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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: In 2015, approximately 42,000 women died as a result of hypertensive disorders of pregnancy worldwide; over 99% of these deaths occurred in low- and middle-income countries. The aim of this paper is to describe the incidence and characteristics of eclampsia and related complications from hypertensive disorders of pregnancy across 10 low- and middle-income geographical regions in 8 countries, in relation to magnesium sulfate availability.Methods and Findings: This is a secondary analysis of a stepped-wedge cluster randomised controlled trial undertaken in sub-Saharan Africa, India, and Haiti. This trial implemented a novel vital sign device and training package in routine maternity care with the aim of reducing a composite outcome of maternal mortality and morbidity. Institutional-level consent was obtained, and all women presenting for maternity care were eligible for inclusion. Data on eclampsia, stroke, admission to intensive care with a hypertensive disorder of pregnancy, and maternal death from a hypertensive disorder of pregnancy were prospectively collected from routine data sources and active case finding, together with data on perinatal outcomes in women with these outcomes. In 536,233 deliveries between 1 April 2016 and 30 November 2017, there were 2,692 women with eclampsia (0.5%). In total 6.9% (n = 186; 3.47/10,000 deliveries) of women with eclampsia died, and a further 51 died from other complications of hypertensive disorders of pregnancy (0.95/10,000). After planned adjustments, the implementation of the CRADLE intervention was not associated with any significant change in the rates of eclampsia, stroke, or maternal death or intensive care admission with a hypertensive disorder of pregnancy. Nearly 1 in 5 (17.9%) women with eclampsia, stroke, or a hypertensive disorder of pregnancy causing intensive care admission or maternal death experienced a stillbirth or neonatal death. A third of eclampsia cases (33.2%; n = 894) occurred in women under 20 years of age, 60.0% in women aged 20-34 years (n = 1,616), and 6.8% (n = 182) in women aged 35 years or over. Rates of eclampsia varied approximately 7-fold between sites (range 19.6/10,000 in Zambia Centre 1 to 142.0/10,000 in Sierra Leone). Over half (55.1%) of first eclamptic fits occurred in a health-care facility, with the remainder in the community. Place of first fit varied substantially between sites (from 5.9% in the central referral facility in Sierra Leone to 85% in Uganda Centre 2). On average, magnesium sulfate was available in 74.7% of facilities (range 25% in Haiti to 100% in Sierra Leone and Zimbabwe). There was no detectable association between magnesium sulfate availability and the rate of eclampsia across sites (p = 0.12). This analysis may have been influenced by the selection of predominantly urban and peri-urban settings, and by collection of only monthly data on availability of magnesium sulfate, and is limited by the lack of demographic data in the population of women delivering in the trial areas.Conclusions: The large variation in eclampsia and maternal and neonatal fatality from hypertensive disorders of pregnancy between countries emphasises that inequality and inequity persist in healthcare for women with hypertensive disorders of pregnancy. Alongside the growing interest in improving community detection and health education for these disorders, efforts to improve quality of care within healthcare facilities are key. Strategies to prevent eclampsia should be informed by local data.Trial Registration: ISRCTN: 41244132. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Reducing sitting time as well as increasing physical activity in inactive people is beneficial for their health. This paper investigates the effectiveness of the European Fans in Training (EuroFIT) programme to improve physical activity and sedentary time in male football fans, delivered through the professional football setting.Methods and Findings: A total of 1,113 men aged 30-65 with self-reported body mass index (BMI) ≥27 kg/m2 took part in a randomised controlled trial in 15 professional football clubs in England, the Netherlands, Norway, and Portugal. Recruitment was between September 19, 2015, and February 2, 2016. Participants consented to study procedures and provided usable activity monitor baseline data. They were randomised, stratified by club, to either the EuroFIT intervention or a 12-month waiting list comparison group. Follow-up measurement was post-programme and 12 months after baseline. EuroFIT is a 12-week, group-based programme delivered by coaches in football club stadia in 12 weekly 90-minute sessions. Weekly sessions aimed to improve physical activity, sedentary time, and diet and maintain changes long term. A pocket-worn device (SitFIT) allowed self-monitoring of sedentary time and daily steps, and a game-based app (MatchFIT) encouraged between-session social support. Primary outcome (objectively measured sedentary time and physical activity) measurements were obtained for 83% and 85% of intervention and comparison participants. Intention-to-treat analyses showed a baseline-adjusted mean difference in sedentary time at 12 months of -1.6 minutes/day (97.5% confidence interval [CI], -14.3-11.0; p = 0.77) and in step counts of 678 steps/day (97.5% CI, 309-1.048; p < 0.001) in favor of the intervention. There were significant improvements in diet, weight, well-being, self-esteem, vitality, and biomarkers of cardiometabolic health in favor of the intervention group, but not in quality of life. There was a 0.95 probability of EuroFIT being cost-effective compared with the comparison group if society is willing to pay £1.50 per extra step/day, a maximum probability of 0.61 if society is willing to pay £1,800 per minute less sedentary time/day, and 0.13 probability if society is willing to pay £30,000 per quality-adjusted life-year (QALY). It was not possible to blind participants to group allocation. Men attracted to the programme already had quite high levels of physical activity at baseline (8,372 steps/day), which may have limited room for improvement. Although participants came from across the socioeconomic spectrum, a majority were well educated and in paid work. There was an increase in recent injuries and in upper and lower joint pain scores post-programme. In addition, although the five-level EuroQoL questionnaire (EQ-5D-5L) is now the preferred measure for cost-effectiveness analyses across Europe, baseline scores were high (0.93), suggesting a ceiling effect for QALYs.Conclusion: Participation in EuroFIT led to improvements in physical activity, diet, body weight, and biomarkers of cardiometabolic health, but not in sedentary time at 12 months. Within-trial analysis suggests it is not cost-effective in the short term for QALYs due to a ceiling effect in quality of life. Nevertheless, decision-makers may consider the incremental cost for increase in steps worth the investment.Trial Registration: International Standard Randomised Controlled Trials, ISRCTN-81935608. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Understanding the past-year prevalence of male-perpetrated intimate partner violence (IPV) and risk factors is essential for building evidence-based prevention and monitoring progress to Sustainable Development Goal (SDG) 5.2, but so far, population-based research on this remains very limited. The objective of this study is to compare the population prevalence rates of past-year male-perpetrated IPV and nonpartner rape from women's and men's reports across 4 countries in Asia and the Pacific. A further objective is to describe the risk factors associated with women's experience of past-year physical or sexual IPV from women's reports and factors driving women's past-year experience of partner violence.Methods and Findings: This paper presents findings from the United Nations Multi-country Study on Men and Violence in Asia and the Pacific. In the course of this study, in population-based cross-sectional surveys, 5,206 men and 3,106 women aged 18-49 years were interviewed from 4 countries: Cambodia, China, Papua New Guinea (PNG), and Sri Lanka. To measure risk factors, we use logistic regression and structural equation modelling to show pathways and mediators. The analysis was not based on a written plan, and following a reviewer's comments, some material was moved to supplementary files and the regression was performed without variable elimination. Men reported more lifetime perpetration of IPV (physical or sexual IPV range 32.5%-80%) than women did experience (physical or sexual IPV range 27.5%-67.4%), but women's reports of past-year experience (physical or sexual IPV range 8.2%-32.1%) were not very clearly different from men's (physical or sexual IPV range 10.1%-34.0%). Women reported much more emotional/economic abuse (past-year ranges 1.4%-5.7% for men and 4.1%-27.7% for women). Reports of nonpartner rape were similar for men (range 0.8%-1.9% in the past year) and women (range 0.4%-2.3% in past year), except in Bougainville, where they were higher for men (11.7% versus 5.7%). The risk factor modelling shows 4 groups of variables to be important in experience of past-year sexual and/or physical IPV: (1) poverty, (2) all childhood trauma, (3) quarrelling and women's limited control in relationships, and (4) partner factors (substance abuse, unemployment, and infidelity). The population attributable fraction (PAF) was largest for quarrelling often, but the second greatest PAF was for the group related to exposure to violence in childhood. The relationship control variable group had the third highest PAF, followed by other partner factors. Currently married women were also more at risk. In the structural model, a resilience pathway showed less poverty, higher education, and more gender-equitable ideas were connected and conveyed protection from IPV. These are all amenable risk factors. This research was cross-sectional, so we cannot be sure of the temporal sequence of exposure, but the outcome being a past-year measure to some extent mitigates this problem.Conclusions: Past-year IPV indicators based on women's reported experience that were developed to track SDG 5 are probably reasonably reliable but will not always give the same prevalence as may be reported by men. Report validity requires further research. Interviews with men to track past-year nonpartner rape perpetration are feasible and important. The findings suggest a range of factors are associated with past-year physical and/or sexual IPV exposure; of particular interest is the resilience pathway suggested by the structural model, which is highly amenable to intervention and explains why combining economic empowerment of women and gender empowerment/relationship skills training has been successful. This study provides additional rationale for scaling up violence prevention interventions that combine economic and gender empowerment/relationship skills building of women, as well as the value of investing in girls' education with a view to long-term violence reduction. [ABSTRACT FROM AUTHOR]

Background: India has 23% of the global burden of active tuberculosis (TB) patients and 27% of the world's "missing" patients, which includes those who may not have received effective TB care and could potentially spread TB to others. The "cascade of care" is a useful model for visualizing deficiencies in case detection and retention in care, in order to prioritize interventions.Methods and Findings: The care cascade constructed in this paper focuses on the Revised National TB Control Programme (RNTCP), which treats about half of India's TB patients. We define the TB cascade as including the following patient populations: total prevalent active TB patients in India, TB patients who reach and undergo evaluation at RNTCP diagnostic facilities, patients successfully diagnosed with TB, patients who start treatment, patients retained to treatment completion, and patients who achieve 1-y recurrence-free survival. We estimate each step of the cascade for 2013 using data from two World Health Organization (WHO) reports (2014-2015), one WHO dataset (2015), and three RNTCP reports (2014-2016). In addition, we conduct three targeted systematic reviews of the scientific literature to identify 39 unique articles published from 2000-2015 that provide additional data on five indicators that help estimate different steps of the TB cascade. We construct separate care cascades for the overall population of patients with active TB and for patients with specific forms of TB-including new smear-positive, new smear-negative, retreatment smear-positive, and multidrug-resistant (MDR) TB. The WHO estimated that there were 2,700,000 (95%CI: 1,800,000-3,800,000) prevalent TB patients in India in 2013. Of these patients, we estimate that 1,938,027 (72%) TB patients were evaluated at RNTCP facilities; 1,629,906 (60%) were successfully diagnosed; 1,417,838 (53%) got registered for treatment; 1,221,764 (45%) completed treatment; and 1,049,237 (95%CI: 1,008,775-1,083,243), or 39%, of 2,700,000 TB patients achieved the optimal outcome of 1-y recurrence-free survival. The separate cascades for different forms of TB highlight different patterns of patient attrition. Pretreatment loss to follow-up of diagnosed patients and post-treatment TB recurrence were major points of attrition in the new smear-positive TB cascade. In the new smear-negative and MDR TB cascades, a substantial proportion of patients who were evaluated at RNTCP diagnostic facilities were not successfully diagnosed. Retreatment smear-positive and MDR TB patients had poorer treatment outcomes than the general TB population. Limitations of our analysis include the lack of available data on the cascade of care in the private sector and substantial uncertainty regarding the 1-y period prevalence of TB in India.Conclusions: Increasing case detection is critical to improving outcomes in India's TB cascade of care, especially for smear-negative and MDR TB patients. For new smear-positive patients, pretreatment loss to follow-up and post-treatment TB recurrence are considerable points of attrition that may contribute to ongoing TB transmission. Future multisite studies providing more accurate information on key steps in the public sector TB cascade and extension of this analysis to private sector patients may help to better target interventions and resources for TB control in India. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: We performed a systematic review to assess whether we can quantify the underreporting of adverse events (AEs) in the published medical literature documenting the results of clinical trials as compared with other nonpublished sources, and whether we can measure the impact this underreporting has on systematic reviews of adverse events.Methods and Findings: Studies were identified from 15 databases (including MEDLINE and Embase) and by handsearching, reference checking, internet searches, and contacting experts. The last database searches were conducted in July 2016. There were 28 methodological evaluations that met the inclusion criteria. Of these, 9 studies compared the proportion of trials reporting adverse events by publication status. The median percentage of published documents with adverse events information was 46% compared to 95% in the corresponding unpublished documents. There was a similar pattern with unmatched studies, for which 43% of published studies contained adverse events information compared to 83% of unpublished studies. A total of 11 studies compared the numbers of adverse events in matched published and unpublished documents. The percentage of adverse events that would have been missed had each analysis relied only on the published versions varied between 43% and 100%, with a median of 64%. Within these 11 studies, 24 comparisons of named adverse events such as death, suicide, or respiratory adverse events were undertaken. In 18 of the 24 comparisons, the number of named adverse events was higher in unpublished than published documents. Additionally, 2 other studies demonstrated that there are substantially more types of adverse events reported in matched unpublished than published documents. There were 20 meta-analyses that reported the odds ratios (ORs) and/or risk ratios (RRs) for adverse events with and without unpublished data. Inclusion of unpublished data increased the precision of the pooled estimates (narrower 95% confidence intervals) in 15 of the 20 pooled analyses, but did not markedly change the direction or statistical significance of the risk in most cases. The main limitations of this review are that the included case examples represent only a small number amongst thousands of meta-analyses of harms and that the included studies may suffer from publication bias, whereby substantial differences between published and unpublished data are more likely to be published.Conclusions: There is strong evidence that much of the information on adverse events remains unpublished and that the number and range of adverse events is higher in unpublished than in published versions of the same study. The inclusion of unpublished data can also reduce the imprecision of pooled effect estimates during meta-analysis of adverse events. [ABSTRACT FROM AUTHOR]

Background: Maternal morbidity is common in Bangladesh, where the maternal mortality rate has plateaued over the last 6 years. Maternal undernutrition and micronutrient deficiencies contribute to morbidity, but few interventions have measured maternal outcomes. We compared reported prevalence of antepartum, intrapartum, and postpartum complications among recently delivered women between maternal nutrition intervention and control areas in Bangladesh.Methods and Findings: We conducted a cross-sectional assessment nested within a population-based cluster-randomized trial comparing a nutrition counseling and micronutrient supplement intervention integrated within a structured home-based maternal, newborn, and child health (MNCH) program to the MNCH program alone in 10 sub-districts each across 4 Bangladesh districts. Eligible consenting women, delivering within 42-60 days of enrollment and identified by community-level health workers, completed an interviewer-administered questionnaire detailing the index pregnancy and delivery and allowed review of their home-based care register. We compared pooled and specific reported antepartum, intrapartum, and postpartum complications between study groups using hierarchical logistic regression. There were 594 women in the intervention group and 506 in the control group; overall, mean age was 24 years, 31% were primiparas, and 39% reported facility-based delivery, with no significant difference by study group. There were no significant differences between the intervention and control groups in household-level characteristics, including reported mean monthly income (intervention, 6,552 taka, versus control, 6,017 taka; p = 0.48), having electricity (69.6% versus 71.4%, p = 0.84), and television ownership (41.1% versus 38.7%, p = 0.81). Women in the intervention group had higher recorded iron and folic acid and calcium supplement consumption and mean dietary diversity scores, but reported anemia rates were similar between the 2 groups (5.7%, intervention; 6.5%, control; p = 0.83). Reported antepartum (69.4%, intervention; 79.2%, control; p = 0.12) and intrapartum (41.4%, intervention; 48.5%, control; p = 0.18) complication rates were high and not significantly different between groups. Reported postpartum complications were significantly lower among women in the intervention group than the control group (33.5% versus 48.2%, p = 0.02), and this difference persisted in adjusted analysis (adjusted odds ratio [AOR] = 0.51, 95% CI 0.32-0.82; p < 0.001). For specific conditions, odds of retained placenta (AOR = 0.35, 95% CI 0.19-0.67; p = 0.001), postpartum bleeding (AOR = 0.37, 95% CI 0.15-0.92; p = 0.033), and postpartum fever/infection (AOR = 0.27, 95% CI 0.11-0.65; p = 0.001) were significantly lower in the intervention group in adjusted analysis. There were no significant differences in reported hospitalization for antepartum (49.8% versus 45.1%, p = 0.37), intrapartum (69.9% versus 59.8%, p = 0.18), or postpartum (36.1% versus 29.9%, p = 0.49) complications between the intervention and control groups. The main limitations of this study are outcome measures based on participant report, non-probabilistic selection of community-level workers' catchment areas for sampling, some missing data for variables derived from secondary sources (e.g., dietary diversity score), and possible recall bias for reported dietary intake and supplement use.Conclusions: Reported overall postpartum and specific intrapartum and postpartum complications were significantly lower for women in intervention areas than control areas, despite similar rates of facility-based delivery and hospitalization for reported complications, in this exploratory analysis. Maternal nutrition interventions providing intensive counseling and micronutrient supplements may reduce some pregnancy complications or impact women's ability to accurately recognize complications, but more rigorous evaluation is needed for these outcomes. [ABSTRACT FROM AUTHOR]

Background: Excellent adherence to tuberculosis (TB) treatment is critical to cure TB and avoid the emergence of resistance. Wirelessly observed therapy (WOT) is a novel patient self-management system consisting of an edible ingestion sensor (IS), external wearable patch, and paired mobile device that can detect and digitally record medication ingestions. Our study determined the accuracy of ingestion detection in clinical and home settings using WOT and subsequently compared, in a randomized control trial (RCT), confirmed daily adherence to medication in persons using WOT or directly observed therapy (DOT) during TB treatment.Methods and Findings: We evaluated WOT in persons with active Mycobacterium tuberculosis complex disease using IS-enabled combination isoniazid 150 mg/rifampin 300 mg (IS-Rifamate). Seventy-seven participants with drug-susceptible TB in the continuation phase of treatment, prescribed daily isoniazid 300 mg and rifampin 600 mg, used IS-Rifamate. The primary endpoints of the trial were determination of the positive detection accuracy (PDA) of WOT, defined as the percentage of ingestions detected by WOT administered under direct observation, and subsequently the proportion of prescribed doses confirmed by WOT compared to DOT. Initially participants received DOT and WOT simultaneously for 2-3 weeks to allow calculation of WOT PDA, and the 95% confidence interval (CI) was estimated using the bootstrap method with 10,000 samples. Sixty-one participants subsequently participated in an RCT to compare the proportion of prescribed doses confirmed by WOT and DOT. Participants were randomized 2:1 to receive WOT or maximal in-person DOT. In the WOT arm, if ingestions were not remotely confirmed, the participant was contacted within 24 hours by text or cell phone to provide support. The number of doses confirmed was collected, and nonparametric methods were used for group and individual comparisons to estimate the proportions of confirmed doses in each randomized arm with 95% CIs. Sensitivity analyses, not prespecified in the trial registration, were also performed, removing all nonworking (weekend and public holiday) and held-dose days. Participants, recruited from San Diego (SD) and Orange County (OC) Divisions of TB Control and Refugee Health, were 43.1 (range 18-80) years old, 57% male, 42% Asian, and 39% white with 49% Hispanic ethnicity. The PDA of WOT was 99.3% (CI 98.1; 100). Intent-to-treat (ITT) analysis within the RCT showed WOT confirmed 93% versus 63% DOT (p < 0.001) of daily doses prescribed. Secondary analysis removing all nonworking days (weekends and public holidays) and held doses from each arm showed WOT confirmed 95.6% versus 92.7% (p = 0.31); WOT was non-inferior to DOT (difference 2.8% CI [-1.8%, 9.1%]). One hundred percent of participants preferred using WOT. WOT associated adverse events were <10%, consisting of minor skin rash and pruritus associated with the patch. WOT provided longitudinal digital reporting in near real time, supporting patient self-management and allowing rapid remote identification of those who needed more support to maintain adherence. This study was conducted during the continuation phase of TB treatment, limiting its generalizability to the entire TB treatment course.Conclusions: In terms of accuracy, WOT was equivalent to DOT. WOT was superior to DOT in supporting confirmed daily adherence to TB medications during the continuation phase of TB treatment and was overwhelmingly preferred by participants. WOT should be tested in high-burden TB settings, where it may substantially support low- and middle-income country (LMIC) TB programs.Trial Registration: ClinicalTrials.gov NCT01960257. [ABSTRACT FROM AUTHOR]

Background: Preterm infants are a group at high risk of having experienced placental insufficiency. It is unclear which growth charts perform best in identifying infants at increased risk of stillbirth and other adverse perinatal outcomes. We compared 2 birthweight charts (population centiles and INTERGROWTH-21st birthweight centiles) and 3 fetal growth charts (INTERGROWTH-21st fetal growth charts, World Health Organization fetal growth charts, and Gestation Related Optimal Weight [GROW] customised growth charts) to identify which chart performed best in identifying infants at increased risk of adverse perinatal outcome in a preterm population.Methods and Findings: We conducted a retrospective cohort study of all preterm infants born at 24.0 to 36.9 weeks gestation in Victoria, Australia, from 2005 to 2015 (28,968 records available for analysis). All above growth charts were applied to the population. Proportions classified as <5th centile and <10th centile by each chart were compared, as were proportions of stillborn infants considered small for gestational age (SGA, <10th centile) by each chart. We then compared the relative performance of non-overlapping SGA cohorts by each chart to our low-risk reference population (infants born appropriate size for gestational age [>10th and <90th centile] by all intrauterine charts [AGAall]) for the following perinatal outcomes: stillbirth, perinatal mortality (stillbirth or neonatal death), Apgar <4 or <7 at 5 minutes, neonatal intensive care unit admissions, suspicion of poor fetal growth leading to expedited delivery, and cesarean section. All intrauterine charts classified a greater proportion of infants as <5th or <10th centile than birthweight charts. The magnitude of the difference between birthweight and fetal charts was greater at more preterm gestations. Of the fetal charts, GROW customised charts classified the greatest number of infants as SGA (22.3%) and the greatest number of stillborn infants as SGA (57%). INTERGROWTH classified almost no additional infants as SGA that were not already considered SGA on GROW or WHO charts; however, those infants classified as SGA by INTERGROWTH had the greatest risk of both stillbirth and total perinatal mortality. GROW customised charts classified a larger proportion of infants as SGA, and these infants were still at increased risk of mortality and adverse perinatal outcomes compared to the AGAall population. Consistent with similar studies in this field, our study was limited in comparing growth charts by the degree of overlap, with many infants classified as SGA by multiple charts. We attempted to overcome this by examining and comparing sub-populations classified as SGA by only 1 growth chart.Conclusions: In this study, fetal charts classified greater proportions of preterm and stillborn infants as SGA, which more accurately reflected true fetal growth restriction. Of the intrauterine charts, INTERGROWTH classified the smallest number of preterm infants as SGA, although it identified a particularly high-risk cohort, and GROW customised charts classified the greatest number at increased risk of perinatal mortality. [ABSTRACT FROM AUTHOR]

Background: Civil registration and vital statistics (CRVS) systems play a key role in upholding human rights and generating data for health and good governance. They also can help monitor progress in achieving the United Nations Sustainable Development Goals. Although many countries have made substantial progress in strengthening their CRVS systems, most low- and middle-income countries still have underdeveloped systems. The objective of this systematic review is to identify national policies that can help countries strengthen their systems.Methods and Findings: The ABI/INFORM, Embase, JSTOR, PubMed, and WHO Index Medicus databases were systematically searched for policies to improve birth and/or death registration on 24 January 2017. Global stakeholders were also contacted for relevant grey literature. For the purposes of this review, policies were categorised as supply, demand, incentive, penalty, or combination (i.e., at least two of the preceding policy approaches). Quantitative results on changes in vital event registration rates were presented for individual comparative articles. Qualitative systematic review methodology, including meta-ethnography, was used for qualitative syntheses on operational considerations encompassing acceptability to recipients and staff, human resource requirements, information technology or infrastructure requirements, costs to the health system, unintended effects, facilitators, and barriers. This study is registered with PROSPERO, number CRD42018085768. Thirty-five articles documenting experience in implementing policies to improve birth and/or death registration were identified. Although 25 countries representing all global regions (Africa, the Americas, Southeast Asia, the Western Pacific, Europe, and the Eastern Mediterranean) were reflected, there were limited countries from the Eastern Mediterranean and Europe regions. Twenty-four articles reported policy effects on birth and/or death registration. Twenty-one of the 24 articles found that the change in registration rate after the policy was positive, with two supply and one penalty articles being the exceptions. The qualitative syntheses identified 15 operational considerations across all policy categories. Human and financial resource requirements were not quantified. The primary limitation of this systematic review was the threat of publication bias wherein many countries may not have documented their experience; this threat is most concerning for policies that had neutral or negative effects.Conclusions: Our systematic review suggests that combination policy approaches, consisting of at least a supply and demand component, were consistently associated with improved registration rates in different geographical contexts. Operational considerations should be interpreted based on health system, governance, and sociocultural context. More evaluations and research are needed from the Eastern Mediterranean and Europe regions. Further research and evaluation are also needed to estimate the human and financial resource requirements required for different policies. [ABSTRACT FROM AUTHOR]

Background: Approximately 250 million (43%) children under the age of 5 years in low- and middle-income countries (LMICs) are failing to meet their developmental potential. Risk factors are recognised to contribute to this loss of human potential. Expanding understanding of the risks that lead to poor outcomes and which protective factors contribute to resilience in children may be critical to improving disparities.Methods and Findings: The Drakenstein Child Health Study is a population-based birth cohort in the Western Cape, South Africa. Pregnant women were enrolled between 20 and 28 weeks' gestation from two community clinics from 2012 to 2015; sociodemographic and psychosocial data were collected antenatally. Mothers and children were followed through birth until 2 years of age. Developmental assessments were conducted by trained assessors blinded to background, using the Bayley-III Scales of Infant and Toddler Development (BSID-III), validated for use in South Africa, at 24 months of age. The study assessed all available children at 24 months; however, some children were not able to attend, because of loss to follow-up or unavailability of a caregiver or child at the correct age. Of 1,143 live births, 1,002 were in follow-up at 24 months, and a total of 734 children (73%) had developmental assessments, of which 354 (48.2%) were girls. This sample was characterised by low household employment (n = 183; 24.9%) and household income (n = 287; 39.1% earning 1 domain affected, and 75 (10.2%) had delay in all domains. Bivariate and multivariable analyses revealed several factors that were associated with developmental outcomes. These included protective factors (maternal education, higher birth weight, and socioeconomic status) and risk factors (maternal anaemia in pregnancy, depression or lifetime intimate partner violence, and maternal HIV infection). Boys consistently performed worse than girls (in cognition [β = -0.74; 95% CI -1.46 to -0.03, p = 0.042], receptive language [β = -1.10; 95% CI -1.70 to -0.49, p < 0.001], expressive language [β = -1.65; 95% CI -2.46 to -0.84, p < 0.001], and fine motor [β = -0.70; 95% CI -1.20 to -0.20, p = 0.006] scales). There was evidence that child sex interacted with risk and protective factors including birth weight, maternal anaemia in pregnancy, and socioeconomic factors. Important limitations of the study include attrition of sample from birth to assessment age and missing data in some exposure areas from those assessed.Conclusions: This study provides reliable developmental data from a sub-Saharan African setting in a well-characterised sample of mother-child dyads. Our findings highlight not only the important protective effects of maternal education, birth weight, and socioeconomic status for developmental outcomes but also sex differences in developmental outcomes and key risk and protective factors for each group. [ABSTRACT FROM AUTHOR]

Background: Torture and other forms of ill treatment have been reported in at least 141 countries, exposing a global crisis. Survivors face multiple physical, psychological, and social difficulties. Psychological consequences for survivors are varied, and evidence on treatment is mixed. We conducted a systematic review and meta-analysis to estimate the benefits and harms of psychological, social, and welfare interventions for torture survivors.Methods and Findings: We updated a 2014 review with published randomised controlled trials (RCTs) for adult survivors of torture comparing any psychological, social, or welfare intervention against treatment as usual or active control from 1 January 2014 through 22 June 2019. Primary outcome was post-traumatic stress disorder (PTSD) symptoms or caseness, and secondary outcomes were depression symptoms, functioning, quality of life, and adverse effects, after treatment and at follow-up of at least 3 months. Standardised mean differences (SMDs) and odds ratios were estimated using meta-analysis with random effects. The Cochrane tool was used to derive risk of bias. Fifteen RCTs were included, with data from 1,373 participants (589 females and 784 males) in 10 countries (7 trials in Europe, 5 in Asia, and 3 in Africa). No trials of social or welfare interventions were found. Compared to mostly inactive (waiting list) controls, psychological interventions reduced PTSD symptoms by the end of treatment (SMD -0.31, 95% confidence interval [CI] -0.52 to -0.09, p = 0.005), but PTSD symptoms at follow-up were not significantly reduced (SMD -0.34, 95% CI -0.74 to 0.06, p = 0.09). No significant improvement was found for PTSD caseness at the end of treatment, and there was possible worsening at follow-up from one study (n = 28). Interventions showed no benefits for depression symptoms at end of treatment (SMD -0.23, 95% CI -0.50 to 0.03, p = 0.09) or follow-up (SMD -0.23, 95% CI -0.70 to 0.24, p = 0.34). A significant improvement in functioning for psychological interventions compared to control was found at end of treatment (SMD -0.38, 95% CI -0.58 to -0.18, p = 0.0002) but not at follow-up from only one study. No significant improvement emerged for quality of life at end of treatment (SMD 0.38, 95% CI -0.28 to 1.05, p = 0.26) with no data available at follow-up. The main study limitations were the difficulty in this field of being certain of capturing all eligible studies, the lack of modelling of maintenance of treatment gains, and the low precision of most SMDs making findings liable to change with the addition of further studies as they are published.Conclusions: Our findings show evidence that psychological interventions improve PTSD symptoms and functioning at the end of treatment, but it is unknown whether this is maintained at follow-up, with a possible worsening of PTSD caseness at follow-up from one study. Further interventions in this population should address broader psychological needs beyond PTSD while taking into account the effect of multiple daily stressors. Additional studies, including social and welfare interventions, will improve precision of estimates of effect, particularly over the longer term. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization recommends "same-day" initiation of antiretroviral therapy (ART) for HIV patients who are eligible and ready. Identifying efficient, safe, and feasible procedures for determining same-day eligibility and readiness is now a priority. The Simplified Algorithm for Treatment Eligibility (SLATE) study evaluated a clinical algorithm that allows healthcare workers to determine eligibility for same-day treatment and to initiate ART at the patient's first clinic visit.Methods and Findings: SLATE was an individually randomized trial at three outpatient clinics in urban settlements in Johannesburg, South Africa and three hospital clinics in western Kenya. Adult, nonpregnant, HIV-positive, ambulatory patients presenting for any HIV care, including HIV testing, but not yet on ART were enrolled and randomized to the SLATE algorithm arm or standard care. The SLATE algorithm used four screening tools-a symptom self-report, medical history questionnaire, physical examination, and readiness assessment-to ascertain eligibility for same-day initiation or refer for further care. Follow-up was by record review, and analysis was conducted by country. We report primary outcomes of 1) ART initiation ≤28 days and 2) initiation ≤28 days and retention in care ≤8 months of enrollment. From March 7, 2017 to April 17, 2018, we enrolled 600 patients (median [IQR] age 34 [29-40] and CD4 count 286 [128-490]; 63% female) in South Africa and 477 patients in Kenya (median [IQR] age 35 [29-43] and CD4 count 283 [117-541]; 58% female). In the intervention arm, 78% of patients initiated ≤28 days in South Africa, compared to 68% in the standard arm (risk difference [RD] [95% confidence interval (CI)] 10% [3%-17%]); in Kenya, 94% of intervention-arm patients initiated ≤28 days compared to 89% in the standard arm (6% [0.5%-11%]). By 8 months in South Africa, 161/298 (54%) intervention-arm patients had initiated and were retained, compared to 146/302 (48%) in the standard arm (6% [(2% to 14%]). By 8 months in Kenya, the corresponding retention outcomes were identical in both arms (137/240 [57%] of intervention-arm patients and 136/237 [57%] of standard-arm patients). Limitations of the trial included limited geographic representativeness, exclusion of patients too ill to participate, missing viral load data, greater study fidelity to the algorithm than might be achieved in standard care, and secular changes in standard care over the course of the study.Conclusions: In South Africa, the SLATE algorithm increased uptake of ART within 28 days by 10% and showed a numerical increase (6%) in retention at 8 months. In Kenya, the algorithm increased uptake of ART within 28 days by 6% but found no difference in retention at 8 months. Eight-month retention was poor in both arms and both countries. These results suggest that a simple structured algorithm for same-day treatment initiation procedures is feasible and can increase and accelerate ART uptake but that early retention on treatment remains problematic.Trial Registration: Clinicaltrials.gov NCT02891135, registered September 1, 2016. First participant enrolled March 6, 2017 in South Africa and July 13, 2017 in Kenya. [ABSTRACT FROM AUTHOR]

Background: Improving quality of intrapartum care will reduce intrapartum stillbirth and neonatal mortality, especially in resource-poor settings. Basic neonatal resuscitation can reduce intrapartum stillbirth and early neonatal mortality, if delivered in a high-quality health system, but there is a dearth of evidence on how to scale up such evidence-based interventions. We evaluated the scaling up of a quality improvement (QI) package for neonatal resuscitation on intrapartum-related mortality (intrapartum stillbirth and first day mortality) at hospitals in Nepal.Methods and Findings: We conducted a stepped-wedge cluster randomized controlled trial in 12 hospitals over a period of 18 months from April 14, 2017, to October 17, 2018. The hospitals were assigned to one of four wedges through random allocation. The QI package was implemented in a stepped-wedge manner with a delay of three months for each step. The QI package included improving hospital leadership on intrapartum care, building health workers' competency on neonatal resuscitation, and continuous facilitated QI processes in clinical units. An independent data collection system was set up at each hospital to gather data on mortality through patient case note review and demographic characteristics of women using semi-structured exit interviews. The generalized linear mixed model (GLMM) and multivariate logistic regression were used for analyses. During this study period, a total of 89,014 women-infant pairs were enrolled. The mean age of the mother in the study period was 24.0 ± 4.3 years, with 54.9% from disadvantaged ethnic groups and 4.0% of them illiterate. Of the total birth cohort, 54.4% were boys, 16.7% had gestational age less than 37 weeks, and 17.1% had birth weight less than 2,500 grams. The incidence of intrapartum-related mortality was 11.0 per 1,000 births during the control period and 8.0 per 1,000 births during the intervention period (adjusted odds ratio [aOR], 0.79; 95% CI, 0.69-0.92; p = 0.002; intra-cluster correlation coefficient [ICC], 0.0286). The incidence of early neonatal mortality was 12.7 per 1,000 live births during the control period and 10.1 per 1,000 live births during the intervention period (aOR, 0.89; 95% CI, 0.78-1.02; p = 0.09; ICC, 0.1538). The use of bag-and-mask ventilation for babies with low Apgar score (<7 at 1 minute) increased from 3.2% in the control period to 4.0% in the intervention period (aOR, 1.52; 95% CI, 1.32-1.77, p = 0.003). There were two major limitations to the study; although a large sample of women-infant pairs were enrolled in the study, the clustering reduced the power of the study. Secondly, the study was not sufficiently powered to detect reduction in early neonatal mortality with the number of clusters provided.Conclusion: These results suggest scaled-up implementation of a QI package for neonatal resuscitation can reduce intrapartum-related mortality and improve clinical care. The QI intervention package is likely to be effective in similar settings. More implementation research is required to assess the sustainability of QI interventions and quality of care.Trial Registration: ISRCTN30829654. [ABSTRACT FROM AUTHOR]

Background: There has been a growing interest in understanding the effects of social networks on health-related behaviour, with a particular backdrop being the emerging prominence of complexity or systems science in public health. Social network interventions specifically use or alter the characteristics of social networks to generate, accelerate, or maintain health behaviours. We conducted a systematic review and meta-analysis to investigate health behaviour outcomes of social network interventions.Methods and Findings: We searched eight databases and two trial registries from 1990 to May 28, 2019, for English-language reports of randomised controlled trials (RCTs) and before-and-after studies investigating social network interventions for health behaviours and outcomes. Trials that did not specifically use social networks or that did not include a comparator group were excluded. We screened studies and extracted data from published reports independently. The primary outcome of health behaviours or outcomes at ≤6 months was assessed by random-effects meta-analysis. Secondary outcomes included those measures at >6-12 months and >12 months. This study is registered with the International Prospective Register of Systematic Reviews, PROSPERO: CRD42015023541. We identified 26,503 reports; after exclusion, 37 studies, conducted between 1996 and 2018 from 11 countries, were eligible for analysis, with a total of 53,891 participants (mean age 32.4 years [SD 12.7]; 45.5% females). A range of study designs were included: 27 used RCT/cluster RCT designs, and 10 used other study designs. Eligible studies addressed a variety of health outcomes, in particular sexual health and substance use. Social network interventions showed a significant intervention effect compared with comparator groups for sexual health outcomes. The pooled odds ratio (OR) was 1.46 (95% confidence interval [CI] 1.01-2.11; I2 = 76%) for sexual health outcomes at ≤6 months and OR 1.51 (95% CI 1.27-1.81; I2 = 40%) for sexual health outcomes at >6-12 months. Intervention effects for drug risk outcomes at each time point were not significant. There were also significant intervention effects for some other health outcomes including alcohol misuse, well-being, change in haemoglobin A1c (HbA1c), and smoking cessation. Because of clinical and measurement heterogeneity, it was not appropriate to pool data on these other behaviours in a meta-analysis. For sexual health outcomes, prespecified subgroup analyses were significant for intervention approach (p < 0.001), mean age of participants (p = 0.002), and intervention length (p = 0.05). Overall, 22 of the 37 studies demonstrated a high risk of bias, as measured by the Cochrane Risk of Bias tool. The main study limitations identified were the inclusion of studies of variable quality; difficulty in isolating the effects of specific social network intervention components on health outcomes, as interventions included other active components; and reliance on self-reported outcomes, which have inherent recall and desirability biases.Conclusions: Our findings suggest that social network interventions can be effective in the short term (<6 months) and longer term (>6 months) for sexual health outcomes. Intervention effects for drug risk outcomes at each time point were not significant. There were also significant intervention effects for some other health outcomes including alcohol misuse, well-being, change in HbA1c, and smoking cessation. [ABSTRACT FROM AUTHOR]

Background: In Bangladesh, neonatal sepsis is the cause of 24% of neonatal deaths, over 65% of which occur in the early-newborn stage (0-6 days). Only 50% of newborns in Bangladesh initiated breastfeeding within 1 hour of birth. The mechanism by which early initiation of breastfeeding reduces neonatal deaths is unclear, although the most likely pathway is by decreasing severe illnesses leading to sepsis. This study explores the effect of breastfeeding initiation time on early newborn danger signs and severe illness.Methods and Findings: We used data from a community-based trial in Bangladesh in which we enrolled pregnant women from 2013 through 2015 covering 30,646 newborns. Severe illness was defined using newborn danger signs reported by The Young Infants Clinical Science Study Group. We categorized the timing of initiation as within 1 hour, 1 to 24 hours, 24 to 48 hours, ≥48 hours of birth, and never breastfed. The analysis includes descriptive statistics, risk attribution, and multivariable mixed-effects logistic regression while adjusting for the clustering effects of the trial design, and maternal/infant characteristics. In total, 29,873 live births had information on breastfeeding among whom 19,914 (66.7%) initiated within 1 hour of birth, and 4,437 (14.8%) neonates had a severe illness by the seventh day after birth. The mean time to initiation was 3.8 hours (SD 16.6 hours). The proportion of children with severe illness increased as the delay in initiation increased from 1 hour (12.0%), 24 hours (15.7%), 48 hours (27.7%), and more than 48 hours (36.7%) after birth. These observations would correspond to a possible reduction by 15.9% (95% CI 13.2-25.9, p < 0.001) of severe illness in a real world population in which all newborns had breastfeeding initiated within 1 hour of birth. Children who initiated after 48 hours (odds ratio [OR] 4.13, 95% CI 3.48-4.89, p < 0.001) and children who never initiated (OR 4.77, 95% CI 3.52-6.47, p < 0.001) had the highest odds of having severe illness. The main limitation of this study is the potential for misclassification because of using mothers' report of newborn danger signs. There could be a potential for recall bias for mothers of newborns who died after being born alive.Conclusions: Breastfeeding initiation within the first hour of birth is significantly associated with severe illness in the early newborn period. Interventions to promote early breastfeeding initiation should be tailored for populations in which newborns are delivered at home by unskilled attendants, the rate of low birth weight (LBW) is high, and postnatal care is limited.Trial Registration: Trial Registration number: anzctr.org.au ID ACTRN12612000588897. [ABSTRACT FROM AUTHOR]

Background: Community management of acute malnutrition (CMAM) is a highly efficacious approach for treating acute malnutrition (AM) in children who would otherwise be at significantly increased risk of mortality. In program settings, however, CMAM's effectiveness is limited because of low screening coverage of AM, in part because of the lack of perceived benefits for caregivers. In Burkina Faso, monthly screening for AM of children <2 years of age is conducted during well-baby consultations (consultation du nourrisson sain [CNS]) at health centers. We hypothesized that the integration of a preventive package including age-appropriate behavior change communication (BCC) on nutrition, health, and hygiene practices and a monthly supply of small-quantity lipid-based nutrient supplements (SQ-LNSs) to the monthly screening would increase AM screening and treatment coverage and decrease the incidence and prevalence of AM.Methods and Findings: We used a cluster-randomized controlled trial and allocated 16 health centers to the intervention group and 16 to a comparison group. Both groups had access to standard CMAM and CNS services; caregivers in the intervention group also received age-appropriate monthly BCC and SQ-LNS for children >6 months of age. We used two study designs: (1) a repeated cross-sectional study of children 0-17 months old (n = 2,318 and 2,317 at baseline and endline 2 years later) to assess impacts on AM screening coverage, treatment coverage, and prevalence; (2) a longitudinal study of 2,113 children enrolled soon after birth and followed up monthly for 18 months to assess impacts on AM screening coverage, treatment coverage, and incidence. Data were analyzed as intent to treat. Level of significance for primary outcomes was α = 0.016 after adjustment for multiple testing. Children's average age was 8.8 ± 4.9 months in the intervention group and 8.9 ± 5.0 months in the comparison group at baseline and, respectively, 0.66 ± 0.32 and 0.67 ± 0.33 months at enrollment in the longitudinal study. Relative to the comparison group, the intervention group had significantly higher monthly AM screening coverage (cross-sectional study: +18 percentage points [pp], 95% CI 10-26, P < 0.001; longitudinal study: +23 pp, 95% CI 17-29, P < 0.001). There were no impacts on either AM treatment coverage (cross-sectional study: +8.0 pp, 95% CI 0.09-16, P = 0.047; longitudinal study: +7.7 pp, 95% CI -1.2 to 17, P = 0.090), AM incidence (longitudinal study: incidence rate ratio = 0.98, 95% CI 0.75-1.3, P = 0.88), or AM prevalence (cross-sectional study: -0.46 pp, 95% CI -4.4 to 3.5, P = 0.82). A study limitation is the referral of AM cases (for ethical reasons) by study enumerators as part of the monthly measurement in the longitudinal study that may have attenuated the detectable impact on AM treatment coverage.Conclusions: Adding a preventive package to CMAM delivered at health facilities in Burkina Faso increased participation in monthly AM screening, thus overcoming a major impediment to CMAM effectiveness. The lack of impact on AM treatment coverage and on AM prevalence and incidence calls for research to address the remaining barriers to uptake of preventive and treatment services at the health center and to identify and test complementary approaches to bring integrated preventive and CMAM services closer to the community while ensuring high-quality implementation and service delivery.Trial Registration: ClinicalTrials.gov NCT02245152. [ABSTRACT FROM AUTHOR]

Background: Community-based management of acute malnutrition (CMAM) has been widely adopted to treat childhood acute malnutrition (AM), but its effectiveness in program settings is often limited by implementation constraints, low screening coverage, and poor treatment uptake and adherence. This study addresses the problem of low screening coverage by testing the impact of distributing small-quantity lipid-based nutrient supplements (SQ-LNSs) at monthly screenings held by community health volunteers (CHVs). Screening sessions included behavior change communication (BCC) on nutrition, health, and hygiene practices (both study arms) and SQ-LNSs (one study arm). Impact was assessed on AM screening and treatment coverage and on AM incidence and prevalence.Methods and Findings: A two-arm cluster-randomized controlled trial in 48 health center catchment areas in the Bla and San health districts in Mali was conducted from February 2015 to April 2017. In both arms, CHVs led monthly AM screenings in children 6-23 months of age and provided BCC to caregivers. The intervention arm also received a monthly supply of SQ-LNSs to stimulate caregivers' participation and supplement children's diet. We used two study designs: i) a repeated cross-sectional study (n = approximately 2,300) with baseline and endline surveys to examine impacts on AM screening and treatment coverage and prevalence (primary study outcomes) and ii) a longitudinal study of children enrolled at 6 months of age (n = 1,132) and followed monthly for 18 months to assess impact on AM screening and treatment coverage and incidence (primary study outcomes). All analyses were done by intent to treat. The intervention significantly increased AM screening coverage (cross-sectional study: +40 percentage points [pp], 95% confidence interval [CI]: 32, 49, p < 0.001; longitudinal study: +28 pp, 95% CI: 23, 33, p < 0.001). No impact on treatment coverage or AM prevalence was found. Children in the intervention arm, however, were 29% (95% CI: 8, 46; p = 0.017) less likely to develop a first AM episode (incidence) and, compared to children in comparison arm, their overall risk of AM (longitudinal prevalence) was 30% (95% CI: 12, 44; p = 0.002) lower. The intervention lowered CMAM enrollment by 10 pp (95% CI: 1.9, 18; p = 0.016), an unintended negative impact likely due to CHVs handing out preventive SQ-LNSs to caregivers of AM children instead of referring them to the CMAM program. Study limitations were i) the referral of AM cases by our research team (for ethical reasons) during monthly measurements in the longitudinal study might have interfered with usual CMAM activities and ii) the outcomes presented by child age also reflect seasonal variations because of the closed cohort design.Conclusions: Incorporating SQ-LNSs into monthly community-level AM screenings and BCC sessions was highly effective at improving screening coverage and reducing AM incidence, but it did not improve AM prevalence or treatment coverage. Future evaluation and implementation research on CMAM should carefully assess and tackle the remaining barriers that prevent AM cases from being correctly diagnosed, referred, and adequately treated.Trial Registration: ClinicalTrials.gov NCT02323815. [ABSTRACT FROM AUTHOR]

Background: One in 5 women experience mental illness in pregnancy or post partum. Universal preventive interventions have not lowered the incidence of perinatal mental illness, perhaps because those at highest risk were not targeted. Outside of pregnancy, chronic physical conditions are known to confer increased risk for mental illness. Our objective was to examine the association between chronic physical conditions and risk of perinatal mental illness.Methods and Findings: We conducted a population-based retrospective cohort study using linked health administrative data sets in Ontario, Canada, in 2005 to 2015. We compared 77,385 women with chronic physical conditions to 780,619 women without such conditions, all of whom had a singleton live birth. Excluded were women with a mental illness diagnosis within 2 years before pregnancy. Chronic physical conditions were captured using the Agency for Healthcare Research and Quality Chronic Condition Indicator, applied to acute healthcare encounters in the 2 years before pregnancy. The outcome was perinatal mental illness, defined by a mental illness or addiction diagnosis arising between conception and 365 days post partum. The outcome was further defined by timing (prenatal or post partum) and specific diagnosis (psychotic disorder, mood or anxiety disorder, substance use disorder, self-harm, or other). Modified Poisson regression generated relative risks and 95% confidence intervals (CIs), adjusted for age, parity, rural residence, income quintile, and remote history of mental health care. Women in the cohort had an average age of 29.6 years (standard deviation 5.4), 44.2% were primiparous, 11.0% lived in a rural area, 40.1% were in the lowest 2 income quintiles, and 47.9% had a remote history of mental health care. More women with (20.4%) than without (15.6%) a chronic physical condition experienced perinatal mental illness-an adjusted relative risk (aRR) of 1.20 (95% CI 1.18-1.22, p < 0.0001). The aRRs were statistically significant for mental illness in pregnancy (1.12, 95% CI 1.10-1.15, p < 0.0001) and post partum (1.25, 95% CI 1.23-1.28, p < 0.0001). Psychotic disorders (aRR 1.50, 95% CI 1.36-1.65, p < 0.0001), mood or anxiety disorders (aRR 1.19, 95% CI 1.17-1.21, p < 0.0001), substance use disorders (aRR 1.47, 95% CI 1.34-1.62, p < 0.0001), and other mental illness (aRR 1.68, 95% CI 1.50-1.87, p < 0.0001) were more likely in women with than without chronic physical conditions, but not self-harm (aRR 1.14, 95% CI 0.87-1.48, p = 0.34). The study was limited by reliance on acute health care encounters to measure chronic physical conditions and the inability to capture undiagnosed mental health problems.Conclusions: Findings from this study suggest that women with a chronic physical condition predating pregnancy may be at heightened risk of developing mental illness in the perinatal period. These women may require targeted efforts to lower the severity of their condition and improve their coping strategies and supports in pregnancy and thereafter. [ABSTRACT FROM AUTHOR]

Background: In order to reach the health-related Sustainable Development Goals (SDGs) by 2030, gains attained in access to primary healthcare must be matched by gains in the quality of services delivered. Despite the broad consensus around the need to address quality, studies on the impact of health system strengthening (HSS) have focused predominantly on measures of healthcare access. Here, we examine changes in the content of maternal and child care as a proxy for healthcare quality, to better evaluate the effectiveness of an HSS intervention in a rural district of Madagascar. The intervention aimed at improving system readiness at all levels of care (community health, primary health centers, district hospital) through facility renovations, staffing, equipment, and training, while removing logistical and financial barriers to medical care (e.g., ambulance network and user-fee exemptions).Methods and Findings: We carried out a district-representative open longitudinal cohort study, with surveys administered to 1,522 households in the Ifanadiana district of Madagascar at the start of the HSS intervention in 2014, and again to 1,514 households in 2016. We examined changes in healthcare seeking behavior and outputs for sick-child care among children <5 years old, as well as for antenatal care and perinatal care among women aged 15-49. We used a difference-in-differences (DiD) analysis to compare trends between the intervention group (i.e., people living inside the HSS catchment area) and the non-intervention comparison group (i.e., the rest of the district). In addition, we used health facility-based surveys, monitoring service availability and readiness, to assess changes in the operational capacities of facilities supported by the intervention. The cohort study included 657 and 411 children (mean age = 2 years) reported to be ill in the 2014 and 2016 surveys, respectively (27.8% and 23.8% in the intervention group for each survey), as well as 552 and 524 women (mean age = 28 years) reported to have a live birth within the previous two years in the 2014 and 2016 surveys, respectively (31.5% and 29.6% in the intervention group for each survey). Over the two-year study period, the proportion of people who reported seeking care at health facilities experienced a relative change of +51.2% (from 41.4% in 2014 to 62.5% in 2016) and -7.1% (from 30.0% to 27.9%) in the intervention and non-intervention groups, respectively, for sick-child care (DiD p-value = 0.01); +11.4% (from 78.3% to 87.2%), and +10.3% (from 67.3% to 74.2%) for antenatal care (p-value = 0.75); and +66.2% (from 23.1% to 38.3%) and +28.9% (from 13.9% to 17.9%) for perinatal care (p-value = 0.13). Most indicators of care content, including rates of medication prescription and diagnostic test administration, appeared to increase more in the intervention compared to in the non-intervention group for the three areas of care we assessed. The reported prescription rate for oral rehydration therapy among children with diarrhea changed by +68.5% (from 29.6% to 49.9%) and -23.2% (from 17.8% to 13.7%) in the intervention and non-intervention groups, respectively (p-value = 0.05). However, trends observed in the care content varied widely by indicator and did not always match the large apparent increases observed in care seeking behavior, particularly for antenatal care, reflecting important gaps in the provision of essential health services for individuals who sought care. The main limitation of this study is that the intervention catchment was not randomly allocated, and some demographic indicators were better for this group at baseline than for the rest of the district, which could have impacted the trends observed.Conclusion: Using a district-representative longitudinal cohort to assess the content of care delivered to the population, we found a substantial increase over the two-year study period in the prescription rate for ill children and in all World Health Organization (WHO)-recommended perinatal care outputs assessed in the intervention group, with more modest changes observed in the non-intervention group. Despite improvements associated with the HSS intervention, this study highlights the need for further quality improvement in certain areas of the district's healthcare system. We show how content of care, measured through standard population-based surveys, can be used as a component of HSS impact evaluations, enabling healthcare leaders to track progress as well as identify and address specific gaps in the provision of services that extend beyond care access. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency (ID) in pregnancy is a common problem that can compromise both maternal and fetal health. Although daily iron supplementation is a simple and effective means of treating ID in pregnancy, ID and ID anemia (IDA) often go unrecognized and untreated due to lack of knowledge of their implications and competing clinical priorities.Methods and Findings: In order to enhance screening and management of ID and IDA in pregnancy, we developed a novel quality-improvement toolkit: ID in pregnancy with maternal iron optimization (IRON MOM), implemented at St. Michael's Hospital in Toronto, Canada. It included clinical pathways for diagnosis and management, educational resources for clinicians and patients, templated laboratory requisitions, and standardized oral iron prescriptions. To assess the impact of IRON MOM, we retrospectively extracted laboratory data of all women seen in both the obstetrics clinic and the inpatient delivery ward settings from the electronic patient record (EPR) to compare measures pre- and post-implementation of the toolkit: a process measure of the rates of ferritin testing, and outcome measures of the proportion of women with an antenatal (predelivery) hemoglobin value below 100 g/L (anemia), the proportion of women who received a red blood cell (RBC) transfusion during pregnancy, and the proportion of women who received an RBC transfusion immediately following delivery or in the 8-week postpartum period. The pre-intervention period was from January 2012 to December 2016, and the post-intervention period was from January 2017 to December 2017. From the EPR, 1,292 and 2,400 ferritin tests and 16,603 and 3,282 antenatal hemoglobin results were extracted pre- and post-intervention, respectively. One year after implementation of IRON MOM, we found a 10-fold increase in the rate of ferritin testing in the obstetric clinics at our hospital and a lower risk of antenatal hemoglobin values below 100 g/L (pre-intervention 13.5% [95% confidence interval (CI) 13.0%-14.11%]; post-intervention 10.6% [95% CI 9.6%-11.7%], p < 0.0001). In addition, a significantly lower proportion of women received an RBC transfusion during their pregnancy (1.2% pre-intervention versus 0.8% post-intervention, p = 0.0499) or immediately following delivery and in the 8 weeks following (2.3% pre-intervention versus 1.6% post-intervention, p = 0.0214). Limitations of this study include the use of aggregate data extracted from the EPR, and lack of a control group.Conclusions: The introduction of a standardized toolkit including diagnostic and management pathways as well as other aids increased ferritin testing and decreased the incidence of anemia among women presenting for delivery at our site. This strategy also resulted in reduced proportions of women receiving RBC transfusion during pregnancy and in the first 8 weeks postpartum. The IRON MOM toolkit is a low-tech strategy that could be easily scaled to other settings. [ABSTRACT FROM AUTHOR]

Background: Occupational medicine seeks to reduce sick leave; however, evidence for an add-on effect to usual care is sparse. The objective of the GOBACK trial was to test whether people with low back pain (LBP) in physically demanding jobs and at risk of sick leave gain additional benefit from a 3-month complex intervention that involves occupational medicine consultations, a work-related evaluation and workplace intervention plan, an optional workplace visit, and a physical activity program, over a single hospital consultation and an MRI.Methods and Findings: We enrolled people from the capital region of Denmark to an open-label, parallel-group randomized controlled trial with a superiority design from March 2014 through December 2015. In a hospital setting 305 participants (99 women) with LBP and in physically demanding jobs were randomized to occupational intervention (n = 153) or no additional intervention (control group; n = 152) added to a single hospital consultation giving a thorough explanation of the pain (i.e., clinical examination and MRI) and instructions to stay active and continue working. Primary outcome was accumulated sick leave days due to LBP during 6 months. Secondary outcomes were changes in neuropathic pain (painDETECT questionnaire [PDQ]), pain 0-10 numerical rating scale (NRS), Fear-Avoidance Beliefs Questionnaire (FABQ), Roland-Morris Disability Questionnaire (RMDQ), Short Form Health Survey (SF-36) for physical and mental health-related quality of life (HRQoL), and self-assessed ability to continue working (range 0-10). An intention-to-treat analysis of sick leave at 6 months showed no significant difference between groups (mean difference in days suggestively in favor of no additional intervention: 3.50 [95% CI -5.08 to 12.07], P = 0.42). Both groups showed significant improvements in average pain score (NRS), disability (RMDQ), fear-avoidance beliefs about physical activities and work (FABQ), and physical HRQoL (SF-36 physical component summary); there were no significant differences between the groups in any secondary outcome. There was no statistically significant improvement in neuropathic pain (PDQ score), mental HRQoL (SF-36 mental component summary), and self-assessed ability to stay in job. Four participants could not complete the MRI or the intervention due to a claustrophobic attack or accentuated back pain. Workplace visits may be an important element in the occupational intervention, although not always needed. A per-protocol analysis that included the 40 participants in the intervention arm who received a workplace visit as part of the additional occupational intervention did not show an add-on benefit in terms of sick leave (available cases after 6 months, mean difference: -0.43 days [95% CI -12.8 to 11.94], P = 0.945). The main limitations were the small number of sick leave days taken and that the comprehensive use of MRI may limit generalization of the findings to other settings, for example, general practice.Conclusions: When given a single hospital consultation and MRI, people in physically demanding jobs at risk of sick leave due to LBP did not benefit from a complex additional occupational intervention. Occupational interventions aimed at limiting biopsychological obstacles (e.g., fear-avoidance beliefs and behaviors), barriers in the workplace, and system barriers seem essential to reduce sick leave in patients with LBP. This study indicates that these obstacles and barriers may be addressed by thorough usual care.Trial Registration: Clinical Trials.gov: NCT02015572. [ABSTRACT FROM AUTHOR]

Background: Infant DNA methylation profiles are associated with their mother's periconceptional nutritional status. DNA methylation relies on nutritional inputs for one-carbon metabolic pathways, including the efficient recycling of homocysteine. This randomised controlled trial in nonpregnant women in rural Gambia tests the efficacy of a novel nutritional supplement designed to improve one-carbon-related nutrient status by reducing plasma homocysteine, and assesses its potential future use in preconception trials.Methods and Findings: We designed a novel drink powder based on determinants of plasma homocysteine in the target population and tested it in a three-arm, randomised, controlled trial. Nonpregnant women aged between 18 and 45 from the West Kiang region of The Gambia were randomised in a 1:1:1 allocation to 12 weeks daily supplementation of either (a) a novel drink powder (4 g betaine, 800 μg folic acid, 5.2 μg vitamin B12, and 2.8 mg vitamin B2), (b) a widely used multiple micronutrient tablet (United Nations Multiple Micronutrient Preparation [UNIMMAP]) containing 15 micronutrients, or (c) no intervention. The trial was conducted between March and July 2018. Supplementation was observed daily. Fasted venepuncture samples were collected at baseline, midline (week 5), and endline (week 12) to measure plasma homocysteine. We used linear regression models to determine the difference in homocysteine between pairs of trial arms at midline and endline, adjusted for baseline homocysteine, age, and body mass index (BMI). Blood pressure and pulse were measured as secondary outcomes. Two hundred and ninety-eight eligible women were enrolled and randomised. Compliance was >97.8% for both interventions. At endline (our primary endpoint), the drink powder and UNIMMAP reduced mean plasma homocysteine by 23.6% (-29.5 to -17.1) and 15.5% (-21.2 to -9.4), respectively (both p < 0.001), compared with the controls. Compared with UNIMMAP, the drink powder reduced mean homocysteine by 8.8% (-15.8 to -1.2; p = 0.025). The effects were stronger at midline. There was no effect of either intervention on blood pressure or pulse compared with the control at endline. Self-reported adverse events (AEs) were similar in both intervention arms. There were two serious AEs reported over the trial duration, both in the drink powder arm, but judged to be unrelated to the intervention. Limitations of the study include the use of a single targeted metabolic outcome, homocysteine.Conclusions: The trial confirms that dietary supplements can influence metabolic pathways that we have shown in previous studies to predict offspring DNA methylation. Both supplements reduced homocysteine effectively and remain potential candidates for future epigenetic trials in pregnancy in rural Gambia.Trial Registration: Clinicaltrials.gov Reference NCT03431597. [ABSTRACT FROM AUTHOR]

Background: Various risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational studies. We used MR to evaluate the association of 12 previously reported risk factors (reproductive, anthropometric, clinical, lifestyle, and molecular factors) with risk of invasive epithelial ovarian cancer, invasive epithelial ovarian cancer histotypes, and low malignant potential tumours.Methods and Findings: Genetic instruments to proxy 12 risk factors were constructed by identifying single nucleotide polymorphisms (SNPs) that were robustly (P < 5 × 10-8) and independently associated with each respective risk factor in previously reported genome-wide association studies. These risk factors included genetic liability to 3 factors (endometriosis, polycystic ovary syndrome, type 2 diabetes) scaled to reflect a 50% higher odds liability to disease. We obtained summary statistics for the association of these SNPs with risk of overall and histotype-specific invasive epithelial ovarian cancer (22,406 cases; 40,941 controls) and low malignant potential tumours (3,103 cases; 40,941 controls) from the Ovarian Cancer Association Consortium (OCAC). The OCAC dataset comprises 63 genotyping project/case-control sets with participants of European ancestry recruited from 14 countries (US, Australia, Belarus, Germany, Belgium, Denmark, Finland, Norway, Canada, Poland, UK, Spain, Netherlands, and Sweden). SNPs were combined into multi-allelic inverse-variance-weighted fixed or random effects models to generate effect estimates and 95% confidence intervals (CIs). Three complementary sensitivity analyses were performed to examine violations of MR assumptions: MR-Egger regression and weighted median and mode estimators. A Bonferroni-corrected P value threshold was used to establish strong evidence (P < 0.0042) and suggestive evidence (0.0042 < P < 0.05) for associations. In MR analyses, there was strong or suggestive evidence that 2 of the 12 risk factors were associated with invasive epithelial ovarian cancer and 8 of the 12 were associated with 1 or more invasive epithelial ovarian cancer histotypes. There was strong evidence that genetic liability to endometriosis was associated with an increased risk of invasive epithelial ovarian cancer (odds ratio [OR] per 50% higher odds liability: 1.10, 95% CI 1.06-1.15; P = 6.94 × 10-7) and suggestive evidence that lifetime smoking exposure was associated with an increased risk of invasive epithelial ovarian cancer (OR per unit increase in smoking score: 1.36, 95% CI 1.04-1.78; P = 0.02). In analyses examining histotypes and low malignant potential tumours, the strongest associations found were between height and clear cell carcinoma (OR per SD increase: 1.36, 95% CI 1.15-1.61; P = 0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset: 1.09, 95% CI 1.02-1.16; P = 0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per 50% higher odds liability: 0.89, 95% CI 0.82-0.96; P = 0.002). There was little evidence for an association of genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone binding globulin with ovarian cancer or its subtypes. The primary limitations of this analysis include the modest statistical power for analyses of risk factors in relation to some less common ovarian cancer histotypes (low grade serous, mucinous, and clear cell carcinomas), the inability to directly examine the association of some ovarian cancer risk factors that did not have robust genetic variants available to serve as proxies (e.g., oral contraceptive use, hormone replacement therapy), and the assumption of linear relationships between risk factors and ovarian cancer risk.Conclusions: Our comprehensive examination of possible aetiological drivers of ovarian carcinogenesis using germline genetic variants to proxy risk factors supports a role for few of these factors in invasive epithelial ovarian cancer overall and suggests distinct aetiologies across histotypes. The identification of novel risk factors remains an important priority for the prevention of epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Metformin is increasingly offered as an acceptable and economic alternative to insulin for treatment of gestational diabetes mellitus (GDM) in many countries. However, the impact of maternal metformin treatment on the trajectory of fetal, infant, and childhood growth is unknown.Methods and Findings: PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov, and the Cochrane database were systematically searched (from database inception to 26 February 2019). Outcomes of GDM-affected pregnancies randomised to treatment with metformin versus insulin were included (randomised controlled trials and prospective randomised controlled studies) from cohorts including European, American, Asian, Australian, and African women. Studies including pregnant women with pre-existing diabetes or non-diabetic women were excluded, as were trials comparing metformin treatment with oral glucose-lowering agents other than insulin. Two reviewers independently assessed articles for eligibility and risk of bias, and conflicts were resolved by a third reviewer. Outcome measures were parameters of fetal, infant, and childhood growth, including weight, height, BMI, and body composition. In total, 28 studies (n = 3,976 participants) met eligibility criteria and were included in the meta-analysis. No studies reported fetal growth parameters; 19 studies (n = 3,723 neonates) reported measures of neonatal growth. Neonates born to metformin-treated mothers had lower birth weights (mean difference -107.7 g, 95% CI -182.3 to -32.7, I2 = 83%, p = 0.005) and lower ponderal indices (mean difference -0.13 kg/m3, 95% CI -0.26 to 0.00, I2 = 0%, p = 0.04) than neonates of insulin-treated mothers. The odds of macrosomia (odds ratio [OR] 0.59, 95% CI 0.46 to 0.77, p < 0.001) and large for gestational age (OR 0.78, 95% CI 0.62 to 0.99, p = 0.04) were lower following maternal treatment with metformin compared to insulin. There was no difference in neonatal height or incidence of small for gestational age between groups. Two studies (n = 411 infants) reported measures of infant growth (18-24 months of age). In contrast to the neonatal phase, metformin-exposed infants were significantly heavier than those in the insulin-exposed group (mean difference 440 g, 95% CI 50 to 830, I2 = 4%, p = 0.03). Three studies (n = 520 children) reported mid-childhood growth parameters (5-9 years). In mid-childhood, BMI was significantly higher (mean difference 0.78 kg/m2, 95% CI 0.23 to 1.33, I2 = 7%, p = 0.005) following metformin exposure than following insulin exposure, although the difference in absolute weights between the groups was not significantly different (p = 0.09). Limited evidence (1 study with data treated as 2 cohorts) suggested that adiposity indices (abdominal [p = 0.02] and visceral [p = 0.03] fat volumes) may be higher in children born to metformin-treated compared to insulin-treated mothers. Study limitations include heterogeneity in metformin dosing, heterogeneity in diagnostic criteria for GDM, and the scarcity of reporting of childhood outcomes.Conclusions: Following intrauterine exposure to metformin for treatment of maternal GDM, neonates are significantly smaller than neonates whose mothers were treated with insulin during pregnancy. Despite lower average birth weight, metformin-exposed children appear to experience accelerated postnatal growth, resulting in heavier infants and higher BMI by mid-childhood compared to children whose mothers were treated with insulin. Such patterns of low birth weight and postnatal catch-up growth have been reported to be associated with adverse long-term cardio-metabolic outcomes. This suggests a need for further studies examining longitudinal perinatal and childhood outcomes following intrauterine metformin exposure. This review protocol was registered with PROSPERO under registration number CRD42018117503. [ABSTRACT FROM AUTHOR]

Background: Some experts have proposed combating rising drug prices by promoting brand-brand competition, a situation that is supposed to arise when multiple US Food and Drug Administration (FDA)-approved brand-name products in the same class are indicated for the same condition. However, numerous reports exist of price increases following the introduction of brand-name competition, suggesting that it may not be effective. We performed a systematic literature review of the peer-reviewed health policy and economics literature to better understand the interplay between new drug entry and intraclass drug prices.Methods and Findings: We searched PubMed and EconLit for original studies on brand-brand competition in the US market published in English between January 1990 and April 2019. We performed a qualitative synthesis of each study's data, recording its primary objective, methodology, and results. We found 10 empirical investigations, with 1 study each on antihypertensives, anti-infectives, central nervous system stimulants for attention deficit/hyperactivity disorder, disease-modifying therapies for multiple sclerosis, histamine-2 (H2) blockers, and tumor necrosis factor (TNF) inhibitors; 2 studies on cancer medications; and 2 studies on all marketed or new drugs. None of the studies reported that brand-brand competition lowers list prices of existing drugs within a class. The findings of 2 studies suggest that such competition may help restrain how new drug prices are set. Other studies found evidence that brand-brand competition was mediated by the relative quality of competing drugs and the extent to which they are marketed, with safer or more effective new drugs and greater marketing associated with higher intraclass list prices. Our investigation was limited by the studies' use of list rather than net prices and the age of some of the data.Conclusions: Our findings suggest that policies to promote brand-brand competition in the US pharmaceutical market, such as accelerating approval of non-first-in-class drugs, will likely not result in lower drug list prices absent additional structural reforms. [ABSTRACT FROM AUTHOR]

Background: Exposure to fine particulate matter pollution (PM2.5) is hazardous to health. Our aim was to directly estimate the health and longevity impacts of current PM2.5 concentrations and the benefits of reductions from 1999 to 2015, nationally and at county level, for the entire contemporary population of the contiguous United States.Methods and Findings: We used vital registration and population data with information on sex, age, cause of death, and county of residence. We used four Bayesian spatiotemporal models, with different adjustments for other determinants of mortality, to directly estimate mortality and life expectancy loss due to current PM2.5 pollution and the benefits of reductions since 1999, nationally and by county. The covariates included in the adjusted models were per capita income; percentage of population whose family income is below the poverty threshold, who are of Black or African American race, who have graduated from high school, who live in urban areas, and who are unemployed; cumulative smoking; and mean temperature and relative humidity. In the main model, which adjusted for these covariates and for unobserved county characteristics through the use of county-specific random intercepts, PM2.5 pollution in excess of the lowest observed concentration (2.8 μg/m3) was responsible for an estimated 15,612 deaths (95% credible interval 13,248-17,945) in females and 14,757 deaths (12,617-16,919) in males. These deaths would lower national life expectancy by an estimated 0.15 years (0.13-0.17) for women and 0.13 years (0.11-0.15) for men. The life expectancy loss due to PM2.5 was largest around Los Angeles and in some southern states such as Arkansas, Oklahoma, and Alabama. At any PM2.5 concentration, life expectancy loss was, on average, larger in counties with lower income and higher poverty rate than in wealthier counties. Reductions in PM2.5 since 1999 have lowered mortality in all but 14 counties where PM2.5 increased slightly. The main limitation of our study, similar to other observational studies, is that it is not guaranteed for the observed associations to be causal. We did not have annual county-level data on other important determinants of mortality, such as healthcare access and quality and diet, but these factors were adjusted for with use of county-specific random intercepts.Conclusions: According to our estimates, recent reductions in particulate matter pollution in the USA have resulted in public health benefits. Nonetheless, we estimate that current concentrations are associated with mortality impacts and loss of life expectancy, with larger impacts in counties with lower income and higher poverty rate. [ABSTRACT FROM AUTHOR]

Background: Pregnant women with metabolic risk factors are at high risk of complications. We aimed to assess whether a Mediterranean-style diet reduces adverse pregnancy outcomes in high-risk women.Methods and Findings: We conducted a multicentre randomised trial in 5 maternity units (4 in London and 1 in Birmingham) between 12 September 2014 and 29 February 2016. We randomised inner-city pregnant women with metabolic risk factors (obesity, chronic hypertension, or hypertriglyceridaemia) to a Mediterranean-style diet with high intake of nuts, extra virgin olive oil, fruits, vegetables, nonrefined grains, and legumes; moderate to high consumption of fish; low to moderate intake of poultry and dairy products; low intake of red and processed meat; and avoidance of sugary drinks, fast food, and food rich in animal fat versus usual care. Participants received individualised dietary advice at 18, 20, and 28 weeks' gestation. The primary endpoints were composite maternal (gestational diabetes or preeclampsia) and composite offspring (stillbirth, small for gestational age, or admission to neonatal care unit) outcomes prioritised by a Delphi survey. We used an intention-to-treat (ITT) analysis with multivariable models and identified the stratification variables and prognostic factors a priori. We screened 7,950 and randomised 1,252 women. Baseline data were available for 593 women in the intervention (93.3% follow-up, 553/593) and 612 in the control (95.6% follow-up, 585/612) groups. Over a quarter of randomised women were primigravida (330/1,205; 27%), 60% (729/1,205) were of Black or Asian ethnicity, and 69% (836/1,205) were obese. Women in the intervention arm consumed more nuts (70.1% versus 22.9%; adjusted odds ratio [aOR] 6.8, 95% confidence interval [CI] 4.3-10.6, p ≤ 0.001) and extra virgin olive oil (93.2% versus 49.0%; aOR 32.2, 95% CI 16.0-64.6, p ≤ 0.001) than controls; increased their intake of fish (p < 0.001), white meat (p < 0.001), and pulses (p = 0.05); and reduced their intake of red meat (p < 0.001), butter, margarine, and cream (p < 0.001). There was no significant reduction in the composite maternal (22.8% versus 28.6%; aOR 0.76, 95% CI 0.56-1.03, p = 0.08) or composite offspring (17.3% versus 20.9%; aOR 0.79, 95% CI 0.58-1.08, p = 0.14) outcomes. There was an apparent reduction in the odds of gestational diabetes by 35% (aOR 0.65, 95% CI 0.47-0.91, p = 0.01) but not in other individual components of the composite outcomes. Mothers gained less gestational weight (mean 6.8 versus 8.3 kg; adjusted difference -1.2 Kg, 95% CI -2.2 to -0.2, p = 0.03) with intervention versus control. There was no difference in any of the other maternal and offspring complications between both groups. When we pooled findings from the Effect of Simple, Targeted Diet in Pregnant Women With Metabolic Risk Factors on Pregnancy Outcomes (ESTEEM) trial with similar trials using random effects meta-analysis, we observed a significant reduction in gestational diabetes (odds ratio [OR] 0.67, 95% CI 0.53-0.84, I2 = 0%), with no heterogeneity (2 trials, 2,397 women). The study's limitations include the use of participant reported tools for adherence to the intervention instead of objective biomarkers.Conclusions: A simple, individualised, Mediterranean-style diet in pregnancy did not reduce the overall risk of adverse maternal and offspring complications but has the potential to reduce gestational weight gain and the risk of gestational diabetes.Trial Registration: ClinicalTrials.gov NCT02218931. [ABSTRACT FROM AUTHOR]

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 (<400 copies/mL) 12 months after AC or DMD enrollment (or comparable time for controls). 12 facilities were randomly allocated to intervention and 12 to control arms in four provinces (Gauteng, North West, Limpopo, and KwaZulu Natal). We calculated adjusted risk differences (aRDs) with cluster adjustment using generalized estimating equations (GEEs) using difference in differences (DiD) with patients eligible for ACs/DMD prior to implementation (Jan 1, 2015) for comparison. For DMD, randomization was not preserved, and the analysis was treated as observational. For ACs, 275 intervention and 294 control patients were enrolled; 72% of patients were female, 61% were aged 30-49 years, and median CD4 count at ART initiation was 268 cells/μL. AC patients had higher 1-year retention (89.5% versus 81.6%, aRD: 8.3%; 95% CI: 1.1% to 15.6%) and comparable sustained 1-year viral suppression (<400 copies/mL any time ≤ 18 months) (80.0% versus 79.6%, aRD: 3.8%; 95% CI: -6.9% to 14.4%). Retention associations were apparently stronger for men than women (men RD: 13.1%, 95% CI: 0.3% to 23.5%; women RD: 6.0%, 95% CI: -0.9% to 12.9%). For DMD, 232 intervention and 346 control patients were enrolled; 71% of patients were female, 65% were aged 30-49 years, and median CD4 count at ART initiation was 270 cells/μL. DMD patients had apparently lower retention (81.5% versus 87.2%, aRD: -5.9%; 95% CI: -12.5% to 0.8%) and comparable viral suppression versus standard of care (77.2% versus 74.3%, aRD: -1.0%; 95% CI: -12.2% to 10.1%), though in both cases, our findings were imprecise. We also noted apparently increased viral suppression among men (RD: 11.1%; 95% CI: -3.4% to 25.5%). The main study limitations were missing data and lack of randomization in the DMD analysis.Conclusions: In this study, we found comparable DMD outcomes versus standard of care at facilities, a benefit for retention of patients in care with ACs, and apparent benefits in terms of retention (for AC patients) and sustained viral suppression (for DMD patients) among men. This suggests the importance of alternative service delivery models for men and of community-based strategies to decongest primary healthcare facilities. Because these strategies also reduce patient inconvenience and decongest clinics, comparable outcomes are a potential success. The cost of all five AGL interventions and possible effects on reducing clinic congestion should be investigated.Clinical Trial Registration: NCT02536768. [ABSTRACT FROM AUTHOR]

Background: The Indian government supports both public- and private-sector provision of hospital care for neonates: neonatal intensive care is offered in public facilities alongside a rising number of private-for-profit providers. However, there are few published reports about mortality levels and care practices in these facilities. We aimed to assess care practices, causes of admission, and outcomes from neonatal intensive care units (NICUs) in public secondary and private tertiary hospitals and both public and private medical colleges enrolled in a quality improvement collaborative in Telangana and Andhra Pradesh-2 Indian states with a respective population of 35 and 50 million.Methods and Findings: We conducted a cross-sectional study between 30 May and 26 August 2016 as part of a baseline evaluation in 52 consenting hospitals (26 public secondary hospitals, 5 public medical colleges, 15 private tertiary hospitals, and 6 private medical colleges) offering neonatal intensive care. We assessed the availability of staff and services, adherence to evidence-based practices at admission, and case fatality after admission to the NICU using a range of tools, including facility assessment, observations of admission, and abstraction of registers and telephone interviews after discharge. Our analysis is adjusted for clustering and weighted for caseload at the hospital level and presents findings stratified by type and ownership of hospitals. In total, the NICUs included just over 3,000 admissions per month. Staffing and infrastructure provision were largely according to government guidelines, except that only a mean of 1 but not the recommended 4 paediatricians were working in public secondary NICUs per 10 beds. On admission, all neonates admitted to private hospitals had auscultation (100%, 19 of 19 observations) but only 42% (95% confidence interval [CI] 25%-62%, p-value for difference is 0.361) in public secondary hospitals. The most common single cause of admission was preterm birth (25%) followed by jaundice (23%). Case-fatality rates at age 28 days after admission to a NICU were 4% (95% CI 2%-8%), 15% (9%-24%), 4% (2%-8%) and 2% (1%-5%) (Chi-squared p = 0.001) in public secondary hospitals, public medical colleges, private tertiary hospitals, and private medical colleges, respectively, according to facility registers. Case fatality according to postdischarge telephone interviews found rates of 12% (95% CI 7%-18%) for public secondary hospitals. Roughly 6% of admitted neonates were referred to another facility. Outcome data were missing for 27% and 8% of admissions to private tertiary hospitals and private medical colleges. Our study faced the limitation of missing data due to incomplete documentation. Further generalizability was limited due to the small sample size among private facilities.Conclusions: Our findings suggest differences in quality of neonatal intensive care and 28-day survival between the different types of hospitals, although comparison of outcomes is complicated by differences in the case mix and referral practices between hospitals. Uniform reporting of outcomes and risk factors across the private and public sectors is required to assess the benefits for the population of mixed-care provision. [ABSTRACT FROM AUTHOR]

Background: Although increasingly used, the benefit of surgical treatment of displaced 2-part proximal humerus fractures has not been proven. This trial evaluates the clinical effectiveness of surgery with locking plate compared with non-operative treatment for these fractures.Methods and Findings: The NITEP group conducted a superiority, assessor-blinded, multicenter randomized trial in 6 hospitals in Finland, Estonia, Sweden, and Denmark. Eighty-eight patients aged 60 years or older with displaced (more than 1 cm or 45 degrees) 2-part surgical or anatomical neck proximal humerus fracture were randomly assigned in a 1:1 ratio to undergo either operative treatment with a locking plate or non-operative treatment. The mean age of patients was 72 years in the non-operative group and 73 years in the operative group, with a female sex distribution of 95% and 87%, respectively. Patients were recruited between February 2011 and April 2016. The primary outcome measure was Disabilities of Arm, Shoulder, and Hand (DASH) score at 2-year follow-up. Secondary outcomes included Constant-Murley score, the visual analogue scale for pain, the quality of life questionnaire 15D, EuroQol Group's 5-dimension self-reported questionnaire EQ-5D, the Oxford Shoulder Score, and complications. The mean DASH score (0 best, 100 worst) at 2 years was 18.5 points for the operative treatment group and 17.4 points for the non-operative group (mean difference 1.1 [95% CI -7.8 to 9.4], p = 0.81). At 2 years, there were no statistically or clinically significant between-group differences in any of the outcome measures. All 3 complications resulting in secondary surgery occurred in the operative group. The lack of blinding in patient-reported outcome assessment is a limitation of the study. Our assessor physiotherapists were, however, blinded.Conclusions: This trial found no significant difference in clinical outcomes at 2 years between surgery and non-operative treatment in patients 60 years of age or older with displaced 2-part fractures of the proximal humerus. These results suggest that the current practice of performing surgery on the majority of displaced proximal 2-part fractures of the humerus in older adults may not be beneficial.Trial Registration: ClinicalTrials.gov NCT01246167. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) is an adverse event that carries significant morbidity. Given that interventions after AKI occurrence have poor performance, there is substantial interest in prediction of AKI prior to its diagnosis. However, integration of real-time prognostic modeling into the electronic health record (EHR) has been challenging, as complex models increase the risk of error and complicate deployment. Our goal in this study was to create an implementable predictive model to accurately predict AKI in hospitalized patients and could be easily integrated within an existing EHR system.Methods and Findings: We performed a retrospective analysis looking at data of 169,859 hospitalized adults admitted to one of three study hospitals in the United States (in New Haven and Bridgeport, Connecticut) from December 2012 to February 2016. Demographics, medical comorbidities, hospital procedures, medications, and laboratory data were used to develop a model to predict AKI within 24 hours of a given observation. Outcomes of AKI severity, requirement for renal replacement therapy, and mortality were also measured and predicted. Models were trained using discrete-time logistic regression in a subset of Hospital 1, internally validated in the remainder of Hospital 1, and externally validated in Hospital 2 and Hospital 3. Model performance was assessed via the area under the receiver-operator characteristic (ROC) curve (AUC). The training set cohort contained 60,701 patients, and the internal validation set contained 30,599 patients. External validation data sets contained 43,534 and 35,025 patients. Patients in the overall cohort were generally older (median age ranging from 61 to 68 across hospitals); 44%-49% were male, 16%-20% were black, and 23%-29% were admitted to surgical wards. In the training set and external validation set, 19.1% and 18.9% of patients, respectively, developed AKI. The full model, including all covariates, had good ability to predict imminent AKI for the validation set, sustained AKI, dialysis, and death with AUCs of 0.74 (95% CI 0.73-0.74), 0.77 (95% CI 0.76-0.78), 0.79 (95% CI 0.73-0.85), and 0.69 (95% CI 0.67-0.72), respectively. A simple model using only readily available, time-updated laboratory values had very similar predictive performance to the complete model. The main limitation of this study is that it is observational in nature; thus, we are unable to conclude a causal relationship between covariates and AKI and do not provide an optimal treatment strategy for those predicted to develop AKI.Conclusions: In this study, we observed that a simple model using readily available laboratory data could be developed to predict imminent AKI with good discrimination. This model may lend itself well to integration into the EHR without sacrificing the performance seen in more complex models. [ABSTRACT FROM AUTHOR]

Background: In October 2017, the United Kingdom Joint Committee on Vaccination and Immunisation (JCVI) recommended removal of one primary dose of the 13-valent pneumococcal conjugate vaccine (PCV13) from the existing 2+1 schedule (2, 4, 12 months). We conducted a mathematical modelling study to investigate the potential impact of a 1+1 (3, 12 month) schedule on invasive pneumococcal disease (IPD) and pneumococcal community-acquired pneumonia (CAP). Our results and those from a 1+1 immunogenicity study formed the key evidence reviewed by JCVI.Methods and Findings: We developed age-structured, dynamic, deterministic models of pneumococcal transmission in England and Wales to describe the impact on IPD of 7-valent PCV (PCV7; introduced in 2006) and PCV13 (introduced in 2010). Key transmission and vaccine parameters were estimated by fitting to carriage data from 2001/2002 and post-PCV IPD data to 2015, using vaccine coverage, mixing patterns between ages, and population data. We considered various models to investigate potential reasons for the rapid increase in non-PCV13 (non-vaccine serotype [NVT]) IPD cases since 2014. After searching a large parameter space, 500 parameter sets were identified with a likelihood statistically close to the maximum and these used to predict future cases (median, prediction range from 500 parameter sets). Our findings indicated that the emergence of individual NVTs with higher virulence resulting from ongoing replacement was likely responsible; the NVT increase was predicted to plateau from 2020. Long-term simulation results suggest that changing to a 1+1 schedule would have little overall impact, as the small increase in vaccine-type IPD would be offset by a reduction in NVT IPD. Our results were robust to changes in vaccine assumptions in a sensitivity analysis. Under the base case scenario, a change to a 1+1 schedule in 2018 was predicted to produce 31 (6, 76) additional IPD cases over five years and 83 (-10, 242) additional pneumococcal-CAP cases, with together 8 (-2, 24) additional deaths, none in children under 15 years. Long-term continuation with the 2+1 schedule, or changing to a 1+1, was predicted to sustain current reductions in IPD cases in under-64-year-olds, but cases in 65+-year-olds would continue to increase because of the effects of an aging population. Limitations of our model include difficulty in fitting to past trends in NVT IPD in some age groups and inherent uncertainty about future NVT behaviour, sparse data for defining the mixing matrix in 65+-year-olds, and the methodological challenge of defining uncertainty on predictions.Conclusions: Our findings suggest that, with the current mature status of the PCV programme in England and Wales, removing one primary dose in the first year of life would have little impact on IPD or pneumococcal CAP cases or associated deaths at any age. A reduction in the number of priming doses would improve programmatic efficiency and facilitate the introduction of new vaccines by reducing the number of coadministered vaccines given at 2 and 4 months of age in the current UK schedule. Our findings should not be applied to other settings with different pneumococcal epidemiology or with immature programmes and poor herd immunity. [ABSTRACT FROM AUTHOR]

Background: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings.Methods and Findings: Large community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 μg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87-1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%-0.1%) and 0.01% (95% CI 0.00%-0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites.Conclusions: In this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA.Trial Registration: Clinicaltrials.gov registration number: NCT02899936. [ABSTRACT FROM AUTHOR]

Background: Helminth and protozoan infections affect more than 1 billion children globally. Improving water quality, sanitation, handwashing, and nutrition could be more sustainable control strategies for parasite infections than mass drug administration, while providing other quality of life benefits.Methods and Findings: We enrolled geographic clusters of pregnant women in rural western Kenya into a cluster-randomized controlled trial (ClinicalTrials.gov NCT01704105) that tested 6 interventions: water treatment, improved sanitation, handwashing with soap, combined water treatment, sanitation, and handwashing (WSH), improved nutrition, and combined WSH and nutrition (WSHN). We assessed intervention effects on parasite infections by measuring Ascaris lumbricoides, Trichuris trichiura, hookworm, and Giardia duodenalis among children born to the enrolled pregnant women (index children) and their older siblings. After 2 years of intervention exposure, we collected stool specimens from 9,077 total children aged 2 to 15 years in 622 clusters, including 2,346 children in an active control group (received household visits but no interventions), 1,117 in the water treatment arm, 1,160 in the sanitation arm, 1,141 in the handwashing arm, 1,064 in the WSH arm, 1,072 in the nutrition arm, and 1,177 in the WSHN arm. In the control group, 23% of children were infected with A. lumbricoides, 1% with T. trichiura, 2% with hookworm, and 39% with G. duodenalis. The analysis included 4,928 index children (median age in years: 2) and 4,149 older siblings (median age in years: 5); study households had an average of 5 people, <10% had electricity access, and >90% had dirt floors. Compared to the control group, Ascaris infection prevalence was lower in the water treatment arm (prevalence ratio [PR]: 0.82 [95% CI 0.67, 1.00], p = 0.056), the WSH arm (PR: 0.78 [95% CI 0.63, 0.96], p = 0.021), and the WSHN arm (PR: 0.78 [95% CI 0.64, 0.96], p = 0.017). We did not observe differences in Ascaris infection prevalence between the control group and the arms with the individual interventions sanitation (PR: 0.89 [95% CI 0.73, 1.08], p = 0.228), handwashing (PR: 0.89 [95% CI 0.73, 1.09], p = 0.277), or nutrition (PR: 86 [95% CI 0.71, 1.05], p = 0.148). Integrating nutrition with WSH did not provide additional benefit. Trichuris and hookworm were rarely detected, resulting in imprecise effect estimates. No intervention reduced Giardia. Reanalysis of stool samples by quantitative polymerase chain reaction confirmed the reductions in Ascaris infections measured by microscopy in the WSH and WSHN groups. Trial limitations included imperfect uptake of targeted intervention behaviors, limited power to detect effects on rare parasite infections, and that it was not feasible to blind participants and sample collectors to treatment status. However, lab technicians and data analysts were blinded to treatment status. The trial was funded by the Bill & Melinda Gates Foundation and the United States Agency for International Development.Conclusions: Integration of improved water quality, sanitation, and handwashing could contribute to sustainable control strategies for Ascaris infections, particularly in similar settings with recent or ongoing deworming programs. Combining nutrition with WSH did not provide further benefits, and water treatment alone was similarly effective to integrated WSH. Our findings provide new evidence that drinking water should be given increased attention as a transmission pathway for Ascaris.Trial Registration: ClinicalTrials.gov NCT01704105. [ABSTRACT FROM AUTHOR]

Background: There is ongoing debate about whether education or socioeconomic status (SES) should be inputs into cardiovascular disease (CVD) prediction algorithms and clinical risk adjustment models. It is also unclear whether intervening on education will affect CVD, in part because there is controversy regarding whether education is a determinant of CVD or merely correlated due to confounding or reverse causation. We took advantage of a natural experiment to estimate the population-level effects of educational attainment on CVD and related risk factors.Methods and Findings: We took advantage of variation in United States state-level compulsory schooling laws (CSLs), a natural experiment that was associated with geographic and temporal differences in the minimum number of years that children were required to attend school. We linked census data on educational attainment (N = approximately 5.4 million) during childhood with outcomes in adulthood, using cohort data from the 1992-2012 waves of the Health and Retirement Study (HRS; N = 30,853) and serial cross-sectional data from 1971-2012 waves of the National Health and Nutrition Examination Survey (NHANES; N = 44,732). We examined self-reported CVD outcomes and related risk factors, as well as relevant serum biomarkers. Using instrumental variables (IV) analysis, we found that increased educational attainment was associated with reduced smoking (HRS β -0.036, 95%CI: -0.06, -0.02, p < 0.01; NHANES β -0.032, 95%CI: -0.05, -0.02, p < 0.01), depression (HRS β -0.049, 95%CI: -0.07, -0.03, p < 0.01), triglycerides (NHANES β -0.039, 95%CI: -0.06, -0.01, p < 0.01), and heart disease (HRS β -0.025, 95%CI: -0.04, -0.002, p = 0.01), and improvements in high-density lipoprotein (HDL) cholesterol (HRS β 1.50, 95%CI: 0.34, 2.49, p < 0.01; NHANES β 0.86, 95%CI: 0.32, 1.48, p < 0.01), but increased BMI (HRS β 0.20, 95%CI: 0.002, 0.40, p = 0.05; NHANES β 0.13, 95%CI: 0.01, 0.32, p = 0.05) and total cholesterol (HRS β 2.73, 95%CI: 0.09, 4.97, p = 0.03). While most findings were cross-validated across both data sets, they were not robust to the inclusion of state fixed effects. Limitations included residual confounding, use of self-reported outcomes for some analyses, and possibly limited generalizability to more recent cohorts.Conclusions: This study provides rigorous population-level estimates of the association of educational attainment with CVD. These findings may guide future implementation of interventions to address the social determinants of CVD and strengthen the argument for including educational attainment in prediction algorithms and primary prevention guidelines for CVD. [ABSTRACT FROM AUTHOR]

Background: Data are lacking from physical activity (PA) trials with long-term follow-up of both objectively measured PA levels and robust health outcomes. Two primary care 12-week pedometer-based walking interventions in adults and older adults (PACE-UP and PACE-Lift) found sustained objectively measured PA increases at 3 and 4 years, respectively. We aimed to evaluate trial intervention effects on long-term health outcomes relevant to walking interventions, using routine primary care data.Methods and Findings: Randomisation was from October 2012 to November 2013 for PACE-UP participants from seven general (family) practices and October 2011 to October 2012 for PACE-Lift participants from three practices. We downloaded primary care data, masked to intervention or control status, for 1,001 PACE-UP participants aged 45-75 years, 36% (361) male, and 296 PACE-Lift participants, aged 60-75 years, 46% (138) male, who gave written informed consent, for 4-year periods following randomisation. The following new events were counted for all participants, including those with preexisting diseases (apart from diabetes, for which existing cases were excluded): nonfatal cardiovascular, total cardiovascular (including fatal), incident diabetes, depression, fractures, and falls. Intervention effects on time to first event post-randomisation were modelled using Cox regression for all outcomes, except for falls, which used negative binomial regression to allow for multiple events, adjusting for age, sex, and study. Absolute risk reductions (ARRs) and numbers needed to treat (NNTs) were estimated. Data were downloaded for 1,297 (98%) of 1,321 trial participants. Event rates were low (<20 per group) for outcomes, apart from fractures and falls. Cox hazard ratios for time to first event post-randomisation for interventions versus controls were nonfatal cardiovascular 0.24 (95% confidence interval [CI] 0.07-0.77, p = 0.02), total cardiovascular 0.34 (95% CI 0.12-0.91, p = 0.03), diabetes 0.75 (95% CI 0.42-1.36, p = 0.34), depression 0.98 (95% CI 0.46-2.07, p = 0.96), and fractures 0.56 (95% CI 0.35-0.90, p = 0.02). Negative binomial incident rate ratio for falls was 1.07 (95% CI 0.78-1.46, p = 0.67). ARR and NNT for cardiovascular events were nonfatal 1.7% (95% CI 0.5%-2.1%), NNT = 59 (95% CI 48-194); total 1.6% (95% CI 0.2%-2.2%), NNT = 61 (95% CI 46-472); and for fractures 3.6% (95% CI 0.8%-5.4%), NNT = 28 (95% CI 19-125). Main limitations were that event rates were low and only events recorded in primary care records were counted; however, any underrecording would not have differed by intervention status and so should not have led to bias.Conclusions: Routine primary care data used to assess long-term trial outcomes demonstrated significantly fewer new cardiovascular events and fractures in intervention participants at 4 years. No statistically significant differences between intervention and control groups were demonstrated for other events. Short-term primary care pedometer-based walking interventions can produce long-term health benefits and should be more widely used to help address the public health inactivity challenge.Trial Registrations: PACE-UP isrctn.com ISRCTN98538934; PACE-Lift isrctn.com ISRCTN42122561. [ABSTRACT FROM AUTHOR]

Background: College affirmative action programs seek to expand socioeconomic opportunities for underrepresented minorities. Between 1996 and 2013, 9 US states-including California, Texas, and Michigan-banned race-based affirmative action in college admissions. Because economic opportunity is known to motivate health behavior, banning affirmative action policies may have important adverse spillover effects on health risk behaviors. We used a quasi-experimental research design to evaluate the association between college affirmative action bans and health risk behaviors among underrepresented minority (Black, Hispanic, and Native American) adolescents.Methods and Findings: We conducted a difference-in-differences analysis using data from the 1991-2015 US national Youth Risk Behavior Survey (YRBS). We compared changes in self-reported cigarette smoking and alcohol use in the 30 days prior to survey among underrepresented minority 11th and 12th graders in states implementing college affirmative action bans (Arizona, California, Florida, Michigan, Nebraska, New Hampshire, Oklahoma, Texas, and Washington) versus outcomes among those residing in states not implementing bans (n = 35 control states). We also assessed whether underrepresented minority adults surveyed in the 1992-2015 Tobacco Use Supplement to the Current Population Survey (TUS-CPS) who were exposed to affirmative action bans during their late high school years continued to smoke cigarettes between the ages of 19 and 30 years. Models adjusted for individual demographic characteristics, state and year fixed effects, and state-specific secular trends. In the YRBS (n = 34,988 to 36,268, depending on the outcome), cigarette smoking in the past 30 days among underrepresented minority 11th-12th graders increased by 3.8 percentage points after exposure to an affirmative action ban (95% CI: 2.0, 5.7; p < 0.001). In addition, there were also apparent increases in past-30-day alcohol use, by 5.9 percentage points (95% CI: 0.3, 12.2; p = 0.041), and past-30-day binge drinking, by 3.5 percentage points (95% CI: -0.1, 7.2, p = 0.058), among underrepresented minority 11th-12th graders, though in both cases adjustment for multiple comparisons resulted in failure to reject the null hypothesis (adjusted p = 0.083 for both outcomes). Underrepresented minority adults in the TUS-CPS (n = 71,575) exposed to bans during their late high school years were also 1.8 percentage points more likely to report current smoking (95% CI: 0.1, 3.6; p = 0.037). Event study analyses revealed a discrete break for all health behaviors timed with policy discussion and implementation. No substantive or statistically significant effects were found for non-Hispanic White adolescents, and the findings were robust to a number of additional specification checks. The limitations of the study include the continued potential for residual confounding from unmeasured time-varying factors and the potential for recall bias due to the self-reported nature of the health risk behavior outcomes.Conclusions: In this study, we found evidence that some health risk behaviors increased among underrepresented minority adolescents after exposure to state-level college affirmative action bans. These findings suggest that social policies that shift socioeconomic opportunities could have meaningful population health consequences. [ABSTRACT FROM AUTHOR]

Background: Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight.Methods and Findings: We performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother-child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, 'leave-one-out', and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight -0.03 g [95% CI -2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15-9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (-20 g [95% CI -44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121-236 g, p = 1.43 × 10-9] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy.Conclusions: Our results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments. [ABSTRACT FROM AUTHOR]

Background: Growing political attention to antimicrobial resistance (AMR) offers a rare opportunity for achieving meaningful action. Many governments have developed national AMR action plans, but most have not yet implemented policy interventions to reduce antimicrobial overuse. A systematic evidence map can support governments in making evidence-informed decisions about implementing programs to reduce AMR, by identifying, describing, and assessing the full range of evaluated government policy options to reduce antimicrobial use in humans.Methods and Findings: Seven databases were searched from inception to January 28, 2019, (MEDLINE, CINAHL, EMBASE, PAIS Index, Cochrane Central Register of Controlled Trials, Web of Science, and PubMed). We identified studies that (1) clearly described a government policy intervention aimed at reducing human antimicrobial use, and (2) applied a quantitative design to measure the impact. We found 69 unique evaluations of government policy interventions carried out across 4 of the 6 WHO regions. These evaluations included randomized controlled trials (n = 4), non-randomized controlled trials (n = 3), controlled before-and-after designs (n = 7), interrupted time series designs (n = 25), uncontrolled before-and-after designs (n = 18), descriptive designs (n = 10), and cohort designs (n = 2). From these we identified 17 unique policy options for governments to reduce the human use of antimicrobials. Many studies evaluated public awareness campaigns (n = 17) and antimicrobial guidelines (n = 13); however, others offered different policy options such as professional regulation, restricted reimbursement, pay for performance, and prescription requirements. Identifying these policies can inform the development of future policies and evaluations in different contexts and health systems. Limitations of our study include the possible omission of unpublished initiatives, and that policies not evaluated with respect to antimicrobial use have not been captured in this review.Conclusions: To our knowledge this is the first study to provide policy makers with synthesized evidence on specific government policy interventions addressing AMR. In the future, governments should ensure that AMR policy interventions are evaluated using rigorous study designs and that study results are published.Protocol Registration: PROSPERO CRD42017067514. [ABSTRACT FROM AUTHOR]

Background: There is a global obesity crisis, particularly among women and disadvantaged populations. Early-life intervention to prevent childhood obesity is a priority for public health, global health, and clinical practice. Understanding the association between childhood obesity and maternal pre-pregnancy weight status would inform policy and practice by allowing one to estimate the potential for offspring health gain through channelling resources into intervention. This systematic review and meta-analysis aimed to examine the dose-response association between maternal body mass index (BMI) and childhood obesity in the offspring.Methods and Findings: Searches in MEDLINE, Child Development & Adolescent Studies, CINAHL, Embase, and PsycInfo were carried out in August 2017 and updated in March 2019. Supplementary searches included hand-searching reference lists, performing citation searching, and contacting authors. Two researchers carried out independent screening, data extraction, and quality assessment. Observational studies published in English and reporting associations between continuous and/or categorical maternal and child BMI or z-score were included. Categorical outcomes were child obesity (≥95th percentile, primary outcome), overweight/obesity (≥85th percentile), and overweight (85th to 95th percentile). Linear and nonlinear dose-response meta-analyses were conducted using random effects models. Studies that could not be included in meta-analyses were summarised narratively. Seventy-nine of 41,301 studies identified met the inclusion criteria (n = 59 cohorts). Meta-analyses of child obesity included 20 studies (n = 88,872); child overweight/obesity, 22 studies (n = 181,800); and overweight, 10 studies (n = 53,238). Associations were nonlinear and there were significantly increased odds of child obesity with maternal obesity (odds ratio [OR] 3.64, 95% CI 2.68-4.95) and maternal overweight (OR 1.89, 95% CI 1.62-2.19). Significantly increased odds were observed for child overweight/obesity (OR 2.69, 95% CI 2.10-3.46) and for child overweight (OR 1.80, 95% CI 1.25, 2.59) with maternal obesity. A limitation of this research is that the included studies did not always report the data in a format that enabled inclusion in this complex meta-analysis.Conclusions: This research has identified a 264% increase in the odds of child obesity when mothers have obesity before conception. This study provides substantial evidence for the need to develop interventions that commence prior to conception, to support women of childbearing age with weight management in order to halt intergenerational obesity. [ABSTRACT FROM AUTHOR]

Background: Primary care antimicrobial stewardship interventions can improve antimicrobial prescribing, but there is less evidence that they reduce rates of resistant infection. This study examined changes in broad-spectrum antimicrobial prescribing in the community and resistance in people admitted to hospital with community-associated coliform bacteraemia associated with a primary care stewardship intervention.Methods and Findings: Segmented regression analysis of data on all patients registered with a general practitioner in the National Health Service (NHS) Tayside region in the east of Scotland, UK, from 1 January 2005 to 31 December 2015 was performed, examining associations between a primary care antimicrobial stewardship intervention in 2009 and primary care prescribing of fluoroquinolones, cephalosporins, and co-amoxiclav and resistance to the same three antimicrobials/classes among community-associated coliform bacteraemia. Prescribing outcomes were the rate per 1,000 population prescribed each antimicrobial/class per quarter. Resistance outcomes were proportion of community-associated (first 2 days of hospital admission) coliform (Escherichia coli, Proteus spp., or Klebsiella spp.) bacteraemia among adult (18+ years) patients resistant to each antimicrobial/class. 11.4% of 3,442,205 oral antimicrobial prescriptions dispensed in primary care over the study period were for targeted antimicrobials. There were large, statistically significant reductions in prescribing at 1 year postintervention that were larger by 3 years postintervention when the relative reduction was -68.8% (95% CI -76.3 to -62.1) and the absolute reduction -6.3 (-7.6 to -5.2) people exposed per 1,000 population per quarter for fluoroquinolones; relative -74.0% (-80.3 to -67.9) and absolute reduction -6.1 (-7.2 to -5.2) for cephalosporins; and relative -62.3% (-66.9 to -58.1) and absolute reduction -6.8 (-7.7 to -6.0) for co-amoxiclav, all compared to their prior trends. There were 2,143 eligible bacteraemia episodes involving 2,004 patients over the study period (mean age 73.7 [SD 14.8] years; 51.4% women). There was no increase in community-associated coliform bacteraemia admissions associated with reduced community broad-spectrum antimicrobial use. Resistance to targeted antimicrobials reduced by 3.5 years postintervention compared to prior trends, but this was not statistically significant for co-amoxiclav. Relative and absolute changes were -34.7% (95% CI -52.3 to -10.6) and -63.5 (-131.8 to -12.8) resistant bacteraemia per 1,000 bacteraemia per quarter for fluoroquinolones; -48.3% (-62.7 to -32.3) and -153.1 (-255.7 to -77.0) for cephalosporins; and -17.8% (-47.1 to 20.8) and -63.6 (-206.4 to 42.4) for co-amoxiclav, respectively. Overall, there was reversal of a previously rising rate of fluoroquinolone resistance and flattening of previously rising rates of cephalosporin and co-amoxiclav resistance. The limitations of this study include that associations are not definitive evidence of causation and that potential effects of underlying secular trends in the postintervention period and/or of other interventions occurring simultaneously cannot be definitively excluded.Conclusions: In this population-based study in Scotland, compared to prior trends, there were very large reductions in community broad-spectrum antimicrobial use associated with the stewardship intervention. In contrast, changes in resistance among coliform bacteraemia were more modest. Prevention of resistance through judicious use of new antimicrobials may be more effective than trying to reverse resistance that has become established. [ABSTRACT FROM AUTHOR]