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Background Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials. Methods and Findings We received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report. None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were “bothersome,” a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that “all adverse events were recorded.” For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student’s t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper. Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs. Conclusions In the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles., In a document analysis, Jeppe B. Schroll and colleagues seek insights into potential bias and underreporting in documentation of adverse events from the mid-1990s clinical trials of the anti-obesity drug orlistat., Author Summary Why Was This Study Done? Most drugs have adverse effects, or harms, that may become evident in clinical trials. Pharmaceutical companies seeking to market a new drug must report adverse effects observed in trial participants in the Clinical Study Reports (CSRs), which they provide to regulatory authorities. Additionally, investigators may report harms in published reports of their trials. We sought to understand the accuracy, and potential bias, in harms reporting for trials of orlistat, a slimming drug from Roche approved in Europe in 1998 and still marketed in Europe today. What Did The Researchers Do And Find? Using a Freedom of Information Act request to the European Medicines Agency (EMA), we obtained CSRs describing seven clinical trials of orlistat. We studied protocol instructions to investigators for reporting harms, the actual reporting of harms in individual CSR records versus summaries, and the final reporting of harms in published papers. We found that protocol instructions to trial investigators had the potential to dilute the appearance of drug-associated harms. Between 3% and 33% of the total adverse effects from CSR summaries were described in published papers. In one trial, we counted adverse events individually and found that both the number of adverse effects and the number of days with adverse effects in participants taking the drug were understated in the corresponding publication. What Do These Findings Mean? The reporting of trials of orlistat in the 1990s understated harms in the summarised results submitted to the EMA for drug approval and in the published papers. Based on the characteristics of harms observed and reported in these trials, we suggest that reports of harms include duration of adverse effects. We also suggest that systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.

In this months editorial, the PLOS Medicine Editors announce an upcoming Special Issue and call for papers, with Guest Editors Carol Brayne and Bruce Miller, on dementia across the lifespan and around the globe.

In this month’s editorial, the PLOS Medicine Editors announce an upcoming Special Issue, with Guest Editors Elaine Mardis and Marc Ladanyi, on actionable advances in research on the cancer genome.

Nicola Low and colleagues announce a call for research papers on sexually transmitted infections, to accompany a Collection on the topic.

Background Tobacco industry interference has been identified as the greatest obstacle to the implementation of evidence-based measures to reduce tobacco use. Understanding and addressing industry interference in public health policy-making is therefore crucial. Existing conceptualisations of corporate political activity (CPA) are embedded in a business perspective and do not attend to CPA’s social and public health costs; most have not drawn on the unique resource represented by internal tobacco industry documents. Building on this literature, including systematic reviews, we develop a critically informed conceptual model of tobacco industry political activity. Methods and Findings We thematically analysed published papers included in two systematic reviews examining tobacco industry influence on taxation and marketing of tobacco; we included 45 of 46 papers in the former category and 20 of 48 papers in the latter (n = 65). We used a grounded theory approach to build taxonomies of “discursive” (argument-based) and “instrumental” (action-based) industry strategies and from these devised the Policy Dystopia Model, which shows that the industry, working through different constituencies, constructs a metanarrative to argue that proposed policies will lead to a dysfunctional future of policy failure and widely dispersed adverse social and economic consequences. Simultaneously, it uses diverse, interlocking insider and outsider instrumental strategies to disseminate this narrative and enhance its persuasiveness in order to secure its preferred policy outcomes. Limitations are that many papers were historical (some dating back to the 1970s) and focused on high-income regions. Conclusions The model provides an evidence-based, accessible way of understanding diverse corporate political strategies. It should enable public health actors and officials to preempt these strategies and develop realistic assessments of the industry’s claims., In this thematic analysis, Selda Ulucanlar and colleagues develop taxonomies and an overall model to describe the political strategies used by the tobacco industry to influence policy around tobacco taxation and marketing., Author Summary Why Was This Study Done? Interference by the tobacco industry in government policy-making is known to be an important reason for governments’ failure to adopt proven measures to reduce tobacco consumption. Our study aimed to systematically review tobacco industry political activity from a critical societal perspective using in-depth empirical evidence. We set out to build a widely applicable model that governments in different countries could use to identify and preempt industry interference in policy. What Did the Researchers Do and Find? We analysed 65 papers included in previous systematic reviews that examined tobacco industry political activity in two policy areas: taxation and marketing of tobacco products. Using constructivist grounded theory, we identified industry arguments and techniques and then grouped these under the more general heading of strategies, finally developing a taxonomy and model of tobacco industry political activity. According to our Policy Dystopia Model, the industry produces an alarmist narrative that proposed policies will fail and lead to a great number of undesirable social and economic consequences (outlined in our taxonomy of discursive strategies). The industry also uses different methods (outlined in our taxonomy of instrumental strategies) to disseminate this narrative and persuade decision-makers in order to block policies. What Do These Findings Mean? Public health actors and policy-makers can use our model and taxonomies to better promote tobacco-related policies and to render ineffective tobacco industry opposition and political activity. In particular, they need to pay attention to alliance formation, information provision, interdisciplinary working, and transparency in policy-making.

Civil registration and vital statistics systems are increasingly recognized as drivers of human rights, health, and development programs—especially for women and children [1]. Vital statistics systems are weak in most low-income countries [2,3], precisely where the burden of maternal and child deaths is highest and, therefore, the need for up-to-date, high-quality estimates of levels and trends in maternal and child mortality is greatest [4]. The UN Commission on Information and Accountability for Women’s and Children’s Health identified the reporting of births and deaths as a cornerstone for vital statistics systems in low-income countries [5]. This has led to intensified efforts to support and strengthen the routine reporting of vital events [6]. In this paper, we synthesize results generated by the Real-Time Monitoring of Under-Five Mortality (RMM) project, and highlight aspects that can inform efforts to strengthen vital statistics systems in low-income countries. Table 1 provides an overview of the methods tested by the RMM project in Ethiopia, Ghana, Malawi, Mali, and Niger. Full details on the design and implementation of RMM methods, the accuracy of the mortality estimates they produce, and their running costs are reported in the papers that form the Collection. Table 1 Real-time mortality monitoring (RMM) approaches tested, by country. Community-based reporting on vital events Adjusted health facility data Rapid household survey methods Paid worker Unpaid worker Repeated Imputed Ethiopia ✓ ✓ ✓ Ghana ✓ ✓ Malawi ✓ ✓ ✓ ✓ Mali ✓ ✓ Niger ✓ ✓ Open in a separate window The RMM project produced two sets of overarching findings: 1) quantitative results on the accuracy of under-five mortality estimates produced by various methodological approaches; and 2) experiential findings on the challenges of generating vital statistics for recent periods in real-world settings.

Background The development of cognitive and socioemotional skills early in life influences later health and well-being. Existing estimates of unmet developmental potential in low- and middle-income countries (LMICs) are based on either measures of physical growth or proxy measures such as poverty. In this paper we aim to directly estimate the number of children in LMICs who would be reported by their caregivers to show low cognitive and/or socioemotional development. Methods and Findings The present paper uses Early Childhood Development Index (ECDI) data collected between 2005 and 2015 from 99,222 3- and 4-y-old children living in 35 LMICs as part of the Multiple Indicator Cluster Survey (MICS) and Demographic and Health Surveys (DHS) programs. First, we estimate the prevalence of low cognitive and/or socioemotional ECDI scores within our MICS/DHS sample. Next, we test a series of ordinary least squares regression models predicting low ECDI scores across our MICS/DHS sample countries based on country-level data from the Human Development Index (HDI) and the Nutrition Impact Model Study. We use cross-validation to select the model with the best predictive validity. We then apply this model to all LMICs to generate country-level estimates of the prevalence of low ECDI scores globally, as well as confidence intervals around these estimates. In the pooled MICS and DHS sample, 14.6% of children had low ECDI scores in the cognitive domain, 26.2% had low socioemotional scores, and 36.8% performed poorly in either or both domains. Country-level prevalence of low cognitive and/or socioemotional scores on the ECDI was best represented by a model using the HDI as a predictor. Applying this model to all LMICs, we estimate that 80.8 million children ages 3 and 4 y (95% CI 48.1 million, 113.6 million) in LMICs experienced low cognitive and/or socioemotional development in 2010, with the largest number of affected children in sub-Saharan Africa (29.4.1 million; 43.8% of children ages 3 and 4 y), followed by South Asia (27.7 million; 37.7%) and the East Asia and Pacific region (15.1 million; 25.9%). Positive associations were found between low development scores and stunting, poverty, male sex, rural residence, and lack of cognitive stimulation. Additional research using more detailed developmental assessments across a larger number of LMICs is needed to address the limitations of the present study. Conclusions The number of children globally failing to reach their developmental potential remains large. Additional research is needed to identify the specific causes of poor developmental outcomes in diverse settings, as well as potential context-specific interventions that might promote children’s early cognitive and socioemotional well-being., Using survey data from 35 low- and middle-income countries, Dana McCoy and colleagues estimate the prevalence of children who are reported by their caregivers to show low cognitive and/or socioemotional development., Author Summary Why Was This Study Done? Previous research suggests that more than 200 million children under age five living in low- and middle-income countries (LMICs) experience malnutrition and poverty. Despite this known risk, little is known about the status of young children’s cognitive and socioemotional development. Estimates of the number of children facing developmental setbacks are important for policy and resource allocation, as well as for tracking progress toward meeting global development goals (for example, the Sustainable Development Goals). What Did the Researchers Do and Find? This study extrapolates data from nearly 100,000 three- and four-year-old children living in 35 LMICs sampled as part of the Multiple Indicator Cluster Survey and the Demographic Health Surveys. The results suggest that one in every three preschool-aged children living in LMICs is failing to meet basic milestones in either their cognitive or socioemotional development, with an additional 16% facing setbacks in their physical growth. What Do These Findings Mean? The results highlight the ongoing challenges faced by young children living in developing countries in meeting basic developmental milestones. Additional intervention is needed to improve children’s cognitive and socioemotional well-being worldwide. Future research should consider additional dimensions of children’s development across a broader age range.

Background Rotavirus vaccination is recommended in all countries to reduce the burden of diarrhea-related morbidity and mortality in children. In resource-limited settings, rotavirus vaccination in the national immunization program has important cost implications, and evidence for protection beyond the first year of life and against the evolving variety of rotavirus strains is important. We assessed the extended and strain-specific vaccine efficacy of a heat-stable, affordable oral rotavirus vaccine (Rotasiil, Serum Institute of India, Pune, India) against severe rotavirus gastroenteritis (SRVGE) among healthy infants in Niger. Methods and findings From August 2014 to November 2015, infants were randomized in a 1:1 ratio to receive 3 doses of Rotasiil or placebo at approximately 6, 10, and 14 weeks of age. Episodes of gastroenteritis were assessed through active and passive surveillance and graded using the Vesikari score. The primary endpoint was vaccine efficacy of 3 doses of vaccine versus placebo against a first episode of laboratory-confirmed SRVGE (Vesikari score ≥ 11) from 28 days after dose 3, as previously reported. At the time of the primary analysis, median age was 9.8 months. In the present paper, analyses of extended efficacy were undertaken for 3 periods (28 days after dose 3 to 1 year of age, 1 to 2 years of age, and the combined period 28 days after dose 3 to 2 years of age) and by individual rotavirus G type. Among the 3,508 infants included in the per-protocol efficacy analysis (mean age at first dose 6.5 weeks; 49% male), the vaccine provided significant protection against SRVGE through the first year of life (3.96 and 9.98 cases per 100 person-years for vaccine and placebo, respectively; vaccine efficacy 60.3%, 95% CI 43.6% to 72.1%) and over the entire efficacy follow-up period up to 2 years of age (2.13 and 4.69 cases per 100 person-years for vaccine and placebo, respectively; vaccine efficacy 54.7%, 95% CI 38.1% to 66.8%), but the difference was not statistically significant in the second year of life. Up to 2 years of age, rotavirus vaccination prevented 2.56 episodes of SRVGE per 100 child-years. Estimates of efficacy against SRVGE by individual rotavirus genotype were consistent with the overall protective efficacy. Study limitations include limited generalizability to settings with administration of oral polio virus due to low concomitant administration, limited power to assess vaccine efficacy in the second year of life owing to a low number of events among older children, potential bias due to censoring of placebo children at the time of study vaccine receipt, and suboptimal adapted severity scoring based on the Vesikari score, which was designed for use in settings with high parental literacy. Conclusions Rotasiil provided protection against SRVGE in infants through an extended follow-up period of approximately 2 years. Protection was significant in the first year of life, when the disease burden and risk of death are highest, and against a changing pattern of rotavirus strains during the 2-year efficacy period. Rotavirus vaccines that are safe, effective, and protective against multiple strains represent the best hope for preventing the severe consequences of rotavirus infection, especially in resource-limited settings, where access to care may be limited. Studies such as this provide valuable information for the planning of national immunization programs and future vaccine development. Trial registration ClinicalTrials.gov NCT02145000., Sheila Isanaka and co-workers report extended follow-up of a rotavirus vaccine trial in Niger., Author summary Why was this study done? The World Health Organization (WHO) recommends rotavirus vaccine use in all countries, but several questions remain for countries that have not yet implemented rotavirus vaccination or are weighing different vaccine options. In resource-limited settings, where rotavirus vaccine delivery has important cost implications, evidence for protection beyond the first year of life and against the evolving variety of rotavirus strains is important. We previously reported on the efficacy and safety of Rotasiil (Serum Institute of India, Pune, India), a heat-stable, affordable oral rotavirus vaccine that was WHO prequalified in 2018, against severe rotavirus gastroenteritis (SRVGE) among healthy infants in Niger. What did the researchers do and find? In the present analysis, we assessed the extended and strain-specific vaccine efficacy of Rotasiil in children up to 24 months of age. Rotasiil provided protection against SRVGE in infants through an extended follow-up period and against a changing pattern of rotavirus strains during the 2-year efficacy period. What do these findings mean? Vaccines that are safe, effective, and protective against multiple strains represent the best hope for preventing the severe consequences of rotavirus infection, and can be expected to greatly reduce the burden of rotavirus disease.

Background Following a reduction in global child mortality due to communicable diseases, the relative contribution of congenital anomalies to child mortality is increasing. Although infant survival of children born with congenital anomalies has improved for many anomaly types in recent decades, there is less evidence on survival beyond infancy. We aimed to systematically review, summarise, and quantify the existing population-based data on long-term survival of individuals born with specific major congenital anomalies and examine the factors associated with survival. Methods and findings Seven electronic databases (Medline, Embase, Scopus, PsycINFO, CINAHL, ProQuest Natural, and Biological Science Collections), reference lists, and citations of the included articles for studies published 1 January 1995 to 30 April 2020 were searched. Screening for eligibility, data extraction, and quality appraisal were performed in duplicate. We included original population-based studies that reported long-term survival (beyond 1 year of life) of children born with a major congenital anomaly with the follow-up starting from birth that were published in the English language as peer-reviewed papers. Studies on congenital heart defects (CHDs) were excluded because of a recent systematic review of population-based studies of CHD survival. Meta-analysis was performed to pool survival estimates, accounting for trends over time. Of 10,888 identified articles, 55 (n = 367,801 live births) met the inclusion criteria and were summarised narratively, 41 studies (n = 54,676) investigating eight congenital anomaly types (spina bifida [n = 7,422], encephalocele [n = 1,562], oesophageal atresia [n = 6,303], biliary atresia [n = 3,877], diaphragmatic hernia [n = 6,176], gastroschisis [n = 4,845], Down syndrome by presence of CHD [n = 22,317], and trisomy 18 [n = 2,174]) were included in the meta-analysis. These studies covered birth years from 1970 to 2015. Survival for children with spina bifida, oesophageal atresia, biliary atresia, diaphragmatic hernia, gastroschisis, and Down syndrome with an associated CHD has significantly improved over time, with the pooled odds ratios (ORs) of surviving per 10-year increase in birth year being OR = 1.34 (95% confidence interval [95% CI] 1.24–1.46), OR = 1.50 (95% CI 1.38–1.62), OR = 1.62 (95% CI 1.28–2.05), OR = 1.57 (95% CI 1.37–1.81), OR = 1.24 (95% CI 1.02–1.5), and OR = 1.99 (95% CI 1.67–2.37), respectively (p < 0.001 for all, except for gastroschisis [p = 0.029]). There was no observed improvement for children with encephalocele (OR = 0.98, 95% CI 0.95–1.01, p = 0.19) and children with biliary atresia surviving with native liver (OR = 0.96, 95% CI 0.88–1.03, p = 0.26). The presence of additional structural anomalies, low birth weight, and earlier year of birth were the most commonly reported predictors of reduced survival for any congenital anomaly type. The main limitation of the meta-analysis was the small number of studies and the small size of the cohorts, which limited the predictive capabilities of the models resulting in wide confidence intervals. Conclusions This systematic review and meta-analysis summarises estimates of long-term survival associated with major congenital anomalies. We report a significant improvement in survival of children with specific congenital anomalies over the last few decades and predict survival estimates up to 20 years of age for those born in 2020. This information is important for the planning and delivery of specialised medical, social, and education services and for counselling affected families. This trial was registered on the PROSPERO database (CRD42017074675)., In a systematic review and meta-analysis, Svetlana V. Glinianaia and colleagues report on temporal trends in long-term survival of children born with specific congenital anomalies., Author summary Why was this study done? Following a reduction in global child mortality due to communicable diseases, the relative contribution of congenital anomalies to child mortality under age 5 years is increasing globally. Identifying and addressing the emerging priority of congenital anomalies, including for children aged 5–9 years, is one of the strategic directions for the post-2015 child health agenda. This research aimed to summarise and quantify the existing population-based evidence on long-term survival of children born with specific major congenital anomalies that manifest in childhood. What did the researchers do and find? This systematic review included 55 international studies that estimated survival beyond 1 year of age of children born with major congenital anomalies. Our meta-analysis results of 41 studies over the birth years 1970–2015 showed a statistically significant improvement in survival over time in children with spina bifida, oesophageal atresia, biliary atresia, congenital diaphragmatic hernia, gastroschisis, and Down syndrome associated with a congenital heart defect, but there was no evidence of improvement in those with encephalocele or biliary atresia with a native liver. The commonest significant independent predictors of reduced survival for any congenital anomaly type were presence of additional structural anomalies, low birth weight, and earlier birth year period. What do these findings mean? A significant improvement in survival of children with specific congenital anomalies over the last few decades reported by individual studies and identified by the meta-analysis has important public health, medical, social, and family implications. Information on predicted survival of children with congenital anomalies up to 20 years of age is important for planning specialised medical, social, and education services for these children and for estimating costs associated with special care needs in childhood and adulthood.

Background While the high prevalence of preterm births and its impact on infant mortality in the US have been widely acknowledged, recent data suggest that even full-term births in the US face substantially higher mortality risks compared to European countries with low infant mortality rates. In this paper, we use the most recent birth records in the US to more closely analyze the primary causes underlying mortality rates among full-term births. Methods and findings Linked birth and death records for the period 2010–2012 were used to identify the state- and cause-specific burden of infant mortality among full-term infants (born at 37–42 weeks of gestation). Multivariable logistic models were used to assess the extent to which state-level differences in full-term infant mortality (FTIM) were attributable to observed differences in maternal and birth characteristics. Random effects models were used to assess the relative contribution of state-level variation to FTIM. Hypothetical mortality outcomes were computed under the assumption that all states could achieve the survival rates of the best-performing states. A total of 10,175,481 infants born full-term in the US between January 1, 2010, and December 31, 2012, were analyzed. FTIM rate (FTIMR) was 2.2 per 1,000 live births overall, and ranged between 1.29 (Connecticut, 95% CI 1.08, 1.53) and 3.77 (Mississippi, 95% CI 3.39, 4.19) at the state level. Zero states reached the rates reported in the 6 low-mortality European countries analyzed (FTIMR < 1.25), and 13 states had FTIMR > 2.75. Sudden unexpected death in infancy (SUDI) accounted for 43% of FTIM; congenital malformations and perinatal conditions accounted for 31% and 11.3% of FTIM, respectively. The largest mortality differentials between states with good and states with poor FTIMR were found for SUDI, with particularly large risk differentials for deaths due to sudden infant death syndrome (SIDS) (odds ratio [OR] 2.52, 95% CI 1.86, 3.42) and suffocation (OR 4.40, 95% CI 3.71, 5.21). Even though these mortality differences were partially explained by state-level differences in maternal education, race, and maternal health, substantial state-level variation in infant mortality remained in fully adjusted models (SIDS OR 1.45, suffocation OR 2.92). The extent to which these state differentials are due to differential antenatal care standards as well as differential access to health services could not be determined due to data limitations. Overall, our estimates suggest that infant mortality could be reduced by 4,003 deaths (95% CI 2,284, 5,587) annually if all states were to achieve the mortality levels of the best-performing state in each cause-of-death category. Key limitations of the analysis are that information on termination rates at the state level was not available, and that causes of deaths may have been coded differentially across states. Conclusions More than 7,000 full-term infants die in the US each year. The results presented in this paper suggest that a substantial share of these deaths may be preventable. Potential improvements seem particularly large for SUDI, where very low rates have been achieved in a few states while average mortality rates remain high in most other areas. Given the high mortality burden due to SIDS and suffocation, policy efforts to promote compliance with recommended sleeping arrangements could be an effective first step in this direction., Using state-level birth and death records, Neha Bairoliya identify state- and cause specific burden of infant mortality among full-term infants in the United States, and uncover opportunities for improvement., Author summary Why was this study done? High infant mortality rates in the US compared to other high-income countries have been well documented in the literature. Most of this literature primarily attributes high infant mortality in the US to the high rates of prematurity. Relatively little is known regarding the survival of infants born full-term. What did the researchers do and find? We compared state-level mortality rates among full-term infants in the US to that of 6 European countries with low mortality rates. We showed that infants born full-term in the US face 50%–200% higher risks of infant mortality compared to these European countries. We found that the largest proportion of infant deaths among children born full-term in the US was due to sudden unexpected deaths of infants, which comprised both sudden infant death syndrome and other unexpected causes such as suffocation and violence. What do these findings mean? Major improvements in full-term infant mortality (through increases in full-term infant survival and increases in pregnancy terminations) seem possible in the US. More research is needed to identify the most effective policies to achieve this objective.

Background Previous research has focused on the mortality associated with armed conflict as the primary measure of the population health effects of war. However, mortality only demonstrates part of the burden placed on a population by conflict. Injuries and resultant disabilities also have long-term effects on a population and are not accounted for in estimates that focus solely on mortality. Our aim was to demonstrate a new method to describe the effects of both lives lost, and years of disability generated by a given conflict, with data from the US-led 2003 invasion and subsequent occupation of Iraq. Methods and findings Our data come from interviews conducted in 2014 in 900 Baghdad households containing 5,148 persons. The average household size was 5.72 persons. The majority of the population (55.8%) were between the ages of 19 and 60. Household composition was evenly divided between males and females. Household sample collection was based on methodology previously designed for surveying households in war zones. Survey questions were answered by the head of household or senior adult present. The questions included year the injury occurred, the mechanism of injury, the body parts injured, whether injury resulted in disability and, if so, the length of disability. We present this modeling study to offer an innovative methodology for measuring “years lived with disability” (YLDs) and “years of life lost” (YLLs) attributable to conflict-related intentional injuries, using the Global Burden of Disease (GBD) approach. YLDs were calculated with disability weights, and YLLs were calculated by comparing the age at death to the GBD standard life table to calculate remaining life expectancy. Calculations were also performed using Iraq-specific life expectancy for comparison. We calculated a burden of injury of 5.6 million disability-adjusted life years (DALYs) lost due to conflict-related injuries in Baghdad from 2003 to 2014. The majority of DALYs lost were attributable to YLLs, rather than YLDs, 4.99 million YLLs lost (95% uncertainty interval (UI) 3.87 million to 6.13 million) versus 616,000 YLDs lost (95% UI 399,000 to 894,000). Cause-based analysis demonstrated that more DALYs were lost to due to gunshot wounds (57%) than any other cause. Our study has several limitations. Recall bias regarding the reporting and attribution of injuries is possible. Second, we have no data past the time of the interview, so we assumed individuals with ongoing disability at the end of data collection would not recover, possibly counting more disability for injuries occurring later. Additionally, incomplete data could have led to misclassification of deaths, resulting in an underestimation of the total burden of injury. Conclusions In this study, we propose a methodology to perform burden of disease calculations for conflict-related injuries (expressed in DALYs) in Baghdad from 2003 to 2014. We go beyond previous reports of simple mortality to assess long-term population health effects of conflict-related intentional injuries. Ongoing disability is, in cross section, a relatively small 10% of the total burden. Yet, this small proportion creates years of demands on the health system, persistent limitations in earning capacity, and continuing burdens of care provision on family members., In a modelling study, Guy Jensen and colleagues propose a method for calculating burden of injury in conflict using data on conflict-related intentional injuries in Baghdad, Iraq 2003-2014., Author summary Why was this study done? The Global Burden of Disease (GBD) project, based at the University of Washington, publishes the estimates of prevalence, incidence, years of life lost (YLLs), and years lived with disability (YLDs) for a comprehensive list of diseases and injuries and for all countries from 1990 to the present. The World Health Organization has also published YLL and YLD estimates. Previous researchers innovated the population-proportionate to size sampling methodology for household surveys in war zones, which we used in this study. Previous papers have attempted to calculate only Iraq War deaths, as mortality is an important population health indicator and is relatively straightforward to measure. Injuries are, along with mortality, an important factor in conflict settings; they measure a more nuanced toll on public health. Ongoing disability is important, especially when associated with demands on the health system, ongoing limitations in earning capacity, and the burdens created for family caregivers. We aim to lay out our application of the GBD methodology, along with our alteration to it for calculation of burden of injury in conflict. Additionally, we aim to describe specifically how these calculations were applied in hopes of developing a methodology for the study of conflict populations. What did the researchers do and find? This study innovates the application of GBD methodology for calculating YLLs and YLDs to data collected in a war zone. We calculated a burden of injury of 5.6 million DALYs lost due to conflict-related injuries in Baghdad from 2003 to 2014. These calculations encompass both mortality as well as the effects of injury and disability on the population of Baghdad. We performed these calculations using a variation of the GBD methodology to better reflect the dynamic nature of conflict. Media reports tend to focus heavily on the more “spectacular” aspects of conflict, such as explosions, shelling, and air strikes. By contrast, our results demonstrate gunshot wounds were the leading contributor to YLDs and YLLs. What do these findings mean? Our results demonstrate the importance of data-driven, epidemiologically sound assessment of conflicts, especially those spanning multiple years. However, it should be noted that our primary goal was to develop a methodology, demonstrated by our calculations with the city of Baghdad, to allow for its use in other conflicts. With more sophisticated methods, epidemiologists might better prevent the most harmful aspects of conflict for civilian populations, might better predict losses in advance of the onset of conflict, and might contribute to health systems in planning for care delivery. Limitations for this study include the possibility for recall bias among the survey participants as well as the possible undercounting of deaths due to injury due to classifying any injuries that did not definitively result in death as YLDs rather than YLLs. Lastly, we did not adjust for changes in the population of Baghdad over the course of the study.

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 Improving oxygen systems may improve clinical outcomes for hospitalised children with acute lower respiratory infection (ALRI). This paper reports the effects of an improved oxygen system on mortality and clinical practices in 12 general, paediatric, and maternity hospitals in southwest Nigeria. Methods and findings We conducted an unblinded stepped-wedge cluster-randomised trial comparing three study periods: baseline (usual care), pulse oximetry introduction, and stepped introduction of a multifaceted oxygen system. We collected data from clinical records of all admitted neonates (, Hamish R. Graham and colleagues reveal outcomes when oxygen is provided to hospitalised children and neonates in Nigeria., Author summary Why was this study done? Oxygen therapy is important for many acute medical conditions, particularly among unwell children and newborns, in whom hypoxaemia (low blood oxygen) is common. Oxygen access and use are suboptimal in many hospitals in low- and middle-income countries. Improved oxygen systems may reduce deaths from pneumonia. To scale up oxygen in resource-limited settings, we need better information about how to improve oxygen systems and stronger evidence on the benefits of improved oxygen systems for newborns and children. What did the researchers do and find? We introduced pulse oximetry and improved oxygen systems in 12 Nigerian hospitals, aiming to provide continuous oxygen therapy for every child and neonate who needed it. We evaluated the impact of pulse oximetry and the improved oxygen system on care practices and clinical outcomes for >24,000 unwell newborns and children. We found that the improved oxygen system had no effect on outcomes for children, when compared against the introduction of pulse oximetry. However, pulse oximetry may have reduced the risk of death from pneumonia by approximately 50% compared to baseline. We found that the improved oxygen system was associated with increased risk of neonatal death, when compared against the introduction of pulse oximetry. However, neither pulse oximetry nor the full oxygen system had any effect on neonatal death when compared against baseline. What do these findings mean? Pulse oximetry should be central to all activities aiming to improve access to oxygen therapy. Where some oxygen is already available, the introduction of pulse oximetry may improve how oxygen is used and may reduce deaths from pneumonia. The negative results for newborns are surprising but should be interpreted cautiously. Analysis of results from individual hospitals shows significant variability in outcomes for newborns and children. Our study was challenged by a major economic recession, resulting in unexpected changes in admission numbers, illness severity, and care practices and low power to detect change in clinical outcomes.

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.

Background Differentiated antiretroviral therapy (ART) delivery models, in which patients are provided with care relevant to their current status (e.g., newly initiating, stable on treatment, or unstable on treatment) has become an essential part of patient-centered health systems. In 2015, the South African government implemented Chronic Disease Adherence Guidelines (AGLs), which involved five interventions: Fast Track Initiation Counseling for newly initiating patients, Enhanced Adherence Counseling for patients with an unsuppressed viral load, Early Tracing of patients who miss visits, and Adherence Clubs (ACs) and Decentralized Medication Delivery (DMD) for stable patients. We evaluated two of these interventions in 24 South African facilities: ACs, in which patients meet in groups outside usual clinic procedures and receive medication; and DMD, in which patients pick up their medication outside usual pharmacy queues. Methods and findings We compared those participating in ACs or receiving DMD at intervention sites to those eligible for ACs or DMD at control sites. Outcomes were retention and sustained viral suppression (, Matthew Fox and colleagues report on outcomes of two tailored service delivery models for HIV therapy in South Africa., Author summary Why was this study done? Antiretroviral therapy (ART) has brought enormous benefits, enabling HIV patients to live longer and healthier lives. However, many patients struggle to adhere to this lifelong treatment, and their retention in care is suboptimal. To address this, South Africa’s National Department of Health has introduced National Adherence Guidelines for Chronic Diseases that recommend key interventions suitable for new patients, clinically stable patients, patients with advanced HIV disease or on a failing ART regimen, and lost-to-follow-up patients. The early implementation of these guidelines from 2015 was evaluated to understand the effectiveness of five interventions and learn about improvements for the guidelines’ rollout. This paper provides the results on adherence clubs and decentralized medication delivery, two interventions for efficient medication pick-up by clinically stable patients. What did the researchers do and find? We used a cluster-randomized evaluation design for adherence clubs and an observational study for decentralized medication delivery across 12 intervention and 12 control health facilities in 4 provinces. The 275 adherence club patients had improved retention in care at one year compared to the 294 controls, especially men, and comparable viral suppression within 18 months. The 232 patients receiving decentralized medication delivery had apparently lower retention in care than the 346 controls (possibly due to medication pick-up data not reaching clinics), and viral suppression was comparable overall, but men on decentralized medication delivery had apparently increased viral suppression. What do these findings mean? This programmatic evaluation with a comparison group provides the National Department of Health with many lessons for the national rollout of the guidelines and the effect one can expect from such alternative medication pick-up services. The control facilities were already offering some adherence and retention services, and the observed benefits of the guideline interventions are therefore additional. The comparable outcomes for decentralized medication delivery against standard of care, the retention benefit by adherence clubs, and the apparent increased effects among men suggest that these interventions can play an important role in South Africa’s ART program. Because the interventions also decentralize ART and reduce patients’ inconvenience, comparable outcomes are a potential success, and further work should investigate the cost–benefit relation and possible effects on decongesting clinics.

Background Globally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved infant and young child feeding (IYCF) on early child development (ECD) among children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. Methods and findings SHINE was a cluster-randomized community-based 2×2 factorial trial. A total of 5,280 pregnant women were enrolled from 211 clusters (defined as the catchment area of 1–4 village health workers [VHWs] employed by the Zimbabwean Ministry of Health and Child Care). Clusters were randomly allocated to standard of care, IYCF (20 g of small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counseling), WASH (ventilated improved pit latrine, handwashing stations, chlorine, liquid soap, and play yard), and WASH + IYCF. Primary outcomes were child length-for-age Z-score and hemoglobin concentration at 18 months of age. Children who completed the 18-month visit and turned 2 years (102–112 weeks) between March 1, 2016, and April 30, 2017, were eligible for the ECD substudy. We prespecified that primary inferences would be drawn from findings of children born to HIV-negative mothers; these results are presented in this paper. A total of 1,655 HIV-unexposed children (64% of those eligible) were recruited into the ECD substudy from 206 clusters and evaluated for ECD at 2 years of age using the Malawi Developmental Assessment Tool (MDAT) to assess gross motor, fine motor, language, and social skills; the MacArthur–Bates Communicative Development Inventories (CDI) to assess vocabulary and grammar; the A-not-B test to assess object permanence; and a self-control task. Outcomes were analyzed in the intention-to-treat population. For all ECD outcomes, there was not a statistical interaction between the IYCF and WASH interventions, so we estimated the effects of the interventions by comparing the 2 IYCF groups with the 2 non-IYCF groups and the 2 WASH groups with the 2 non-WASH groups. The mean (95% CI) total MDAT score was modestly higher in the IYCF groups compared to the non-IYCF groups in unadjusted analysis: 1.35 (0.24, 2.46; p = 0.017); this difference did not persist in adjusted analysis: 0.79 (−0.22, 1.68; p = 0.057). There was no evidence of impact of the IYCF intervention on the CDI, A-not-B, or self-control tests. Among children in the WASH groups compared to those in the non-WASH groups, mean scores were not different for the MDAT, A-not-B, or self-control tests; mean CDI score was not different in unadjusted analysis (0.99 [95% CI −1.18, 3.17]) but was higher in children in the WASH groups in adjusted analysis (1.81 [0.01, 3.61]). The main limitation of the study was the specific time window for substudy recruitment, meaning not all children from the main trial were enrolled. Conclusions We found little evidence that the IYCF and WASH interventions implemented in SHINE caused clinically important improvements in child development at 2 years of age. Interventions that directly target neurodevelopment (e.g., early stimulation) or that more comprehensively address the multifactorial nature of neurodevelopment may be required to support healthy development of vulnerable children. Trial registration ClinicalTrials.gov NCT01824940, In this substudy from a 2x2 factorial cluster-randomized trial, Melissa Gladstone and colleagues assess whether improved WASH and/or feeding provide a benefit to early child development., Author summary Why was this study done? Some 43% of children globally fail to reach their full developmental potential due to stunting and poverty. Current evidence shows that improved nutrition has a modest effect on early child development. Improving water, sanitation, and hygiene (WASH) may plausibly benefit neurodevelopment through reduced illness and improved gut health (through improving nutrient absorption and optimizing gut–brain communication). What did the researchers do and find? The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial tested the individual and combined effects of improved complementary feeding (provision of a small quantity of lipid-based nutrient supplement from 6 to 18 months of age, with complementary feeding counseling) and improved household WASH (provision of a pit latrine, handwashing stations, soap, chlorine, and hygiene counseling) on early child development at 24 months. In all, 1,655 children born to HIV-negative women were assessed for gross motor, fine motor, language, cognitive, and social development using tools that were designed and adapted for rural Zimbabwe. We found little evidence that the complementary feeding or WASH interventions tested improved child neurodevelopment at 2 years of age. What do these findings mean? Complementary feeding and WASH interventions (as described above) may not have a clinically significant impact on child neurodevelopment. More holistic approaches and interventions that explicitly target early child development may be needed to substantially impact child neurodevelopment.

Introduction Inequalities in maternal and newborn health persist in many high-income countries, including for women of refugee background. The Bridging the Gap partnership programme in Victoria, Australia, was designed to find new ways to improve the responsiveness of universal maternity and early child health services for women and families of refugee background with the codesign and implementation of iterative quality improvement and demonstration initiatives. One goal of this ‘whole-of-system’ approach was to improve access to antenatal care. The objective of this paper is to report refugee women’s access to hospital-based antenatal care over the period of health system reforms. Methods and findings The study was designed using an interrupted time series analysis using routinely collected data from two hospital networks (four maternity hospitals) at 6-month intervals during reform activity (January 2014 to December 2016). The sample included women of refugee background and a comparison group of Australian-born women giving birth over the 3 years. We describe the proportions of women of refugee background (1) attending seven or more antenatal visits and (2) attending their first hospital visit at less than 16 weeks’ gestation compared over time and to Australian-born women using logistic regression analyses. In total, 10% of births at participating hospitals were to women of refugee background. Refugee women were born in over 35 countries, and at one participating hospital, 40% required an interpreter. Compared with Australian-born women, women of refugee background were of similar age at the time of birth and were more likely to be having their second or subsequent baby and have four or more children. At baseline, 60% of refugee-background women and Australian-born women attended seven or more antenatal visits. Similar trends of improvement over the 6-month time intervals were observed for both populations, increasing to 80% of women at one hospital network having seven or more visits at the final data collection period and 73% at the other network. In contrast, there was a steady decrease in the proportion of women having their first hospital visit at less than 16 weeks’ gestation, which was most marked for women of refugee background. Using an interrupted time series of observational data over the period of improvement is limited compared with using a randomisation design, which was not feasible in this setting. Conclusions Accurate ascertainment of ‘harder-to-reach’ populations and ongoing monitoring of quality improvement initiatives are essential to understand the impact of system reforms. Our findings suggest that improvement in total antenatal visits may have been at the expense of recommended access to public hospital antenatal care within 16 weeks of gestation., Jane Yelland and colleagues report refugee women's access to antenatal services in Australia during a period of health systems reform., Author summary Why was the study done? Women of refugee background have rates of stillbirth and perinatal mortality two to three times higher than Australian-born women. Antenatal care is a key preventive strategy for the optimal health of pregnant women and newborn babies and is critical to addressing modifiable factors for poor health outcomes. Refugee women experience barriers in accessing and engaging in antenatal care, and healthcare providers report challenges in responding to the social context and needs of refugee families. What did the researchers do and find? We codesigned and implemented multiple quality improvement and demonstration initiatives in universal health services, including four maternity hospitals. We used an interrupted time series design to assess the timing and number of antenatal clinical visits for refugee women compared with Australian-born women over 3 years of reform. Applying a method devised by the partnership, we identified from routinely collected data that 10% of all women giving birth at the participating hospitals were of refugee background. There was an increase over time in the proportion of refugee and Australian-born women attending the standard number of visits, with women of refugee background commencing hospital antenatal care well past the recommended gestation. What do these findings mean? For women of refugee background, delayed access to hospital-based care increases the likelihood of missing out on critical elements of pregnancy care vital to optimising maternal and child outcomes. Accurate ascertainment of this ‘harder-to-reach’ population is essential to evaluating the impact of quality improvement initiatives on refugee families’ access to healthcare. An interrupted time series design with a comparison group is suited to measuring change in number and timing of antenatal visits, although data quality, contextual influences, and qualitative insights into system change are important for interpreting outcomes. Ongoing monitoring of quality improvement initiatives on populations vulnerable to poor health outcomes is essential to understand the impact of system reforms and efforts to reduce inequalities.

Background Adult height reflects childhood circumstances and is associated with health, longevity, and maternal–fetal outcomes. Mean height is an important population metric, and declines in height have occurred in several low- and middle-income countries, especially in Africa, over the last several decades. This study examines changes at the population level in the distribution of height over time across a broad range of low- and middle-income countries during the past half century. Methods and findings The study population comprised 1,122,845 women aged 25–49 years from 59 countries with women’s height measures available from four 10-year birth cohorts from 1950 to 1989 using data from the Demographic and Health Surveys (DHS) collected between 1993 and 2013. Multilevel regression models were used to examine the association between (1) mean height and standard deviation (SD) of height (a population-level measure of inequality) and (2) median height and the 5th and 95th percentiles of height. Mean-difference plots were used to conduct a graphical analysis of shifts in the distribution within countries over time. Overall, 26 countries experienced a significant increase, 26 experienced no significant change, and 7 experienced a significant decline in mean height between the first and last birth cohorts. Rwanda experienced the greatest loss in height (−1.4 cm, 95% CI: −1.84 cm, −0.96 cm) while Colombia experienced the greatest gain in height (2.6 cm, 95% CI: 2.36 cm, 2.84 cm). Between 1950 and 1989, 24 out of 59 countries experienced a significant change in the SD of women’s height, with increased SD in 7 countries—all of which are located in sub-Saharan Africa. The distribution of women’s height has not stayed constant across successive birth cohorts, and regression models suggest there is no evidence of a significant relationship between mean height and the SD of height (β = 0.015 cm, 95% CI: −0.032 cm, 0.061 cm), while there is evidence for a positive association between median height and the 5th percentile (β = 0.915 cm, 95% CI: 0.820 cm, 1.002 cm) and 95th percentile (β = 0.995 cm, 95% CI: 0.925 cm, 1.066 cm) of height. Benin experienced the largest relative expansion in the distribution of height. In Benin, the ratio of variance between the latest and earliest cohort is estimated as 1.5 (95% CI: 1.4, 1.6), while Lesotho and Uganda experienced the greatest relative contraction of the distribution, with the ratio of variance between the latest and earliest cohort estimated as 0.8 (95% CI: 0.7, 0.9) in both countries. Limitations of the study include the representativeness of DHS surveys over time, age-related height loss, and consistency in the measurement of height between surveys. Conclusions The findings of this study indicate that the population-level distribution of women’s height does not stay constant in relation to mean changes. Because using mean height as a summary population measure does not capture broader distributional changes, overreliance on the mean may lead investigators to underestimate disparities in the distribution of environmental and nutritional determinants of health., Using dats from Demographic Health Surveys in 59 low- and middle-income countries, Fahad Razak and colleagues examine changes at the population-level in the distribution of height over time., Author summary Why was this study done? An adult’s height may provide important insight into childhood health circumstances. Height is also related to longevity, mortality from a variety of noncommunicable diseases, maternal mortality, and quality of life. Mean height has decreased in some low- and middle-income countries and increased in others, but it is unclear if everyone in the population experiences similar changes in height. This paper examines the relationship between changes in the mean of women’s height and the distribution of women’s height across a population. What did the researchers do and find? Data from 59 low- and middle-income countries (n = 1,122,845 women, aged 25–49 years) was obtained from the Demographic and Health Surveys, nationally representative surveys conducted at regular intervals around the world. Mean-difference plots were used to visually examine changes in mean women’s height in relation to the distribution of height across countries. Statistical analyses were conducted to examine the global associations between mean height and the standard deviation of height, as well as median height and the 95th and 5th percentile. Seven countries experienced a decline in mean height (all located in sub-Saharan Africa), and 25 countries experienced a change in the standard deviation of height. There was an inconsistent relationship between mean height and its standard deviation. What do these findings mean? Changes observed in the distribution of height indicate that transitions in living standards and nutrition have not been experienced equally across many populations. A focus on mean women’s height does not capture these changes. Future research on height as a population measure of well-being should include assessment of changes in the distribution as well as the mean.

Background Operational research is required to design delivery of pre-exposure prophylaxis (PrEP) and early antiretroviral treatment (ART). This paper presents the primary analysis of programmatic data, as well as demographic, behavioural, and clinical data, from the TAPS Demonstration Project, which offered both interventions to female sex workers (FSWs) at 2 urban clinic sites in South Africa. Methods and findings The TAPS study was conducted between 30 March 2015 and 30 June 2017, with the enrolment period ending on 31 July 2016. TAPS was a prospective observational cohort study with 2 groups receiving interventions delivered in existing service settings: (1) PrEP as part of combination prevention for HIV-negative FSWs and (2) early ART for HIV-positive FSWs. The main outcome was programme retention at 12 months of follow-up. Of the 947 FSWs initially seen in clinic, 692 were HIV tested. HIV prevalence was 49%. Among those returning to clinic after HIV testing and clinical screening, 93% of the women who were HIV-negative were confirmed as clinically eligible for PrEP (n = 224/241), and 41% (n = 110/270) of the women who were HIV-positive had CD4 counts within National Department of Health ART initiation guidelines at assessment. Of the remaining women who were HIV-positive, 93% were eligible for early ART (n = 148/160). From those eligible, 98% (n = 219/224) and 94% (n = 139/148) took up PrEP and early ART, respectively. At baseline, a substantial fraction of women had a steady partner, worked in brothels, and were born in Zimbabwe. Of those enrolled, 22% on PrEP (n = 49/219) and 60% on early ART (n = 83/139) were seen at 12 months; we observed high rates of loss to follow-up: 71% (n = 156/219) and 30% (n = 42/139) in the PrEP and early ART groups, respectively. Little change over time was reported in consistent condom use or the number of sexual partners in the last 7 days, with high levels of consistent condom use with clients and low use with steady partners in both study groups. There were no seroconversions on PrEP and 7 virological failures on early ART among women remaining in the study. Reported adherence to PrEP varied over time between 70% and 85%, whereas over 90% of participants reported taking pills daily while on early ART. Data on provider-side costs were also collected and analysed. The total cost of service delivery was approximately US$126 for PrEP and US$406 for early ART per person-year. The main limitations of this study include the lack of a control group, which was not included due to ethical considerations; clinical study requirements imposed when PrEP was not approved through the regulatory system, which could have affected uptake; and the timing of the implementation of a national sex worker HIV programme, which could have also affected uptake and retention. Conclusions PrEP and early ART services can be implemented within FSW routine services in high prevalence, urban settings. We observed good uptake for both PrEP and early ART; however, retention rates for PrEP were low. Retention rates for early ART were similar to retention rates for the current standard of care. While the cost of the interventions was higher than previously published, there is potential for cost reduction at scale. The TAPS Demonstration Project results provided the basis for the first government PrEP and early ART guidelines and the rollout of the national sex worker HIV programme in South Africa., In an observational study, Gabriela Gomez and colleagues report on provision of pre-exposure prophylaxis and antiretroviral treatment for female sex workers in South Africa., Author summary Why was this study done? Female sex workers are a vulnerable population at risk of HIV, and, in some areas of South Africa, nearly 3 out of 4 sex workers are already infected. Pre-exposure prophylaxis (PrEP) and early antiretroviral treatment (ART) are interventions being piloted by national programmes to test whether (and how) they can be successfully delivered in clinics and the public sector. We conducted a study in existing sex-worker-specific clinics to see if female sex workers would take up and use PrEP and early ART if these interventions were offered. We partnered with the South African government to align and incorporate our results into national HIV programming. What did the researchers do and find? We offered PrEP to HIV-negative female sex workers and early ART to HIV-positive female sex workers in 2 clinics located in Johannesburg and Pretoria in South Africa. Over time, we assessed how many women were contacted for the intervention, how many came to the clinic for HIV testing, how many were HIV-negative and -positive, and how many took up the interventions. We then monitored those who participated for at least 12 months to see whether they stayed in the programme and used PrEP or early ART. We found an HIV prevalence of 49% among the 692 women tested. Among those returning to clinic after HIV testing and clinical screening, 93% were confirmed eligible for PrEP, and 94% for early ART. From those eligible, 98% and 94% took up PrEP and early ART, respectively. At the end of the 12-month assessment, 22% remained on PrEP, while 60% remained on early ART, at our clinic sites. It is possible that some women moved to other sites without our knowledge, as other sites started offering PrEP and early ART. The drugs were safe to use with few side effects. We also found that women who stayed in the study reported taking their pills regularly. None of the women who remained in the study in the PrEP group got HIV, and very few women taking early ART had issues supressing the virus. The overall cost of the programme came to approximately US$126 for PrEP and $406 for early ART per person-year. What do these findings mean? These findings suggest that female sex workers may be interested in both PrEP and early ART and that the interventions work well when taken, but longer term commitment may be a challenge. These interventions have already been introduced by the South African government into sex worker programmes, including those for male, female, and transgender people.

Background Type 2 diabetes (T2D) is a heterogeneous disease for which (1) disease-causing pathways are incompletely understood and (2) subclassification may improve patient management. Unlike other biomarkers, germline genetic markers do not change with disease progression or treatment. In this paper, we test whether a germline genetic approach informed by physiology can be used to deconstruct T2D heterogeneity. First, we aimed to categorize genetic loci into groups representing likely disease mechanistic pathways. Second, we asked whether the novel clusters of genetic loci we identified have any broad clinical consequence, as assessed in four separate subsets of individuals with T2D. Methods and findings In an effort to identify mechanistic pathways driven by established T2D genetic loci, we applied Bayesian nonnegative matrix factorization (bNMF) clustering to genome-wide association study (GWAS) results for 94 independent T2D genetic variants and 47 diabetes-related traits. We identified five robust clusters of T2D loci and traits, each with distinct tissue-specific enhancer enrichment based on analysis of epigenomic data from 28 cell types. Two clusters contained variant-trait associations indicative of reduced beta cell function, differing from each other by high versus low proinsulin levels. The three other clusters displayed features of insulin resistance: obesity mediated (high body mass index [BMI] and waist circumference [WC]), “lipodystrophy-like” fat distribution (low BMI, adiponectin, and high-density lipoprotein [HDL] cholesterol, and high triglycerides), and disrupted liver lipid metabolism (low triglycerides). Increased cluster genetic risk scores were associated with distinct clinical outcomes, including increased blood pressure, coronary artery disease (CAD), and stroke. We evaluated the potential for clinical impact of these clusters in four studies containing individuals with T2D (Metabolic Syndrome in Men Study [METSIM], N = 487; Ashkenazi, N = 509; Partners Biobank, N = 2,065; UK Biobank [UKBB], N = 14,813). Individuals with T2D in the top genetic risk score decile for each cluster reproducibly exhibited the predicted cluster-associated phenotypes, with approximately 30% of all individuals assigned to just one cluster top decile. Limitations of this study include that the genetic variants used in the cluster analysis were restricted to those associated with T2D in populations of European ancestry. Conclusion Our approach identifies salient T2D genetically anchored and physiologically informed pathways, and supports the use of genetics to deconstruct T2D heterogeneity. Classification of patients by these genetic pathways may offer a step toward genetically informed T2D patient management., Using a clustering Bayesian approach applied to GWAS, Jose Florez and colleagues identify traits and loci associated with type 2 diabetes that may be used to classify patients., Author summary Why was this study done? Clinical experience and physiological phenotyping suggest that type 2 diabetes (T2D) is a heterogeneous disease. Recent studies leveraged phenotypic data to identify subtypes of individuals with T2D but have not included genetic data as a driving component of the clustering process. Previous efforts to cluster T2D genetic loci used unsupervised hierarchical clustering, a “hard clustering” method that restricts the membership of a given genetic locus to a single cluster. What did the researchers do and find? We applied a novel “soft clustering” method termed Bayesian nonnegative matrix factorization to cluster variant-trait associations ascertained from publicly available genome-wide association studies for 94 known T2D variants and 47 diabetes-related traits. We identified five novel robust clusters of T2D loci, two related to insulin deficiency and three related to insulin resistance, and showed that these clusters are differentially enriched for relevant tissue-specific enhancers and promoters. In up to 17,365 individuals with T2D from four distinct studies, about 30% of individuals have a genetic risk score in the top decile of uniquely one cluster, and these individuals have cluster-specific phenotypic traits that distinguish them from others with T2D. What do these findings mean? Soft clustering of genetic loci associated with T2D produced biologically supported mechanistic pathways, illuminating how loci might impact T2D risk. Classification of individuals by these genetic pathways may offer a step toward genetically anchored but physiologically informed diagnosis, surveillance, and management of patients with T2D.

Background Empirical studies and population-level policy simulations show the importance of voluntary medical male circumcision (VMMC) in generalized epidemics. This paper complements available scenario-based studies (projecting costs and outcomes over some policy period, typically spanning decades) by adopting an incremental approach—analyzing the expected consequences of circumcising one male individual with specific characteristics in a specific year. This approach yields more precise estimates of VMMC’s cost-effectiveness and identifies the outcomes of current investments in VMMC (e.g., within a fiscal budget period) rather than of investments spread over the entire policy period. Methods/Findings The model has three components. We adapted the ASSA2008 model, a demographic and epidemiological model of the HIV epidemic in South Africa, to analyze the impact of one VMMC on HIV incidence over time and across the population. A costing module tracked the costs of VMMC and the resulting financial savings owing to reduced HIV incidence over time. Then, we used several financial indicators to assess the cost-effectiveness of and financial return on investments in VMMC. One circumcision of a young man up to age 20 prevents on average over 0.2 HIV infections, but this effect declines steeply with age, e.g., to 0.08 by age 30. Net financial savings from one VMMC at age 20 are estimated at US$617 at a discount rate of 5% and are lower for circumcisions both at younger ages (because the savings occur later and are discounted more) and at older ages (because male circumcision becomes less effective). Investments in male circumcision carry a financial rate of return of up to 14.5% (for circumcisions at age 20). The cost of a male circumcision is refinanced fastest, after 13 y, for circumcisions at ages 20 to 25. Principal limitations of the analysis arise from the long time (decades) over which the effects of VMMC unfold—the results are therefore sensitive to the discount rate applied, and more generally to the future course of the epidemic and of HIV/AIDS-related policies pursued by the government. Conclusions VMMC in South Africa is highly effective in reducing both HIV incidence and the financial costs of the HIV response. The return on investment is highest if males are circumcised between ages 20 and 25, but this return on investment declines steeply with age., Medical male circumcision reduces incidences of HIV. Gorgens and colleagues present a new model that identifies the best age for this treatment, in terms of cost efficiencies and disease incidence., Editors' Summary Background Every year, about 2 million people become infected with HIV, the virus that causes AIDS. Although antiretroviral therapy can keep HIV in check, there is no cure for AIDS. Consequently, prevention of HIV transmission is an important component of efforts to control the AIDS epidemic. Because HIV is most often spread through unprotected sex with an infected partner, individuals can reduce their risk of becoming infected by abstaining from sex, by having only one or a few sexual partners, and by using male or female condoms. In addition, three trials undertaken in sub-Saharan Africa a decade ago showed that male circumcision—the surgical removal of the foreskin, a loose fold of skin that covers the head of the penis—can halve the sexual transmission of HIV from HIV-positive women to HIV-negative men. In 2007, the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommended that individuals living in countries with generalized HIV epidemics (countries where more than 1% of the general population is HIV positive) should be offered voluntary medical male circumcision (VMMC) to help prevent HIV transmission. Why Was This Study Done? In 2011, following several studies that assessed the population-level effectiveness and cost-effectiveness of VMMC scale-up, WHO/UNAIDS set a target of having at least 80% of all men aged 15–49 circumcised in 14 priority countries in Africa by 2015. Good progress towards this target was made, but VMMC scale-up needs further improvement. Scenario-based studies provide estimates of the overall costs and impacts of VMMC policies over the whole policy period, which can span several decades, but policy makers sometimes need to know the returns on investments in VMMC over the current financial year. Here, the researchers use an “incremental” cost-effectiveness approach (one that analyzes the expected consequences of circumcising one male with specific characteristics in a specific year) to provide estimates of the impacts of current VMMC investments and to obtain more precise estimates of VMMC’s cost-effectiveness for HIV prevention in South Africa, a country with a generalized HIV epidemic. What Did the Researchers Do and Find? The researchers developed a mathematical model consisting of three elements: a demographic and epidemiological model of the South African HIV epidemic adapted to analyze the impact of one VMMC on HIV incidence over time and across the population; a module to track the costs of VMMC and financial savings from HIV infections averted by VMMC; and several financial indicators to assess the cost-effectiveness of and financial return on investments in VMMC. Using this model, the researchers estimate that the circumcision of a young man up to age 20 prevents, on average, 0.2 HIV infections, and that the number of infections averted by VMMC declines steeply with age at circumcision. Estimated financial savings from one VMMC at age 20 are US$617 at a discount rate of 5% (discounting translates future costs and benefits into present-day values); VMMC at younger and older ages results in lower financial savings. From a purely financial perspective, circumcisions at age 20 are most effective with a financial return of 14.5% (they are equivalent to a financial investment yielding an interest of 14.5% annually). Finally, the costs of a circumcision are refinanced (covered by reductions in the costs associated with HIV infection) fastest for circumcisions at ages 20–25. What Do These Findings Mean? Because the effects of VMMC unfold over many decades, the accuracy of these findings is likely to be affected by the future course of the AIDS epidemic, by HIV/AIDS policies adopted by the South African government, and by the discount rate applied in the cost-effectiveness analysis. Moreover, some of the assumptions made by the researchers in their model may affect the accuracy of their findings. Overall, however, these findings, which provide estimates of the consequences of current VMMC policies, suggest that VMMC in South Africa (and possibly in settings where a lower proportion of the population is HIV positive) is a highly effective HIV prevention intervention that is cost-saving under many circumstances. These findings also indicate how age at circumcision affects the impacts of circumcision. Specifically, they suggest that the return on investment is highest if males are circumcised between ages 20 and 25 but declines steeply with increasing age. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1002012. 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, summaries of recent research findings on HIV care and treatment, information on male circumcision for the prevention of HIV transmission, and personal stories about living with HIV/AIDS Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on how HIV is transmitted, on voluntary medical male circumcision for HIV prevention, and on HIV/AIDS in sub-Saharan Africa; Avert also provides personal stories about living with HIV/AIDS The World Health Organization provides information on all aspects of HIV/AIDS (in several languages), including information on voluntary medical male circumcision for HIV prevention UNAIDS provides up-to-information about the AIDS epidemic and detailed information about HIV/AIDS in South Africa The Clearinghouse on Male Circumcision for HIV Prevention provides up-to-date information and resources on male circumcision for HIV prevention

Background Reductions in smoking in Arizona and California have been shown to be associated with reduced per capita healthcare expenditures in these states compared to control populations in the rest of the US. This paper extends that analysis to all states and estimates changes in healthcare expenditure attributable to changes in aggregate measures of smoking behavior in all states. Methods and Findings State per capita healthcare expenditure is modeled as a function of current smoking prevalence, mean cigarette consumption per smoker, other demographic and economic factors, and cross-sectional time trends using a fixed effects panel data regression on annual time series data for each the 50 states and the District of Columbia for the years 1992 through 2009. We found that 1% relative reductions in current smoking prevalence and mean packs smoked per current smoker are associated with 0.118% (standard error [SE] 0.0259%, p < 0.001) and 0.108% (SE 0.0253%, p < 0.001) reductions in per capita healthcare expenditure (elasticities). The results of this study are subject to the limitations of analysis of aggregate observational data, particularly that a study of this nature that uses aggregate data and a relatively small sample size cannot, by itself, establish a causal connection between smoking behavior and healthcare costs. Historical regional variations in smoking behavior (including those due to the effects of state tobacco control programs, smoking restrictions, and differences in taxation) are associated with substantial differences in per capita healthcare expenditures across the United States. Those regions (and the states in them) that have lower smoking have substantially lower medical costs. Likewise, those that have higher smoking have higher medical costs. Sensitivity analysis confirmed that these results are robust. Conclusions Changes in healthcare expenditure appear quickly after changes in smoking behavior. A 10% relative drop in smoking in every state is predicted to be followed by an expected $63 billion reduction (in 2012 US dollars) in healthcare expenditure the next year. State and national policies that reduce smoking should be part of short term healthcare cost containment., James Lightwood and Stanton Glantz report on a modeling study in which health spending across US States during 1992–2009 was studied as a function of smoking prevalence, indicating that reduced smoking could yield substantial early benefits in healthcare expenditure as well as long-term improvements in health., Author Summary Why Was This Study Done? There have been many estimates of the medical costs of smoking at both the national and state levels, but these estimates do not capture the changes in health care expenditure over time that are associated with changes in smoking behavior and the effects of tobacco control programs. Estimates from California and Arizona have shown that medical savings accrue quickly as the prevalence and intensity of smoking decreases, when adjusted for the history of smoking reduction and tobacco control program activity in the United States. What Did the Researchers Do and Find? This study examined the year-to-year relationship between changes in smoking and changes in medical costs for the entire United States, taking into account differences between different states and historical national trends in smoking behavior and healthcare expenditures. The study found that 1% relative reductions in current smoking prevalence and mean packs smoked per current smoker are associated with 0.118% and 0.108% reductions, respectively, in per capita healthcare expenditure (elasticities). Historical regional variations in smoking behavior (including those due to the effects of state tobacco control programs, smoking restrictions, and differences in cigarette taxation rates) are associated with substantial differences in per capita healthcare expenditures across the United States. A 10% relative drop in smoking in every state is predicted to be followed by a $63 billion reduction (in 2012 US dollars) in healthcare expenditure the next year. What Do These Findings Mean? Changes in healthcare costs appear quickly after changes in smoking behavior. State and national policies that reduce smoking should be part of short term healthcare cost containment.

Background Homicide of children is a global problem. The under-5-y age group is the second largest homicide age group after 15–19 y olds, but has received little research attention. Understanding age and gender patterns is important for assisting with developing prevention interventions. Here we present an age and gender analysis of homicides among children under 5 y in South Africa from a national study that included a focus on neonaticide and infanticide. Methods and Findings A retrospective national cross-sectional study was conducted using a random sample of 38 medico-legal laboratories operating in 2009 to identify homicides of children under 5 y. Child data were abstracted from the mortuary files and autopsy reports, and both child and perpetrator data data were collected from police interviews. We erred towards applying a conservative definition of homicide and excluded sudden infant death syndrome cases. We estimated that 454 (95% CI 366, 541) children under the age of 5 y were killed in South Africa in 2009. More than half (53.2%; 95% CI 46.7%, 59.5%) were neonates (0–28 d), and 74.4% (95% CI 69.3%, 78.9%) were infants (under 1 y), giving a neonaticide rate of 19.6 per 100,000 live births and an infanticide rate of 28.4 per 100,000 live births. The majority of the neonates died in the early neonatal period (0–6 d), and abandonment accounted for 84.9% (95% CI 81.5%, 87.8%) of all the neonates killed. Distinct age and gender patterns were found, with significantly fewer boy children killed in rural settings compared to urban settings (odds ratio 0.6; 95% CI 0.4, 0.9; p = 0.015). Abuse-related killings and evidence of sexual assault were more common among older girls than in all other age and gender groups. Mothers were identified as the perpetrators in all of the neonaticides and were the most common perpetrators overall (71.0%; 95% CI 63.9%, 77.2%). Abandoned neonates were mainly term babies, with a mean gestational age of 38 wk. We did not have information on abandonment motives for all newborns and did not know if babies were abandoned with the intention that they would die or with the hope that they would be found alive. We therefore considered all abandoned babies as homicides. Conclusions Homicide of children is an extreme form or consequence of violence against children. This national study provides one of the first analyses of neonaticide and infanticide by age and gender and shows the failure of reproductive and mental health and social services to identify and help vulnerable mothers. Multi-sectoral prevention strategies are needed., Jewkes and colleagues present a cross-sectional study that reveals levels of child homicide in South Africa. Identifying causes and vulnerable mothers will lead to prevention methods and strategies., Editors' Summary Background Child mortality (death) is a global public health concern. In 2015, 5.9 million children (43 out of every 1,000 children born alive) died before their fifth birthday. Nearly half of these deaths occurred among neonates (babies 28 days old or younger); three-quarters of them occurred among infants (children less than one year old). Most of these deaths happened in resource-limited countries following delivery complications, infections, and other natural causes. Some, however, were homicides. Infanticide (the killing of a child under one year old) and neonaticide (the killing of a newborn within 24 hours or 28 days of birth, depending on the definition used) can be active (deliberate killing by, for example, suffocation) or passive (killing through nutritional, physical, or emotional neglect). Many infanticides and neonaticides are the result of abandonment—the mother leaves her infant or newborn in a place without care or protection, either with the intention of killing the child or with the hope that someone will find and care for him/her. Unwanted pregnancies are the most common cause of infanticide and neonaticide, but some infants are also killed because they are disabled or of the wrong gender—in some cultures male children are considered more socially valuable than female children. Why Was This Study Done? To develop interventions to prevent child homicide, we need to understand when, where, and why these deaths occur. However, little research has been done on neonaticide and infanticide, particularly in resource-limited settings, because these deaths are often poorly identified and reported. In Africa, for example, although quantitative (numerical) research on child homicide is rare, Dar es Salaam, Tanzania, has one of the highest reported rates of neonaticide (27.7 homicides within 24 hours of birth per 100,000 live births); by comparison, a review of studies undertaken in the US, UK, and New Zealand reported incidences of infanticide and neonaticide ranging between 2.1 and 6.9 per 100,000 live births. Here, the researchers use data collected in a national cross-sectional mortuary-based study of child homicides committed in 2009 to investigate patterns among homicides of neonates, infants, and children under five years old in South Africa. What Did the Researchers Do and Find? The researchers chose a random sample of 38 medico-legal laboratories (mortuaries where postmortem examinations were performed on all unnatural deaths) across South Africa. They used data extracted from mortuary files, autopsy reports, and police interviews to identify homicides of children under five years old. The researchers estimated that 454 children under five years old were killed in South Africa in 2009. More than half of the children who died were neonates, and nearly three-quarters were infants, giving a neonaticide rate (defined in this study as homicide within the first 28 days of life) of 19 per 100,000 live births and an infanticide rate of 28 per 100,000 live births. Most of the neonates died in the early neonatal period—only eight out of 241 neonates were more than six days old when they died. Abandonment accounted for 84.9% of neonaticides, and abandoned neonates were mainly term babies. Overall, there was no gender bias among child homicides, but 56% of homicides of boys took place in an urban setting, compared to 44% of homicides of girls. Finally, young mothers were the most common perpetrators of child homicide. What Do These Findings Mean? These findings show that, in 2009, the rates of infanticide and neonaticide in South Africa were much higher than the rates previously reported for the US, UK, and New Zealand. The rates reported here are likely to be underestimates because it is often difficult to distinguish infanticide from other causes of death during infancy. Another important limitation of this study is the lack of data on the motive for abandonment of newborns. Importantly, however, these findings suggest that a child born in South Africa is at the highest risk of being killed during its first six days of life. This may mean that mothers who abandon their babies simply do not want a child, and suggests that reproductive, mental health, and social services are failing to identify and help vulnerable mothers in South Africa. The researchers suggest, therefore, that multi-sectoral prevention strategies are needed to reduce child homicides in South Africa. A pilot child death review system that has been initiated in South Africa to identify and describe patterns and causes of child death could assist in the development of such prevention strategies. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1002003. This study is further discussed in a PLOS Medicine Perspective by Delan Devakumar and David Osrin The World Health Organization (WHO) provides information on child health and child mortality and global efforts to reduce child mortality and a factsheet on child maltreatment (available in several languages); a previous paper by the researchers on child homicide is available on the WHO website The United Nations Children’s Fund (UNICEF) works for children’s rights, survival, development, and protection around the world; its UNICEF Data website provides detailed statistics about child health and mortality; its 2014 report Children in Danger: Act to End Violence against Children provides detailed information about violence against children; Hidden in Plain Sight is a 2014 UNICEF statistical analysis of violence against children The international non-governmental organization Humanium, which works to stop violations of children’s rights worldwide, has an article on infanticide (in several languages) Child Trends is a US not-for-profit organization that aims to improve the lives and prospects of children and youth in the US by conducting research; it provides up-to-date information about infanticide in the US Information on the South African pilot child death review system is available; a guide on the child death review system in the UK for parents and carers is available

At the moment, there are many collections of human biological samples stored for medical—scientific research purposes that include samples from children [1]. These pediatric biobanks facilitate research, which is considered important for improving (pediatric) health care by generating biomedical knowledge [2,3]. However, pediatric biobank research gives rise to specific ethical issues. At the time of inclusion, many children cannot, or are legally not allowed to, consent for themselves, and typically parental permission is required. Samples may still be stored and used by biobanks when children become autonomous adults. The question arises whether children should be re-contacted to obtain their own consent, or give the opportunity to withdraw their samples, when they reach adulthood. Often, this is referred to as re-consent [4–6]. This term, however, is a misnomer, since the child has not consented in the first place. We therefore use the terms re-contact and consent. In practice, biobanks have adopted different approaches to re-contact and consent. A study on six birth cohort studies found that only the cohorts that follow children into adolescence or past childhood recognize a need to seek consent as the child matures [7], or biobanks attribute a role to parents/guardians to inform their child about the tissue that has been stored and used for research [8]. Furthermore, our international case study on consent procedures in pediatric biobanking [9] shows that regulation plays a key role when pediatric biobanks design their consent procedures. However, major guidelines do not provide sufficient guidance on re-contact and consent [10–12], and there is only very limited literature that analyses the issue in depth [4–6,13]. Given the fact that biobanks already include pediatric samples, and in light of the rapid developments in biobank research, it is important to address the issue of re-contact and consent now. In this paper, we discuss the arguments in favor and against re-contacting participants at maturity and examine different re-contact policies that can be considered.

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.

Resistance to first-line treatments for Plasmodium falciparum malaria and the insecticides used for Anopheles vector control are threatening malaria elimination efforts. Suboptimal responses to drugs and insecticides are both spreading geographically and emerging independently and are being seen at increasing intensities. Whilst resistance is unavoidable, its effects can be mitigated through resistance management practices, such as exposing the parasite or vector to more than one selective agent. Resistance contributed to the failure of the 20th century Global Malaria Eradication Programme, and yet the global response to this issue continues to be slow and poorly coordinated—too often, too little, too late. The Malaria Eradication Research Agenda (malERA) Refresh process convened a panel on resistance of both insecticides and antimalarial drugs. This paper outlines developments in the field over the past 5 years, highlights gaps in knowledge, and proposes a research agenda focused on managing resistance. A deeper understanding of the complex biological processes involved and how resistance is selected is needed, together with evidence of its public health impact. Resistance management will require improved use of entomological and parasitological data in decision making, and optimisation of the useful life of new and existing products through careful implementation, combination, and evaluation. A proactive, collaborative approach is needed from basic science and the development of new tools to programme and policy interventions that will ensure that the armamentarium of drugs and insecticides is sufficient to deal with the challenges of malaria control and its elimination., Janet Hemingway and colleagues examine progress in research on insecticide and drug resistance in malaria elimination and eradication and propose a research agenda.

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.

Since the turn of the century, a remarkable expansion has been achieved in the range and effectiveness of products and strategies available to prevent, treat, and control malaria, including advances in diagnostics, drugs, vaccines, and vector control. These advances have once again put malaria elimination on the agenda. However, it is clear that even with the means available today, malaria control and elimination pose a formidable challenge in many settings. Thus, currently available resources must be used more effectively, and new products and approaches likely to achieve these goals must be developed. This paper considers tools (both those available and others that may be required) to achieve and maintain malaria elimination. New diagnostics are needed to direct treatment and detect transmission potential; new drugs and vaccines to overcome existing resistance and protect against clinical and severe disease, as well as block transmission and prevent relapses; and new vector control measures to overcome insecticide resistance and more powerfully interrupt transmission. It is also essential that strategies for combining new and existing approaches are developed for different settings to maximise their longevity and effectiveness in areas with continuing transmission and receptivity. For areas where local elimination has been recently achieved, understanding which measures are needed to maintain elimination is necessary to prevent rebound and the reestablishment of transmission. This becomes increasingly important as more countries move towards elimination., David Kaslow and colleagues examine the progress in reasearch for diagnostics, drugs, vaccines, and vector control in malaria elimination and eradication and propose a research agenda.