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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.

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 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 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 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 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.

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 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.

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.