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Background: Few studies have evaluated the association between preexisting vitamin D deficiency and incident tuberculosis (TB). We assessed the impact of baseline vitamins D levels on TB disease risk.Methods and Findings: We assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6,751 HIV-negative household contacts of TB patients enrolled between September 1, 2009, and August 29, 2012, in Lima, Peru. We screened for TB disease at 2, 6, and 12 months after enrollment. We defined cases as household contacts who developed TB disease at least 15 days after enrollment of the index patient. For each case, we randomly selected four controls from among contacts who did not develop TB disease, matching on gender and year of age. We also conducted a one-stage individual-participant data (IPD) meta-analysis searching PubMed and Embase to identify prospective studies of vitamin D and TB disease until June 8, 2019. We included studies that assessed vitamin D before TB diagnosis. In the primary analysis, we defined vitamin D deficiency as 25-(OH)D < 50 nmol/L, insufficiency as 50-75 nmol/L, and sufficiency as >75nmol/L. We estimated the association between baseline vitamin D status and incident TB using conditional logistic regression in the Lima cohort and generalized linear mixed models in the meta-analysis. We further defined severe vitamin D deficiency as 25-(OH)D < 25 nmol/L and performed stratified analyses by HIV status in the IPD meta-analysis. In the Lima cohort, we analyzed 180 cases and 709 matched controls. The adjusted odds ratio (aOR) for TB risk among participants with baseline vitamin D deficiency compared to sufficient vitamin D was 1.63 (95% CI 0.75-3.52; p = 0.22). We included seven published studies in the meta-analysis and analyzed 3,544 participants. In the pooled analysis, the aOR was 1.48 (95% CI 1.04-2.10; p = 0.03). The aOR for severe vitamin D deficiency was 2.05 (95% CI 0.87-4.87; p trend for decreasing 25-(OH)D levels from sufficient vitamin D to severe deficiency = 0.02). Among 1,576 HIV-positive patients, vitamin D deficiency conferred a 2-fold (aOR 2.18, 95% CI 1.22-3.90; p = 0.01) increased risk of TB, and the aOR for severe vitamin D deficiency compared to sufficient vitamin D was 4.28 (95% CI 0.85-21.45; p = 0.08). Our Lima cohort study is limited by the short duration of follow-up, and the IPD meta-analysis is limited by the number of possible confounding covariates available across all studies.Conclusion: Our findings suggest vitamin D predicts TB disease risk in a dose-dependent manner and that the risk of TB disease is highest among HIV-positive individuals with severe vitamin D deficiency. Randomized control trials are needed to evaluate the possible role of vitamin D supplementation on reducing TB disease risk. [ABSTRACT FROM AUTHOR]

Background: Severe falciparum malaria is a medical emergency characterised by potentially lethal vital organ dysfunction. Patient fatality rates even with parenteral artesunate treatment remain high. Despite considerable research into adjuvant therapies targeting organ and tissue dysfunction, none have shown efficacy apart from renal replacement therapy. Understanding the causal contributions of clinical and laboratory abnormalities to mortality is essential for the design and evaluation of novel therapeutic interventions.Methods and Findings: We used a structural model causal inference approach to investigate causal relationships between epidemiological, laboratory, and clinical variables in patients with severe falciparum malaria enrolled in clinical trials and their in-hospital mortality. Under this causal model, we analysed records from 9,040 hospitalised children (0-12 years, n = 5,635) and adults (n = 3,405, 12-87 years) with severe falciparum malaria from 15 countries in Africa and Asia who were studied prospectively over the past 35 years. On admission, patient covariates associated with increased in-hospital mortality were severity of acidosis (odds ratio [OR] 2.10 for a 7-mEq/L increase in base deficit [95% CI 1.93-2.28]), renal impairment (OR 1.71 for a 2-fold increase in blood urea nitrogen [95% CI 1.58, 1.86]), coma (OR 3.59 [95% CI 3.07-4.21]), seizures (OR 1.40 [95% CI 1.16-1.68]), shock (OR 1.51 [95% CI 1.14-1.99]), and presumed pulmonary oedema (OR 1.58 [95% CI 1.04-2.39]). Lower in-hospital mortality was associated with moderate anaemia (OR 0.87 for a decrease of 10 percentage points in haematocrit [95% CI 0.80-0.95]). Circulating parasite density was not associated with mortality (OR 1.02 for a 6-fold increase [95% CI 0.94-1.11]), so the pathological effects of parasitaemia appear to be mediated entirely by the downstream effects of sequestration. Treatment with an artemisinin derivative decreased mortality compared with quinine (OR 0.64 [95% CI 0.56-0.74]). These estimates were consistent across children and adults (mainly representing African and Asian patients, respectively). Using inverse probability weighting, transfusion was not estimated to be beneficial in children with admission haematocrit values between 15% and 25% (OR 0.99 [95% CI 0.97-1.02]). Except for the effects of artemisinin treatment and transfusion, causal interpretations of these estimates could be biased by unmeasured confounding from severe bacterial sepsis, immunity, and duration of illness.Conclusion: These data suggest that moderate anaemia is associated with a reduced risk of death in severe falciparum malaria. This is possibly a direct causal association. The severe anaemia threshold criteria for a definition of severe falciparum malaria should be reconsidered. [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: 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: 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: Children with medically complicated severe acute malnutrition (SAM) have high risk of inpatient mortality. Diarrhea, carbohydrate malabsorption, and refeeding syndrome may contribute to early mortality and delayed recovery. We tested the hypothesis that a lactose-free, low-carbohydrate F75 milk would serve to limit these risks, thereby reducing the number of days in the stabilization phase.Methods and Findings: In a multicenter double-blind trial, hospitalized severely malnourished children were randomized to receive standard formula (F75) or isocaloric modified F75 (mF75) without lactose and with reduced carbohydrate. The primary endpoint was time to stabilization, as defined by the World Health Organization (WHO), with intention-to-treat analysis. Secondary outcomes included in-hospital mortality, diarrhea, and biochemical features of malabsorption and refeeding syndrome. The trial was registered at clinicaltrials.gov (NCT02246296). Four hundred eighteen and 425 severely malnourished children were randomized to F75 and mF75, respectively, with 516 (61%) enrolled in Kenya and 327 (39%) in Malawi. Children with a median age of 16 months were enrolled between 4 December 2014 and 24 December 2015. One hundred ninety-four (46%) children assigned to F75 and 188 (44%) to mF75 had diarrhea at admission. Median time to stabilization was 3 days (IQR 2-5 days), which was similar between randomized groups (0.23 [95% CI -0.13 to 0.60], P = 0.59). There was no evidence of effect modification by diarrhea at admission, age, edema, or HIV status. Thirty-six and 39 children died before stabilization in the F75 and in mF75 arm, respectively (P = 0.84). Cumulative days with diarrhea (P = 0.27), enteral (P = 0.42) or intravenous fluids (P = 0.19), other serious adverse events before stabilization, and serum and stool biochemistry at day 3 did not differ between groups. The main limitation was that the primary outcome of clinical stabilization was based on WHO guidelines, comprising clinical evidence of recovery from acute illness as well as metabolic stabilization evidenced by recovery of appetite.Conclusions: Empirically treating hospitalized severely malnourished children during the stabilization phase with lactose-free, reduced-carbohydrate milk formula did not improve clinical outcomes. The biochemical analyses suggest that the lactose-free formulae may still exceed a carbohydrate load threshold for intestinal absorption, which may limit their usefulness in the context of complicated SAM.Trial Registration: ClinicalTrials.gov NCT02246296. [ABSTRACT FROM AUTHOR]

Background: In low-income countries, care for people with mental, neurological, and substance use (MNS) disorders is largely absent, especially in rural settings. To increase treatment coverage, integration of mental health services into community and primary healthcare settings is recommended. While this strategy is being rolled out globally, rigorous evaluation of outcomes at each stage of the service delivery pathway from detection to treatment initiation to individual outcomes of care has been missing.Methods and Findings: A combination of methods were employed to evaluate the impact of a district mental healthcare plan for depression, psychosis, alcohol use disorder (AUD), and epilepsy as part of the Programme for Improving Mental Health Care (PRIME) in Chitwan District, Nepal. We evaluated 4 components of the service delivery pathway: (1) contact coverage of primary care mental health services, evaluated through a community study (N = 3,482 combined for all waves of community surveys) and through service utilisation data (N = 727); (2) detection of mental illness among participants presenting in primary care facilities, evaluated through a facility study (N = 3,627 combined for all waves of facility surveys); (3) initiation of minimally adequate treatment after diagnosis, evaluated through the same facility study; and (4) treatment outcomes of patients receiving primary-care-based mental health services, evaluated through cohort studies (total N = 449 depression, N = 137; AUD, N = 175; psychosis, N = 95; epilepsy, N = 42). The lack of structured diagnostic assessments (instead of screening tools), the relatively small sample size for some study components, and the uncontrolled nature of the study are among the limitations to be noted. All data collection took place between 15 January 2013 and 15 February 2017. Contact coverage increased 7.5% for AUD (from 0% at baseline), 12.2% for depression (from 0%), 11.7% for epilepsy (from 1.3%), and 50.2% for psychosis (from 3.2%) when using service utilisation data over 12 months; community survey results did not reveal significant changes over time. Health worker detection of depression increased by 15.7% (from 8.9% to 24.6%) 6 months after training, and 10.3% (from 8.9% to 19.2%) 24 months after training; for AUD the increase was 58.9% (from 1.1% to 60.0%) and 11.0% (from 1.1% to 12.1%) for 6 months and 24 months, respectively. Provision of minimally adequate treatment subsequent to diagnosis for depression was 93.9% at 6 months and 66.7% at 24 months; for AUD these values were 95.1% and 75.0%, respectively. Changes in treatment outcomes demonstrated small to moderate effect sizes (9.7-point reduction [d = 0.34] in AUD symptoms, 6.4-point reduction [d = 0.43] in psychosis symptoms, 7.2-point reduction [d = 0.58] in depression symptoms) at 12 months post-treatment.Conclusions: These combined results make a promising case for the feasibility and impact of community- and primary-care-based services delivered through an integrated district mental healthcare plan in reducing the treatment gap and increasing effective coverage for MNS disorders. While the integrated mental healthcare approach does lead to apparent benefits in most of the outcome metrics, there are still significant areas that require further attention (e.g., no change in community-level contact coverage, attrition in AUD detection rates over time, and relatively low detection rates for depression). [ABSTRACT FROM AUTHOR]

Background: Clinical guidelines recommend psychosocial interventions for cocaine and/or amphetamine addiction as first-line treatment, but it is still unclear which intervention, if any, should be offered first. We aimed to estimate the comparative effectiveness of all available psychosocial interventions (alone or in combination) for the short- and long-term treatment of people with cocaine and/or amphetamine addiction.Methods and Findings: We searched published and unpublished randomised controlled trials (RCTs) comparing any structured psychosocial intervention against an active control or treatment as usual (TAU) for the treatment of cocaine and/or amphetamine addiction in adults. Primary outcome measures were efficacy (proportion of patients in abstinence, assessed by urinalysis) and acceptability (proportion of patients who dropped out due to any cause) at the end of treatment, but we also measured the acute (12 weeks) and long-term (longest duration of study follow-up) effects of the interventions and the longest duration of abstinence. Odds ratios (ORs) and standardised mean differences were estimated using pairwise and network meta-analysis with random effects. The risk of bias of the included studies was assessed with the Cochrane tool, and the strength of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We followed the PRISMA for Network Meta-Analyses (PRISMA-NMA) guidelines, and the protocol was registered in PROSPERO (CRD 42017042900). We included 50 RCTs evaluating 12 psychosocial interventions or TAU in 6,942 participants. The strength of evidence ranged from high to very low. Compared to TAU, contingency management (CM) plus community reinforcement approach was the only intervention that increased the number of abstinent patients at the end of treatment (OR 2.84, 95% CI 1.24-6.51, P = 0.013), and also at 12 weeks (OR 7.60, 95% CI 2.03-28.37, P = 0.002) and at longest follow-up (OR 3.08, 95% CI 1.33-7.17, P = 0.008). At the end of treatment, CM plus community reinforcement approach had the highest number of statistically significant results in head-to-head comparisons, being more efficacious than cognitive behavioural therapy (CBT) (OR 2.44, 95% CI 1.02-5.88, P = 0.045), non-contingent rewards (OR 3.31, 95% CI 1.32-8.28, P = 0.010), and 12-step programme plus non-contingent rewards (OR 4.07, 95% CI 1.13-14.69, P = 0.031). CM plus community reinforcement approach was also associated with fewer dropouts than TAU, both at 12 weeks and the end of treatment (OR 3.92, P < 0.001, and 3.63, P < 0.001, respectively). At the longest follow-up, community reinforcement approach was more effective than non-contingent rewards, supportive-expressive psychodynamic therapy, TAU, and 12-step programme (OR ranging between 2.71, P = 0.026, and 4.58, P = 0.001), but the combination of community reinforcement approach with CM was superior also to CBT alone, CM alone, CM plus CBT, and 12-step programme plus non-contingent rewards (ORs between 2.50, P = 0.039, and 5.22, P < 0.001). The main limitations of our study were the quality of included studies and the lack of blinding, which may have increased the risk of performance bias. However, our analyses were based on objective outcomes, which are less likely to be biased.Conclusions: To our knowledge, this network meta-analysis is the most comprehensive synthesis of data for psychosocial interventions in individuals with cocaine and/or amphetamine addiction. Our findings provide the best evidence base currently available to guide decision-making about psychosocial interventions for individuals with cocaine and/or amphetamine addiction and should inform patients, clinicians, and policy-makers. [ABSTRACT FROM AUTHOR]

Background: Face-to-face brief interventions for problem drinking are effective, but they have found limited implementation in routine care and the community. Internet-based interventions could overcome this treatment gap. We investigated effectiveness and moderators of treatment outcomes in internet-based interventions for adult problem drinking (iAIs).Methods and Findings: Systematic searches were performed in medical and psychological databases to 31 December 2016. A one-stage individual patient data meta-analysis (IPDMA) was conducted with a linear mixed model complete-case approach, using baseline and first follow-up data. The primary outcome measure was mean weekly alcohol consumption in standard units (SUs, 10 grams of ethanol). Secondary outcome was treatment response (TR), defined as less than 14/21 SUs for women/men weekly. Putative participant, intervention, and study moderators were included. Robustness was verified in three sensitivity analyses: a two-stage IPDMA, a one-stage IPDMA using multiple imputation, and a missing-not-at-random (MNAR) analysis. We obtained baseline data for 14,198 adult participants (19 randomised controlled trials [RCTs], mean age 40.7 [SD = 13.2], 47.6% women). Their baseline mean weekly alcohol consumption was 38.1 SUs (SD = 26.9). Most were regular problem drinkers (80.1%, SUs 44.7, SD = 26.4) and 19.9% (SUs 11.9, SD = 4.1) were binge-only drinkers. About one third were heavy drinkers, meaning that women/men consumed, respectively, more than 35/50 SUs of alcohol at baseline (34.2%, SUs 65.9, SD = 27.1). Post-intervention data were available for 8,095 participants. Compared with controls, iAI participants showed a greater mean weekly decrease at follow-up of 5.02 SUs (95% CI -7.57 to -2.48, p < 0.001) and a higher rate of TR (odds ratio [OR] 2.20, 95% CI 1.63-2.95, p < 0.001, number needed to treat [NNT] = 4.15, 95% CI 3.06-6.62). Persons above age 55 showed higher TR than their younger counterparts (OR = 1.66, 95% CI 1.21-2.27, p = 0.002). Drinking profiles were not significantly associated with treatment outcomes. Human-supported interventions were superior to fully automated ones on both outcome measures (comparative reduction: -6.78 SUs, 95% CI -12.11 to -1.45, p = 0.013; TR: OR = 2.23, 95% CI 1.22-4.08, p = 0.009). Participants treated in iAIs based on personalised normative feedback (PNF) alone were significantly less likely to sustain low-risk drinking at follow-up than those in iAIs based on integrated therapeutic principles (OR = 0.52, 95% CI 0.29-0.93, p = 0.029). The use of waitlist control in RCTs was associated with significantly better treatment outcomes than the use of other types of control (comparative reduction: -9.27 SUs, 95% CI -13.97 to -4.57, p < 0.001; TR: OR = 3.74, 95% CI 2.13-6.53, p < 0.001). The overall quality of the RCTs was high; a major limitation included high study dropout (43%). Sensitivity analyses confirmed the robustness of our primary analyses.Conclusion: To our knowledge, this is the first IPDMA on internet-based interventions that has shown them to be effective in curbing various patterns of adult problem drinking in both community and healthcare settings. Waitlist control may be conducive to inflation of treatment outcomes. [ABSTRACT FROM AUTHOR]

Background: Obesity increases the risk for developing gestational diabetes mellitus (GDM) and preeclampsia (PE), which both associate with increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in women in later life. In the general population, metabolic syndrome (MetS) associates with T2DM and CVD. The impact of maternal MetS on pregnancy outcomes, in nulliparous pregnant women, has not been investigated.Methods and Findings: Low-risk, nulliparous women were recruited to the multi-centre, international prospective Screening for Pregnancy Endpoints (SCOPE) cohort between 11 November 2004 and 28 February 2011. Women were assessed for a range of demographic, lifestyle, and metabolic health variables at 15 ± 1 weeks' gestation. MetS was defined according to International Diabetes Federation (IDF) criteria for adults: waist circumference ≥80 cm, along with any 2 of the following: raised trigycerides (≥1.70 mmol/l [≥150 mg/dl]), reduced high-density lipoprotein cholesterol (<1.29 mmol/l [<50 mg/dl]), raised blood pressure (BP) (i.e., systolic BP ≥130 mm Hg or diastolic BP ≥85 mm Hg), or raised plasma glucose (≥5.6 mmol/l). Log-binomial regression analyses were used to examine the risk for each pregnancy outcome (GDM, PE, large for gestational age [LGA], small for gestational age [SGA], and spontaneous preterm birth [sPTB]) with each of the 5 individual components for MetS and as a composite measure (i.e., MetS, as defined by the IDF). The relative risks, adjusted for maternal BMI, age, study centre, ethnicity, socioeconomic index, physical activity, smoking status, depression status, and fetal sex, are reported. A total of 5,530 women were included, and 12.3% (n = 684) had MetS. Women with MetS were at an increased risk for PE by a factor of 1.63 (95% CI 1.23 to 2.15) and for GDM by 3.71 (95% CI 2.42 to 5.67). In absolute terms, for PE, women with MetS had an adjusted excess risk of 2.52% (95% CI 1.51% to 4.11%) and, for GDM, had an adjusted excess risk of 8.66% (95% CI 5.38% to 13.94%). Diagnosis of MetS was not associated with increased risk for LGA, SGA, or sPTB. Increasing BMI in combination with MetS increased the estimated probability for GDM and decreased the probability of an uncomplicated pregnancy. Limitations of this study are that there are several different definitions for MetS in the adult population, and as there are none for pregnancy, we cannot be sure that the IDF criteria are the most appropriate definition for pregnancy. Furthermore, MetS was assessed in the first trimester and may not reflect pre-pregnancy metabolic health status.Conclusions: We did not compare the impact of individual metabolic components with that of MetS as a composite, and therefore cannot conclude that MetS is better at identifying women at risk. However, more than half of the women who had MetS in early pregnancy developed a pregnancy complication compared with just over a third of women who did not have MetS. Furthermore, while increasing BMI increases the probability of GDM, the addition of MetS exacerbates this probability. Further studies are required to determine if individual MetS components act synergistically or independently. [ABSTRACT FROM AUTHOR]

In a Perspective, Hannah Nissan and Declan Conway discuss the implications of uncertainty about projected impacts of climate change on health. [ABSTRACT FROM AUTHOR]

Background: Human health is dependent upon environmental health. Air pollution is a leading cause of morbidity and mortality globally, and climate change has been identified as the single greatest public health threat of the 21st century. As a large, resource-intensive sector of the Canadian economy, healthcare itself contributes to pollutant emissions, both directly from facility and vehicle emissions and indirectly through the purchase of emissions-intensive goods and services. Together these are termed life cycle emissions. Here, we estimate the extent of healthcare-associated life cycle emissions as well as the public health damages they cause.Methods and Findings: We use a linked economic-environmental-epidemiological modeling framework to quantify pollutant emissions and their implications for public health, based on Canadian national healthcare expenditures over the period 2009-2015. Expenditures gathered by the Canadian Institute for Health Information (CIHI) are matched to sectors in a national environmentally extended input-output (EEIO) model to estimate emissions of greenhouse gases (GHGs) and >300 other pollutants. Damages to human health are then calculated using the IMPACT2002+ life cycle impact assessment model, considering uncertainty in the damage factors used. On a life cycle basis, Canada's healthcare system was responsible for 33 million tonnes of carbon dioxide equivalents (CO2e), or 4.6% of the national total, as well as >200,000 tonnes of other pollutants. We link these emissions to a median estimate of 23,000 disability-adjusted life years (DALYs) lost annually from direct exposures to hazardous pollutants and from environmental changes caused by pollution, with an uncertainty range of 4,500-610,000 DALYs lost annually. A limitation of this national-level study is the use of aggregated data and multiple modeling steps to link healthcare expenditures to emissions to health damages. While informative on a national level, the applicability of these findings to guide decision-making at individual institutions is limited. Uncertainties related to national economic and environmental accounts, model representativeness, and classification of healthcare expenditures are discussed.Conclusions: Our results for GHG emissions corroborate similar estimates for the United Kingdom, Australia, and the United States, with emissions from hospitals and pharmaceuticals being the most significant expenditure categories. Non-GHG emissions are responsible for the majority of health damages, predominantly related to particulate matter (PM). This work can guide efforts by Canadian healthcare professionals toward more sustainable practices. [ABSTRACT FROM AUTHOR]

Background: A modal shift to cycling has the potential to reduce greenhouse gas emissions and provide health co-benefits. Methods, models, and tools are needed to estimate the potential for cycling uptake and communicate to policy makers the range of impacts this would have.Methods and Findings: The Impacts of Cycling Tool (ICT) is an open source model with a web interface for visualising travel patterns and comparing the impacts of different scenarios of cycling uptake. It is currently applied to England. The ICT allows users to visualise individual and trip-level data from the English National Travel Survey (NTS), 2004-2014 sample, 132,000 adults. It models scenarios in which there is an increase in the proportion of the population who cycle regularly, using a distance-based propensity approach to model which trips would be cycled. From this, the model estimates likely impact on travel patterns, health, and greenhouse gas emissions. Estimates of nonoccupational physical activity are generated by fusing the NTS with the English Active People Survey (APS, 2013-2014, 559,515 adults) to create a synthetic population. Under 'equity' scenarios, we investigate what would happen if cycling levels increased equally among all age and gender categories, as opposed to in proportion to the profile of current cyclists. Under electric assist bike (pedelecs or 'e-bike') scenarios, the probability of cycling longer trips increases, based on the e-bike data from the Netherlands, 2013-2014 Dutch Travel Survey (50,868 adults).Outcomes are presented across domains including transport (trip duration and trips by mode), health (physical activity levels, years of life lost), and car transport-related CO2 emissions. Results can be visualised for the whole population and various subpopulations (region, age, gender, and ethnicity). The tool is available at www.pct.bike/ict. If the proportion of the English population who cycle regularly increased from 4.8% to 25%, then there would be notable reductions in car miles and passenger related CO2 emissions (2.2%) and health benefits (2.1% reduction in years of life lost due to premature mortality). If the new cyclists had access to e-bikes, then mortality reductions would be similar, while the reduction in car miles and CO2 emissions would be larger (2.7%). If take-up of cycling occurred equally by gender and age (under 80 years), then health benefits would be marginally greater (2.2%) but reduction in CO2 slightly smaller (1.8%). The study is limited by the quality and comparability of the input data (including reliance on self-report behaviours). As with all modelling studies, many assumptions are required and potentially important pathways excluded (e.g. injury, air pollution, and noise pollution).Conclusion: This study demonstrates a generalisable approach for using travel survey data to model scenarios of cycling uptake that can be applied to a wide range of settings. The use of individual-level data allows investigation of a wide range of outcomes, and variation across subgroups. Future work should investigate the sensitivity of results to assumptions and omissions, and if this varies across setting. [ABSTRACT FROM AUTHOR]

Background: Heatwaves are a critical public health problem. There will be an increase in the frequency and severity of heatwaves under changing climate. However, evidence about the impacts of climate change on heatwave-related mortality at a global scale is limited.Methods and Findings: We collected historical daily time series of mean temperature and mortality for all causes or nonexternal causes, in periods ranging from January 1, 1984, to December 31, 2015, in 412 communities within 20 countries/regions. We estimated heatwave-mortality associations through a two-stage time series design. Current and future daily mean temperature series were projected under four scenarios of greenhouse gas emissions from 1971-2099, with five general circulation models. We projected excess mortality in relation to heatwaves in the future under each scenario of greenhouse gas emissions, with two assumptions for adaptation (no adaptation and hypothetical adaptation) and three scenarios of population change (high variant, median variant, and low variant). Results show that, if there is no adaptation, heatwave-related excess mortality is expected to increase the most in tropical and subtropical countries/regions (close to the equator), while European countries and the United States will have smaller percent increases in heatwave-related excess mortality. The higher the population variant and the greenhouse gas emissions, the higher the increase of heatwave-related excess mortality in the future. The changes in 2031-2080 compared with 1971-2020 range from approximately 2,000% in Colombia to 150% in Moldova under the highest emission scenario and high-variant population scenario, without any adaptation. If we considered hypothetical adaptation to future climate, under high-variant population scenario and all scenarios of greenhouse gas emissions, the heatwave-related excess mortality is expected to still increase across all the countries/regions except Moldova and Japan. However, the increase would be much smaller than the no adaptation scenario. The simple assumptions with respect to adaptation as follows: no adaptation and hypothetical adaptation results in some uncertainties of projections.Conclusions: This study provides a comprehensive characterisation of future heatwave-related excess mortality across various regions and under alternative scenarios of greenhouse gas emissions, different assumptions of adaptation, and different scenarios of population change. The projections can help decision makers in planning adaptation and mitigation strategies for climate change. [ABSTRACT FROM AUTHOR]

Background: Air pollution damages health by promoting the onset of some non-communicable diseases (NCDs), putting additional strain on the National Health Service (NHS) and social care. This study quantifies the total health and related NHS and social care cost burden due to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) in England.Method and Findings: Air pollutant concentration surfaces from land use regression models and cost data from hospital admissions data and a literature review were fed into a microsimulation model, that was run from 2015 to 2035. Different scenarios were modelled: (1) baseline 'no change' scenario; (2) individuals' pollutant exposure is reduced to natural (non-anthropogenic) levels to compute the disease cases attributable to PM2.5 and NO2; (3) PM2.5 and NO2 concentrations reduced by 1 μg/m3; and (4) NO2 annual European Union limit values reached (40 μg/m3). For the 18 years after baseline, the total cumulative cost to the NHS and social care is estimated at £5.37 billion for PM2.5 and NO2 combined, rising to £18.57 billion when costs for diseases for which there is less robust evidence are included. These costs are due to the cumulative incidence of air-pollution-related NCDs, such as 348,878 coronary heart disease cases estimated to be attributable to PM2.5 and 573,363 diabetes cases estimated to be attributable to NO2 by 2035. Findings from modelling studies are limited by the conceptual model, assumptions, and the availability and quality of input data.Conclusions: Approximately 2.5 million cases of NCDs attributable to air pollution are predicted by 2035 if PM2.5 and NO2 stay at current levels, making air pollution an important public health priority. In future work, the modelling framework should be updated to include multi-pollutant exposure-response functions, as well as to disaggregate results by socioeconomic status. [ABSTRACT FROM AUTHOR]

Background: Policies to mitigate climate change by reducing greenhouse gas (GHG) emissions can yield public health benefits by also reducing emissions of hazardous co-pollutants, such as air toxics and particulate matter. Socioeconomically disadvantaged communities are typically disproportionately exposed to air pollutants, and therefore climate policy could also potentially reduce these environmental inequities. We sought to explore potential social disparities in GHG and co-pollutant emissions under an existing carbon trading program-the dominant approach to GHG regulation in the US and globally.Methods and Findings: We examined the relationship between multiple measures of neighborhood disadvantage and the location of GHG and co-pollutant emissions from facilities regulated under California's cap-and-trade program-the world's fourth largest operational carbon trading program. We examined temporal patterns in annual average emissions of GHGs, particulate matter (PM2.5), nitrogen oxides, sulfur oxides, volatile organic compounds, and air toxics before (January 1, 2011-December 31, 2012) and after (January 1, 2013-December 31, 2015) the initiation of carbon trading. We found that facilities regulated under California's cap-and-trade program are disproportionately located in economically disadvantaged neighborhoods with higher proportions of residents of color, and that the quantities of co-pollutant emissions from these facilities were correlated with GHG emissions through time. Moreover, the majority (52%) of regulated facilities reported higher annual average local (in-state) GHG emissions since the initiation of trading. Neighborhoods that experienced increases in annual average GHG and co-pollutant emissions from regulated facilities nearby after trading began had higher proportions of people of color and poor, less educated, and linguistically isolated residents, compared to neighborhoods that experienced decreases in GHGs. These study results reflect preliminary emissions and social equity patterns of the first 3 years of California's cap-and-trade program for which data are available. Due to data limitations, this analysis did not assess the emissions and equity implications of GHG reductions from transportation-related emission sources. Future emission patterns may shift, due to changes in industrial production decisions and policy initiatives that further incentivize local GHG and co-pollutant reductions in disadvantaged communities.Conclusions: To our knowledge, this is the first study to examine social disparities in GHG and co-pollutant emissions under an existing carbon trading program. Our results indicate that, thus far, California's cap-and-trade program has not yielded improvements in environmental equity with respect to health-damaging co-pollutant emissions. This could change, however, as the cap on GHG emissions is gradually lowered in the future. The incorporation of additional policy and regulatory elements that incentivize more local emission reductions in disadvantaged communities could enhance the local air quality and environmental equity benefits of California's climate change mitigation efforts. [ABSTRACT FROM AUTHOR]

Background: In many regions globally, buildings designed for harnessing heat during the cold exacerbate thermal exposures during heat waves (HWs) by maintaining elevated indoor temperatures even when high ambient temperatures have subdued. While previous experimental studies have documented the effects of ambient temperatures on cognitive function, few have observed HW effects on indoor temperatures following subjects' habitual conditions. The objective was to evaluate the differential impact of having air conditioning (AC) on cognitive function during a HW among residents of AC and non-AC buildings using a prospective observational cohort study.Methods: We followed 44 students (mean age = 20.2 years; SD = 1.8 years) from a university in the Greater Boston area, Massachusetts in the United States living in AC (n = 24) and non-AC (n = 20) buildings before, during, and after a HW. Two cognition tests were self-administered daily for a period of 12 days (July 9-July 20, 2016), the Stroop color-word test (STROOP) to assess selective attention/processing speed and a 2-digit, visual addition/subtraction test (ADD) to evaluate cognitive speed and working memory. The effect of the HW on cognitive function was evaluated using difference-in-differences (DiD) modelling.Findings: Mean indoor temperatures in the non-AC group (mean = 26.3°C; SD = 2.5°C; range = 19.6-30.4°C) were significantly higher (p < 0.001) than in the AC group (mean = 21.4°C; SD = 1.9°C; range = 17.5-25.0°C). DiD estimates show an increase in reaction time (STROOP = 13.4%, p < 0001; ADD = 13.3%, p < 0.001) and reduction in throughput (STROOP = -9.9%, p < 0.001; ADD = -6.3%, p = 0.08) during HWs among non-AC residents relative to AC residents at baseline. While ADD showed a linear relationship with indoor temperatures, STROOP was described by a U-shaped curve with linear effects below and above an optimum range (indoor temperature = 22°C-23°C), with an increase in reaction time of 16 ms/°C and 24 ms/°C for STROOP and ADD, respectively. Cognitive tests occurred right after waking, so the study is limited in that it cannot assess whether the observed effects extended during the rest of the day. Although the range of students' ages also represents a limitation of the study, the consistent findings in this young, healthy population might indicate that greater portions of the population are susceptible to the effects of extreme heat.Conclusions: Cognitive function deficits resulting from indoor thermal conditions during HWs extend beyond vulnerable populations. Our findings highlight the importance of incorporating sustainable adaptation measures in buildings to preserve educational attainment, economic productivity, and safety in light of a changing climate. [ABSTRACT FROM AUTHOR]

Background: Rising atmospheric carbon dioxide concentrations are anticipated to decrease the zinc and iron concentrations of crops. The associated disease burden and optimal mitigation strategies remain unknown. We sought to understand where and to what extent increasing carbon dioxide concentrations may increase the global burden of nutritional deficiencies through changes in crop nutrient concentrations, and the effects of potential mitigation strategies.Methods and Findings: For each of 137 countries, we incorporated estimates of climate change, crop nutrient concentrations, dietary patterns, and disease risk into a microsimulation model of zinc and iron deficiency. These estimates were obtained from the Intergovernmental Panel on Climate Change, US Department of Agriculture, Statistics Division of the Food and Agriculture Organization of the United Nations, and Global Burden of Disease Project, respectively. In the absence of increasing carbon dioxide concentrations, we estimated that zinc and iron deficiencies would induce 1,072.9 million disability-adjusted life years (DALYs) globally over the period 2015 to 2050 (95% credible interval [CrI]: 971.1-1,167.7). In the presence of increasing carbon dioxide concentrations, we estimated that decreasing zinc and iron concentrations of crops would induce an additional 125.8 million DALYs globally over the same period (95% CrI: 113.6-138.9). This carbon-dioxide-induced disease burden is projected to disproportionately affect nations in the World Health Organization's South-East Asia and African Regions (44.0 and 28.5 million DALYs, respectively), which already have high existing disease burdens from zinc and iron deficiencies (364.3 and 299.5 million DALYs, respectively), increasing global nutritional inequalities. A climate mitigation strategy such as the Paris Agreement (an international agreement to keep global temperatures within 2°C of pre-industrial levels) would be expected to avert 48.2% of this burden (95% CrI: 47.8%-48.5%), while traditional public health interventions including nutrient supplementation and disease control programs would be expected to avert 26.6% of the burden (95% CrI: 23.8%-29.6%). Of the traditional public health interventions, zinc supplementation would be expected to avert 5.5%, iron supplementation 15.7%, malaria mitigation 3.2%, pneumonia mitigation 1.6%, and diarrhea mitigation 0.5%. The primary limitations of the analysis include uncertainty regarding how food consumption patterns may change with climate, how disease mortality rates will change over time, and how crop zinc and iron concentrations will decline from those at present to those in 2050.Conclusions: Effects of increased carbon dioxide on crop nutrient concentrations are anticipated to exacerbate inequalities in zinc and iron deficiencies by 2050. Proposed Paris Agreement strategies are expected to be more effective than traditional public health measures to avert the increased inequality. [ABSTRACT FROM AUTHOR]

Background: Climate change is likely to further worsen ozone pollution in already heavily polluted areas, leading to increased ozone-related health burdens. However, little evidence exists in China, the world's largest greenhouse gas emitter and most populated country. As China is embracing an aging population with changing population size and falling age-standardized mortality rates, the potential impact of population change on ozone-related health burdens is unclear. Moreover, little is known about the seasonal variation of ozone-related health burdens under climate change. We aimed to assess near-term (mid-21st century) future annual and seasonal excess mortality from short-term exposure to ambient ozone in 104 Chinese cities under 2 climate and emission change scenarios and 6 population change scenarios.Methods and Findings: We collected historical ambient ozone observations, population change projections, and baseline mortality rates in 104 cities across China during April 27, 2013, to October 31, 2015 (2013-2015), which included approximately 13% of the total population of mainland China. Using historical ozone monitoring data, we performed bias correction and spatially downscaled future ozone projections at a coarse spatial resolution (2.0° × 2.5°) for the period April 27, 2053, to October 31, 2055 (2053-2055), from a global chemistry-climate model to a fine spatial resolution (0.25° × 0.25°) under 2 Intergovernmental Panel on Climate Change Representative Concentration Pathways (RCPs): RCP4.5, a moderate global warming and emission scenario where global warming is between 1.5°C and 2.0°C, and RCP8.5, a high global warming and emission scenario where global warming exceeds 2.0°C. We then estimated the future annual and seasonal ozone-related acute excess mortality attributable to both climate and population changes using cause-specific, age-group-specific, and season-specific concentration-response functions (CRFs). We used Monte Carlo simulations to obtain empirical confidence intervals (eCIs), quantifying the uncertainty in CRFs and the variability across ensemble members (i.e., 3 predictions of future climate and air quality from slightly different starting conditions) of the global model. Estimates of future changes in annual ozone-related mortality are sensitive to the choice of global warming and emission scenario, decreasing under RCP4.5 (-24.0%) due to declining ozone precursor emissions but increasing under RCP8.5 (10.7%) due to warming climate in 2053-2055 relative to 2013-2015. Higher ambient ozone occurs under the high global warming and emission scenario (RCP8.5), leading to an excess 1,476 (95% eCI: 898 to 2,977) non-accidental deaths per year in 2053-2055 relative to 2013-2015. Future ozone-related acute excess mortality from cardiovascular diseases was 5-8 times greater than that from respiratory diseases. Ozone concentrations increase by 15.1 parts per billion (10-9) in colder months (November to April), contributing to a net yearly increase of 22.3% (95% eCI: 7.7% to 35.4%) in ozone-related mortality under RCP8.5. An aging population, with the proportion of the population aged 65 years and above increased from 8% in 2010 to 24%-33% in 2050, will substantially amplify future ozone-related mortality, leading to a net increase of 23,838 to 78,560 deaths (110% to 363%). Our analysis was mainly limited by using a single global chemistry-climate model and the statistical downscaling approach to project ozone changes under climate change.Conclusions: Our analysis shows increased future ozone-related acute excess mortality under the high global warming and emission scenario RCP8.5 for an aging population in China. Comparison with the lower global warming and emission scenario RCP4.5 suggests that climate change mitigation measures are needed to prevent a rising health burden from exposure to ambient ozone pollution in China. [ABSTRACT FROM AUTHOR]

Background: Climate change negatively impacts human health through heat stress and exposure to worsened air pollution, amongst other pathways. Indoor use of air conditioning can be an effective strategy to reduce heat exposure. However, increased air conditioning use increases emissions of air pollutants from power plants, in turn worsening air quality and human health impacts. We used an interdisciplinary linked model system to quantify the impacts of heat-driven adaptation through building cooling demand on air-quality-related health outcomes in a representative mid-century climate scenario.Methods and Findings: We used a modeling system that included downscaling historical and future climate data with the Weather Research and Forecasting (WRF) model, simulating building electricity demand using the Regional Building Energy Simulation System (RBESS), simulating power sector production and emissions using MyPower, simulating ambient air quality using the Community Multiscale Air Quality (CMAQ) model, and calculating the incidence of adverse health outcomes using the Environmental Benefits Mapping and Analysis Program (BenMAP). We performed simulations for a representative present-day climate scenario and 2 representative mid-century climate scenarios, with and without exacerbated power sector emissions from adaptation in building energy use. We find that by mid-century, climate change alone can increase fine particulate matter (PM2.5) concentrations by 58.6% (2.50 μg/m3) and ozone (O3) by 14.9% (8.06 parts per billion by volume [ppbv]) for the month of July. A larger change is found when comparing the present day to the combined impact of climate change and increased building energy use, where PM2.5 increases 61.1% (2.60 μg/m3) and O3 increases 15.9% (8.64 ppbv). Therefore, 3.8% of the total increase in PM2.5 and 6.7% of the total increase in O3 is attributable to adaptive behavior (extra air conditioning use). Health impacts assessment finds that for a mid-century climate change scenario (with adaptation), annual PM2.5-related adult mortality increases by 13,547 deaths (14 concentration-response functions with mean incidence range of 1,320 to 26,481, approximately US$126 billion cost) and annual O3-related adult mortality increases by 3,514 deaths (3 functions with mean incidence range of 2,175 to 4,920, approximately US$32.5 billion cost), calculated as a 3-month summer estimate based on July modeling. Air conditioning adaptation accounts for 654 (range of 87 to 1,245) of the PM2.5-related deaths (approximately US$6 billion cost, a 4.8% increase above climate change impacts alone) and 315 (range of 198 to 438) of the O3-related deaths (approximately US$3 billion cost, an 8.7% increase above climate change impacts alone). Limitations of this study include modeling only a single month, based on 1 model-year of future climate simulations. As a result, we do not project the future, but rather describe the potential damages from interactions arising between climate, energy use, and air quality.Conclusions: This study examines the contribution of future air-pollution-related health damages that are caused by the power sector through heat-driven air conditioning adaptation in buildings. Results show that without intervention, approximately 5%-9% of exacerbated air-pollution-related mortality will be due to increases in power sector emissions from heat-driven building electricity demand. This analysis highlights the need for cleaner energy sources, energy efficiency, and energy conservation to meet our growing dependence on building cooling systems and simultaneously mitigate climate change. [ABSTRACT FROM AUTHOR]

Background: Observational studies have reported that higher plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with lower risks of diabetes, but it is unclear if these associations are causal. The aim of this study was to test the relevance of 25(OH)D for type 2 diabetes using genetically instrumented differences in plasma 25(OH)D concentrations.Methods and Findings: Data were available on four 25(OH)D single nucleotide polymorphisms (SNPs; n = 82,464), plasma 25(OH)D concentrations (n = 13,565), and cases with diabetes (n = 5,565) in the China Kadoorie Biobank (CKB). The effects on risk of diabetes were assessed by a genetic score using two 25(OH)D synthesis SNPs (DHCR7-rs12785878 and CYP2R1-rs10741657), with and without the addition of SNPs affecting the transport (GC/DBP-rs2282679) and catabolism (CYP24A1-rs6013897) of 25(OH)D. The CKB results were combined in a meta-analysis of 10 studies for the 2 synthesis SNPs (n = 58,312 cases) and 7 studies for all 4 SNPs (n = 32,796 cases). Mean (SD) 25(OH)D concentration was 62 (20) nmol/l in CKB, and the per allele effects of genetic scores on 25(OH)D were 2.87 (SE 0.39) for the synthesis SNPs and 3.54 (SE 0.32) for all SNPs. A 25-nmol/l higher biochemically measured 25(OH)D was associated with a 9% (95% CI: 0%-18%) lower risk of diabetes in CKB. In a meta-analysis of all studies, a 25-nmol/l higher genetically instrumented 25(OH)D concentration was associated with a 14% (95% CI: 3%-23%) lower risk of diabetes (p = 0.01) using the 2 synthesis SNPs. An equivalent difference in 25(OH)D using a genetic score with 4 SNPs was not significantly associated with diabetes (odds ratio 8%, 95% CI: -1% to 16%, lower risk, p = 0.07), but had some evidence of pleiotropy. A limitation of the meta-analysis was the access only to study level rather than individual level data.Conclusions: The concordant risks of diabetes for biochemically measured and genetically instrumented differences in 25(OH)D using synthesis SNPs provide evidence for a causal effect of higher 25(OH)D for prevention of diabetes. [ABSTRACT FROM AUTHOR]

Background: Tobacco addiction is a complex, multicomponent phenomenon stemming from nicotine's pharmacology and the user's biology, psychology, sociology, and environment. After decades of public denial, the tobacco industry now agrees with public health authorities that nicotine is addictive. In 2000, Philip Morris became the first major tobacco company to admit nicotine's addictiveness. Evolving definitions of addiction have historically affected subsequent policymaking. This article examines how Philip Morris internally conceptualized addiction immediately before and after this announcement.Methods and Findings: We analyzed previously secret, internal Philip Morris documents made available as a result of litigation against the tobacco industry. We compared these documents to public company statements and found that Philip Morris's move from public denial to public affirmation of nicotine's addictiveness coincided with pressure on the industry from poor public approval ratings, the Master Settlement Agreement (MSA), the United States government's filing of the Racketeer Influenced and Corrupt Organizations (RICO) suit, and the Institute of Medicine's (IoM's) endorsement of potentially reduced risk products. Philip Morris continued to research the causes of addiction through the 2000s in order to create successful potentially reduced exposure products (PREPs). While Philip Morris's public statements reinforce the idea that nicotine's pharmacology principally drives smoking addiction, company scientists framed addiction as the result of interconnected biological, social, psychological, and environmental determinants, with nicotine as but one component. Due to the fragmentary nature of the industry document database, we may have missed relevant information that could have affected our analysis.Conclusions: Philip Morris's research suggests that tobacco industry activity influences addiction treatment outcomes. Beyond nicotine's pharmacology, the industry's continued aggressive advertising, lobbying, and litigation against effective tobacco control policies promotes various nonpharmacological determinants of addiction. To help tobacco users quit, policy makers should increase attention on the social and environmental dimensions of addiction alongside traditional cessation efforts. [ABSTRACT FROM AUTHOR]

Background: Babies born preterm are at an increased risk of dying in the first weeks of life, and those who survive have a higher rate of cerebral palsy (CP) compared with babies born at term. The aim of this individual participant data (IPD) meta-analysis (MA) was to assess the effects of antenatal magnesium sulphate, compared with no magnesium treatment, given to women at risk of preterm birth on important maternal and fetal outcomes, including survival free of CP, and whether effects differed by participant or treatment characteristics such as the reason the woman was at risk of preterm birth, why treatment was given, the gestational age at which magnesium sulphate treatment was received, or the dose and timing of the administration of magnesium sulphate.Methods and Findings: Trials in which women considered at risk of preterm birth (<37 weeks' gestation) were randomised to magnesium sulphate or control treatment and where neurologic outcomes for the baby were reported were eligible for inclusion. The primary outcomes were infant death or CP and severe maternal outcome potentially related to treatment. Studies were identified based on the Cochrane Pregnancy and Childbirth search strategy using the terms [antenatal or prenatal] and [magnesium] and [preterm or premature or neuroprotection or 'cerebral palsy']. The date of the last search was 28 February 2017. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. For each prespecified outcome, IPD were analysed using a 1-stage approach. All 5 trials identified were included, with 5,493 women and 6,131 babies. Overall, there was no clear effect of magnesium sulphate treatment compared with no treatment on the primary infant composite outcome of death or CP (relative risk [RR] 0.94, 95% confidence interval (CI) 0.85 to 1.05, 6,131 babies, 5 trials, p = 0.07 for heterogeneity of treatment effect across trials). In the prespecified sensitivity analysis restricted to data from the 4 trials in which the intent of treatment was fetal neuroprotection, there was a significant reduction in the risk of death or CP with magnesium sulphate treatment compared with no treatment (RR 0.86, 95% CI 0.75 to 0.99, 4,448 babies, 4 trials), with no significant heterogeneity (p = 0.28). The number needed to treat (NNT) to benefit was 41 women/babies to prevent 1 baby from either dying or having CP. For the primary outcome of severe maternal outcome potentially related to magnesium sulphate treatment, no events were recorded from the 2 trials providing data. When the individual components of the composite infant outcome were assessed, no effect was seen for death overall (RR 1.03, 95% CI 0.91 to 1.17, 6,131 babies, 5 trials) or in the analysis of death using only data from trials with the intent of fetal neuroprotection (RR 0.95, 95% CI 0.80 to 1.13, 4,448 babies, 4 trials). For cerebral palsy in survivors, magnesium sulphate treatment had a strong protective effect in both the overall analysis (RR 0.68, 95% CI 0.54 to 0.87, 4,601 babies, 5 trials, NNT to benefit 46) and the neuroprotective intent analysis (RR 0.68, 95% CI 0.53 to 0.87, 3,988 babies, 4 trials, NNT to benefit 42). No statistically significant differences were seen for any of the other secondary outcomes. The treatment effect varied little by the reason the woman was at risk of preterm birth, the gestational age at which magnesium sulphate treatment was given, the total dose received, or whether maintenance therapy was used. A limitation of the study was that not all trials could provide the data required for the planned analyses so that combined with low event rates for some important clinical events, the power to find a difference was limited.Conclusions: Antenatal magnesium sulphate given prior to preterm birth for fetal neuroprotection prevents CP and reduces the combined risk of fetal/infant death or CP. Benefit is seen regardless of the reason for preterm birth, with similar effects across a range of preterm gestational ages and different treatment regimens. Widespread adoption worldwide of this relatively inexpensive, easy-to-administer treatment would lead to important global health benefits for infants born preterm. [ABSTRACT FROM AUTHOR]

Background: Counselling for Alcohol Problems (CAP), a brief intervention delivered by lay counsellors, enhanced remission and abstinence over 3 months among male primary care attendees with harmful drinking in a setting in India. We evaluated the sustainability of the effects after treatment termination, the cost-effectiveness of CAP over 12 months, and the effects of the hypothesized mediator 'readiness to change' on clinical outcomes.Methods and Findings: Male primary care attendees aged 18-65 years screening with harmful drinking on the Alcohol Use Disorders Identification Test (AUDIT) were randomised to either CAP plus enhanced usual care (EUC) (n = 188) or EUC alone (n = 189), of whom 89% completed assessments at 3 months, and 84% at 12 months. Primary outcomes were remission and mean standard ethanol consumed in the past 14 days, and the proposed mediating variable was readiness to change at 3 months. CAP participants maintained the gains they showed at the end of treatment through the 12-month follow-up, with the proportion with remission (AUDIT score < 8: 54.3% versus 31.9%; adjusted prevalence ratio [aPR] 1.71 [95% CI 1.32, 2.22]; p < 0.001) and abstinence in the past 14 days (45.1% versus 26.4%; adjusted odds ratio 1.92 [95% CI 1.19, 3.10]; p = 0.008) being significantly higher in the CAP plus EUC arm than in the EUC alone arm. CAP participants also fared better on secondary outcomes including recovery (AUDIT score < 8 at 3 and 12 months: 27.4% versus 15.1%; aPR 1.90 [95% CI 1.21, 3.00]; p = 0.006) and percent of days abstinent (mean percent [SD] 71.0% [38.2] versus 55.0% [39.8]; adjusted mean difference 16.1 [95% CI 7.1, 25.0]; p = 0.001). The intervention effect for remission was higher at 12 months than at 3 months (aPR 1.50 [95% CI 1.09, 2.07]). There was no evidence of an intervention effect on Patient Health Questionnaire 9 score, suicidal behaviour, percentage of days of heavy drinking, Short Inventory of Problems score, WHO Disability Assessment Schedule 2.0 score, days unable to work, or perpetration of intimate partner violence. Economic analyses indicated that CAP plus EUC was dominant over EUC alone, with lower costs and better outcomes; uncertainty analysis showed a 99% chance of CAP being cost-effective per remission achieved from a health system perspective, using a willingness to pay threshold equivalent to 1 month's wages for an unskilled manual worker in Goa. Readiness to change level at 3 months mediated the effect of CAP on mean standard ethanol consumption at 12 months (indirect effect -6.014 [95% CI -13.99, -0.046]). Serious adverse events were infrequent, and prevalence was similar by arm. The methodological limitations of this trial are the susceptibility of self-reported drinking to social desirability bias, the modest participation rates of eligible patients, and the examination of mediation effects of only 1 mediator and in only half of our sample.Conclusions: CAP's superiority over EUC at the end of treatment was largely stable over time and was mediated by readiness to change. CAP provides better outcomes at lower costs from a societal perspective.Trial Registration: ISRCTN registry ISRCTN76465238. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is a major contributor to morbidity and mortality. Computerized tomography (CT) scanning of the brain is essential for diagnostic screening of intracranial injuries in need of neurosurgical intervention, but may also provide information concerning patient prognosis and enable baseline risk stratification in clinical trials. Novel CT scoring systems have been developed to improve current prognostic models, including the Stockholm and Helsinki CT scores, but so far have not been extensively validated. The primary aim of this study was to evaluate the Stockholm and Helsinki CT scores for predicting functional outcome, in comparison with the Rotterdam CT score and Marshall CT classification. The secondary aims were to assess which individual components of the CT scores best predict outcome and what additional prognostic value the CT scoring systems contribute to a clinical prognostic model.Methods and Findings: TBI patients requiring neuro-intensive care and not included in the initial creation of the Stockholm and Helsinki CT scoring systems were retrospectively included from prospectively collected data at the Karolinska University Hospital (n = 720 from 1 January 2005 to 31 December 2014) and Helsinki University Hospital (n = 395 from 1 January 2013 to 31 December 2014), totaling 1,115 patients. The Marshall CT classification and the Rotterdam, Stockholm, and Helsinki CT scores were assessed using the admission CT scans. Known outcome predictors at admission were acquired (age, pupil responsiveness, admission Glasgow Coma Scale, glucose level, and hemoglobin level) and used in univariate, and multivariable, regression models to predict long-term functional outcome (dichotomizations of the Glasgow Outcome Scale [GOS]). In total, 478 patients (43%) had an unfavorable outcome (GOS 1-3). In the combined cohort, overall prognostic performance was more accurate for the Stockholm CT score (Nagelkerke's pseudo-R2 range 0.24-0.28) and the Helsinki CT score (0.18-0.22) than for the Rotterdam CT score (0.13-0.15) and Marshall CT classification (0.03-0.05). Moreover, the Stockholm and Helsinki CT scores added the most independent prognostic value in the presence of other known clinical outcome predictors in TBI (6% and 4%, respectively). The aggregate traumatic subarachnoid hemorrhage (tSAH) component of the Stockholm CT score was the strongest predictor of unfavorable outcome. The main limitations were the retrospective nature of the study, missing patient information, and the varying follow-up time between the centers.Conclusions: The Stockholm and Helsinki CT scores provide more information on the damage sustained, and give a more accurate outcome prediction, than earlier classification systems. The strong independent predictive value of tSAH may reflect an underrated component of TBI pathophysiology. A change to these newer CT scoring systems may be warranted. [ABSTRACT FROM AUTHOR]

In a Perspective, Hasan Alam discusses emerging treatment approaches in trauma care. [ABSTRACT FROM AUTHOR]

Background: Early revascularization of ischemic organs is key to improving outcomes, yet consequent reperfusion injury may be harmful. Reperfusion injury is largely attributed to excess mitochondrial production of reactive oxygen species (ROS). Sulfide inhibits mitochondria and reduces ROS production. Ammonium tetrathiomolybdate (ATTM), a copper chelator, releases sulfide in a controlled and novel manner, and may offer potential therapeutic utility.Methods and Findings: In vitro, ATTM releases sulfide in a time-, pH-, temperature-, and thiol-dependent manner. Controlled sulfide release from ATTM reduces metabolism (measured as oxygen consumption) both in vivo in awake rats and ex vivo in skeletal muscle tissue, with a superior safety profile compared to standard sulfide generators. Given intravenously at reperfusion/resuscitation to rats, ATTM significantly reduced infarct size following either myocardial or cerebral ischemia, and conferred survival benefit following severe hemorrhage. Mechanistic studies (in vitro anoxia/reoxygenation) demonstrated a mitochondrial site of action (decreased MitoSOX fluorescence), where the majority of damaging ROS is produced.Conclusions: The inorganic thiometallate ATTM represents a new class of sulfide-releasing drugs. Our findings provide impetus for further investigation of this compound as a novel adjunct therapy for reperfusion injury. [ABSTRACT FROM AUTHOR]

Background: Low circulating vitamin D levels have been associated with risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). These epidemiological associations, if true, would have public health importance, since vitamin D insufficiency is common and correctable.Methods and Findings: We aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology to control bias owing to confounding and reverse causation. The study employed data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, we conducted MR studies to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p ≥ 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90-1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69-1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92-1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was -0.40 (95% CI -1.65 to 0.85, p = 0.54). These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways. The main limitations of this study are that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, and the analyses were restricted to white populations of European ancestry. This research has been conducted using the UK Biobank Resource and data from the SUNLIGHT, GABRIEL and EAGLE Eczema consortia.Conclusions: In this study, we found no evidence that genetically determined reduction in 25OHD levels conferred an increased risk of asthma, atopic dermatitis, or elevated total serum IgE, suggesting that efforts to increase vitamin D are unlikely to reduce risks of atopic disease. [ABSTRACT FROM AUTHOR]

Background: Animal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment.Methods and Findings: Electronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model. There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08-1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36-1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6-12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54-2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26-2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52-2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%-3.5%]) and quinine exposures (1.2% [95% CI 0.6%-2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns.Conclusions: Compared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens.Review Registration: PROSPERO CRD42015032371. [ABSTRACT FROM AUTHOR]

Background: Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with resistance to treatment, including steroids, which are currently the cornerstone for treating ALL; moreover, initial steroid response strongly predicts survival and cure. However, the cellular mechanisms underlying steroid resistance in T-ALL patients are poorly understood. In this study, we combined various genomic datasets in order to identify candidate genetic mechanisms underlying steroid resistance in children undergoing T-ALL treatment.Methods and Findings: We performed whole genome sequencing on paired pre-treatment (diagnostic) and post-treatment (remission) samples from 13 patients, and targeted exome sequencing of pre-treatment samples from 69 additional T-ALL patients. We then integrated mutation data with copy number data for 151 mutated genes, and this integrated dataset was tested for associations of mutations with clinical outcomes and in vitro drug response. Our analysis revealed that mutations in JAK1 and KRAS, two genes encoding components of the interleukin 7 receptor (IL7R) signaling pathway, were associated with steroid resistance and poor outcome. We then sequenced JAK1, KRAS, and other genes in this pathway, including IL7R, JAK3, NF1, NRAS, and AKT, in these 69 T-ALL patients and a further 77 T-ALL patients. We identified mutations in 32% (47/146) of patients, the majority of whom had a specific T-ALL subtype (early thymic progenitor ALL or TLX). Based on the outcomes of these patients and their prednisolone responsiveness measured in vitro, we then confirmed that these mutations were associated with both steroid resistance and poor outcome. To explore how these mutations in IL7R signaling pathway genes cause steroid resistance and subsequent poor outcome, we expressed wild-type and mutant IL7R signaling molecules in two steroid-sensitive T-ALL cell lines (SUPT1 and P12 Ichikawa cells) using inducible lentiviral expression constructs. We found that expressing mutant IL7R, JAK1, or NRAS, or wild-type NRAS or AKT, specifically induced steroid resistance without affecting sensitivity to vincristine or L-asparaginase. In contrast, wild-type IL7R, JAK1, and JAK3, as well as mutant JAK3 and mutant AKT, had no effect. We then performed a functional study to examine the mechanisms underlying steroid resistance and found that, rather than changing the steroid receptor's ability to activate downstream targets, steroid resistance was associated with strong activation of MEK-ERK and AKT, downstream components of the IL7R signaling pathway, thereby inducing a robust antiapoptotic response by upregulating MCL1 and BCLXL expression. Both the MEK-ERK and AKT pathways also inactivate BIM, an essential molecule for steroid-induced cell death, and inhibit GSK3B, an important regulator of proapoptotic BIM. Importantly, treating our cell lines with IL7R signaling inhibitors restored steroid sensitivity. To address clinical relevance, we treated primary T-ALL cells obtained from 11 patients with steroids either alone or in combination with IL7R signaling inhibitors; we found that including a MEK, AKT, mTOR, or dual PI3K/mTOR inhibitor strongly increased steroid-induced cell death. Therefore, combining these inhibitors with steroid treatment may enhance steroid sensitivity in patients with ALL. The main limitation of our study was the modest cohort size, owing to the very low incidence of T-ALL.Conclusions: Using an unbiased sequencing approach, we found that specific mutations in IL7R signaling molecules underlie steroid resistance in T-ALL. Future prospective clinical studies should test the ability of inhibitors of MEK, AKT, mTOR, or PI3K/mTOR to restore or enhance steroid sensitivity and improve clinical outcome. [ABSTRACT FROM AUTHOR]

In a Perspective, Pieter Van Vlierberghe and Steven Goossens discuss Meijerink and colleagues' findings on steroid resistance in pediatric T cell acute lymphoblastic leukemia. [ABSTRACT FROM AUTHOR]

Background: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question.Methods and Findings: Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10-25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes.Conclusions: Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Neonatal hypoglycaemia is common, affecting up to 15% of newborns, and can cause brain damage. Currently, there are no strategies, beyond early feeding, to prevent neonatal hypoglycaemia. Our aim was to determine a dose of 40% oral dextrose gel that will prevent neonatal hypoglycaemia in newborn babies at risk.Methods and Findings: We conducted a randomised, double-blind, placebo-controlled dose-finding trial of buccal dextrose gel to prevent neonatal hypoglycaemia at two hospitals in New Zealand. Babies at risk of hypoglycaemia (infant of a mother with diabetes, late preterm delivery, small or large birthweight, or other risk factors) but without indication for admission to a neonatal intensive care unit (NICU) were randomly allocated either to one of four treatment groups: 40% dextrose at one of two doses (0.5 ml/kg = 200 mg/kg, or 1 ml/kg = 400 mg/kg), either once at 1 h of age or followed by three additional doses of dextrose (0.5 ml/kg before feeds in the first 12 h); or to one of four corresponding placebo groups. Treatments were administered by massaging gel into the buccal mucosa. The primary outcome was hypoglycaemia (<2.6 mM) in the first 48 h. Secondary outcomes included admission to a NICU, admission for hypoglycaemia, and breastfeeding at discharge and at 6 wk. Prespecified potential dose limitations were tolerance of gel, time taken to administer, messiness, and acceptability to parents. From August 2013 to November 2014, 416 babies were randomised. Compared to babies randomised to placebo, the risk of hypoglycaemia was lowest in babies randomised to a single dose of 200 mg/kg dextrose gel (relative risk [RR] 0.68; 95% confidence interval [CI] 0.47-0.99, p = 0.04) but was not significantly different between dose groups (p = 0.21). Compared to multiple doses, single doses of gel were better tolerated, quicker to administer, and less messy, but these limitations were not different between dextrose and placebo gel groups. Babies who received any dose of dextrose gel were less likely to develop hypoglycaemia than those who received placebo (RR 0.79; 95% CI 0.64-0.98, p = 0.03; number needed to treat = 10, 95% CI 5-115). Rates of NICU admission were similar (RR 0.64; 95% CI 0.33-1.25, p = 0.19), but admission for hypoglycaemia was less common in babies randomised to dextrose gel (RR 0.46; 95% CI 0.21-1.01, p = 0.05). Rates of breastfeeding were similar in both groups. Adverse effects were uncommon and not different between groups. A limitation of this study was that most of the babies in the trial were infants of mothers with diabetes (73%), which may reduce the applicability of the results to babies from other risk groups.Conclusions: The incidence of neonatal hypoglycaemia can be reduced with a single dose of buccal 40% dextrose gel 200 mg/kg. A large randomised trial (Hypoglycaemia Prevention with Oral Dextrose [hPOD]) is under way to determine the effects on NICU admission and later outcomes.Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12613000322730. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) is commonly managed in primary care, but most guidelines have a secondary care perspective emphasizing the risk of end-stage kidney disease (ESKD) and need for renal replacement therapy. In this prospective cohort study, we sought to study in detail the natural history of CKD in primary care to better inform the appropriate emphasis for future guidance.Methods and Findings: In this study, 1,741 people with CKD stage 3 were individually recruited from 32 primary care practices in Derbyshire, United Kingdom. Study visits were undertaken at baseline, year 1, and year 5. Binomial logistic regression and Cox proportional hazards models were used to model progression, CKD remission, and all-cause mortality. We used Kidney Disease: Improving Global Outcomes (KDIGO) criteria to define CKD progression and defined CKD remission as the absence of diagnostic criteria (estimated glomerular filtration rate [eGFR] >60 ml/min/1.73 m2 and urine albumin-to-creatinine ratio [uACR] <3 mg/mmol) at any study visit. Participants were predominantly elderly (mean ± standard deviation (SD) age 72.9 ± 9.0 y), with relatively mild reduction in GFR (mean ± SD eGFR 53.5 ± 11.8 mL/min/1,73 m2) and a low prevalence of albuminuria (16.9%). After 5 y, 247 participants (14.2%) had died, most of cardiovascular causes. Only 4 (0.2%) developed ESKD, but 308 (17.7%) evidenced CKD progression by KDIGO criteria. Stable CKD was observed in 593 participants (34.1%), and 336 (19.3%) met the criteria for remission. Remission at baseline and year 1 was associated with a high likelihood of remission at year 5 (odds ratio [OR] = 23.6, 95% CI 16.5-33.9 relative to participants with no remission at baseline and year 1 study visits). Multivariable analyses confirmed eGFR and albuminuria as key risk factors for predicting adverse as well as positive outcomes. Limitations of this study include reliance on GFR estimated using the Modification of Diet in Renal Disease study (MDRD) equation for recruitment (but not subsequent analysis) and a study population that was predominantly elderly and white, implying that the results may not be directly applicable to younger populations of more diverse ethnicity.Conclusions: Management of CKD in primary care should focus principally on identifying the minority of people at high risk of adverse outcomes, to allow intervention to slow CKD progression and reduce cardiovascular events. Efforts should also be made to identify and reassure the majority who are at low risk of progression to ESKD. Consideration should be given to adopting an age-calibrated definition of CKD to avoid labelling a large group of people with age-related decline in GFR and low associated risk as having CKD. [ABSTRACT FROM AUTHOR]

Background: Surgical resection with microscopically negative margins remains the main curative option for pancreatic cancer; however, in practice intraoperative delineation of resection margins is challenging. Ambient mass spectrometry imaging has emerged as a powerful technique for chemical imaging and real-time diagnosis of tissue samples. We applied an approach combining desorption electrospray ionization mass spectrometry imaging (DESI-MSI) with the least absolute shrinkage and selection operator (Lasso) statistical method to diagnose pancreatic tissue sections and prospectively evaluate surgical resection margins from pancreatic cancer surgery.Methods and Findings: Our methodology was developed and tested using 63 banked pancreatic cancer samples and 65 samples (tumor and specimen margins) collected prospectively during 32 pancreatectomies from February 27, 2013, to January 16, 2015. In total, mass spectra for 254,235 individual pixels were evaluated. When cross-validation was employed in the training set of samples, 98.1% agreement with histopathology was obtained. Using an independent set of samples, 98.6% agreement was achieved. We used a statistical approach to evaluate 177,727 mass spectra from samples with complex, mixed histology, achieving an agreement of 81%. The developed method showed agreement with frozen section evaluation of specimen margins in 24 of 32 surgical cases prospectively evaluated. In the remaining eight patients, margins were found to be positive by DESI-MSI/Lasso, but negative by frozen section analysis. The median overall survival after resection was only 10 mo for these eight patients as opposed to 26 mo for patients with negative margins by both techniques. This observation suggests that our method (as opposed to the standard method to date) was able to detect tumor involvement at the margin in patients who developed early recurrence. Nonetheless, a larger cohort of samples is needed to validate the findings described in this study. Careful evaluation of the long-term benefits to patients of the use of DESI-MSI for surgical margin evaluation is also needed to determine its value in clinical practice.Conclusions: Our findings provide evidence that the molecular information obtained by DESI-MSI/Lasso from pancreatic tissue samples has the potential to transform the evaluation of surgical specimens. With further development, we believe the described methodology could be routinely used for intraoperative surgical margin assessment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

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: Diabetes is a well-known risk factor for tuberculosis (TB) and is increasingly prevalent in low- and middle-income countries, where the burden of TB is high. Glycemic control has the potential to modify the risk of TB. However, there are few studies on the association between glycemic control and TB risk, and the results are inconsistent.Methods and Findings: We assembled a cohort using 123,546 individuals who participated in a community-based health screening service in northern Taiwan from 5 March 2005 to 27 July 2008. Glycemic control was measured using fasting plasma glucose (FPG) at the time of screening. The cohort was followed up to 31 December 2012 for the occurrence of TB by cross-matching the screening database to the national health insurance database. Multiple imputation was used to handle missing information. During a median follow-up of 4.6 y, 327 cases of TB occurred. In the multivariable Cox regression model, diabetic patients with poor glycemic control (FPG > 130 mg/dl) had a significantly higher hazard of TB (adjusted hazard ratio [aHR] 2.21, 95% CI 1.63-2.99, p < 0.001) compared to those without diabetes. The hazard of TB in diabetic patients with good glycemic control (FPG ≤ 130 mg/dl) did not differ significantly from that in nondiabetic individuals (aHR 0.69, 95% CI 0.35-1.36, p = 0.281). In the linear dose-response analysis, the hazard of TB increased with FPG (aHR 1.06 per 10-mg/dl increase in FPG, 95% CI 1.03-1.08, p < 0.001). Assuming the observed association between glycemic control and TB was causal, an estimated 7.5% (95% CI 4.1%-11.5%) of incident TB in the study population could be attributed to poor glycemic control. Limitations of the study include one-time measurement of fasting glucose at baseline and voluntary participation in the health screening service.Conclusions: Good glycemic control could potentially modify the risk of TB among diabetic patients and may contribute to the control of TB in settings where diabetes and TB are prevalent. [ABSTRACT FROM AUTHOR]

Background: There is limited, poorly characterized information about adverse events occurring during maintenance treatment of bipolar disorder. We aimed to determine adverse event rates during treatment with lithium, valproate, olanzapine, and quetiapine.Methods and Findings: We conducted a propensity score adjusted cohort study using nationally representative United Kingdom electronic health records from January 1, 1995, until December 31, 2013. We included patients who had a diagnosis of bipolar disorder and were prescribed lithium (n = 2148), valproate (n = 1670), olanzapine (n = 1477), or quetiapine (n = 1376) as maintenance mood stabilizer treatment. Adverse outcomes were chronic kidney disease, thyroid disease, hypercalcemia, weight gain, hypertension, type 2 diabetes mellitus, cardiovascular disease, and hepatotoxicity. The propensity score included important demographic, physical health, and mental health predictors of drug treatment allocation. The median duration of drug treatment was 1.48 y (interquartile range 0.64-3.43). Compared to patients prescribed lithium, those taking valproate, olanzapine, and quetiapine had reduced rates of chronic kidney disease stage 3 or more severe, following adjustment for propensity score, age, and calendar year, and accounting for clustering by primary care practice (valproate hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.45-0.69; p < 0.001, olanzapine HR 0.57; 95% CI 0.45-0.71; p < 0.001, quetiapine HR 0.62; 95% CI 0.47-0.80; p < 0.001). Hypothyroidism was reduced in those taking valproate (HR 0.60; 95% CI 0.40-0.89; p = 0.012) and olanzapine (HR 0.48; 95% CI 0.29-0.77; p = 0.003), compared to those taking lithium. Rates of new onset hyperthyroidism (valproate HR 0.24; 95% CI 0.09-0.61; p = 0.003, olanzapine HR 0.31; 95% CI 0.13-0.73; p = 0.007) and hypercalcemia (valproate HR 0.25; 95% CI 0.10-0.60; p = 0.002, olanzapine HR 0.32; 95% CI 0.14-0.76; p = 0.008, quetiapine HR 0.23; 95% CI 0.07-0.73; p = 0.013) were also reduced relative to lithium. However, rates of greater than 15% weight gain on valproate, olanzapine, and quetiapine were higher (valproate HR 1.62; 95% CI 1.31-2.01; p < 0.001, olanzapine HR 1.84; 95% CI 1.47-2.30; p < 0.001, quetiapine HR 1.67; 95% CI 1.24-2.20; p < 0.001) than in individuals prescribed lithium, as were rates of hypertension in the olanzapine treated group (HR 1.41, 95% CI 1.06-1.87; p = 0.017). We found no significant difference in rates of chronic kidney disease stage 4 or more severe, type 2 diabetes mellitus, cardiovascular disease, or hepatotoxicity. Despite estimates being robust following sensitivity analyses, limitations include the potential for residual confounding and ascertainment bias and an inability to examine dosage effects.Conclusions: Lithium use is associated with more renal and endocrine adverse events but less weight gain than commonly used alternative mood stabilizers. Risks need to be offset with the effectiveness and anti-suicidal benefits of lithium and the potential metabolic side effects of alternative treatment options. [ABSTRACT FROM AUTHOR]

Background: Effects of major dietary macronutrients on glucose-insulin homeostasis remain controversial and may vary by the clinical measures examined. We aimed to assess how saturated fat (SFA), monounsaturated fat (MUFA), polyunsaturated fat (PUFA), and carbohydrate affect key metrics of glucose-insulin homeostasis.Methods and Findings: We systematically searched multiple databases (PubMed, EMBASE, OVID, BIOSIS, Web-of-Knowledge, CAB, CINAHL, Cochrane Library, SIGLE, Faculty1000) for randomised controlled feeding trials published by 26 Nov 2015 that tested effects of macronutrient intake on blood glucose, insulin, HbA1c, insulin sensitivity, and insulin secretion in adults aged ≥18 years. We excluded trials with non-isocaloric comparisons and trials providing dietary advice or supplements rather than meals. Studies were reviewed and data extracted independently in duplicate. Among 6,124 abstracts, 102 trials, including 239 diet arms and 4,220 adults, met eligibility requirements. Using multiple-treatment meta-regression, we estimated dose-response effects of isocaloric replacements between SFA, MUFA, PUFA, and carbohydrate, adjusted for protein, trans fat, and dietary fibre. Replacing 5% energy from carbohydrate with SFA had no significant effect on fasting glucose (+0.02 mmol/L, 95% CI = -0.01, +0.04; n trials = 99), but lowered fasting insulin (-1.1 pmol/L; -1.7, -0.5; n = 90). Replacing carbohydrate with MUFA lowered HbA1c (-0.09%; -0.12, -0.05; n = 23), 2 h post-challenge insulin (-20.3 pmol/L; -32.2, -8.4; n = 11), and homeostasis model assessment for insulin resistance (HOMA-IR) (-2.4%; -4.6, -0.3; n = 30). Replacing carbohydrate with PUFA significantly lowered HbA1c (-0.11%; -0.17, -0.05) and fasting insulin (-1.6 pmol/L; -2.8, -0.4). Replacing SFA with PUFA significantly lowered glucose, HbA1c, C-peptide, and HOMA. Based on gold-standard acute insulin response in ten trials, PUFA significantly improved insulin secretion capacity (+0.5 pmol/L/min; 0.2, 0.8) whether replacing carbohydrate, SFA, or even MUFA. No significant effects of any macronutrient replacements were observed for 2 h post-challenge glucose or insulin sensitivity (minimal-model index). Limitations included a small number of trials for some outcomes and potential issues of blinding, compliance, generalisability, heterogeneity due to unmeasured factors, and publication bias.Conclusions: This meta-analysis of randomised controlled feeding trials provides evidence that dietary macronutrients have diverse effects on glucose-insulin homeostasis. In comparison to carbohydrate, SFA, or MUFA, most consistent favourable effects were seen with PUFA, which was linked to improved glycaemia, insulin resistance, and insulin secretion capacity. [ABSTRACT FROM AUTHOR]

Background: Malaria transmission is highly heterogeneous, generating malaria hotspots that can fuel malaria transmission across a wider area. Targeting hotspots may represent an efficacious strategy for reducing malaria transmission. We determined the impact of interventions targeted to serologically defined malaria hotspots on malaria transmission both inside hotspots and in surrounding communities.Methods and Findings: Twenty-seven serologically defined malaria hotspots were detected in a survey conducted from 24 June to 31 July 2011 that included 17,503 individuals from 3,213 compounds in a 100-km2 area in Rachuonyo South District, Kenya. In a cluster-randomized trial from 22 March to 15 April 2012, we randomly allocated five clusters to hotspot-targeted interventions with larviciding, distribution of long-lasting insecticide-treated nets, indoor residual spraying, and focal mass drug administration (2,082 individuals in 432 compounds); five control clusters received malaria control following Kenyan national policy (2,468 individuals in 512 compounds). Our primary outcome measure was parasite prevalence in evaluation zones up to 500 m outside hotspots, determined by nested PCR (nPCR) at baseline and 8 wk (16 June-6 July 2012) and 16 wk (21 August-10 September 2012) post-intervention by technicians blinded to the intervention arm. Secondary outcome measures were parasite prevalence inside hotpots, parasite prevalence in the evaluation zone as a function of distance from the hotspot boundary, Anopheles mosquito density, mosquito breeding site productivity, malaria incidence by passive case detection, and the safety and acceptability of the interventions. Intervention coverage exceeded 87% for all interventions. Hotspot-targeted interventions did not result in a change in nPCR parasite prevalence outside hotspot boundaries (p ≥ 0.187). We observed an average reduction in nPCR parasite prevalence of 10.2% (95% CI -1.3 to 21.7%) inside hotspots 8 wk post-intervention that was statistically significant after adjustment for covariates (p = 0.024), but not 16 wk post-intervention (p = 0.265). We observed no statistically significant trend in the effect of the intervention on nPCR parasite prevalence in the evaluation zone in relation to distance from the hotspot boundary 8 wk (p = 0.27) or 16 wk post-intervention (p = 0.75). Thirty-six patients with clinical malaria confirmed by rapid diagnostic test could be located to intervention or control clusters, with no apparent difference between the study arms. In intervention clusters we caught an average of 1.14 female anophelines inside hotspots and 0.47 in evaluation zones; in control clusters we caught an average of 0.90 female anophelines inside hotspots and 0.50 in evaluation zones, with no apparent difference between study arms. Our trial was not powered to detect subtle effects of hotspot-targeted interventions nor designed to detect effects of interventions over multiple transmission seasons.Conclusions: Despite high coverage, the impact of interventions targeting malaria vectors and human infections on nPCR parasite prevalence was modest, transient, and restricted to the targeted hotspot areas. Our findings suggest that transmission may not primarily occur from hotspots to the surrounding areas and that areas with highly heterogeneous but widespread malaria transmission may currently benefit most from an untargeted community-wide approach. Hotspot-targeted approaches may have more validity in settings where human settlement is more nuclear.Trial Registration: ClinicalTrials.gov NCT01575613. [ABSTRACT FROM AUTHOR]

Jean Adams and colleagues argue that population interventions that require individuals to use a low level of agency to benefit are likely to be most effective and most equitable. [ABSTRACT FROM AUTHOR]

In a Perspective, James Boyce and Michael Ash discuss Lara Cushing and colleagues' research study on the implications of California's policy on carbon trading. [ABSTRACT FROM AUTHOR]

In a Perspective, Kristie Ebi and Lewis Ziska discuss Weyant and colleagues' accompanying study on the projected effects of atmospheric carbon dioxide on nutrition and disease. [ABSTRACT FROM AUTHOR]