if high-quality health systems could effectively deliver this subset of evidence-based interventions to mothers and their newborns who are already seeking care, there would be an estimated 28% decrease in maternal deaths, 28% decrease in neonatal deaths, and 22% fewer stillbirths compared to a scenario without any change or improvement in quality of care. Totals of 86,000 (range, 77,800–92,400) maternal and 0.67 million (range, 0.59 million–0.75 million) neonatal lives could be saved, and 0.52 million (range, 0.48 million–0.55 million) stillbirths could be prevented across the 81 countries in the calendar year 2020 when adequate quality care is provided at current levels of utilization. Limitations include the paucity of data to individually assess quality of care for each intervention in all LMICs and the necessary assumption that quality of care being provided among the subset of countries with linked datasets is comparable or representative of LMICs overall. Conclusions Our findings suggest that efforts to close the quality gap would still produce substantial benefits at current levels of access or utilization. With estimated mortality rate declines of 21%–32% on average, gains from this first step would be significant if quality was improved for selected antenatal, intrapartum, and postnatal interventions to benefit pregnant women and newborns seeking care. Interventions provided at or around the time of childbirth are most critical and accounted for 64% of the impact overall estimated in this quality improvement analysis., Victoria Chou and colleagues estimate the implications of poor-quality care for maternal and child health outcomes in low- and middle-income countries., Author summary Why was this study done? In low- and middle-income countries, health systems struggle to provide high-quality medical care to pregnant women and their newborns in need. Delivery of key health interventions is critical to save lives and prevent morbidity and mortality in high-burden settings. The impact of extant or poor quality of care at a population level is poorly understood, and quantifying the benefits of improving quality among those already seeking or accessing care would be a critical first step for prioritization. What did the researchers do and find? To examine the global impact of improvement in the quality of care, we used a linking approach, which combines health facility and population-level survey data to estimate baseline for a subset of important evidence-based interventions. Intervention coverage trends were modeled in 81 countries by setting current levels of reported utilization as the final country-specific targets for 2020. If those seeking medical attention arrived at facilities reimagined with adequate resources and receive high-quality care, our systematic tally indicates that almost one quarter of the maternal deaths, neonatal deaths, and stillbirths would be preventable during the period 2016–2020 if the gaps in quality of care were eliminated. What do these findings mean? Countries and current health systems are far from ensuring that skilled providers with adequate supplies are providing timely and appropriate healthcare to existing populations in need. Our analysis of potential gains quantifies the consequences of these missed opportunities, ranging from the prenatal to postnatal periods. Bolstering the quality of care is an essential checkpoint because efforts to increase utilization will rely on the same health systems where vulnerable populations are presently accessing care. With greater attention focused on tracking country-level progress, more data will hopefully become available to effectively monitor changes in coverage for key maternal and neonatal interventions. As these parameters or inputs are better defined, modeling can contribute to the body of knowledge by offering an informed approach to examine quality of care gaps so that better strategies can be developed to improve health among mothers and their children seeking care in this context.

Background Prospective cohort studies of incident HIV and associated factors among gay, bisexual, and other men who have sex with men (GBMSM) in the United Kingdom are lacking. We report time trends in and factors associated with HIV incidence between 2013 and 2019 among a cohort of GBMSM: the AURAH2 prospective study. Methods and findings Participants were recruited through 1 of 3 sexual health clinics in London and Brighton (July 2013 to April 2016) and self-completed a baseline paper questionnaire and subsequent 4-monthly and annual online questionnaires (March 2015 to March 2018), including information on sociodemographics, lifestyle, health and well-being, HIV status, sexual/HIV-related behaviours, and preexposure prophylaxis and postexposure prophylaxis (PrEP/PEP). Incident HIV was ascertained by linkage with national HIV surveillance data from Public Health England (PHE). We investigated the associations of HIV incidence with (1) baseline factors using mixed-effects Weibull proportional hazard models, unadjusted and adjusted for age, country of birth and ethnicity, sexuality, and education level; and (2) time-updated factors, using mixed-effects Poisson regression models. In total, 1,162 men (mean age 34 years, 82% white, 94% gay, 74% university-educated) were enrolled in the study. Thirty-three HIV seroconversions occurred over 4,618.9 person-years (PY) of follow-up: an overall HIV incidence rate (IR) of 0.71 (95% confidence interval (CI) 0.51 to 1.00) per 100 PY. Incidence declined from 1.47 (95% CI 0.48 to 4.57) per 100 PY in 2013/2014 to 0.25 (95% CI 0.08 to 0.78) per 100 PY in 2018/2019; average annual decline was 0.85-fold (p < 0.001). Baseline factors associated with HIV acquisition included the following: injection drug use (6/38 men who reported injection drug-acquired HIV; unadjusted conditional hazard ratio (HR) 27.96, 95% CI 6.99 to 111.85, p < 0.001), noninjection chemsex-related drug use (13/321; HR 6.45, 95% CI 1.84 to 22.64, p < 0.001), condomless anal sex (CLS) (26/741; HR 3.75, 95% CI 1.31 to 10·74, p = 0.014); higher number of CLS partners (HRs >10 partners [7/57]; 5 to 10 partners [5/60]; and 2 to 4 partners [11/293]: 14.04, 95% CI 4.11 to 47.98; 9.60, 95% CI 2.58 to 35.76; and 4.05, 95% CI 1.29 to 12.72, respectively, p < 0.001); CLS with HIV–positive partners (14/147; HR 6.45, 95% CI 3.15 to 13.22, p < 0.001), versatile CLS role (21/362; HR 6.35, 95% CI 2.18 to 18.51, p < 0.001), group sex (64/500; HR 8.81, 95% CI 3.07 to 25.24, p < 0.001), sex for drugs/money (4/55, HR 3.27, 95% CI 1.14 to 9.38, p = 0.027) (all in previous 3 months); previous 12-month report of a bacterial sexually transmitted infection (STI) diagnoses (21/440; HR 3.95, 95% CI 1.81 to 8.63, p < 0.001), and more than 10 new sexual partners (21/471, HRs 11 to 49, 50 to 99, and >100 new partners: 3.17, 95% CI 1.39 to 7.26; 4.40, 95% CI 1.35 to 14.29; and 4.84, 95% CI 1.05 to 22.4, respectively, p < 0.001). Results were broadly consistent for time-updated analysis (n = 622 men). The study’s main limitation is that men may not be representative of the broader GBMSM population in England. Conclusions We observed a substantial decline in HIV incidence from 2013 to 2019 among GBMSM attending sexual health clinics. Injection drug use, chemsex use, and measures of high-risk sexual behaviour were strongly associated with incident HIV. Progress towards zero new infections could be achieved if combination HIV prevention including Test and Treat strategies and routine commissioning of a PrEP programme continues across the UK and reaches all at-risk populations., Nadia Hanum and colleagues analyze trends in HIV incidence among gay, bisexual, and other Men Who Have Sex with Men attending sexual health clinics in England., Author summary Why was the study done? A decline has been observed in new HIV diagnoses among gay, bisexual, and other men who have sex with men (GBMSM) in the United Kingdom. Internationally, an overall decline in HIV diagnoses and incidence among GBMSM has also been reported in several cities in developed countries such as Australia, the United States, the Netherlands, and some other European countries between 2013 and 2019. To our knowledge, no prospectively followed cohort studies of GBMSM in England have reported trends in HIV incidence in recent years or on factors associated with incident HIV. What did the researches do and find? We estimated trends in HIV incidence between 2013 and 2019 among a cohort of GBMSM attending sexual health clinics, and we found a declining trend. We also assessed factors associated with HIV incidence, and our findings emphasise the importance of awareness of high-risk sexual behaviours and recreational drug use (particularly injection drug use and chemsex-associated drug use) as factors associated with HIV acquisition. Despite observing significant declines in HIV incidence, incidence rates (IRs) remained high among men who reported injection drugs use, chemsex drug use, condomless sex with multiple partners, and group sex. What do these findings mean? Growing evidence shows that the HIV transmission declines may potentially be attributed to the comprehensive control and HIV treatment efforts in the UK. The continuation of intensification of HIV testing, immediate antiretroviral therapy (ART) initiation, the use of condoms, and routine commissioning of a preexposure prophylaxis (PrEP) programme could potentially ensure that the decline in HIV incidence is felt across all groups impacted by the epidemic.

Strengthening civil registration and vital statistics (CVRS) systems in low-income countries is a central component of emerging plans for the post-2015 development agenda [1], and a major investment area for key global health and development funders [2]. A dominant theme in the investment case for CRVS is the potential of such systems to generate valid and timely population data to support sound program planning, management, and evaluation. Can CRVS systems fulfill this promise and produce population data of adequate quality to support policy and program decisions? Few formal studies have addressed this question, and global leaders have called urgently for new evidence to inform the CRVS agenda [3,4]. The PLOS Collection on Real-Time Monitoring of Under-Five Mortality (RMM) contributes to this process by reporting on a seven-year program of work in five countries in sub-Saharan Africa that aimed to develop and test methods for generating annual estimates of under-five mortality, a key measure for health investments, for recent periods. This paper introduces readers to the origins and rationale of the RMM project, describes how it was implemented, and outlines the aims of the PLOS Collection on RMM.

This paper summarises key advances and priorities since the 2011 presentation of the Malaria Eradication Research Agenda (malERA), with a focus on the combinations of intervention tools and strategies for elimination and their evaluation using modelling approaches. With an increasing number of countries embarking on malaria elimination programmes, national and local decisions to select combinations of tools and deployment strategies directed at malaria elimination must address rapidly changing transmission patterns across diverse geographic areas. However, not all of these approaches can be systematically evaluated in the field. Thus, there is potential for modelling to investigate appropriate ‘packages’ of combined interventions that include various forms of vector control, case management, surveillance, and population-based approaches for different settings, particularly at lower transmission levels. Modelling can help prioritise which intervention packages should be tested in field studies, suggest which intervention package should be used at a particular level or stratum of transmission intensity, estimate the risk of resurgence when scaling down specific interventions after local transmission is interrupted, and evaluate the risk and impact of parasite drug resistance and vector insecticide resistance. However, modelling intervention package deployment against a heterogeneous transmission background is a challenge. Further validation of malaria models should be pursued through an iterative process, whereby field data collected with the deployment of intervention packages is used to refine models and make them progressively more relevant for assessing and predicting elimination outcomes., Richard Steketee and colleagues propose an updated research agenda for combination interventions and modelling in malaria elimination and eradication.

David Levy and colleagues use the SimSmoke model to estimate the effect of Brazil's recent stronger tobacco control policies on smoking prevalence and associated premature mortality, and the effect that additional policies may have., Background Brazil has reduced its smoking rate by about 50% in the last 20 y. During that time period, strong tobacco control policies were implemented. This paper estimates the effect of these stricter policies on smoking prevalence and associated premature mortality, and the effect that additional policies may have. Methods and Findings The model was developed using the SimSmoke tobacco control policy model. Using policy, population, and smoking data for Brazil, the model assesses the effect on premature deaths of cigarette taxes, smoke-free air laws, mass media campaigns, marketing restrictions, packaging requirements, cessation treatment programs, and youth access restrictions. We estimate the effect of past policies relative to a counterfactual of policies kept to 1989 levels, and the effect of stricter future policies. Male and female smoking prevalence in Brazil have fallen by about half since 1989, which represents a 46% (lower and upper bounds: 28%–66%) relative reduction compared to the 2010 prevalence under the counterfactual scenario of policies held to 1989 levels. Almost half of that 46% reduction is explained by price increases, 14% by smoke-free air laws, 14% by marketing restrictions, 8% by health warnings, 6% by mass media campaigns, and 10% by cessation treatment programs. As a result of the past policies, a total of almost 420,000 (260,000–715,000) deaths had been averted by 2010, increasing to almost 7 million (4.5 million–10.3 million) deaths projected by 2050. Comparing future implementation of a set of stricter policies to a scenario with 2010 policies held constant, smoking prevalence by 2050 could be reduced by another 39% (29%–54%), and 1.3 million (0.9 million–2.0 million) out of 9 million future premature deaths could be averted. Conclusions Brazil provides one of the outstanding public health success stories in reducing deaths due to smoking, and serves as a model for other low and middle income nations. However, a set of stricter policies could further reduce smoking and save many additional lives. Please see later in the article for the Editors' Summary, Editors' Summary Background Tobacco kills up to half its users—more than 5 million smokers die every year from tobacco-related causes. It also kills more than half a million non-smokers annually who have been exposed to second-hand smoke. If current trends continue, annual tobacco-related deaths could increase to more than 8 million by 2030. In response to this global tobacco epidemic, the World Health Organization has developed an international instrument for tobacco control called the Framework Convention on Tobacco Control (FCTC). Since it came into force in February 2005, 176 countries have become parties to the FCTC. As such, they agree to implement comprehensive bans on tobacco advertizing, promotion, and sponsorship; to ban misleading and deceptive terms on tobacco packaging; to protect people from exposure to cigarette smoke in public spaces and indoor workplaces; to implement tax policies aimed at reducing tobacco consumption; and to combat illicit trade in tobacco products. Why Was This Study Done? Brazil has played a pioneering role in providing support for tobacco control measures in low and middle income countries. It introduced its first cigarette-specific tax in 1990 and, in 1996, it placed the first warnings on cigarette packages and introduced smoke-free air laws. Many of these measures have subsequently been strengthened. Over the same period, the prevalence of smoking among adults (the proportion of the population that smokes) has halved in Brazil, falling from 34.8% in 1989 to 18.5% in 2008. But did the introduction of tobacco control policies contribute to this decline, and if so, which were the most effective policies? In this study, the researchers use a computational model called the SimSmoke tobacco control policy model to investigate this question and to examine the possible effect of introducing additional control policies consistent with the FCTC, which Brazil has been a party to since 2006. What Did the Researchers Do and Find? The researchers developed Brazil SimSmoke by incorporating policy, population, and smoking data for Brazil into the SimSmoke simulation model; Brazil SimSmoke estimates smoking prevalence and smoking-attributable deaths from 1989 forwards. They then compared smoking prevalences and smoking-attributable deaths estimated by Brazil SimSmoke for 2010 with and without the inclusion of the tobacco control policies that were introduced between 1989 and 2010. The model estimated that the smoking prevalence in Brazil in 2010 was reduced by 46% by the introduction of tobacco control measures. Almost half of this reduction was explained by price increases, 14% by smoke-free laws, 14% by marketing restrictions, 8% by health warnings, 6% by anti-smoking media campaigns, and 10% by cessation treatment programs. Moreover, as a result of past policies, the model estimated that almost 420,000 tobacco-related deaths had been averted by 2010 and that almost 7 million deaths will have been averted by 2050. Finally, using the model to compare the effects of a scenario that includes stricter policies (for example, an increase in tobacco tax) with a scenario that includes the 2010 policies only, indicated that stricter control policies would reduce the estimated smoking prevalence by an extra 39% between 2010 and 2050 and avert about 1.3 million additional premature deaths. What Do These Findings Mean? These findings indicate that the introduction of tobacco control policies has been a critical factor in the rapid decline in smoking prevalence in Brazil over the past 20 years. They also suggest that the introduction of stricter policies that are fully consistent with the FCTC has the potential to reduce the prevalence of smoking further and save many additional lives. Although the reduction in smoking prevalence in Brazil between 1989 and 2010 predicted by the Brazil SimSmoke model is close to the recorded reduction over that period, these findings need to be interpreted with caution because of the many assumptions incorporated in the model. Moreover, the accuracy of the model's predictions depends on the accuracy of the data fed into it, some of which was obtained from other countries and may not accurately reflect the situation in Brazil. Importantly, however, these findings show that, even for a middle income nation, reducing tobacco use is a “winnable battle” that carries huge dividends in terms of reducing illness and death without requiring unlimited resources. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001336. The World Health Organization provides information about the dangers of tobacco (in several languages), about the Framework Convention on Tobacco Control, and about tobacco control in Brazil The Framework Convention Alliance provides more information about the FCTC The Brazilian National Cancer Institute (INCA) provides information on tobacco control policies in Brazil; additional information about tobacco control laws in Brazil is available on the Tobacco Control Laws interactive website, which provides information about tobacco control legislation worldwide More information on the SimSmoke model of tobacco control policies is available in document or slideshow form SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking

In cluster randomized trials (CRTs), the units of allocation, intervention, and outcome measurement may differ within a single trial. As a result of the unique design of CRTs, the interpretation of existing research ethics guidelines is complicated. The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials aims to provide researchers and research ethics committees (RECs) with detailed guidance on the ethical design, conduct, and review of CRTs. A five-year mixed methods research project explored the ethical challenges of CRTs. Empirical studies documented the reporting of ethical issues in published CRTs, interviewed experienced trialists, and surveyed trialists and REC chairs. The ethical issues identified were explored in a series of background papers that provided detailed ethical analyses and policy options, and a panel of experts using a systematic process developed a consensus statement. The Ottawa Statement sets out 15 recommendations for the ethical design and conduct of CRTs. The recommendations provide guidance on the justification of a cluster randomized design, the need for REC review, the identification of research participants, obtaining informed consent, the role of gatekeepers in protecting group interests, the assessment of benefits and harms, and the protection of vulnerable participants.

JC has an unpaid relationship with the World Health Organization in the Department of Global Alert and Response (Infection Prevention and Control Unit). All other authors have declared that no competing interests exist. The authors received no specific funding to write this paper. JC received financial support for a sabbatical leave from the University of Calgary, Calgary, Canada. Provenance: Not commissioned; externally peer reviewed.

Sollom and colleagues report the findings from a household survey study carried out in Western Burma; they report a high prevalence of human rights violations such as forced labor, food theft, forced displacement, beatings, and ethnic persecution., Background The Chin State of Burma (also known as Myanmar) is an isolated ethnic minority area with poor health outcomes and reports of food insecurity and human rights violations. We report on a population-based assessment of health and human rights in Chin State. We sought to quantify reported human rights violations in Chin State and associations between these reported violations and health status at the household level. Methods and Findings Multistaged household cluster sampling was done. Heads of household were interviewed on demographics, access to health care, health status, food insecurity, forced displacement, forced labor, and other human rights violations during the preceding 12 months. Ratios of the prevalence of household hunger comparing exposed and unexposed to each reported violation were estimated using binomial regression, and 95% confidence intervals (CIs) were constructed. Multivariate models were done to adjust for possible confounders. Overall, 91.9% of households (95% CI 89.7%–94.1%) reported forced labor in the past 12 months. Forty-three percent of households met FANTA-2 (Food and Nutrition Technical Assistance II project) definitions for moderate to severe household hunger. Common violations reported were food theft, livestock theft or killing, forced displacement, beatings and torture, detentions, disappearances, and religious and ethnic persecution. Self reporting of multiple rights abuses was independently associated with household hunger. Conclusions Our findings indicate widespread self-reports of human rights violations. The nature and extent of these violations may warrant investigation by the United Nations or International Criminal Court. Please see later in the article for the Editors' Summary, Editors' Summary Background More than 60 years after the adoption of the Universal Declaration of Human Rights, thousands of people around the world are still deprived of their basic human rights—life, liberty, and security of person. In many countries, people live in fear of arbitrary arrest and detention, torture, forced labor, religious and ethnic persecution, forced displacement, and murder. In addition, ongoing conflicts and despotic governments deprive them of the ability to grow sufficient food (resulting in food insecurity) and deny them access to essential health care. In Burma, for example, the military junta, which seized power in 1962, frequently confiscates land unlawfully, demands forced labor, and uses violence against anyone who protests. Burma is also one of the world's poorest countries in terms of health indicators. Its average life expectancy is 54 years, its maternal mortality rate (380 deaths among women from pregnancy-related causes per 100,000 live births) is nearly ten times higher than that of neighboring Thailand, and its under-five death rate (122/1000 live births) is twice that of nearby countries. Moreover, nearly half of Burmese children under 5 are stunted, and a third of young children are underweight, indicators of malnutrition in a country that, on paper, has a food surplus. Why Was This Study Done? Investigators are increasingly using population-based methods to quantify the associations between human rights violations and health outcomes. In eastern Burma, for example, population-based research has recently revealed a link between human rights violations and reduced access to maternal health-care services. In this study, the researchers undertake a population-based assessment of health and human rights in Chin State, an ethnic minority area in western Burma where multiple reports of human rights abuses have been documented and from which thousands of people have fled. In particular, the researchers investigate correlations between household hunger and household experiences of human rights violations—food security in Chin State is affected by periodic expansions of rat populations that devastate crop yields, by farmers being forced by the government to grow an inedible oil crop (jatropha), and by the Burmese military regularly stealing food and livestock. What Did the Researchers Do and Find? Local surveyors questioned the heads of randomly selected households in Chin State about their household's access to health care and its health status, and about forced labor and other human rights violations experienced by the household during the preceding 12 months. They also asked three standard questions about food availability, the answers to which were combined to provide a measure of household hunger. Of the 621 households interviewed, 91.9% reported at least one episode of a household member being forced to work in the preceding 12 months. The Burmese military imposed two-thirds of these forced labor demands. Other human rights violations reported included beating or torture (14.8% of households), religious or ethnic persecutions (14.1% of households), and detention or imprisonment of a family member (5.9% of households). Forty-three percent of the households met the US Agency for International Development Food and Nutrition Technical Assistance (FANTA) definition for moderate to severe household hunger, and human rights violations related to food insecurity were common. For example, more than half the households were forced to give up food out of fear of violence. A statistical analysis of these data indicated that the prevalence of household hunger was 6.51 times higher in households that had experienced three food-related human rights violations than in households that had not experienced such violations. What Do These Findings Mean? These findings quantify the extent to which the Chin ethnic minority in Burma is subjected to multiple human rights violations and indicate the geographical spread of these abuses. Importantly, they show that the health impacts of human rights violations in Chin State are substantial. In addition, they suggest that the indirect health outcomes of human rights violations probably dwarf the mortality from direct killings. Although this study has some limitations (for example, surveyors had to work in secret and it was not safe for them to collect biological samples that could have given a more accurate indication of the health status of households than questions alone), these findings should encourage the international community to intensify its efforts to reduce human rights violations in Burma. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001007. The UN Universal Declaration of Human Rights is available in numerous languages The Burma Campaign UK and Human Rights Watch provide detailed information about human rights violations in Burma (in several languages) The World Health Organization provides information on health in Burma and on human rights (in several languages) The Mae Tao clinic also provides general information about Burma and its health services (including some information in Thai) A PLoS Medicine Research Article by Luke Mullany and colleagues provides data on human rights violations and maternal health in Burma The Chin Human Rights Organization is working to protect and promote the rights of the Chin people The Global Health Access Program (GHAP) provides information on health in Burma FANTA works to improve nutrition and global food security policies

This paper estimates the lives that could be saved by scaling up proven health interventions in a variety of health systems categorized by skilled birth attendance categories to maximize progress towards Millennium Development Goals (MDGs) 4 and 5. It describes the two methods that were employed for this analysis including country information intervention selection modeling and costing and shares the results and implications.

The poor availability of surgical services in developing countries is a long neglected problem that has recently gained attention [1],[2]. Violence, injury, and obstetric emergencies are among leading causes of mortality and morbidity that can be mitigated through surgical intervention. Surgically treatable problems are estimated to account for up to 11% of the world's disability-adjusted life years [1]. In addition to this massive disease burden there are problems that are seriously debilitating (cataract) or stigmatizing (fistula). Surgical interventions are often viewed as expensive and complex, but many common problems amenable to surgery in resource-limited settings are cost-effective and do not require specialized staff and equipment. The World Health Organization (WHO) has prioritized a list of cost-effective surgical interventions for developing countries including emergency care of trauma, obstetrical complications, and acute abdomens as well as elective care of hernias, clubfoot, cataracts, hydroceles, and otitis media [3]. One of the main barriers to surgical care—defined as the safe provision of pre-operative, operative, and post-operative surgical and anesthesia services—in resource-limited settings is the shortage of trained health workers. Africa accounts for 24% of the global disease burden but only 3% of the global health workforce [4]. The reasons for this are well documented and include inadequate salaries and poor working conditions leading to staff attrition, unwillingness of international donors to support financing for human resources [5], an insufficiency of medical schools [6], and the brain drain of health staff to resource-rich countries [4],[7],[8]. The human resource crisis is most acute at the level of specialists, including surgeons and anesthesiologists [9],[10]. In East Africa, there are 0.25 fully trained surgeons per 100,000 persons compared to 5.69 per 100,000 in the United States [11],[12]. The actual minimum number of surgeons required is unknown. Given the unlikelihood of even a modest increase in the number of surgeons and anesthesiologists working in Africa in the near future, a number of approaches are being piloted to overcome the skills shortage. These include surgical camps and specialist outreach programs (often supported by international experts) and the mobilization of non-physician clinicians (NPCs) to perform surgical and anesthetic tasks [13]. This latter approach, which involves the shifting of tasks from surgeons and anesthesiologists to non-specialists, has the greatest potential to provide coverage of basic surgical care, especially in rural areas. Task shifting involves the delegation of certain medical responsibilities to less specialized health care workers. In sub-Saharan Africa, task shifting has recently been promoted and formalized to help address the HIV/AIDS epidemic [14]. This paper discusses some of the experiences of surgical task shifting to date, and outlines lessons from task shifting in the delivery of HIV/AIDS care.

Background Although environmental lead exposure is associated with significant deficits in cognition, executive functions, social behaviors, and motor abilities, the neuroanatomical basis for these impairments remains poorly understood. In this study, we examined the relationship between childhood lead exposure and adult brain volume using magnetic resonance imaging (MRI). We also explored how volume changes correlate with historic neuropsychological assessments. Methods and Findings Volumetric analyses of whole brain MRI data revealed significant decreases in brain volume associated with childhood blood lead concentrations. Using conservative, minimum contiguous cluster size and statistical criteria (700 voxels, unadjusted p < 0.001), approximately 1.2% of the total gray matter was significantly and inversely associated with mean childhood blood lead concentration. The most affected regions included frontal gray matter, specifically the anterior cingulate cortex (ACC). Areas of lead-associated gray matter volume loss were much larger and more significant in men than women. We found that fine motor factor scores positively correlated with gray matter volume in the cerebellar hemispheres; adding blood lead concentrations as a variable to the model attenuated this correlation. Conclusions Childhood lead exposure is associated with region-specific reductions in adult gray matter volume. Affected regions include the portions of the prefrontal cortex and ACC responsible for executive functions, mood regulation, and decision-making. These neuroanatomical findings were more pronounced for males, suggesting that lead-related atrophic changes have a disparate impact across sexes. This analysis suggests that adverse cognitive and behavioral outcomes may be related to lead's effect on brain development producing persistent alterations in structure. Using a simple model, we found that blood lead concentration mediates brain volume and fine motor function., Using magnetic resonance imaging to assess brain volumes, Kim Cecil and colleagues find that inner-city children with higher blood lead levels showed regions of decreased gray matter as adults., Editors' Summary Background. Lead is a highly toxic metal that is present throughout the environment because of various human activities. In particular, for many years, large amounts of lead were used in paint, in solder for water pipes, in gasoline, and in ceramic glazes. But, as the harmful health effects of lead have become clear, its use in these and other products has been gradually phased out. Breathing air, drinking water, or eating food that contains lead can damage almost every organ in the human body. The organ that is most sensitive to lead exposure is the brain, and children's brains are particularly vulnerable because they are still developing. Children who swallow large amounts of lead can develop widespread brain damage that causes convulsions and sometimes death. Children who are repeatedly exposed to low to moderate amounts of lead (e.g., through accidentally swallowing residues of old lead paint or contaminated soil) can develop learning or behavioral problems. Why Was This Study Done? Lead exposure has been linked with various types of brain damage. These include problems with thinking (cognition); difficulties with organizing actions, decisions, and behaviors (executive functions); abnormal social behavior (including aggression); and difficulties in coordinating fine movements, such as picking up small objects (fine motor control). However, we know little about how lead damages the brain in this way and little about which brain regions are affected by exposure to low to moderate levels of lead during childhood. In this study, the researchers wanted to test the possibility that childhood lead exposure might lead to shrinking (“volume loss”) parts of the brain, particularly the parts that are crucial to cognition and behavior. They therefore studied the relationship between childhood lead exposure and adult brain volume. They also explored whether there is a relationship between brain volume and measures of brain functioning, such as fine motor control, memory, and learning assessed during adolescence. What Did the Researchers Do and Find? Between 1979 and 1984, the researchers recruited babies born in poor areas of Cincinnati, where there were many old, lead-contaminated houses, into the Cincinnati Lead Study. They measured their blood lead levels regularly from birth until they were 78 months old and calculated each child's average blood lead level over this period. They then used brain scans (known as magnetic resonance imaging, or MRI) to measure the brain volumes of the participants when they were 19–24 years old. The researchers found that exposure to lead as a child was linked with brain volume loss in adulthood, particularly in men. There was a “dose-response” effect—in other words, the greatest brain volume loss was seen in participants with the greatest lead exposure in childhood. The brain volume loss was most noticeable in a part of the brain called the prefrontal cortex—especially a region called the “anterior cingulate cortex.” When they examined the relationship between brain volume and measures of brain functioning, they found a link between brain volume and fine motor control, but not with the other measures. What Do These Findings Mean? These findings indicate that childhood lead exposure is associated with brain volume loss in adults, in specific regions of the brain. These brain regions are responsible for executive functions, regulating behavior, and fine motor control. Lead exposure has a larger effect on brain volumes in men than in women, which might help to explain the higher incidence of antisocial behaviors among men than women. Overall, these findings may explain why children and adults who have a history of lead exposure have behavioral and other problems, and support ongoing efforts to reduce childhood lead exposure in the US and other countries. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050112. A PLoS Medicine Perspective article by David Bellinger further discusses this study and a related paper on child exposure to lead and criminal arrests in adulthood Toxtown, an interactive site from the US National Library of Medicine, provides information on environmental health concerns including exposure to lead (in English and Spanish) The US Environmental Protection Agency provides information on lead in paint, dust, and soil and on protecting children from lead poisoning (in English and Spanish) Medline Plus and the US National Library of Medicine Specialized Information Services provide lists of links to information on lead and human health (in English and Spanish) The US Centers for Disease Control and Prevention provides information about its Childhood Lead Poisoning Prevention Program The UK Health Protection Agency also provides information about lead and its health hazards

Background The importance of understanding age when estimating the impact of influenza on hospitalizations and deaths has been well described, yet existing surveillance systems have not made adequate use of age-specific data. Monitoring influenza-related morbidity using electronic health data may provide timely and detailed insight into the age-specific course, impact and epidemiology of seasonal drift and reassortment epidemic viruses. The purpose of this study was to evaluate the use of emergency department (ED) chief complaint data for measuring influenza-attributable morbidity by age and by predominant circulating virus. Methods and Findings We analyzed electronically reported ED fever and respiratory chief complaint and viral surveillance data in New York City (NYC) during the 2001–2002 through 2005–2006 influenza seasons, and inferred dominant circulating viruses from national surveillance reports. We estimated influenza-attributable impact as observed visits in excess of a model-predicted baseline during influenza periods, and epidemic timing by threshold and cross correlation. We found excess fever and respiratory ED visits occurred predominantly among school-aged children (8.5 excess ED visits per 1,000 children aged 5–17 y) with little or no impact on adults during the early-2002 B/Victoria-lineage epidemic; increased fever and respiratory ED visits among children younger than 5 y during respiratory syncytial virus-predominant periods preceding epidemic influenza; and excess ED visits across all ages during the 2003–2004 (9.2 excess visits per 1,000 population) and 2004–2005 (5.2 excess visits per 1,000 population) A/H3N2 Fujian-lineage epidemics, with the relative impact shifted within and between seasons from younger to older ages. During each influenza epidemic period in the study, ED visits were increased among school-aged children, and each epidemic peaked among school-aged children before other impacted age groups. Conclusions Influenza-related morbidity in NYC was highly age- and strain-specific. The impact of reemerging B/Victoria-lineage influenza was focused primarily on school-aged children born since the virus was last widespread in the US, while epidemic A/Fujian-lineage influenza affected all age groups, consistent with a novel antigenic variant. The correspondence between predominant circulating viruses and excess ED visits, hospitalizations, and deaths shows that excess fever and respiratory ED visits provide a reliable surrogate measure of incident influenza-attributable morbidity. The highly age-specific impact of influenza by subtype and strain suggests that greater age detail be incorporated into ongoing surveillance. Influenza morbidity surveillance using electronic data currently available in many jurisdictions can provide timely and representative information about the age-specific epidemiology of circulating influenza viruses., Don Olson and colleagues report that influenza-related morbidity in NYC from 2001 to 2006 was highly age- and strain-specific and conclude that surveillance using electronic data can provide timely and representative information about the epidemiology of circulating influenza viruses., Editors' Summary Background. Seasonal outbreaks (epidemics) of influenza (a viral infection of the nose, throat, and airways) send millions of people to their beds every winter. Most recover quickly, but flu epidemics often disrupt daily life and can cause many deaths. Seasonal epidemics occur because influenza viruses continually make small changes to the viral proteins (antigens) that the human immune system recognizes. Consequently, an immune response that combats influenza one year may provide partial or no protection the following year. Occasionally, an influenza virus with large antigenic changes emerges that triggers an influenza pandemic, or global epidemic. To help prepare for both seasonal epidemics and pandemics, public-health officials monitor influenza-related illness and death, investigate unusual outbreaks of respiratory diseases, and characterize circulating strains of the influenza virus. While traditional influenza-related illness surveillance systems rely on relatively slow voluntary clinician reporting of cases with influenza-like illness symptoms, some jurisdictions have also started to use “syndromic” surveillance systems. These use electronic health-related data rather than clinical impression to track illness in the community. For example, increased visits to emergency departments for fever or respiratory (breathing) problems can provide an early warning of an influenza outbreak. Why Was This Study Done? Rapid illness surveillance systems have been shown to detect flu outbreaks earlier than is possible through monitoring deaths from pneumonia or influenza. Increases in visits to emergency departments by children for fever or respiratory problems can provide an even earlier indicator. Researchers have not previously examined in detail how fever and respiratory problems by age group correlate with the predominant circulating respiratory viruses. Knowing details like this would help public-health officials detect and respond to influenza epidemics and pandemics. In this study, the researchers have used data collected between 2001 and 2006 in New York City emergency departments to investigate these aspects of syndromic surveillance for influenza. What Did the Researchers Do and Find? The researchers analyzed emergency department visits categorized broadly into a fever and respiratory syndrome (which provides an estimate of the total visits attributable to influenza) or more narrowly into an influenza-like illness syndrome (which specifically indicates fever with cough and/or sore throat) with laboratory-confirmed influenza surveillance data. They found that emergency department visits were highest during peak influenza periods, and that the affect on different age groups varied depending on the predominant circulating viruses. In early 2002, an epidemic reemergence of B/Victoria-lineage influenza viruses caused increased visits among school-aged children, while adult visits did not increase. By contrast, during the 2003–2004 season, when the predominant virus was an A/H3N2 Fujian-lineage influenza virus, excess visits occurred in all age groups, though the relative increase was greatest and earliest among school-aged children. During periods of documented respiratory syncytial virus (RSV) circulation, increases in fever and respiratory emergency department visits occurred in children under five years of age regardless of influenza circulation. Finally, the researchers found that excess visits to emergency departments for fever and respiratory symptoms preceded deaths from pneumonia or influenza by about two weeks. What Do These Findings Mean? These findings indicate that excess emergency department visits for fever and respiratory symptoms can provide a reliable and timely surrogate measure of illness due to influenza. They also provide new insights into how different influenza viruses affect people of different ages and how the timing and progression of each influenza season differs. These results, based on data collected over only five years in one city, might not be generalizable to other settings or years, warn the researchers. However, the present results strongly suggest that the routine monitoring of influenza might be improved by using electronic health-related data, such as emergency department visit data, and by examining it specifically by age group. Furthermore, by showing that school-aged children can be the first people to be affected by seasonal influenza, these results highlight the important role this age group plays in community-wide transmission of influenza, an observation that could influence the implementation of public-health strategies such as vaccination that aim to protect communities during influenza epidemics and pandemics. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040247. • US Centers for Disease Control and Prevention provides information on influenza for patients and health professionals and on influenza surveillance in the US (in English, Spanish, and several other languages) • World Health Organization has a fact sheet on influenza and on global surveillance for influenza (in English, Spanish, French, Russian, Arabic, and Chinese) • The MedlinePlus encyclopedia contains a page on flu (in English and Spanish) • US National Institute of Allergy and Infectious Diseases has a feature called “focus on flu” • A detailed report from the US Centers for Disease Control and Prevention titled “Framework for Evaluating Public Health Surveillance Systems for Early Detection of Outbreaks” includes a simple description of syndromic surveillance • The International Society for Disease Surveillance has a collaborative syndromic surveillance public wiki • The Anthropology of the Contemporary Research Collaboratory includes working papers and discussions by cultural anthropologists studying modern vital systems security and syndromic surveillance

Armed conflict and HIV infection have had a profound impact on the societies of sub-Saharan Africa. The number of countries engaged in armed conflict has fluctuated, totalling 24 African states in 2004 [1]; most of these conflicts are intrastate and chronic. The region also bears the world's highest burden of HIV, with more than 25 million people reported to be infected [2]. Although the inter-relationship between HIV and conflict is increasingly clear [3–6], the effect of conflict and instability on the incidence and prevalence of HIV can be unpredictable [6]. Much of the evidence on risks is unreliable, and conflict may both protect a population from HIV by isolating communities from the spread of infection, and increase an individual's risk through displacement, sexual violence, and breakdown of communities and health-care institutions. Despite an often significant burden of HIV-related mortality and morbidity, few HIV care programmes have been attempted in conflict regions. There is a perception that it will be too difficult to perform safely and effectively, and that HIV prevention and treatment are of secondary importance to concerns such as food, shelter, water and sanitation, basic medical care, and personal security. As outlined in Table 1, providing HIV care in conflict settings involves additional obstacles to those generally encountered in other resource-limited settings. Table 1 Obstacles to Providing HIV Care in Resource-Limited Chronic Conflict Settings This paper describes lessons from three years' experience of providing HIV care, including antiretroviral therapy (ART), to a conflict-affected population in the Democratic Republic of the Congo (DRC).

Although its title attracted me to read this paper [1], I was quickly disappointed. First, it advances a Malthusian approach that applauds the “potential benefits” of AIDS-related stigma. Second, it reflects a poor understanding of some of the existing literature on AIDS-related stigma cited in the article. The authors claim that the idea that stigma and discrimination thwart efforts to control the epidemic and constitute barriers for prevention and treatment is said over and over, with no evidence, “like a shibboleth,” and cite eleven references that are meant as examples of this uncritical repetition. Surprisingly though, at least one of the articles cited already argues that “confusion surrounds debate over stigma as a barrier to introducing antiretrovirals to poor countries or to making voluntary HIV tests accessible” and that “to assess AIDS-related stigma and declare it a cause rather than both cause and consequence of inequality will probably weaken efforts to address AIDS among those with heightened risk of HIV because of poverty, racism, and gender inequality” [2]. Finally, the authors show limited understanding of social and sexual dynamics. Their distinction between “subpopulations” and “the general population” seems to imply that the former, such as the subpopulation of sex workers, lives in isolation of the latter and that it takes a certain amount of time for HIV to go from one to the other; it implies, for example, that sex workers first transmit HIV amongst themselves and then at some later point they transmit it to “the general population.” I am afraid that the authors are actually conceptualizing HIV transmission within the similar linear frameworks that they are trying, unsuccessfully, to criticize.

Background Adherence to highly active antiretroviral therapy (HAART) medication is the greatest patient-enabled predictor of treatment success and mortality for those who have access to drugs. We systematically reviewed the literature to determine patient-reported barriers and facilitators to adhering to antiretroviral therapy. Methods and Findings We examined both developed and developing nations. We searched the following databases: AMED (inception to June 2005), Campbell Collaboration (inception to June 2005), CinAhl (inception to June 2005), Cochrane Library (inception to June 2005), Embase (inception to June 2005), ERIC (inception to June 2005), MedLine (inception to June 2005), and NHS EED (inception to June 2005). We retrieved studies conducted in both developed and developing nation settings that examined barriers and facilitators addressing adherence. Both qualitative and quantitative studies were included. We independently, in duplicate, extracted data reported in qualitative studies addressing adherence. We then examined all quantitative studies addressing barriers and facilitators noted from the qualitative studies. In order to place the findings of the qualitative studies in a generalizable context, we meta-analyzed the surveys to determine a best estimate of the overall prevalence of issues. We included 37 qualitative studies and 47 studies using a quantitative methodology (surveys). Seventy-two studies (35 qualitative) were conducted in developed nations, while the remaining 12 (two qualitative) were conducted in developing nations. Important barriers reported in both economic settings included fear of disclosure, concomitant substance abuse, forgetfulness, suspicions of treatment, regimens that are too complicated, number of pills required, decreased quality of life, work and family responsibilities, falling asleep, and access to medication. Important facilitators reported by patients in developed nation settings included having a sense of self-worth, seeing positive effects of antiretrovirals, accepting their seropositivity, understanding the need for strict adherence, making use of reminder tools, and having a simple regimen. Among 37 separate meta-analyses examining the generalizability of these findings, we found large heterogeneity. Conclusions We found that important barriers to adherence are consistent across multiple settings and countries. Research is urgently needed to determine patient-important factors for adherence in developing world settings. Clinicians should use this information to engage in open discussion with patients to promote adherence and identify barriers and facilitators within their own populations., An analysis of qualitative and quantitative studies found consistent barriers to adherence to HIV therapy across multiple settings and countries, ranging from access to medication to problems with complicated regimens., Editors' Summary Background. The World Health Organization has estimated that in 2005, about 38 million people worldwide were living with HIV/AIDS; the mortality caused by HIV/AIDS is very high. Antiretroviral drugs are effective at controlling the disease and extending life span. However, it is important for people to stick to the drug regimens exactly in order to keep levels of HIV low, prevent it from becoming resistant to drugs, and stop the illness from progressing. However, many people find it very difficult to take antiretroviral drugs precisely as they should. There is already some evidence from research studies on the reasons why this is the case. There are two different research approaches taken by these studies: “qualitative” methods, which try to find out about attitudes and behaviors using focus groups, interviews, or other techniques; and “quantitative” methods, which try to find out about peoples' opinions and experience using surveys with set questions for the participants to answer, and then count the different responses. Why Was This Study Done? The investigators wanted to put together all of the available evidence from published research studies (called doing a “systematic review”) on which factors affected people's adherence to antiretroviral drugs. They wanted to do a systematic review because it is thought to be a very rigorous way of appraising all the available evidence (although there is considerable debate about the value of using such a method to analyze the results of qualitative research). What Did the Researchers Do and Find? The study team searched biomedical literature databases as well as conference abstracts and research registries using a defined set of search queries. They screened all the scientific papers they found; those reporting results of original research into factors affecting antiretroviral adherence were then analyzed in more detail. 84 relevant studies were identified, of which 37 used “qualitative” methods (focus groups, interviews, open-ended questioning) and 47 used “quantitative” methods (surveys). Most of these studies had been carried out in the developed world. Then, the researchers extracted the factors affecting adherence from the original studies, which could be either “positive” factors (helping adherence) or “negative” ones (making adherence more difficult). They classified the factors into four key themes: “patient related” (e.g., seeing positive results, fear of disclosure, being depressed); “beliefs about medication” (e.g., faith in how well the drugs worked, side effects); “daily schedules” (e.g., using reminder tools, disruptions to routine); and “interpersonal relationships” (e.g., trusting relations with health-care provider; social isolation). Many barriers to adherence were common to both developed and developing settings. Some factors were unique to the studies conducted in the developing world, such as financial constraints and problems with traveling to get access to treatment. Fear of disclosure was an important barrier identified in many of the studies. What Do These Findings Mean? The researchers combined the results of many different studies and identified factors that help or obstruct adherence to antiretroviral treatment. By identifying influences common to the different settings, greater weight can be placed on the factors that were identified. Only 12 of the studies included in this research were from the developing world, where the majority of HIV/AIDS patients live; hence more work is needed to examine and address the factors influencing antiretroviral adherence in these parts of the world. This study provides researchers and health policy makers with a starting point for changes that might help to ensure greater adherence to antiretroviral treatment. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030438. Medline Plus information on AIDS medicines (Medline Plus is a service of the US National Library of Medicine and the National Institutes of Health) Joint United Nations Programme on HIV/AIDS has information about the state of the HIV/AIDS epidemic worldwide The World Health Organization has an HIV/AIDS program site providing comprehensive information on the HIV/AIDS epidemic worldwide The World Health Organization pages on antiretroviral therapy

While congratulating the authors of this informative article [1] for throwing light on a serious, yet much neglected health hazard, snakebite envenomation, we would like to add one more vital and cryptic cause for the abnormally high statistics in developing Asian countries: religion. Both Nepal, cited in the paper as having the highest number of casualties, and India are predominantly populated by Hindus (in fact the only two countries in the world with Hindu majorities). In Hinduism, the cobra is, from time immemorial, revered as a vital element among the Hindu pantheon of holies. Cobra worship for countering infertility, ill fortune, or for tempering the wrath of divine curses, is not only widespread, but also firmly believed and perpetuated. India is dotted with thousands of shrines and roadside temples dedicated to the “nag-deva” (cobra deity). Cobras are rarely, if ever killed when discovered in unwelcome locales; the trespassing serpents are usually trapped and released out of harm’s way [2]. The universal dread of incurring holy herpetological hexes not only allows the poisonous snake a second life, but also allows it to add its might to the ever increasing gene pool and population. It is futile in this scenario to talk about education and awareness campaigns; thousands of years of religious indoctrination cannot be negated by education or literacy. The best, and perhaps only way, global intervention and funding can contribute to minimizing snakebite casualties is through ensuring anti-venom availability in large quantities over wide geo-locales in sub-continental Asia.

We wish to thank Dr. Zimmer and colleagues [1] for critically reviewing our paper [2] and bringing to our knowledge their results. We partly agree with their comments, especially the part when they affirm that a direct comparison of the results is difficult. First of all, the design of the two investigations was different: ours was prospective and theirs was retrospective. Secondly, their data can hardly be interpreted and so cannot be a matter of contention. In fact, they merely report a mean platelet count of 88 × 109/l for the untreated group of 62 idiopathic thrombocytopenic purpura patients and of 66 × 109/l for the 31 patients later reclassified as having chronic idiopathic thrombocytopenic purpura. More importantly, they do not specify the number of their patients with a platelet count between 100 × 109/l and 150 × 109/l, i.e., the class of individuals that was the focus of our study. As an additional confounding factor, they report a follow-up period of 1.9 to 59 months for the entire untreated group. If a median is not reported, this does not make much sense statistically. Theoretically, 31 patients might have been followed for 1.9 months, 30 patients for six months, and one single patient for 59 months. If this was the case, no wonder they did not observe a single case of autoimmune disease in their cohort. We do not share Dr. Zimmer's point about a platelet count of 51 × 109/l to 100 × 109/l as equivalent to a higher count. Subjects who have a platelet count in the range of 50 × 109/l to 80 × 109/l are limited in their performance of particular physical jobs or traumatic activities such as contact sports. Besides, current guidelines suggest that a “safe” platelet count for major surgery, cesarean section, and spinal or epidural anesthesia should be at least 80 × 109/l [3]. Therefore, these patients may occasionally require an evaluation and possibly treatment that is not required for those with a borderline thrombocytopenia. Finally, we definitely rebut the issue of creating an unneeded clinical entity. The goal of our study was simply to describe the long-term outcome of individuals who were incidentally found with a platelet count between 101 × 109/l and 150 × 109/l. The terms “borderline thrombocytopenia” should be interpreted only as the definition of a count in that range, not as a new clinical entity. In fact, we have clearly underlined that the majority of individuals will retain their borderline platelet count indefinitely without developing diseases. Only a prospective case-control study would establish whether such individuals have a higher risk of developing autoimmune disorders than the general population. Until then, these cases should be interpreted only as healthy individuals with a platelet count in the lower range of normal.

Background Over 75% of the annual estimated 9.5 million deaths in India occur in the home, and the large majority of these do not have a certified cause. India and other developing countries urgently need reliable quantification of the causes of death. They also need better epidemiological evidence about the relevance of physical (such as blood pressure and obesity), behavioral (such as smoking, alcohol, HIV-1 risk taking, and immunization history), and biological (such as blood lipids and gene polymorphisms) measurements to the development of disease in individuals or disease rates in populations. We report here on the rationale, design, and implementation of the world's largest prospective study of the causes and correlates of mortality. Methods and Findings We will monitor nearly 14 million people in 2.4 million nationally representative Indian households (6.3 million people in 1.1 million households in the 1998–2003 sample frame and 7.6 million people in 1.3 million households in the 2004–2014 sample frame) for vital status and, if dead, the causes of death through a well-validated verbal autopsy (VA) instrument. About 300,000 deaths from 1998–2003 and some 700,000 deaths from 2004–2014 are expected; of these about 850,000 will be coded by two physicians to provide causes of death by gender, age, socioeconomic status, and geographical region. Pilot studies will evaluate the addition of physical and biological measurements, specifically dried blood spots. Preliminary results from over 35,000 deaths suggest that VA can ascertain the leading causes of death, reduce the misclassification of causes, and derive the probable underlying cause of death when it has not been reported. VA yields broad classification of the underlying causes in about 90% of deaths before age 70. In old age, however, the proportion of classifiable deaths is lower. By tracking underlying demographic denominators, the study permits quantification of absolute mortality rates. Household case-control, proportional mortality, and nested case-control methods permit quantification of risk factors. Conclusions This study will reliably document not only the underlying cause of child and adult deaths but also key risk factors (behavioral, physical, environmental, and eventually, genetic). It offers a globally replicable model for reliably estimating cause-specific mortality using VA and strengthens India's flagship mortality monitoring system. Despite the misclassification that is still expected, the new cause-of-death data will be substantially better than that available previously., This paper reports the rationale, design, and implementation of the world's largest prospective study of the causes and correlates of mortality.

Using a method that offered complete privacy to participants, Rachel Jewkes and colleagues conducted a survey among South African men about their lifetime same-sex experiences. Please see later in the article for the Editors' Summary, Background In sub-Saharan Africa the population prevalence of men who have sex with men (MSM) is unknown, as is the population prevalence of male-on-male sexual violence, and whether male-on-male sexual violence may relate to HIV risk. This paper describes lifetime prevalence of consensual male–male sexual behavior and male-on-male sexual violence (victimization and perpetration) in two South African provinces, socio-demographic factors associated with these experiences, and associations with HIV serostatus. Methods and Findings In a cross-sectional study conducted in 2008, men aged 18–49 y from randomly selected households in the Eastern Cape and KwaZulu-Natal provinces provided anonymous survey data and dried blood spots for HIV serostatus assessment. Interviews were completed in 1,737 of 2,298 (75.6%) of enumerated and eligible households. From these households, 1,705 men (97.1%) provided data on lifetime history of same-sex experiences, and 1,220 (70.2%) also provided dried blood spots for HIV testing. 5.4% (n = 92) of participants reported a lifetime history of any consensual sexual activity with another man; 9.6% (n = 164) reported any sexual victimization by a man, and 3.0% (n = 51) reported perpetrating sexual violence against another man. 85.0% (n = 79) of men with a history of consensual sex with men reported having a current female partner, and 27.7% (n = 26) reported having a current male partner. Of the latter, 80.6% (n = 21/26) also reported having a female partner. Men reporting a history of consensual male–male sexual behavior are more likely to have been a victim of male-on-male sexual violence (adjusted odds ratio [aOR] = 7.24; 95% CI 4.26–12.3), and to have perpetrated sexual violence against another man (aOR = 3.10; 95% CI 1.22–7.90). Men reporting consensual oral/anal sex with a man were more likely to be HIV+ than men with no such history (aOR = 3.11; 95% CI 1.24–7.80). Men who had raped a man were more likely to be HIV+ than non-perpetrators (aOR = 3.58; 95% CI 1.17–10.9). Conclusions In this sample, one in 20 men (5.4%) reported lifetime consensual sexual contact with a man, while about one in ten (9.6%) reported experience of male-on-male sexual violence victimization. Men who reported having had sex with men were more likely to be HIV+, as were men who reported perpetrating sexual violence towards other men. Whilst there was no direct measure of male–female concurrency (having overlapping sexual relationships with men and women), the data suggest that this may have been common. These findings suggest that HIV prevention messages regarding male–male sex in South Africa should be mainstreamed with prevention messages for the general population, and sexual health interventions and HIV prevention interventions for South African men should explicitly address male-on-male sexual violence. Please see later in the article for the Editors' Summary, Editors' Summary Background AIDS first emerged in the early 1980s among gay men living in the US, but it soon became clear that AIDS also infects heterosexual men and women. Now, three decades on, globally, 34 million people (two-thirds of whom live in sub-Saharan Africa and half of whom are women) are infected with HIV, the virus that causes AIDS, and 2.5 million people become infected every year. HIV is most often spread by having unprotected sex with an infected partner, and most sexual transmission of HIV now occurs during heterosexual sex. However, 5%–10% of all new HIV infections still occur in men who have sex with men (MSM; homosexual, bisexual, and transgender men, and heterosexual men who sometimes have consensual sex with men). Moreover, in the concentrated HIV epidemics of high-income countries (epidemics in which the prevalence of HIV infection is more than 5% in at-risk populations such as sex workers but less than 1% in the general population), male-to-male sexual contact remains the most important transmission route, and MSM often have a higher prevalence of HIV infection than heterosexual men. Why Was This Study Done? By contrast to high-income countries, HIV epidemics in sub-Saharan Africa are generalized—the prevalence of HIV infection is 1% or more in the general population. Because male-to-male sexual behavior is criminalized in many African countries and because homosexuality is widely stigmatized, little is known about the prevalence of consensual male–male sexual behavior in sub-Saharan Africa. This information and a better understanding of male–female sexual concurrency (having overlapping sexual relationships with men and women) and of how male-to-male transmission contributes to generalized HIV epidemics is needed to inform the design of HIV prevention strategies for use in sub-Saharan Africa. In addition, very little is known about male-on-male sexual violence. Such violence is potentially important to study because we know that male-on-female violence is associated with increased HIV risk for both victims and perpetrators. In this cross-sectional study (an investigation that measures population characteristics at a single time point), the researchers use data from a population-based household survey to investigate the lifetime prevalence of consensual male–male sexual behavior and male-on-male sexual violence (victimization and perpetration) among men in South Africa and the association of these experiences with HIV infection. What Did the Researchers Do and Find? About 1,700 adult men from randomly selected households in the Eastern Cape and KwaZulu-Natal provinces of South Africa self-completed a survey that included questions about their lifetime history of same-sex experiences using audio-enhanced personal digital assistants, a data collection method that provided a totally private and anonymous environment for the disclosure of illegal and stigmatized behavior; 1,220 of them also provided dried blood spots for HIV testing. Ninety-two men (5.4% of the participants) reported consensual sexual activity (for example, anal or oral sex) with another man at some time during their life; 9.6% of the men reported that they had been forced to have sex with another man (sexual victimization), and 3% reported that they had perpetrated sexual violence against another man. Most of the men who reported consensual sex with men, including those with current male partners, reported that they had a current female partner. Men with a history of consensual male–male sexual behavior were more likely to have been a victim or perpetrator of male-on-male sexual violence than men without a history of such experiences. Finally, men who reported consensual oral or anal sex with a man were more likely to be HIV+ than men without such a history, and perpetrators of male-on-male sexual violence were more likely to be HIV+ than non-perpetrators. What Do These Findings Mean? These findings provide new information about male–male sexual behaviors, male-on-male sexual violence, male–female concurrency, and HIV prevalence among men in two South African provinces. The precision of these findings is likely to be affected by the small numbers of men reporting a history of consensual male–male sexual behavior and of male-on-male sexual violence. Importantly, because the study was cross-sectional, these findings cannot indicate whether the association between consensual male–male sexual behaviors and increased risk of male-on-male sexual violence is causal. Moreover, these findings may not be generalizable to other regions of South Africa or to other African countries. Nevertheless, these findings suggest that information about the risks of male–male sexual behaviors should be included in HIV prevention strategies targeted at the general population in South Africa and that HIV prevention interventions for South African men should explicitly address male-on-male sexual violence. Similar HIV prevention strategies may also be suitable for other African countries, but are likely to succeed only in countries that have, like South Africa, decriminalized consensual homosexual behavior. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001472. This study is further discussed in a PLOS Medicine Perspective by Jerome Singh Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS NAM/aidsmap provides basic information about HIV/AIDS, including summaries of recent research findings on HIV care and treatment Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and men who have sex with men, on HIV prevention, and on AIDS in Africa (in English and Spanish) The US Centers for Disease Control and Prevention also has information about HIV/AIDS among men who have sex with men (in English and Spanish) Patient stories about living with HIV/AIDS are available through Avert; the charity website Healthtalkonline also provides personal stories about living with HIV

Kim Dickson and colleagues analyze the progress made by 13 priority countries toward scale-up of medical male circumcision programs, finding that the most successful programs involve country ownership of the program and have sustained leadership at all levels., Background Following confirmation of the effectiveness of voluntary medical male circumcision (VMMC) for HIV prevention, the World Health Organization and the Joint United Nations Programme on HIV/AIDS issued recommendations in 2007. Less than 5 y later, priority countries are at different stages of program scale-up. This paper analyzes the progress towards the scale-up of VMMC programs. It analyzes the adoption of VMMC as an additional HIV prevention strategy and explores the factors may have expedited or hindered the adoption of policies and initial program implementation in priority countries to date. Methods and Findings VMMCs performed in priority countries between 2008 and 2010 were recorded and used to classify countries into five adopter categories according to the Diffusion of Innovations framework. The main predictors of VMMC program adoption were determined and factors influencing subsequent scale-up explored. By the end of 2010, over 550,000 VMMCs had been performed, representing approximately 3% of the target coverage level in priority countries. The “early adopter” countries developed national VMMC policies and initiated VMMC program implementation soon after the release of the WHO recommendations. However, based on modeling using the Decision Makers' Program Planning Tool (DMPPT), only Kenya appears to be on track towards achievement of the DMPPT-estimated 80% coverage goal by 2015, having already achieved 61.5% of the DMPPT target. None of the other countries appear to be on track to achieve their targets. Potential predicators of early adoption of male circumcision programs include having a VMMC focal person, establishing a national policy, having an operational strategy, and the establishment of a pilot program. Conclusions Early adoption of VMMC policies did not necessarily result in rapid program scale-up. A key lesson is the importance of not only being ready to adopt a new intervention but also ensuring that factors critical to supporting and accelerating scale-up are incorporated into the program. The most successful program had country ownership and sustained leadership to translate research into a national policy and program. Please see later in the article for the Editors' Summary, Editors' Summary Background Every year, more than 2.5 million people (mostly in sub-Saharan Africa) become infected with HIV, the virus that causes AIDS. There is no cure for HIV/AIDS and no HIV vaccine. Consequently, global efforts to combat HIV/AIDS are concentrating on evidence-based prevention strategies such as voluntary medical male circumcision (VMMC). Circumcision—the removal of the foreskin, a loose fold of skin that covers the head of the penis—reduced HIV transmission through sexual intercourse by 60% in men in trials undertaken in sub-Saharan Africa, so in 2007, the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommended implementation of VMMC programs in countries with a generalized HIV epidemic and low levels of male circumcision. They also identified 13 countries in southern and eastern Africa as high priority countries for rapid VMMC scale-up. Mathematical modeling suggests that 20.3 million circumcisions by 2015 and 8.4 million circumcisions between 2016 and 2025 are needed to reach 80% VMMC coverage in these countries. If this coverage is achieved, it will avert about 3.4 million new HIV infections through 2025. Why Was This Study Done? Despite convincing evidence that VMMC is an effective, cost-saving intervention in the fight against HIV/AIDS, national VMMC scale-up programs in the priority countries are currently at very different stages. A better understanding of the challenges faced by these programs would help countries still in the early stages of VMMC scale-up implement their national programs and would facilitate implementation of other HIV prevention strategies. In this study, the researchers use the Diffusion of Innovations (DOI) theory to analyze progress towards VMMC scale-up in the priority countries and to identify the factors that may have expedited or hindered program scale-up. This theory seeks to explain how, why, and at what rate new ideas and technology spread through cultures. It posits that a few individuals (“innovators”) adopt new ideas before they become mainstream ideas. A few more individuals—the “early adopters”—follow the innovators. The “early majority” is the next group to adopt the innovation, followed by the “late majority” and the “laggards.” What Did the Researchers Do and Find? The researchers used the annual number of VMMCs performed in the priority countries since 2008 to classify the countries into DOI adopter categories. They calculated a total scale-up score for each country based on six key elements of program scale-up (such as whether and when a VMMC policy had been approved). Finally, they analyzed the association between the DOI adopter category and the scores for the individual scale-up elements to determine which elements predict adoption and VMMC scale-up. By the end of 2010, about 560,000 VMMCs had been completed, less than 3% of the target coverage for the priority countries. Kenya, the only DOI innovator country, had completed nearly two-thirds of the VMMCs needed to reach its target coverage and was the only country on track to reach its target. The early adopters (South Africa, Zambia, and Swaziland) had initiated VMMC program scale-up soon after the release of the 2007 recommendations and had started VMMC scale-up pilot programs in 2008 but were far from achieving their VMMC targets. Having a VMMC focal person, establishing a national policy, having an operational strategy, and establishing a pilot program all predicted early adoption of VMMC scale-up. What Do These Findings Mean? These findings show that, three years after the WHO/UNAIDS recommendation to integrate VMMC into comprehensive HIV prevention programs, VMMC scale-up activities had been initiated in all the priority countries but that progress towards the 80% coverage target was variable and generally poor. Importantly, they show that early adoption of VMMC as a national program had not necessarily resulted in rapid program scale-up. Although these findings may not be generalizable to other settings, they suggest that countries endeavoring to scale up VMMC (or other HIV prevention strategies) must not only be ready to adopt VMMC but must also ensure that all the factors critical to supporting and accelerating scale-up are incorporated into the scale-up program. Finally, these findings show that the most successful national programs are those that involve country ownership of the program and that have sustained leadership at all levels to facilitate the translation of research into national policies and programs. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001133. This study is part of a PLoS Collection of articles on VMMC (http://www.ploscollections.org/VMMC2011) and is further discussed in a PLoS Medicine Review Article by Hankins et al. (http://dx.doi.org/10.1371/journal.pmed.1001127) Information is available from WHO, UNAIDS, and PEPFAR on all aspects of HIV/AIDS NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and information on male circumcision for the prevention of HIV transmission Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on aspects of HIV prevention, and on HIV/AIDS in Africa (in English and Spanish) The Clearinghouse on Male Circumcision, a resource provided by WHO, UNAIDS, and other international bodies, provides information and tools for VMMC policy development and program implementation Wikipedia has a page on Diffusion of Innovations theory (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) Personal stories about living with HIV/AIDS are available through Avert, through NAM/aidsmap, and through the charity website Healthtalkonline

Vicente Corrales-Medina and colleagues report estimates of the risk of cardiac complications among patients with community-acquired pneumonia from a systematic review and meta-analysis., Background Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality. CAP can trigger acute cardiac events. We sought to determine the incidence of major cardiac complications in CAP patients to characterize the magnitude of this problem. Methods and Findings Two investigators searched MEDLINE, Scopus, and EMBASE for observational studies of immunocompetent adults with clinical and radiological evidence of CAP that reported any of the following: overall cardiac complications, incident heart failure, acute coronary syndromes (ACS), or incident cardiac arrhythmias occurring within 30 days of CAP diagnosis. At a minimum, studies had to establish enrolment procedures and inclusion and exclusion criteria, enrol their patients sequentially, and report the incidence of cardiac complications as a function of their entire cohorts. Studies with focus on nosocomial or health care–associated pneumonia were not included. Review of 2,176 citations yielded 25 articles that met eligibility and minimum quality criteria. Seventeen articles (68%) reported cohorts of CAP inpatients. In this group, the pooled incidence rates for overall cardiac complications (six cohorts, 2,119 patients), incident heart failure (eights cohorts, 4,215 patients), acute coronary syndromes (six cohorts, 2,657 patients), and incident cardiac arrhythmias (six cohorts, 2,596 patients), were 17.7% (confidence interval [CI] 13.9–22.2), 14.1% (9.3–20.6), 5.3% (3.2–8.6), and 4.7% (2.4–8.9), respectively. One article reported cardiac complications in CAP outpatients, four in low-risk (not severely ill) inpatients, and three in high-risk inpatients. The incidences for all outcomes except overall cardiac complications were lower in the two former groups and higher in the latter. One additional study reported on CAP outpatients and low-risk inpatients without discriminating between these groups. Twelve studies (48%) asserted the evaluation of cardiac complications in their methods but only six (24%) provided a definition for them. Only three studies, all examining ACS, carried out risk factor analysis for these events. No study analyzed the association between cardiac complications and other medical complications or their impact on other CAP outcomes. Conclusions Major cardiac complications occur in a substantial proportion of patients with CAP. Physicians and patients need to appreciate the significance of this association for timely recognition and management of these events. Strategies aimed at preventing pneumonia (i.e., influenza and pneumococcal vaccination) in high-risk populations need to be optimized. Further research is needed to understand the mechanisms underlying this association, measure the impact of cardiac complications on other CAP outcomes, identify those patients with CAP at high risk of developing cardiac complications, and design strategies to prevent their occurrence in this population. Please see later in the article for the Editors' Summary, Editors' Summary Background Community-acquired pneumonia (CAP), that is, pneumonia infections contracted outside of hospital or health care settings, is a common condition and can be fatal, particularly to older people. For example, every year, an estimated 5–6 million people contract this form of pneumonia in the US, leading to 1.1 million people being admitted to hospitals and causing 60,000 deaths—the most frequent cause of infectious disease-related mortality. In the US for example, more than half of older patients who present to the hospital with CAP have preexisting chronic cardiac conditions—an important fact given that acute infections, such as CAP, can affect the cardiovascular system in various ways and precipitate acute cardiac events, such as heart failure, heart attacks, and cardiac arrhythmias. Why Was This Study Done? Although it is bio-medically plausible that a considerable proportion of patients with CAP have cardiac complications, systematic data on the scale of this potential problem are lacking—a concerning omission given the important implications for health policy-making and direct patient care. Therefore, in this study, the researchers conducted a systematic review to examine the published literature on cardiac complications in patients with CAP in order to characterize the nature and significance of this association, and to identify areas that require further research and investigation. What Did the Researchers Do and Find? The researchers searched MEDLINE, Scopus, and EMBASE for all relevant articles published in English, French, or Spanish languages until June 2010. The researchers used strict criteria to select appropriate articles (such as radiographic evidence of CAP) and only selected studies that had outcomes of the incidence of cardiac complications, such as incident (new or worsening) heart failure, acute coronary syndromes (acute myocardial infarction or unstable angina), and incident cardiac arrhythmias within 30 days of diagnosis of CAP. Using these methods, the researchers identified 2,176 articles for review and selected 25 eligible papers for their analysis. Seventeen articles (68%) reported cohorts of CAP inpatients. In this group, the pooled incidence rates of overall cardiac complications (six cohorts, 2,119 patients), incident heart failure (eight cohorts, 4,215 patients), acute coronary syndromes (six cohorts, 2,657 patients), and incident cardiac arrhythmias (six cohorts, 2,596 patients), were 17.7%, 14.1%, 5.3%, and 4.7% respectively. Only three studies, (all of acute coronary syndromes) did risk factor analysis for these events. Possible risk factors identified included older age, preexisting congestive heart failure, severity of pneumonia, and the use of insulin by glucose sliding scales in hospitalized patients. No study analyzed the association between cardiac complications and other medical complications (such as acute renal failure, respiratory failure, shock, etc.) or their impact on other outcomes, such as death, in patients with CAP. What Do These Findings Mean? Although limited to a mostly descriptive analysis, these findings clearly show that major cardiac complications occur in a significant proportion of patients with CAP, especially in those admitted to hospital. These findings have important clinical and public health implications. Clinicians should be more aware of the significance of the association between CAP and cardiac complications to better inform, treat, and manage patients. Physicians and health officials need to increase efforts to optimize the rates of influenza and pneumococcal vaccination among older people and those with chronic cardiac conditions to reduce the incidence of CAP in these high-risk populations. There needs to be more consideration given to the potential impact of cardiac complications on mortality and costs associated with CAP. Finally, these findings highlight the need for prospective, well-designed, and adequately powered studies of cardiac complications in patients with CAP. More research attention should be given to this important area in order to improve the outcomes for patients with CAP and to decrease the consequent burden on health care systems through recognition of risk, prevention, and intervention on acute cardiac complications. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001048. Information can be found on Wikipedia on community-acquired pneumonia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) The US Centers for Disease Control provide patient information on community-acquired pneumonia The American Heart Association provides information on heart failure, acute coronary syndromes, and arrhythmias

Molly Franke, Megan Murray, and colleagues report that early cART reduces mortality among HIV-infected adults with tuberculosis and improves retention in care, regardless of CD4 count., Background Randomized clinical trials examining the optimal time to initiate combination antiretroviral therapy (cART) in HIV-infected adults with sputum smear-positive tuberculosis (TB) disease have demonstrated improved survival among those who initiate cART earlier during TB treatment. Since these trials incorporated rigorous diagnostic criteria, it is unclear whether these results are generalizable to the vast majority of HIV-infected patients with TB, for whom standard diagnostic tools are unavailable. We aimed to examine whether early cART initiation improved survival among HIV-infected adults who were diagnosed with TB in a clinical setting. Methods and Findings We retrospectively reviewed charts for 308 HIV-infected adults in Rwanda with a CD4 count≤350 cells/µl and a TB diagnosis. We estimated the effect of cART on survival using marginal structural models and simulated 2-y survival curves for the cohort under different cART strategies:start cART 15, 30, 60, or 180 d after TB treatment or never start cART. We conducted secondary analyses with composite endpoints of (1) death, default, or lost to follow-up and (2) death, hospitalization, or serious opportunistic infection. Early cART initiation led to a survival benefit that was most marked for individuals with low CD4 counts. For individuals with CD4 counts of 50 or 100 cells/µl, cART initiation at day 15 yielded 2-y survival probabilities of 0.82 (95% confidence interval: [0.76, 0.89]) and 0.86 (95% confidence interval: [0.80, 0.92]), respectively. These were significantly higher than the probabilities computed under later start times. Results were similar for the endpoint of death, hospitalization, or serious opportunistic infection. cART initiation at day 15 versus later times was protective against death, default, or loss to follow-up, regardless of CD4 count. As with any observational study, the validity of these findings assumes that biases from residual confounding by unmeasured factors and from model misspecification are small. Conclusions Early cART reduced mortality among individuals with low CD4 counts and improved retention in care, regardless of CD4 count. Please see later in the article for the Editors' Summary, Editors' Summary Background HIV infection has exacerbated the global tuberculosis (TB) epidemic, especially in sub-Saharan Africa, in which in some countries, 70% of people with TB are currently also HIV positive—a condition commonly described as HIV/TB co-infection. The management of patients with HIV/TB co-infection is a major public health concern. There is relatively little good evidence on the best time to initiate combination antiretroviral therapy (cART) in adults with HIV/TB co-infection. Clinicians sometimes defer cART in individuals initiating TB treatment because of concerns about complications (such as immune reconstitution inflammatory syndrome) and the risk of reduced adherence if patients have to remember to take two sets of pills. However, starting cART later in those patients who are infected with both HIV and TB can result in potentially avoidable deaths during therapy. Why Was This Study Done? Several randomized control trials (RCTs) have been carried out, and the results of three of these studies suggest that, among individuals with severe immune suppression, early initiation of cART (two to four weeks after the start of TB treatment) leads to better survival than later ART initiation (two to three months after the start of TB treatment). These results were reported in abstract form, but the full papers have not yet been published. One problem with RCTs is that they are carried out under controlled conditions that might not represent well the conditions in varied settings around the world. Therefore, observational studies that examine how effective a treatment is in routine clinical conditions can provide information that complements that obtained during clinical trials. In this study, the researchers aimed to confirm the results from RCTs among a cohort of adult patients with HIV/TB co-infection in Rwanda, diagnosed under routine program conditions and using routinely collected clinical data. The researchers also wanted to investigate whether early cART initiation reduced the risk of other adverse outcomes, including treatment default and loss to follow-up. What Did the Researchers Do and Find? The researchers retrospectively reviewed the charts and other program records of 308 patients with HIV, who had CD4 counts≤350 cells/µl, were aged 15 years or more, had never previously taken cART, and received their first TB treatment at one of five cART sites (two urban, three rural) in Rwanda between January 2004 and February 2007. Using this method, the researchers collected baseline demographic and clinical variables and relevant clinical follow-up data. They then used this data to estimate the effect of cART on survival by using sophisticated statistical models that calculated the effects of initiating cART at 15, 30, 60, or 180 d after the start of TB treatment or not at all. The researchers then conducted a further analysis to assess combined outcomes of (1) death, default, lost to follow-up, and (2) death, hospitalization due to any cause, or occurrence of severe opportunistic infections, such as Kaposi's sarcoma. The researchers used the resulting multivariable model to estimate survival probabilities for each individual, based on his/her baseline characteristics. The researchers found that when they set their model to first CD4 cell counts of 50 and 100 cells/µl, and starting cART at day 15, mean survival probabilities at two years were 0.82 and 0.86, respectively, statistically significantly higher than the survival probabilities calculated for each of the other treatment strategies, where cART was started later. They observed a similar pattern for the combined outcome of death, hospitalization, or serious opportunistic infection In addition, two-year outcomes for death or lost to follow-up were also improved with early cART, regardless of CD4 count at treatment initiation. What Do These Findings Mean? These findings show that in a real world program setting, starting cART 15 d after the start of TB treatment is more beneficial (measured by differences in survival probabilities) among patients with HIV/TB co-infection who have CD4 cell counts≤100 cells/µl than starting later. Early cART initiation may also increase retention in care for all individuals with CD4 cell counts≤350 cells/µl. As the outcomes of this modeling study are based on data from a retrospective observational study, the biases associated with use of these data must be carefully addressed. However, the results support the recommendation of cART initiation after 15 d of TB treatment for patients with CD4 cell counts≤100 cells/µl and can be used as an advocacy base for TB treatment to be used as an opportunity to refer and retain HIV-infected individuals in care, regardless of CD4 cell count. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001029. Information is available on HIV/TB co-infection from the World Health Organization, the US Centers for Disease Control and Prevention, and the International AIDS Society

BackgroundOne of the fundamental building blocks for determining the burden of disease in populations is to reliably measure the level and pattern of mortality by age and sex. Where well-functioning registration systems exist, this task is relatively straightforward. Results from many civil registration systems, however, remain uncertain because of a lack of confidence in the completeness of death registration. Incomplete registration systems mean not all deaths are counted, and resulting estimates of death rates for the population are then underestimated. Death distribution methods (DDMs) are a suite of demographic methods that attempt to estimate the fraction of deaths that are registered and counted by the civil registration system. Although widely applied and used, the methods have at least three types of limitations. First, a wide range of variants of these methods has been applied in practice with little scientific literature to guide their selection. Second, the methods have not been extensively validated in real population conditions where violations of the assumptions of the methods most certainly occur. Third, DDMs do not generate uncertainty intervals.Methods and findingsIn this paper, we systematically evaluate the performance of 234 variants of DDM methods in three different validation environments where we know or have strong beliefs about the true level of completeness of death registration. Using these datasets, we identify three variants of the DDMs that generally perform the best. We also find that even these improved methods yield uncertainty intervals of roughly +/- one-quarter of the estimate. Finally, we demonstrate the application of the optimal variants in eight countries.ConclusionsThere continues to be a role for partial vital registration data in measuring adult mortality levels and trends, but such results should only be interpreted alongside all other data sources on adult mortality and the uncertainty of the resulting levels, trends, and age-patterns of adult death considered. Please see later in the article for the Editors' Summary.

Philip Clarke and colleagues examined patient-level data for over 11,000 participants with type 2 diabetes from 20 countries and find that major complications of diabetes significantly increased hospital use and costs across settings., Background Diabetes imposes a substantial burden globally in terms of premature mortality, morbidity, and health care costs. Estimates of economic outcomes associated with diabetes are essential inputs to policy analyses aimed at prevention and treatment of diabetes. Our objective was to estimate and compare event rates, hospital utilization, and costs associated with major diabetes-related complications in high-, middle-, and low-income countries. Methods and Findings Incidence and history of diabetes-related complications, hospital admissions, and length of stay were recorded in 11,140 patients with type 2 diabetes participating in the Action in Diabetes and Vascular Disease (ADVANCE) study (mean age at entry 66 y). The probability of hospital utilization and number of days in hospital for major events associated with coronary disease, cerebrovascular disease, congestive heart failure, peripheral vascular disease, and nephropathy were estimated for three regions (Asia, Eastern Europe, and Established Market Economies) using multiple regression analysis. The resulting estimates of days spent in hospital were multiplied by regional estimates of the costs per hospital bed-day from the World Health Organization to compute annual acute and long-term costs associated with the different types of complications. To assist, comparability, costs are reported in international dollars (Int$), which represent a hypothetical currency that allows for the same quantities of goods or services to be purchased regardless of country, standardized on purchasing power in the United States. A cost calculator accompanying this paper enables the estimation of costs for individual countries and translation of these costs into local currency units. The probability of attending a hospital following an event was highest for heart failure (93%–96% across regions) and lowest for nephropathy (15%–26%). The average numbers of days in hospital given at least one admission were greatest for stroke (17–32 d across region) and heart failure (16–31 d) and lowest for nephropathy (12–23 d). Considering regional differences, probabilities of hospitalization were lowest in Asia and highest in Established Market Economies; on the other hand, lengths of stay were highest in Asia and lowest in Established Market Economies. Overall estimated annual hospital costs for patients with none of the specified events or event histories ranged from Int$76 in Asia to Int$296 in Established Market Economies. All complications included in this analysis led to significant increases in hospital costs; coronary events, cerebrovascular events, and heart failure were the most costly, at more than Int$1,800, Int$3,000, and Int$4,000 in Asia, Eastern Europe, and Established Market Economies, respectively. Conclusions Major complications of diabetes significantly increase hospital use and costs across various settings and are likely to impose a high economic burden on health care systems. Please see later in the article for the Editors' Summary, Editors' Summary Background Worldwide, nearly 250 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous amounts of sugar (glucose) in the blood. Blood sugar levels are normally controlled by insulin, a hormone produced by the pancreas. Blood sugar control fails in people with diabetes because they make no insulin (type 1 diabetes) or, more commonly, because the fat and muscle cells that usually respond to insulin by removing excess sugar from the blood have become insulin insensitive (type 2 diabetes). Type 2 diabetes can be prevented and controlled by eating a healthy diet and exercising regularly. It can also be treated with drugs that help the pancreas make more insulin or that increase insulin sensitivity. Major long-term complications of diabetes include kidney failure and an increased risk of cardiovascular problems such as heart attacks, heart failure, stroke, and problems with the blood vessels in the arms and legs. Because of these complications, the life expectancy of people with diabetes is about ten years shorter than that of people without diabetes. Why Was This Study Done? Diabetes imposes considerable demands on health care systems but little is known about the direct medical costs associated with treating this chronic disease in low- and middle-income countries where more than three-quarters of affected people live. In particular, although estimates have been made of the overall resources devoted to the treatment of diabetes, very little is known about how the different long-term complications of diabetes contribute to health care costs in different countries. Public-health experts and governments need this information to help them design effective and sustainable policies for the prevention and treatment of diabetes. In this study, the researchers estimate the resource use associated with diabetes-related complications in three economic regions using information collected in the Action in Diabetes and Vascular Disease (ADVANCE) study. This multinational clinical trial is investigating how drugs that control blood pressure and blood sugar levels affect the long-term complications of diabetes. What Did the Researchers Do and Find? The researchers recorded diabetes-related complications, hospital admissions for these complications, and length of hospital stays in 11,140 patients with severe diabetes from 20 countries who participated in the ADVANCE study. They used “multiple regression analysis” to estimate the number of days spent in hospital for diabetes-related complications in Asia, Eastern Europe, and the Established Market Economies (Canada, Australia, New Zealand, and several Western European countries). Finally, they calculated the economic costs of each complication using regional estimates of the costs per bed-day from the World Health Organization's CHOICE project (CHOosing Interventions that are Cost Effective). Nearly everyone in the study who developed heart failure attended a hospital, but only 15%–26% of people attended a hospital for kidney problems. The chances of hospitalization for any complication were lowest in Asia and highest in the Established Market Economies; conversely, lengths of stay were longest in Asia and shortest in the Established Market Economies. Finally, the estimated annual hospital costs for patients who had a coronary event, stroke, or heart failure were more than Int$1,800, Int$3,000, and Int$4,000 in Asia, Eastern Europe, and the Established Market Economies, respectively (the international dollar, Int$, is a hypothetical currency that has the same purchasing power in all countries), compared to Int$76, Int$156, and Int$296 for patients who experienced none of these events. What Do These Findings Mean? Because the ADVANCE trial had strict entry criteria, the findings of this study may not be generalizable to the broader population of people with diabetes. Nevertheless, given the lack of information about the costs associated with diabetes-related complications in low- and middle-income countries, these findings provide important new information about the patterns of hospital resource use and costs in these countries. Specifically, these findings show that the major complications of diabetes greatly increase hospital use and costs in all three economic regions considered and impose a high economic burden on health care systems that is likely to increase as the diabetes epidemic develops. Importantly, these findings should help policy makers anticipate the future health care costs associated with diabetes and should help them evaluate which therapies aimed at preventing diabetes-related complications will reduce these costs most effectively. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000236. The International Diabetes Federation provides information about all aspects of diabetes The US National Diabetes Information Clearinghouse provides detailed information about diabetes for patients, health care professionals, and the general public (in English and Spanish) The UK National Health Service also provides information for patients and caregivers about type 2 diabetes (in several languages) Information about the ADVANCE study is available The World Health Organization's CHOICE Web site provides information about the analysis of the cost effectiveness of health care interventions

BackgroundMathematical modelling of infectious diseases transmitted by the respiratory or close-contact route (e.g., pandemic influenza) is increasingly being used to determine the impact of possible interventions. Although mixing patterns are known to be crucial determinants for model outcome, researchers often rely on a priori contact assumptions with little or no empirical basis. We conducted a population-based prospective survey of mixing patterns in eight European countries using a common paper-diary methodology.Methods and findings7,290 participants recorded characteristics of 97,904 contacts with different individuals during one day, including age, sex, location, duration, frequency, and occurrence of physical contact. We found that mixing patterns and contact characteristics were remarkably similar across different European countries. Contact patterns were highly assortative with age: schoolchildren and young adults in particular tended to mix with people of the same age. Contacts lasting at least one hour or occurring on a daily basis mostly involved physical contact, while short duration and infrequent contacts tended to be nonphysical. Contacts at home, school, or leisure were more likely to be physical than contacts at the workplace or while travelling. Preliminary modelling indicates that 5- to 19-year-olds are expected to suffer the highest incidence during the initial epidemic phase of an emerging infection transmitted through social contacts measured here when the population is completely susceptible.ConclusionsTo our knowledge, our study provides the first large-scale quantitative approach to contact patterns relevant for infections transmitted by the respiratory or close-contact route, and the results should lead to improved parameterisation of mathematical models used to design control strategies.

Background Peer review is considered crucial to the selection and publication of quality science, but very little is known about the previous experiences and training that might identify high-quality peer reviewers. The reviewer selection processes of most journals, and thus the qualifications of their reviewers, are ill defined. More objective selection of peer reviewers might improve the journal peer review process and thus the quality of published science. Methods and Findings 306 experienced reviewers (71% of all those associated with a specialty journal) completed a survey of past training and experiences postulated to improve peer review skills. Reviewers performed 2,856 reviews of 1,484 separate manuscripts during a four-year study period, all prospectively rated on a standardized quality scale by editors. Multivariable analysis revealed that most variables, including academic rank, formal training in critical appraisal or statistics, or status as principal investigator of a grant, failed to predict performance of higher-quality reviews. The only significant predictors of quality were working in a university-operated hospital versus other teaching environment and relative youth (under ten years of experience after finishing training). Being on an editorial board and doing formal grant (study section) review were each predictors for only one of our two comparisons. However, the predictive power of all variables was weak. Conclusions Our study confirms that there are no easily identifiable types of formal training or experience that predict reviewer performance. Skill in scientific peer review may be as ill defined and hard to impart as is “common sense.” Without a better understanding of those skills, it seems unlikely journals and editors will be successful in systematically improving their selection of reviewers. This inability to predict performance makes it imperative that all but the smallest journals implement routine review ratings systems to routinely monitor the quality of their reviews (and thus the quality of the science they publish)., A survey of experienced reviewers, asked about training they had received in peer review, found there are no easily identifiable types of formal training and experience that predict reviewer performance., Editors' Summary Background. When medical researchers have concluded their research and written it up, the next step is to get it published as an article in a journal, so that the findings can be circulated widely. These published findings help determine subsequent research and clinical use. The editors of reputable journals, including PLoS Medicine, have to decide whether the articles sent to them are of good quality and accurate and whether they will be of interest to the readers of their journal. To do this they need to obtain specialist advice, so they contact experts in the topic of the research article and ask them to write reports. This is the process of scientific peer review, and the experts who write such reports are known as “peer reviewers.” Although the editors make the final decision, the advice and criticism of these peer reviewers to the editors is essential in making decisions on publication, and usually in requiring authors to make changes to their manuscript. The contribution that peer reviewers have made to the article by the time it is finally published may, therefore, be quite considerable. Although peer review is accepted as a key part of the process for the publishing of medical research, many people have argued that there are flaws in the system. For example, there may be an element of luck involved; one author might find their paper being reviewed by a reviewer who is biased against the approach they have adopted or who is a very critical person by nature, and another author may have the good fortune to have their work considered by someone who is much more favorably disposed toward their work. Some reviewers are more knowledgeable and thorough in their work than others. The editors of medical journals try to take in account such biases and quality factors in their choice of peer reviewers or when assessing the reviews. Some journals have run training courses for experts who review for them regularly to try to make the standard of peer review as high as possible. Why Was This Study Done? It is hard for journal editors to know who will make a good peer reviewer, and there is no proven system for choosing them. The authors of this study wanted to identify the previous experiences and training that make up the background of good peer reviewers and compare them with the quality of the reviews provided. This would help journal editors select good people for the task in future, and as a result will affect the quality of science they publish for readers, including other researchers. What Did the Researchers Do and Find? The authors contacted all the regular reviewers from one specialist journal (Annals of Emergency Medicine). A total of 306 of these experienced reviewers (71% of all those associated with the journal) completed a survey of past training and experiences that might be expected to improve peer review skills. These reviewers had done 2,856 reviews of 1,484 separate manuscripts during a four-year study period, and during this time the quality of the reviews had been rated by the journal's editors. Surprisingly, most variables, including academic rank, formal training in critical appraisal or statistics, or status as principal investigator of a grant, failed to predict performance of higher-quality reviews. The only significant predictors of quality were working in a university-operated hospital versus other teaching environment and relative youth (under ten years of experience after finishing training), and even these were only weak predictors. What Do These Findings Mean? This study suggest that there are no easily identifiable types of formal training or experience that predict peer reviewer performance, although it is clear that some reviewers (and reviews) are better than others. The authors suggest that it is essential therefore that journals routinely monitor the quality of reviews submitted to them to ensure they are getting good advice (a practice that is not universal). Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040040 • WAME is an association of editors from many countries who seek to foster international cooperation among editors of peer-reviewed medical journals • The Fifth International Congress on Peer Review and Biomedical Publication is one of a series of conferences on peer review • The PLoS Medicine guidelines for reviewers outline what we look for in a review • The Council of Science Editors promotes ethical scientific publishing practices • An editorial also published in this issue of PLoS Medicine discusses the peer review process further

We wish to comment on the paper by Milane et al. [1] and also refer to the Perspective by Baune and Hay [2] in the June issue of PLoS Medicine on the effect of fluoxetine prescriptions on the suicide rate in the United States. Milane et al. examined two sets of variables: the number of prescriptions for fluoxetine in the United States, and the Census Bureau mortality tables with the age adjusted suicide rates for the years 1988 to 2002. The date 1988 is chosen because in that year fluoxetine was introduced in the US. The authors report that the Spearman correlation coefficient between the two sets of variables equals −0.92 with a p-value of less than 0.001. The less suicides, the more tablets of fluoxetine are prescribed, or vice versa. The least-squares regression line is displayed in Figure 1. Figure 1 Correlation between Suicide Rates and Fluoxetine Prescriptions From this simple association they build an elaborate edifice, predicting what the suicide trends would have been had fluoxetine not been prescribed, and they calculate figures for “the thousands of lives saved” for both men and women...even though it is not known how many of these prescriptions were for men or for women, whether the patients took the tablets or not, or for how long they took the medication. In addition, the baseline period used to calculate the suicide trend, and thus to predict the future, was arbitrary: from 1960 to 1987, when the suicide rates had a slight gradual increase in the 1970s. Had they used the period 1950 to 1987, a different “trend” would have been obtained, since the suicide rates decreased during the economic expansion of the 1950s [3]. It is widely known that one cannot infer causality simply based on statistical association. Baune and Hay pointed this out and wrote: “In a study like this, it is also important to consider other potential explanations for the fall of suicide rates, such as improvements in the economy...” In this letter we report on the association of other variables with the suicide rates, for we find that the most glaring defect of the Milane et al. article is the total absence of analysis to address likely confounding by many other factors. Suicide is the final outcome of many conditions, and there have been, for many decades, scholarly articles indicating the many risk factors which increase the likelihood of suicide: poverty, loss of employment, and several other economic indicators have been shown to have a strong effect upon suicide rates. For example, during the Great Depression of the 1930s the rate of suicide rose significantly, and fell when the economy improved and unemployment decreased in the 1940s. On this matter, the literature is quite clear and the references abundant [4–8]. In the 1990s there was a very substantial and prolonged improvement of the US economy [9], which could partially explain a lowering of the suicide rate. We have chosen three economic indicators for the period from 1988 to 2002 and correlated them with the suicide rate, using the Spearman correlation coefficient to quantify the strength of the association. The yearly data for the suicide rates and numbers of fluoxetine prescriptions, for the three economic indicators (Dow Jones average, food stamp rate, and unemployment rate) and for the property crime and burglary rates are all contained in Table 1. The findings are not surprising: The unemployment rate during those years has a strong positive correlation with the suicide rate: r = 0.62, p = 0.014. Table 1 Raw Data by Year The percentage of the US population eligible for the Food Stamp Program, a reasonable indicator of poverty rates, has a stronger positive correlation with the suicide rates: r = 0.84, p = 0.0002. The Dow Jones industrial average for each of those years, when compared with the suicide rate of the US population, gives an even stronger (negative) correlation: r = −0.98, p < 0.0001 (see Figure 2). Figure 2 Correlation between Suicide Rates and the Dow Jones Average We also calculated the correlation between fluoxetine prescriptions and the Dow Jones average. Not surprisingly, there is a very strong positive correlation: r = 0.925, p < .0001 (see Figure 3). Figure 3 Correlation between Fluoxetine Prescriptions and the Dow Jones Average We doubt that many will advance the thesis that the increasing sales of fluoxetine were, somehow, one of the causes of the rise of the Dow Jones index. In fact, if the number of fluoxetine prescriptions is correlated with any variable that also steadily increased, or decreased, during all those years (1988–2002), a statistically significant association is most likely to be demonstrated. For example, the rate of crimes against property, obtained from the US Department of Justice, for the period 1988–2002 also exhibits a very high negative correlation with the fluoxetine prescriptions: r = −0.99, p < 0.0001. The rate of burglaries does also: r = −0.99, p < 0.0001. These relationships are not causal. Most scholars would relate the decrease in crime rates to the improvement of the economy during those years, rather than to increased sales of fluoxetine. The Spearman correlation coefficients for all possible pair-wise comparisons are contained in Table 2. Table 2 Spearman Correlation Coefficients (p-Value, Sample Size) Given these findings, we decided to explore the relationship of suicide rates with both fluoxetine prescriptions and Dow Jones averages as potentially associative factors in a single multivariate model. Results are displayed in Table 3. This allowed us to assess the association between fluoxetine and suicide adjusting for the Dow Jones, an economic indicator. Statistically, the association is quantified with a “partial” Spearman correlation coefficient. With this analysis the fluoxetine association was not significantly correlated with the suicide rate: fluoxetine had an adjusted Spearman correlation of −0.18 (p = 0.54) whereas the adjusted Dow Jones correlation remained high at −0.88 (p < 0.0001). Table 3 Type III Analysis of Variance Table for Regression of Suicide Rate on Dow Jones Averages and Number of Fluoxetine Prescriptions In conclusion, we believe that there is little likelihood that the increasing sales of fluoxetine from 1988 to 2002 were the cause of the modest decrease in the suicide rate during those years. It appears more likely that factors such as those connected with the sustained economic recovery of the 1990s were responsible.

Background Global and regional projections of mortality and burden of disease by cause for the years 2000, 2010, and 2030 were published by Murray and Lopez in 1996 as part of the Global Burden of Disease project. These projections, which are based on 1990 data, continue to be widely quoted, although they are substantially outdated; in particular, they substantially underestimated the spread of HIV/AIDS. To address the widespread demand for information on likely future trends in global health, and thereby to support international health policy and priority setting, we have prepared new projections of mortality and burden of disease to 2030 starting from World Health Organization estimates of mortality and burden of disease for 2002. This paper describes the methods, assumptions, input data, and results. Methods and Findings Relatively simple models were used to project future health trends under three scenarios—baseline, optimistic, and pessimistic—based largely on projections of economic and social development, and using the historically observed relationships of these with cause-specific mortality rates. Data inputs have been updated to take account of the greater availability of death registration data and the latest available projections for HIV/AIDS, income, human capital, tobacco smoking, body mass index, and other inputs. In all three scenarios there is a dramatic shift in the distribution of deaths from younger to older ages and from communicable, maternal, perinatal, and nutritional causes to noncommunicable disease causes. The risk of death for children younger than 5 y is projected to fall by nearly 50% in the baseline scenario between 2002 and 2030. The proportion of deaths due to noncommunicable disease is projected to rise from 59% in 2002 to 69% in 2030. Global HIV/AIDS deaths are projected to rise from 2.8 million in 2002 to 6.5 million in 2030 under the baseline scenario, which assumes coverage with antiretroviral drugs reaches 80% by 2012. Under the optimistic scenario, which also assumes increased prevention activity, HIV/AIDS deaths are projected to drop to 3.7 million in 2030. Total tobacco-attributable deaths are projected to rise from 5.4 million in 2005 to 6.4 million in 2015 and 8.3 million in 2030 under our baseline scenario. Tobacco is projected to kill 50% more people in 2015 than HIV/AIDS, and to be responsible for 10% of all deaths globally. The three leading causes of burden of disease in 2030 are projected to include HIV/AIDS, unipolar depressive disorders, and ischaemic heart disease in the baseline and pessimistic scenarios. Road traffic accidents are the fourth leading cause in the baseline scenario, and the third leading cause ahead of ischaemic heart disease in the optimistic scenario. Under the baseline scenario, HIV/AIDS becomes the leading cause of burden of disease in middle- and low-income countries by 2015. Conclusions These projections represent a set of three visions of the future for population health, based on certain explicit assumptions. Despite the wide uncertainty ranges around future projections, they enable us to appreciate better the implications for health and health policy of currently observed trends, and the likely impact of fairly certain future trends, such as the ageing of the population, the continued spread of HIV/AIDS in many regions, and the continuation of the epidemiological transition in developing countries. The results depend strongly on the assumption that future mortality trends in poor countries will have a relationship to economic and social development similar to those that have occurred in the higher-income countries., The presented projections suggest a dramatic shift in the distribution of deaths from younger to older ages and from communicable, maternal, perinatal, and nutritional causes to non-communicable disease causes. HIV/AIDS and tobacco remain major killers and possible targets for intervention., Editors' Summary Background. For most of human history, little has been known about the main causes of illness in different countries and which diseases kill most people. But public-health officials need to know whether heart disease kills more people than cancer in their country, for example, or whether diabetes causes more disability than mental illness so that they can use their resources wisely. They also have to have some idea about how patterns of illness (morbidity) and death (mortality) are likely to change so that they can plan for the future. In the early 1990s, the World Bank sponsored the 1990 Global Burden of Disease study carried out by researchers at Harvard University and the World Health Organization (WHO). This study provided the first comprehensive, global estimates of death and illness by age, sex, and region. It also provided projections of the global burden of disease and mortality up to 2020 using models that assumed that health trends are related to a set of independent variables. These variables were income per person (as people become richer, they, live longer), average number of years of education (as this “human capital” increases, so does life expectancy), time (to allow for improved knowledge about various diseases), and tobacco use (a major global cause of illness and death). Why Was This Study Done? These health projections have been widely used by WHO and governments to help them plan their health policies. However, because they are based on the 1990 estimates of the global burden of disease, the projections now need updating, particularly since they underestimate the spread of HIV/AIDS and the associated increase in death from tuberculosis. In this study, the researchers used similar methods to those used in the 1990 Global Burden of Disease study to prepare new projections of mortality and burden of disease up to 2030 starting from the 2002 WHO global estimates of mortality and burden of disease. What Did the Researchers Do and Find? As before, the researchers used projections of socio-economic development to model future patterns of mortality and illness for a baseline scenario, a pessimistic scenario that assumed a slower rate of socio-economic development, and an optimistic scenario that assumed a faster rate of growth. Their analysis predicts that between 2002 and 2030 for all three scenarios life expectancy will increase around the world, fewer children younger than 5 years will die, and the proportion of people dying from non-communicable diseases such as heart disease and cancer will increase. Although deaths from infectious diseases will decrease overall, HIV/AIDS deaths will continue to increase; the exact magnitude of the increase will depend on how many people have access to antiretroviral drugs and the efficacy of prevention programs. But, even given the rise in HIV/AIDS deaths, the new projections predict that more people will die of tobacco-related disease than of HIV/AIDS in 2015. The researchers also predict that by 2030, the three leading causes of illness will be HIV/AIDS, depression, and ischaemic heart disease (problems caused by a poor blood supply to the heart) in the baseline and pessimistic scenarios; in the optimistic scenario, road-traffic accidents will replace heart disease as the third leading cause (there will be more traffic accidents with faster economic growth). What Do These Findings Mean? The models used by the researchers provide a wealth of information about possible patterns of global death and illness between 2002 and 2030, but because they include many assumptions, like all models, they can provide only indications of future trends, not absolute figures. For example, based on global mortality data from 2002, the researchers estimate that global deaths in 2030 will be 64.9 million under the optimistic scenario. However, the actual figure may be quite a bit bigger or smaller because accurate baseline counts of deaths were not available for every country in the world. Another limitation of the study is that the models used assume that future increases in prosperity in developing countries will affect their population's health in the same way as similar increases affected health in the past in countries with death registration data (these are mostly developed countries). However, even given these and other limitations, the projections reported in this study provide useful insights into the future health of the world. These can now be used by public-health officials to plan future policy and to monitor the effect of new public-health initiatives on the global burden of disease and death. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030442. World Health Organization, provides information on the Global Burden of Disease Project and links to other related resources Global Burden of Disease Project Harvard School of Public Health, Burden of Disease Unit, offers information on the 1990 Global Burden of Disease study and its projections Harvard School of Public Health

Background Through major efforts to reduce costs and expand access to antiretroviral therapy worldwide, widespread delivery of effective treatment to people living with HIV/AIDS is now conceivable even in severely resource-constrained settings. However, the potential epidemiologic impact of treatment in the context of a broader strategy for HIV/AIDS control has not yet been examined. In this paper, we quantify the opportunities and potential risks of large-scale treatment roll-out. Methods and Findings We used an epidemiologic model of HIV/AIDS, calibrated to sub-Saharan Africa, to investigate a range of possible positive and negative health outcomes under alternative scenarios that reflect varying implementation of prevention and treatment. In baseline projections, reflecting “business as usual,” the numbers of new infections and AIDS deaths are expected to continue rising. In two scenarios representing treatment-centered strategies, with different assumptions about the impact of treatment on transmissibility and behavior, the change in the total number of new infections through 2020 ranges from a 10% increase to a 6% reduction, while the number of AIDS deaths through 2020 declines by 9% to 13%. A prevention-centered strategy provides greater reductions in incidence (36%) and mortality reductions similar to those of the treatment-centered scenarios by 2020, but more modest mortality benefits over the next 5 to 10 years. If treatment enhances prevention in a combined response, the expected benefits are substantial—29 million averted infections (55%) and 10 million averted deaths (27%) through the year 2020. However, if a narrow focus on treatment scale-up leads to reduced effectiveness of prevention efforts, the benefits of a combined response are considerably smaller—9 million averted infections (17%) and 6 million averted deaths (16%). Combining treatment with effective prevention efforts could reduce the resource needs for treatment dramatically in the long term. In the various scenarios the numbers of people being treated in 2020 ranges from 9.2 million in a treatment-only scenario with mixed effects, to 4.2 million in a combined response scenario with positive treatment–prevention synergies. Conclusions These analyses demonstrate the importance of integrating expanded care activities with prevention activities if there are to be long-term reductions in the number of new HIV infections and significant declines in AIDS mortality. Treatment can enable more effective prevention, and prevention makes treatment affordable. Sustained progress in the global fight against HIV/AIDS will be attained only through a comprehensive response., Combining the two approaches of prevention and treatment of HIV/AIDS could avert more than 29 million new HIV infections by 2020