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Background: Australia has one of the highest skin cancer rates in the world. 'SunSmart' is a multi-component, internationally recognised community-wide skin cancer prevention program implemented in Melbourne, Australia, since summer 1988-1989. Following recent reductions in melanoma rates among younger Australian cohorts, the extent of behaviour change and the potential contribution of prevention programs to this decline in melanoma rates are of interest. Sun protection is a multifaceted behaviour. Measures previously applied to monitor change over time in preventive behaviour for this population focused on individual behaviours. The omission of multiple behaviours that reduce exposure to ultraviolet radiation (UV) may have led to underestimates of behaviour change, meriting further analysis of long-term trends to contribute to this debate.Methods and Findings: A population-based survey was conducted in Melbourne in the summer before SunSmart commenced (1987-1988) and across summers in 3 subsequent decades (1988-2017). During summer months, residents (14-69 years) were recruited to cross-sectional weekly telephone interviews assessing their tanning attitudes, sun protection behaviour, and sunburn incidence on the weekend prior to interview. Quotas were used to ensure the sample was proportional to the population by age and sex, while younger respondents were oversampled in some years. The majority of the respondents reported their skin was susceptible to sunburn. Changes in sun protection behaviour were analysed for N = 13,285 respondents in multivariable models, cumulating surveys within decades (1987-1988: N = 1,655; 1990s: N = 5,258; 2000s: N = 3,385; 2010s: N = 2,987) and adjusting for relevant ambient weather conditions and UV levels on weekend dates. We analysed specific and composite behaviours including a novel analysis of the use of maximal sun protection, which considered those people who stayed indoors during peak UV hours together with those people well-protected when outdoors. From a low base, use of sun protection increased rapidly in the decade after SunSmart commenced. The odds of use of at least 1 sun protection behaviours on summer weekends was 3 times higher in the 1990s than pre-SunSmart (adjusted odds ratio [AOR] 3.04, 95% CI 2.52-3.68, p < 0.001). There was a smaller increase in use of maximal sun protection including shade (AOR = 1.68, 95% CI 1.44-1.97, p < 0.001). These improvements were sustained into the 2000s and continued to increase in the 2010s. Inferences about program effects are limited by the self-reported data, the absence of a control population, the cross-sectional study design, and the fact that the survey was not conducted in all years. Other potential confounders may include increasing educational attainment among respondents over time and exposure to other campaigns such as tobacco and obesity prevention.Conclusions: With an estimated 20-year lag between sun exposure and melanoma incidence, our findings are consistent with SunSmart having contributed to the reduction in melanoma among younger cohorts. [ABSTRACT FROM AUTHOR]

Background: Disparities in type 2 diabetes (T2D) care provision and clinical outcomes have been reported in the last 2 decades in the UK. Since then, a number of initiatives have attempted to address this imbalance. The aim was to evaluate contemporary data as to whether disparities exist in glycaemic control, monitoring, and prescribing in people with T2D.Methods and Findings: A T2D cohort was identified from the Royal College of General Practitioners Research and Surveillance Centre dataset: a nationally representative sample of 164 primary care practices (general practices) across England. Diabetes healthcare provision and glucose-lowering medication use between 1 January 2012 and 31 December 2016 were studied. Healthcare provision included annual HbA1c, renal function (estimated glomerular filtration rate [eGFR]), blood pressure (BP), retinopathy, and neuropathy testing. Variables potentially associated with disparity outcomes were assessed using mixed effects logistic and linear regression, adjusted for age, sex, ethnicity, and socioeconomic status (SES) using the Index of Multiple Deprivation (IMD), and nested using random effects within general practices. Ethnicity was defined using the Office for National Statistics ethnicity categories: White, Mixed, Asian, Black, and Other (including Arab people and other groups not classified elsewhere). From the primary care adult population (n = 1,238,909), we identified a cohort of 84,452 (5.29%) adults with T2D. The mean age of people with T2D in the included cohort at 31 December 2016 was 68.7 ± 12.6 years; 21,656 (43.9%) were female. The mean body mass index was 30.7 ± SD 6.4 kg/m2. The most deprived groups (IMD quintiles 1 and 2) showed poorer HbA1c than the least deprived (IMD quintile 5). People of Black ethnicity had worse HbA1c than those of White ethnicity. Asian individuals were less likely than White individuals to be prescribed insulin (odds ratio [OR] 0.86, 95% CI 0.79-0.95; p < 0.01), sodium-glucose cotransporter-2 (SGLT2) inhibitors (OR 0.68, 95% CI 0.58-0.79; p < 0.001), and glucagon-like peptide-1 (GLP-1) agonists (OR 0.37, 95% CI 0.31-0.44; p < 0.001). Black individuals were less likely than White individuals to be prescribed SGLT2 inhibitors (OR 0.50, 95% CI 0.39-0.65; p < 0.001) and GLP-1 agonists (OR 0.45, 95% CI 0.35-0.57; p < 0.001). Individuals in IMD quintile 5 were more likely than those in the other IMD quintiles to have annual testing for HbA1c, BP, eGFR, retinopathy, and neuropathy. Black individuals were less likely than White individuals to have annual testing for HbA1c (OR 0.89, 95% CI 0.79-0.99; p = 0.04) and retinopathy (OR 0.82, 95% CI 0.70-0.96; p = 0.011). Asian individuals were more likely than White individuals to have monitoring for HbA1c (OR 1.10, 95% CI 1.01-1.20; p = 0.023) and eGFR (OR 1.09, 95% CI 1.00-1.19; p = 0.048), but less likely for retinopathy (OR 0.88, 95% CI 0.79-0.97; p = 0.01) and neuropathy (OR 0.88, 95% CI 0.80-0.97; p = 0.01). The study is limited by the nature of being observational and defined using retrospectively collected data. Disparities in diabetes care may show regional variation, which was not part of this evaluation.Conclusions: Our findings suggest that disparity in glycaemic control, diabetes-related monitoring, and prescription of newer therapies remains a challenge in diabetes care. Both SES and ethnicity were important determinants of inequality. Disparities in glycaemic control and other areas of care may lead to higher rates of complications and adverse outcomes for some groups. [ABSTRACT FROM AUTHOR]

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

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

Background: Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax.Methods and Findings: Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups.Conclusions: In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis. [ABSTRACT FROM AUTHOR]

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

Background: Diabetes mellitus (DM) increases the risk of adverse maternal and neonatal outcomes, and optimization of glycemic control during pregnancy can help mitigate risks associated with diabetes. However, studies seldom focus precisely on maternal blood glucose level prior to pregnancy. We aimed to evaluate the associations between preconception blood fasting plasma glucose (FPG) level and subsequent pregnancy outcomes.Methods and Findings: We conducted a population-based retrospective cohort study among 6,447,339 women aged 20-49 years old who participated in National Free Pre-Pregnancy Checkups Project and completed pregnancy outcomes follow-up between 2010 and 2016 in China. During the preconception health examination, serum FPG concentration was measured, and self-reported history of DM was collected. Women were classified into three groups (normal FPG group: FPG < 5.6 mmol/L and no self-reported history of DM; impaired fasting glucose [IFG]: FPG 5.6-6.9 mmol/L and no self-reported history of DM; and DM: FPG ≥ 7.0 mmol/L or self-reported history of DM). The primary outcomes were adverse pregnancy outcomes, including spontaneous abortion, preterm birth (PTB), macrosomia, small for gestational age infant (SGA), birth defect, and perinatal infant death. Logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI) after adjusting for confounding variables. The mean age of women was 25.24 years, 91.47% were of Han nationality, and 92.85% were from rural areas. The incidence of DM and IFG was 1.18% (76,297) and 13.15% (847,737), respectively. Only 917 (1.20%) women reported a history of DM (awareness of their DM status), of whom 37.28% (337) had an elevated preconception FPG level (≥ 5.6 mmol/L), regarded as noncontrolled DM. A total of 1,005,568 (15.60%) women had adverse pregnancy outcomes. Compared with women with normal FPG, women with IFG had higher risks of spontaneous abortion (OR 1.08; 95% CI 1.06-1.09; P < 0.001), PTB (1.02; 1.01-1.03; P < 0.001), macrosomia (1.07; 1.06-1.08; P < 0.001), SGA (1.06; 1.02-1.10; P = 0.007), and perinatal infant death (1.08; 1.03-1.12; P < 0.001); the corresponding ORs for women with DM were 1.11 (95% CI 1.07-1.15; P < 0.001), 1.17 (1.14-1.20; P < 0.001), 1.13 (1.09-1.16; P < 0.001), 1.17 (1.04-1.32; P = 0.008), and 1.59 (1.44-1.76; P < 0.001). Women with DM also had a higher risk of birth defect (OR 1.42; 95% CI 1.15-1.91; P = 0.002). Among women without self-reported history of DM, there was a positive linear association between FPG levels and spontaneous abortion, PTB, macrosomia, SGA, and perinatal infant death (P for trend <0.001, <0.001, <0.001, 0.001, <0.001). Information about hypoglycemic medication before or during pregnancy was not collected, and we cannot adjust it in the analysis, which could result in underestimation of risks. Data on 2-hour plasma glucose level and HbA1c concentration were not available, and the glycemic control status was evaluated according to FPG value in women with DM.Conclusions: Women with preconception IFG or DM had higher risk of adverse pregnancy outcomes, including spontaneous abortion, PTB, macrosomia, SGA, and perinatal infant death. Preconception glycemic control through appropriate methods is one of the most important aspects of preconception care and should not be ignored by policy makers. [ABSTRACT FROM AUTHOR]

Background: Intimate partner violence (IPV) against women is a major global health issue, particularly in low- and middle-income countries (LMICs), that is associated with poor physical and mental health, but its association with breastfeeding practices is understudied. Both the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) recommend that children initiate breastfeeding within the first hour of birth and be exclusively breastfed for the first 6 months of life. Breastfeeding within the first hour of birth is critical to newborn survival, and exclusive breastfeeding for 6 months is recognised to offer significant health benefits to mothers and their infants. We examined the association of maternal exposure to IPV with early initiation of breastfeeding (within 1 hour of birth) and exclusive breastfeeding in the first 6 months.Methods and Findings: We assessed population-based cross-sectional Demographic and Health Surveys (DHS) from 51 LMICs. Data from the most recent DHS in each country (conducted between January 2000 and January 2019) with data available on IPV and breastfeeding practices were used. By WHO region, 52.9% (27/51) were from Africa, 11.8% (6/51) from the Americas, 7.8% (4/51) from the Eastern Mediterranean, 11.8% (6/51) from Europe, 11.8% (6/51) from South-East Asia, and 3.9% (2/51) from the Western Pacific. We estimated multilevel logistic regression models for any IPV and each type of IPV separately (physical violence, sexual violence, and emotional violence), accounting for demographic and socioeconomic factors. Depending on specification, the sample size varied between 95,320 and 102,318 mother-infant dyads. The mean age of mothers was 27.5 years, and the prevalence of any lifetime exposure to IPV among mothers was 33.3% (27.6% for physical violence, 8.4% for sexual violence, and 16.4% for emotional violence). Mothers exposed to any IPV were less likely to initiate breastfeeding early (adjusted odds ratio [AOR]: 0.88 [95% CI 0.85-0.97], p < 0.001) and breastfeed exclusively in the first 6 months (AOR: 0.87 [95% CI 0.82-0.92], p < 0.001). The associations were similar for each type of IPV and were overall consistent across infant's sex and WHO regions. After simultaneously adjusting for all 3 types of IPV, all 3 types of IPV were independently associated with decreased likelihood of early breastfeeding initiation, but only exposure to physical violence was independently associated with a decreased likelihood of exclusively breastfeeding in the first 6 months. The main limitations of this study included the use of cross-sectional datasets, the possibility of residual confounding of the observed associations by household wealth, and the possibility of underreporting of IPV experiences attenuating the magnitude of observed associations.Conclusions: Our study indicates that mothers exposed to any form of IPV (physical, sexual, or emotional violence) were less likely to initiate breastfeeding early and breastfeed exclusively in the first 6 months. These findings may inform the argument for antenatal screening for IPV in LMICs and the provision of services to not only improve mothers' safety and well-being, but also support them in adopting recommended breastfeeding practices. [ABSTRACT FROM AUTHOR]

Background: Malaria in pregnancy is associated with adverse birth outcomes. However, the underlying mechanisms remain poorly understood. Tight regulation of angiogenic, metabolic, and inflammatory pathways are essential for healthy pregnancies. We hypothesized that malaria disrupts these pathways leading to preterm birth (PTB).Methods and Findings: We conducted a secondary analysis of a randomized trial of malaria prevention in pregnancy conducted in Malawi from July 21, 2011, to March 18, 2013. We longitudinally assessed circulating mediators of angiogenic, metabolic, and inflammatory pathways during pregnancy in a cohort of HIV-negative women (n = 1,628), with a median age of 21 years [18, 25], and 562 (35%) were primigravid. Pregnancies were ultrasound dated, and samples were analyzed at 13 to 23 weeks (Visit 1), 28 to 33 weeks (Visit 2), and/or 34 to 36 weeks (Visit 3). Malaria prevalence was high; 70% (n = 1,138) had PCR-positive Plasmodium falciparum infection at least once over the course of pregnancy and/or positive placental histology. The risk of delivering preterm in the entire cohort was 20% (n = 304/1506). Women with malaria before 24 weeks gestation had a higher risk of PTB (24% versus 18%, p = 0.005; adjusted relative risk [aRR] 1.30, 95% confidence interval [CI] 1.04-1.63, p = 0.021); and those who were malaria positive only before week 24 had an even greater risk of PTB (28% versus 17%, p = 0.02; with an aRR of 1.67, 95% CI 1.20-2.30, p = 0.002). Using linear mixed-effects modeling, malaria before 24 weeks gestation was associated with altered kinetics of inflammatory (C-Reactive Protein [CRP], Chitinase 3-like protein-1 [CHI3L1], Interleukin 18 Binding Protein [IL-18BP], soluble Tumor Necrosis Factor receptor II [sTNFRII], soluble Intercellular Adhesion Molecule-1 [sICAM-1]), angiogenic (soluble Endoglin [sEng]), and metabolic mediators (Leptin, Angiopoietin-like 3 [Angptl3]) over the course of pregnancy (χ2 > 13.0, p ≤ 0.001 for each). Limitations include being underpowered to assess the impact on nonviable births, being unable to assess women who had not received any antimalarials, and, because of the exposure to antimalarials in the second trimester, there were limited numbers of malaria infections late in pregnancy.Conclusions: Current interventions for the prevention of malaria in pregnancy are initiated at the first antenatal visit, usually in the second trimester. In this study, we found that many women are already malaria-infected by their first visit. Malaria infection before 24 weeks gestation was associated with dysregulation of essential regulators of angiogenesis, metabolism, and inflammation and an increased risk of PTB. Preventing malaria earlier in pregnancy may reduce placental dysfunction and thereby improve birth outcomes in malaria-endemic settings. [ABSTRACT FROM AUTHOR]

Background: Physical exercise has been shown to be effective in relation to fatigue, aerobic fitness, and lower body strength in men with prostate cancer. However, research into the clinically relevant effects of interventions conducted in heterogeneous patient populations and in real-life clinical practice settings is warranted.Methods and Findings: We conducted a pragmatic, multicentre, parallel randomised controlled trial in 5 Danish urological departments. Recruitment began in May 2015, the first participant was randomised in June 2015, and the last participant was included in February 2017. In total, 214 men with prostate cancer were randomly assigned to either 6 months of free-of-charge football training twice weekly at a local club (football group [FG]) (n = 109) or usual care (usual care group [UG]) (n = 105), including brief information on physical activity recommendations at randomisation. Participants were on average 68.4 (SD 6.2) years old, 157 (73%) were retired, 87 (41%) were on castration-based treatment, 19 (9%) had received chemotherapy, and 41 (19%) had skeletal metastases at baseline. In this 1-year follow-up study, we evaluated the effects of community-based football training on the following outcomes: primary outcome, quality of life; secondary outcomes: continuation of football after 6 months, hip and lumbar spine bone mineral density (BMD), mental health score, fat and lean body mass, and safety outcomes, i.e., fractures, falls, and hospital admissions. Intention to treat (ITT) and per protocol (PP) analyses were conducted. No statistically significant between-group difference was observed in change in prostate-cancer-specific quality of life (ITT: 1.9 points [95% CI -1.9 to 5.8], p = 0.325; PP: 3.6 points [95% CI -0.9 to 8.2], p = 0.119). A statistically significant between-group difference was observed in change in total hip BMD, in favour of FG (0.007 g/cm2 [95% CI 0.004 to 0.013], p = 0.037). No differences were observed in change in lumbar spine BMD or lean body mass. Among patients allocated to football, 59% chose to continue playing football after the end of the 6-month intervention period. At 1-year follow-up in the PP population, FG participants had more improvement on the Mental Component Summary (2.9 [95% CI 0.0 to 5.7], p = 0.048 points higher) than UG participants, as well as a greater loss of fat mass (-0.9 kg [95% CI -1.7 to -0.1], p = 0.029). There were no differences between groups in relation to fractures or falls. Hospital admissions were more frequent in UG compared to FG (33 versus 20; the odds ratio based on PP analysis was 0.34 for FG compared to UG). There were 3 deaths in FG and 4 in UG. Main limitations of the study were the physically active control group and assessment of physical activity by means of self-report.Conclusions: In this trial, participants allocated to football appeared to have improved hip BMD and fewer hospital admissions. Men who played football more than once a week for 1 year lost fat mass and reported improved mental health. Community-based football proved to be acceptable, even when club membership was not subsidised.Trial Registration: ClinicalTrials.gov NCT02430792. [ABSTRACT FROM AUTHOR]

Background: Timely diagnosis of infant HIV infection is essential for antiretroviral therapy (ART) initiation. In a randomized controlled trial, we found the Texting Improves Testing (TextIT) intervention (a theory-based text messaging system) to be efficacious for improving infant HIV testing rates and maternal retention in prevention of mother-to-child HIV transmission (PMTCT) programs. Using an implementation science approach, we aimed to evaluate real-world effectiveness of the intervention.Methods and Findings: In a pragmatic, cluster-randomized, stepped-wedge trial with 2 time periods of observation, we randomly allocated 10 clinics to begin implementing the intervention immediately and 10 clinics to begin implementing 6 months later. To approximate real-world conditions, inclusion criteria were broad. Women at clinics implementing the intervention received up to 14 text messages during pregnancy and after delivery and had the option to respond to text messages, call, or send inquiry text messages to a designated clinic phone. The primary outcomes were infant HIV testing and maternal retention in care during the first 8 weeks after delivery. We used modified Poisson regression with robust variance estimation to estimate the relative risk and 95% confidence intervals (CIs). Generalized estimating equations were applied on individual-level data to account for clustering by site. Between February 2015 and December 2016, 4,681 women were assessed for study participation, and 2,515 were included. Participant characteristics at enrollment did not differ by study arm. Overall median age was 27 years (interquartile range [IQR] 23-30), median gestational age was 30 weeks (IQR 28-34), 99% were receiving ART, and 87% who enrolled during intervention phases owned a phone. Of 2,326 infants analyzed, 1,466 of 1,613 (90.9%) in the intervention group and 609 of 713 (85.4%) in the control group met the primary outcome of HIV virologic testing performed before 8 weeks after birth (adjusted relative risk [aRR] 1.03; 95% CI 0.97-1.10; P = 0.3). Of 2,472 women analyzed, 1,548 of 1,725 (90%) in the intervention group and 571 of 747 (76%) in the control group met the primary outcome of retention in care during the first 8 weeks after delivery (aRR 1.12; 95% CI 0.97-1.30; P = 0.1). This study had two main limitations. Staff at all facilities were aware of ongoing observation, which may have contributed to increased rates of infant HIV testing and maternal retention in care at both intervention and control facilities, and programmatic initiatives to improve maternal and infant retention in care were ongoing at all facilities at the time of this study, which likely limited the ability to demonstrate effectiveness of the trial intervention.Conclusions: In this study, a larger proportion of infants in the intervention group received HIV testing compared with the control group, but the difference was small and not statistically significant. There was also a nonsignificant increase in maternal postpartum retention in the intervention periods. Despite the lack of a significant effect of the intervention, key lessons emerged, both for strengthening PMTCT and for implementation research in general. Perhaps most important, improving the implementation of usual care may have been sufficient to substantially improve infant HIV testing rates.Trial Registration: ClinicalTrials.gov Trial Number NCT02350140. [ABSTRACT FROM AUTHOR]

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

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

Background: The precise age distribution and calculated stroke risk of screen-detected atrial fibrillation (AF) is not known. Therefore, it is not possible to determine the number needed to screen (NNS) to identify one treatable new AF case (NNS-Rx) (i.e., Class-1 oral anticoagulation [OAC] treatment recommendation) in each age stratum. If the NNS-Rx is known for each age stratum, precise cost-effectiveness and sensitivity simulations can be performed based on the age distribution of the population/region to be screened. Such calculations are required by national authorities and organisations responsible for health system budgets to determine the best age cutoffs for screening programs and decide whether programs of screening should be funded. Therefore, we aimed to determine the exact yield and calculated stroke-risk profile of screen-detected AF and NNS-Rx in 5-year age strata.Methods and Findings: A systematic review of Medline, Pubmed, and Embase was performed (January 2007 to February 2018), and AF-SCREEN international collaboration members were contacted to identify additional studies. Twenty-four eligible studies were identified that performed a single time point screen for AF in a general ambulant population, including people ≥65 years. Authors from eligible studies were invited to collaborate and share patient-level data. Statistical analysis was performed using random effects logistic regression for AF detection rate, and Poisson regression modelling for CHA2DS2-VASc scores. Nineteen studies (14 countries from a mix of low- to middle- and high-income countries) collaborated, with 141,220 participants screened and 1,539 new AF cases. Pooled yield of screening was greater in males across all age strata. The age/sex-adjusted detection rate for screen-detected AF in ≥65-year-olds was 1.44% (95% CI, 1.13%-1.82%) and 0.41% (95% CI, 0.31%-0.53%) for <65-year-olds. New AF detection rate increased progressively with age from 0.34% (<60 years) to 2.73% (≥85 years). Neither the choice of screening methodology or device, the geographical region, nor the screening setting influenced the detection rate of AF. Mean CHA2DS2-VASc scores (n = 1,369) increased with age from 1.1 (<60 years) to 3.9 (≥85 years); 72% of ≥65 years had ≥1 additional stroke risk factor other than age/sex. All new AF ≥75 years and 66% between 65 and 74 years had a Class-1 OAC recommendation. The NNS-Rx is 83 for ≥65 years, 926 for 60-64 years; and 1,089 for <60 years. The main limitation of this study is there are insufficient data on sociodemographic variables of the populations and possible ascertainment biases to explain the variance in the samples.Conclusions: People with screen-detected AF are at elevated calculated stroke risk: above age 65, the majority have a Class-1 OAC recommendation for stroke prevention, and >70% have ≥1 additional stroke risk factor other than age/sex. Our data, based on the largest number of screen-detected AF collected to date, show the precise relationship between yield and estimated stroke risk profile with age, and strong dependence for NNS-RX on the age distribution of the population to be screened: essential information for precise cost-effectiveness calculations. [ABSTRACT FROM AUTHOR]

Background: Weight loss interventions based solely on text messaging (short message service [SMS]) have been shown to be modestly effective for short periods of time and in some populations, but limited evidence is available for positive longer-term outcomes and for efficacy in Hispanic populations. Also, little is known about the comparative efficacy of weight loss interventions that use SMS coupled with brief, technology-mediated contact with health coaches, an important issue when considering the scalability and cost of interventions. We examined the efficacy of a 1-year intervention designed to reduce weight among overweight and obese English- and Spanish-speaking adults via SMS alone (ConTxt) or in combination with brief, monthly health-coaching calls. ConTxt offered 2-4 SMS/day that were personalized, tailored, and interactive. Content was theory- and evidence-based and focused on reducing energy intake and increasing energy expenditure. Monthly health-coaching calls (5-10 minutes' duration) focused on goal-setting, identifying barriers to achieving goals, and self-monitoring.Methods and Findings: English- and Spanish-speaking adults were recruited from October 2011 to March 2013. A total of 298 overweight (body mass index [BMI] 27.0 to 39.9 kg/m2) adults (aged 21-60 years; 77% female; 41% Hispanic; 21% primarily Spanish speaking; 44% college graduates or higher; 22% unemployed) were randomly assigned (1:1) to receive either ConTxt only (n = 101), ConTxt plus health-coaching calls (n = 96), or standard print materials on weight reduction (control group, n = 101). We used computer-based permuted-block randomization with block sizes of three or six, stratified by sex and Spanish-speaking status. Participants, study staff, and investigators were masked until the intervention was assigned. The primary outcome was objectively measured percent of weight loss from baseline at 12 months. Differences between groups were evaluated using linear mixed-effects regression within an intention-to-treat framework. A total of 261 (87.2%) and 253 (84.9%) participants completed 6- and 12-month visits, respectively. Loss to follow-up did not differ by study group. Mean (95% confidence intervals [CIs]) percent weight loss at 12 months was -0.61 (-1.99 to 0.77) in the control group, -1.68 (-3.08 to -0.27) in ConTxt only, and -3.63 (-5.05 to -2.81) in ConTxt plus health-coaching calls. At 12 months, mean (95% CI) percent weight loss, adjusted for baseline BMI, was significantly different between ConTxt plus health-coaching calls and the control group (-3.0 [-4.99 to -1.04], p = 0.003) but not between the ConTxt-only and the control group (-1.07 [-3.05 to 0.92], p = 0.291). Differences between ConTxt plus health-coaching calls and ConTxt only were not significant (-1.95 [-3.96 to 0.06], p = 0.057). These findings were consistent across other weight-related secondary outcomes, including changes in absolute weight, BMI, and percent body fat at 12 months. Exploratory subgroup analyses suggested that Spanish speakers responded more favorably to ConTxt plus health-coaching calls than English speakers (Spanish contrast: -7.90 [-11.94 to -3.86], p < 0.001; English contrast: -1.82 [-4.03 to 0.39], p = 0.107). Limitations include the unblinded delivery of the intervention and recruitment of a predominantly female sample from a single site.Conclusions: A 1-year intervention that delivered theory- and evidence-based weight loss content via daily personalized, tailored, and interactive SMS was most effective when combined with brief, monthly phone calls.Trial Registration: ClinicalTrials.gov NCT01171586. [ABSTRACT FROM AUTHOR]

Background: Policy consensus in high-income countries supports offering pregnant women with previous cesarean section a choice between planning an elective repeat cesarean section (ERCS) or attempting a vaginal birth, known as a planned vaginal birth after previous cesarean (VBAC), provided they do not have contraindications to planned VBAC. However, robust comprehensive information on the associated outcomes to counsel eligible women about this choice is lacking. This study investigated the short-term maternal and perinatal outcomes associated with planned mode of delivery after previous cesarean section among women delivering a term singleton and considered eligible to have a planned VBAC.Methods and Findings: A population-based cohort of 74,043 term singleton births in Scotland between 2002 and 2015 to women with one or more previous cesarean sections was conducted using linked Scottish national datasets. Logistic or modified Poisson regression, as appropriate, was used to estimate the effect of planned mode of delivery on maternal and perinatal outcomes adjusted for sociodemographic, maternal medical, and obstetric-related characteristics. A total of 45,579 women gave birth by ERCS, and 28,464 had a planned VBAC, 28.4% of whom went on to have an in-labor nonelective repeat cesarean section. Compared to women delivering by ERCS, those who had a planned VBAC were significantly more likely to have uterine rupture (0.24%, n = 69 versus 0.04%, n = 17, adjusted odds ratio [aOR] 7.3, 95% confidence interval [CI] 3.9-13.9, p < 0.001), a blood transfusion (1.14%, n = 324 versus 0.50%, n = 226, aOR 2.3, 95% CI 1.9-2.8, p < 0.001), puerperal sepsis (0.27%, n = 76 versus 0.17%, n = 78, aOR 1.8, 95% CI 1.3-2.7, p = 0.002), and surgical injury (0.17% versus 0.09%, n = 40, aOR 3.0, 95% CI 1.8-4.8, p < 0.001) and experience adverse perinatal outcomes including perinatal death, admission to a neonatal unit, resuscitation requiring drugs and/or intubation, and an Apgar score < 7 at 5 minutes (7.99%, n = 2,049 versus 6.37%, n = 2,570, aOR 1.6, 95% CI 1.5-1.7, p < 0.001). However, women who had a planned VBAC were more likely than those delivering by ERCS to breastfeed at birth or hospital discharge (63.6%, n = 14,906 versus 54.5%, n = 21,403, adjusted risk ratio [aRR] 1.2, 95% CI 1.1-1.2, p < 0.001) and were more likely to breastfeed at 6-8 weeks postpartum (43.6%, n = 10,496 versus 34.5%, n = 13,556, aRR 1.2, 95% CI 1.2-1.3, p < 0.001). The effect of planned mode of delivery on the mother's risk of having a postnatal stay greater than 5 days, an overnight readmission to hospital within 42 days of birth, and other puerperal infection varied according to whether she had any prior vaginal deliveries and, in the case of length of postnatal stay, also varied according to the number of prior cesarean sections. The study is mainly limited by the potential for residual confounding and misclassification bias.Conclusions: Among women considered eligible to have a planned VBAC, planned VBAC compared to ERCS is associated with an increased risk of the mother having serious birth-related maternal and perinatal complications. Conversely, planned VBAC is associated with an increased likelihood of breastfeeding, whereas the effect on other maternal outcomes differs according to whether a woman has any prior vaginal deliveries and the number of prior cesarean sections she has had. However, the absolute risk of adverse outcomes is small for either delivery approach. This information can be used to counsel and manage the increasing number of women with previous cesarean section, but more research is needed on longer-term outcomes. [ABSTRACT FROM AUTHOR]

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

Background: Asians are predisposed to a lean heart failure (HF) phenotype. Data on the 'obesity paradox', reported in Western populations, are scarce in Asia and have only utilised the traditional classification of body mass index (BMI). We aimed to investigate the association between obesity (defined by BMI and abdominal measures) and HF outcomes in Asia.Methods and Findings: Utilising the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry (11 Asian regions including Taiwan, Hong Kong, China, India, Malaysia, Thailand, Singapore, Indonesia, Philippines, Japan, and Korea; 46 centres with enrolment between 1 October 2012 and 6 October 2016), we prospectively examined 5,964 patients with symptomatic HF (mean age 61.3 ± 13.3 years, 26% women, mean BMI 25.3 ± 5.3 kg/m2, 16% with HF with preserved ejection fraction [HFpEF; ejection fraction ≥ 50%]), among whom 2,051 also had waist-to-height ratio (WHtR) measurements (mean age 60.8 ± 12.9 years, 24% women, mean BMI 25.0 ± 5.2 kg/m2, 7% HFpEF). Patients were categorised by BMI quartiles or WHtR quartiles or 4 combined groups of BMI (low, <24.5 kg/m2 [lean], or high, ≥24.5 kg/m2 [obese]) and WHtR (low, <0.55 [thin], or high, ≥0.55 [fat]). Cox proportional hazards models were used to examine a 1-year composite outcome (HF hospitalisation or mortality). Across BMI quartiles, higher BMI was associated with lower risk of the composite outcome (ptrend < 0.001). Contrastingly, higher WHtR was associated with higher risk of the composite outcome. Individuals in the lean-fat group, with low BMI and high WHtR (13.9%), were more likely to be women (35.4%) and to be from low-income countries (47.7%) (predominantly in South/Southeast Asia), and had higher prevalence of diabetes (46%), worse quality of life scores (63.3 ± 24.2), and a higher rate of the composite outcome (51/232; 22%), compared to the other groups (p < 0.05 for all). Following multivariable adjustment, the lean-fat group had higher adjusted risk of the composite outcome (hazard ratio 1.93, 95% CI 1.17-3.18, p = 0.01), compared to the obese-thin group, with high BMI and low WHtR. Results were consistent across both HF subtypes (HFpEF and HF with reduced ejection fraction [HFrEF]; pinteraction = 0.355). Selection bias and residual confounding are potential limitations of such multinational observational registries.Conclusions: In this cohort of Asian patients with HF, the 'obesity paradox' is observed only when defined using BMI, with WHtR showing the opposite association with the composite outcome. Lean-fat patients, with high WHtR and low BMI, have the worst outcomes. A direct correlation between high WHtR and the composite outcome is apparent in both HFpEF and HFrEF.Trial Registration: Asian Sudden Cardiac Death in HF (ASIAN-HF) Registry ClinicalTrials.gov Identifier: NCT01633398. [ABSTRACT FROM AUTHOR]

Background: The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3).Methods and Findings: In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3-8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum.Conclusion: Despite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy.Trial Registration: clinicaltrials.gov NCT02245022. [ABSTRACT FROM AUTHOR]

Background: Although many studies have compared birth-weight charts to determine which better identify infants at risk of adverse perinatal outcomes, less attention has been given to the threshold used to define small or large for gestational age (SGA or LGA) infants. Our aim was to explore different thresholds associated with increased risk of adverse perinatal outcomes using population, customised, and Intergrowth centile charts.Methods and Findings: This is a population-based cohort study (Swedish Medical Birth Registry), which included term singleton births between 2006 and 2015 from women with available data on first-trimester screening. Population, customised, and Intergrowth charts were studied. Outcomes included cesarean section, postpartum haemorrhage, severe perineal tear, Apgar score at 5 minutes, neonatal morbidity, and perinatal mortality. Odds for each outcome were assessed in intervals of 5 centiles of birth weight (reference being 40th-60th centiles) using logistic regression. Intervals of 5% of the population were also explored. Sensitivity for fixed false-positive rates (FPRs) was reported for neonatal outcomes. Data from 212,101 births were analysed. Mean age was 33 ± 5 years, 48% of women were nulliparous, and 80% were born in Sweden. Prevalence of SGA (<10th centile) was 10.1%, 10.0%, and 3.1%, and prevalence of LGA (>90th centile) was 10.0%, 8.2%, and 25.1%, assessed using population, customised, and Intergrowth charts, respectively. In small infants, the risk of perinatal mortality was consistently increased below the 15th, 10th, and 35th birth-weight centiles for the respective charts (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.05-2.39, p = 0.03 for 10th-15th population centile; OR 2.54, 95% CI 1.74-3.71, p < 0.001 for 5th-10th customised centile; OR 1.81, 95% CI 1.07-3.04, p = 0.03 for 30th-35th Intergrowth centile). The strength of association with adverse perinatal outcomes was different between infants below the 5th birth-weight centile for each chart (OR 4.47, 95% CI 3.30-6.04, p < 0.001 for the population chart; OR 5.78, 95% CI 4.22-7.91, p < 0.001 for the customised chart; OR 10.74, 95% CI 7.32-15.77, p < 0.001 for the Intergrowth chart) but similar in the smallest 5% of the population (OR 4.34, 95% CI 3.22-5.86, p < 0.001 for the population chart; OR 5.23, 95% CI 3.85-7.11, p < 0.001 for the customised chart; OR 4.69, 95% CI 3.47-6.34, p < 0.001 for the Intergrowth chart). For a fixed FPR of 10%, different thresholds for each chart achieved similar sensitivity for perinatal mortality in small infants (29% for all charts). Similar behaviour of different thresholds and similar risk/sensitivity for fixed FPR were observed in relation to other outcomes and for LGA infants. Limitations of this study include the relative homogeneity of the Swedish population, which limits generalisability to other populations; customised centiles may perform differently in populations with increased heterogeneity of ethnic background.Conclusions: The risk of adverse outcomes was consistent across proportions of the population but did not reflect fixed thresholds, such as the 10th or 90th centiles, across different growth charts. Chart-specific thresholds for the population should be considered in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Mental illness stigma is a fundamental barrier to improving mental health worldwide, but little is known about how to durably reduce it. Understanding of mental illness as a treatable medical condition may influence stigmatizing beliefs, but available evidence to inform this hypothesis has been derived solely from high-income countries. We embedded a randomized survey experiment within a whole-population cohort study in rural southwestern Uganda to assess the extent to which portrayals of mental illness treatment effectiveness influence personal beliefs and perceived norms about mental illness and about persons with mental illness.Methods and Findings: Study participants were randomly assigned to receive a vignette describing a typical woman (control condition) or one of nine variants describing a different symptom presentation (suggestive of schizophrenia, bipolar, or major depression) and treatment course (no treatment, treatment with remission, or treatment with remission followed by subsequent relapse). Participants then answered questions about personal beliefs and perceived norms in three domains of stigma: willingness to have the woman marry into their family, belief that she is receiving divine punishment, and belief that she brings shame on her family. We used multivariable Poisson and ordered logit regression models to estimate the causal effect of vignette treatment assignment on each stigma-related outcome. Of the participants randomized, 1,355 were successfully interviewed (76%) from November 2016 to June 2018. Roughly half of respondents were women (56%), half had completed primary school (57%), and two-thirds were married or cohabiting (64%). The mean age was 42 years. Across all types of mental illness and treatment scenarios, relative to the control vignette (22%-30%), substantially more study participants believed the woman in the vignette was receiving divine punishment (31%-54%) or believed she brought shame on her family (51%-73%), and most were unwilling to have her marry into their families (80%-88%). In multivariable Poisson regression models, vignette portrayals of untreated mental illness, relative to the control condition, increased the risk that study participants endorsed stigmatizing personal beliefs about mental illness and about persons with mental illness, irrespective of mental illness type (adjusted risk ratios [ARRs] varied from 1.7-3.1, all p < 0.001). Portrayals of effectively treated mental illness or treatment followed by subsequent relapse also increased the risk of responses indicating stigmatizing personal beliefs relative to control (ARRs varied from 1.5-3.0, all p < 0.001). The magnitudes of the estimates suggested that portrayals of initially effective treatment (whether followed by relapse or not) had little moderating influence on stigmatizing responses relative to vignettes portraying untreated mental illness. Responses to questions about perceived norms followed similar patterns. The primary limitations of this study are that the vignettes may have omitted context that could have influenced stigma and that generalizability beyond rural Uganda may be limited.Conclusions: In a population-based, randomized survey experiment conducted in rural southwestern Uganda, portrayals of effectively treated mental illness did not appear to reduce endorsement of stigmatizing beliefs about mental illness or about persons with mental illness. These findings run counter to evidence from the United States. Further research is necessary to understand the relationship between mental illness treatment and stigmatizing attitudes in Uganda and other countries worldwide.Trial Registration: The experimental procedures for this study were registered with ClinicalTrials.gov as "Measuring Beliefs and Norms About Persons With Mental Illness" (NCT03656770). [ABSTRACT FROM AUTHOR]

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

Background: Unfavorable psychosocial working conditions have been associated with cognitive decline and chronic diseases, both of which may subsequently accelerate functional dependence. This study aimed to investigate the association between job demand-control-support combinations and trajectories of disability in later life and to further explore the role of cognitive decline and the co-occurrence of chronic diseases in mediating this association.Methods and Findings: In this cohort study, 2,937 community dwellers aged 60+ years (mean age 73 ± 10.6; 62.9% female) residing in the Kungsholmen District of Stockholm, Sweden, participated in the baseline survey (2001-2004) and were followed up to 12 years. Lifelong occupational history was obtained through a standardized interview; job demands, job control, and social support at work in the longest-held occupation were graded with a psychosocial job-exposure matrix. Job control, demands, and social support were dichotomized using the median values from the matrix, respectively, to further generate demand-control-support combinations. Disability was measured by summing the number of impaired basic and instrumental activities of daily living. Global cognitive function was assessed by Mini-Mental State Examination. Chronic conditions were ascertained by clinical examinations, medical history, and patient clinical records; the total number of chronic diseases was summed. Data were analyzed using linear mixed-effects models and mediation analysis. Age, sex, education, alcohol consumption, smoking, leisure activity engagement, early-life socioeconomic status, occupational characteristic and physical demands, and baseline cognitive function and number of chronic diseases were adjusted for in the analyses. Compared with active jobs (high control/high demands; n = 1,807), high strain (low control/high demands; n = 328), low strain (high control/low demands; n = 495), and passive jobs (low control/low demands; n = 307) were all associated with a faster rate of disability progression (β = 0.07, 95% CI 0.02-0.13, p = 0.01; β = 0.10, 95% CI 0.06-0.15, p < 0.001; β = 0.11, 95% CI 0.05-0.18, p < 0.001). The association between high strain and disability progression was only shown in people with low social support at work (β = 0.13, 95% CI 0.07-0.19, p < 0.001), but not in those with high social support (β = 0.004, 95% CI -0.09 to 0.10, p = 0.93). Moreover, we estimated that the association between demand-control status and disability trajectories was mediated 38.5% by cognitive decline and 18.4% by accumulation of chronic diseases during the follow-up period. The limitations of this study include unmeasured confounding, self-reported work experience, and the reliance on a psychosocial job-exposure matrix that does not consider variabilities in individuals' perception on working conditions or job characteristics within occupations.Conclusions: Our findings suggest that negative psychosocial working conditions during working life may accelerate disability progression in later life. Notably, social support at work may buffer the detrimental effect of high strain on disability progression. Cognitive decline and chronic-disease accumulation, and especially the former, partially mediate the association of psychosocial working conditions with trajectories of disability. Further studies are required to explore more mechanisms that underlie the association between psychosocial working conditions and disability trajectories. [ABSTRACT FROM AUTHOR]

Background: Despite dietary recommendations of polyunsaturated fatty acids (PUFAs) for cardiometabolic health, n-3 and n-6 PUFAs and their interplay in relation to diabetes risk remain debated. Importantly, data among pregnant women are scarce. We investigated individual plasma phospholipid n-3 and n-6 PUFAs in early to midpregnancy in relation to subsequent risk of gestational diabetes mellitus (GDM).Methods and Findings: Within the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort (n = 2,802), individual plasma phospholipid n-3 and n-6 PUFAs levels were measured at gestational weeks (GWs) 10-14, 15-26, 23-31, and 33-39 among 107 GDM cases (ascertained on average at GW 27) and 214 non-GDM controls. Conditional logistic regression was used, adjusting for major risk factors for GDM. After adjusting for covariates, individual n-3 eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) were inversely correlated with insulin-resistance markers, whereas individual n-6 dihomo-gamma-linolenic acid (DGLA) was positively correlated with insulin-resistance markers. At GW 15-26, a standard deviation (SD) increase in total n-3 PUFAs and individual n-3 DPA was associated with a 36% (adjusted odds ratio 0.64; 95% CI 0.42-0.96; P = 0.042) and 33% (0.67; 95% CI 0.45-0.99; P = 0.047) lower risk of GDM, respectively; however, the significance did not persist after post hoc false-discovery rate (FDR) correction (FDR-corrected P values > 0.05). Associations between total n-6 PUFAs and GDM were null, whereas associations with individual n-6 PUFAs were differential. Per SD increase, gamma-linolenic acid (GLA) at GWs 10-14 and DGLA at GWs 10-14 and 15-26 were significantly associated with a 1.40- to 1.95-fold higher risk of GDM, whereas docosatetraenoic acid (DTA) at GW 15-26 was associated with a 45% (0.55; 95% CI 0.37-0.83) lower risk of GDM (all FDR-corrected P values < 0.05). Null associations were observed for linoleic acid (LA) in either gestational window in relation to risk of GDM. Women with high (≥median) n-3 PUFAs and low (Conclusions: Our findings may suggest a potential role of primarily endogenously metabolized plasma phospholipid n-6 PUFAs including GLA, DGLA, and DTA in early to midpregnancy in the development of GDM. Null findings on primarily diet-derived n-3 EPA and DHA and n-6 LA do not provide strong evidence to suggest a beneficial role in prevention of GDM, although not excluding the potential benefit of EPA and DHA on glucose-insulin homeostasis given the inverse associations with insulin-resistance markers. Our findings highlight the importance of assessing individual circulating PUFAs to investigate their distinct pathophysiologic roles in glucose homeostasis in pregnancy. [ABSTRACT FROM AUTHOR]

Background: Infection is a major complication in liver cirrhosis and causes major morbidity and mortality. However, the incidence and mortality related to these conditions in patients infected with hepatitis C virus (HCV) are unclear, as is whether antiviral therapy could change their infection risk.Methods and Findings: In this community-based cohort study, a total of 115,336 adults (mean age 52.2 years; 35.6% men) without cirrhosis participating in the New Taipei City Health Screening in 2005-2008 were classified as having noncirrhotic HCV (NC-HCV) (n = 2,839), noncirrhotic hepatitis B virus (NC-HBV) (n = 8,316), or no HBV or HCV infection (NBNC) (n = 104,181). Participants were followed to their first hospitalization for infection or death after data linkage with the Taiwan National Health Insurance Research Database (NHIRD) and Death Registry. A Cox proportional hazard regression model, adjusted for age, sex, body mass index (BMI), smoking, alcohol consumption, education level, diabetes, renal function, systemic steroids, and history of hospitalization, was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and individual sites of infection and infection-related mortality. The reference group was NBNC participants with normal to mildly elevated alanine aminotransferase (ALT) (<1.5 times upper normal limit [UNL]) levels. To further address the impact of antiviral treatment on infection risk, we conducted analyses of data from the nationwide NHIRD and compared the risks for hospitalization because of infections and infection-related deaths between patients with HCV who received antiviral therapy (n = 20,264) and those who remained untreated (n = 104,360). During a median 8.2-year follow-up, the incidence of hospitalization for infection was substantially higher in NC-HCV patients. Compared to the reference group, NC-HCV was associated with a significantly higher risk for hospitalization because of overall infections (adjusted HR: 1.22; 95% CI: 1.12-1.33), but we observed no increased risk for patients in the NC-HBV (adjusted HR: 0.94; 95% CI: 0.88-1.01) or NBNC group with moderate to markedly elevated ALT levels (adjusted HR: 1.03; 95% CI: 0.93-1.14). For specific sites of infection, the NC-HCV group had increased risks for septicemia and lower respiratory tract, reproductive, and urinary tract infections. We noted no increased risk for infection-related death among patients with NC-HCV. Patients with HCV who received antiviral therapy had significantly reduced infection-related hospitalization and death risks (adjusted HR: 0.79; 95% CI: 0.73-0.84 for infection-related hospitalization and adjusted HR: 0.08; 95% CI: 0.04-0.16 for infection-related deaths). Study limitations include the exclusion of patients with cirrhosis from the cohort, the possibility of unmeasured confounding, and the lack of information on direct-acting antiviral agents (DAAs).Conclusions: In this study, patients with NC-HCV were at increased risk for hospitalization for infection, while no increased risk was observed for NC-HBV-infected patients. [ABSTRACT FROM AUTHOR]

Background: The Developmental Origins of Health and Disease (DOHaD) hypothesis postulates that exposures during early life, such as maternal dietary intake during pregnancy, may have a lifelong impact on the individual's susceptibility to diseases. The individual's own lifestyle habits are obviously an additional factor, but we have only limited knowledge regarding how it may interact with prenatal exposures in determining later disease. To gain further insight into these potentially complex relationships, we examined the longitudinal association between maternal diet quality during pregnancy and diet quality in early adolescence in a contemporary cohort.Methods and Findings: From 1996 to 2003, the Danish National Birth Cohort (DNBC) was established. Women from across the country were enrolled, and dietary intake in midpregnancy was assessed concurrently with a 360-item food frequency questionnaire (FFQ) (https://www.dnbc.dk/-/media/arkiv/projekt-sites/dnbc/kodeboeger/dnbc-food-frequency-questionnaire/dnbc-food-frequency-questionnaire-pdf.pdf?la=en). During 2013-2018, dietary intake was assessed at age 14 years with a 150-item FFQ (https://www.dnbc.dk/-/media/arkiv/projekt-sites/dnbc/kodeboeger/ffq-14/dnbc-ffq-14-english-translation.pdf?la=en) in the DNBC children. Among the 19,582 mother-offspring pairs included in the analyses, the mean age (±standard deviation [SD]) was 30.7 (±4.1) years and 14.0 (±0.0) years for mothers and offspring, respectively. The majority of both mothers (67%) and offspring (76%) were classified as normal weight. For both questionnaires, a Healthy Eating Index (HEI) was developed as an indicator for diet quality based on current Danish Food-Based Dietary Guidelines (FBDG) including eight components: fruits and vegetables, fish, dietary fibres, red meat, saturated fatty acids (SFAs), sodium, sugar-sweetened beverages (SSBs), and added sugar. The HEI score was divided into quartiles; individuals in the highest quartile represented those with the most optimal diet. The maternal HEI score was correlated positively with offspring HEI score (Pearson r = 0.22, p < 0.001). A log-linear binomial model was used to estimate the relative risk of the offspring being in the highest quartile of HEI at age 14 years if the mother was ranked in quartile 4 during pregnancy. Results showed that offspring born to mothers who were in the highest HEI quartile during pregnancy were more likely themselves to be located in the highest HEI quartile at age 14 years (risk ratio [RR]: 2.1, 95% confidence interval [CI]: 2.0, 2.3, p < 0.001). Adjusting for maternal prepregnancy body mass index (BMI), parity, education, alcohol intake, physical activity, smoking, and breastfeeding, as well as offspring total energy intake and sex, did not influence the effect estimates. The limitations of our study include that some attrition bias towards more healthy participants was observed when comparing participants with nonparticipants. Bias in the FFQ method may also have resulted in underrepresentation of adolescents with poorer diet quality.Conclusions: In this study using data from a large national birth cohort, we observed that maternal diet quality during pregnancy was associated with diet quality of the offspring at age 14 years. These findings indicate the importance of separating early dietary exposures from later dietary exposures when studying dietary aetiologies of diseases postulated to have developmental origins such as, for instance, obesity or asthma in observational settings. [ABSTRACT FROM AUTHOR]

Background: The inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis).Methods and Findings: This study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481). In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (β: -0.85, p < 0.001, 95% CI -1.28 to -0.42) and 6 months (β: -1.05, p < 0.001, 95% CI -1.50 to -0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (β: -1.04, p < 0.001, 95% CI -1.52 to -0.55) and 6 months (β: -1.24, p < 0.001, 95% CI -1.75 to -0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs.Conclusions: In this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D.Trial Registration: The trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481. [ABSTRACT FROM AUTHOR]

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: In situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorisation (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorisation recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorisation remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and postauthorisation measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorised through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies.Methods and Findings: We used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorised through CMA or AA pathways during January 1, 2011 to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomised controlled trials supporting the surrogate-clinical outcome relationship were rated as 'validated'. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorised based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being 'reasonably likely' (n = 30; 61%) or of having 'biological plausibility' (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorisations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalisable to products authorised through the standard assessment pathway.Conclusions: The pivotal trial evidence supporting marketing authorisations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorisations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, postauthorisation measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorisation holders. [ABSTRACT FROM AUTHOR]

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

Background: Effective and cost-effective primary care treatments for low back pain (LBP) are required to reduce the burden of the world's most disabling condition. This study aimed to compare the clinical effectiveness and cost-effectiveness of the Fear Reduction Exercised Early (FREE) approach to LBP (intervention) with usual general practitioner (GP) care (control).Methods and Findings: This pragmatic, cluster-randomised controlled trial with process evaluation and parallel economic evaluation was conducted in the Hutt Valley, New Zealand. Eight general practices were randomly assigned (stratified by practice size) with a 1:1 ratio to intervention (4 practices; 34 GPs) or control group (4 practices; 29 GPs). Adults presenting to these GPs with LBP as their primary complaint were recruited. GPs in the intervention practices were trained in the FREE approach, and patients presenting to these practices received care based on the FREE approach. The FREE approach restructures LBP consultations to prioritise early identification and management of barriers to recovery. GPs in control practices did not receive specific training for this study, and patients presenting to these practices received usual care. Between 23 September 2016 and 31 July 2017, 140 eligible patients presented to intervention practices (126 enrolled) and 110 eligible patients presented to control practices (100 enrolled). Patient mean age was 46.1 years (SD 14.4), and 46% were female. The duration of LBP was less than 6 weeks in 88% of patients. Primary outcome was change from baseline in patient participant Roland Morris Disability Questionnaire (RMDQ) score at 6 months. Secondary patient outcomes included pain, satisfaction, and psychosocial indices. GP outcomes included attitudes, knowledge, confidence, and GP LBP management behaviour. There was active and passive surveillance of potential harms. Patients and outcome assessors were blind to group assignment. Analysis followed intention-to-treat principles. A total of 122 (97%) patients from 32 GPs in the intervention group and 99 (99%) patients from 25 GPs in the control group were included in the primary outcome analysis. At 6 months, the groups did not significantly differ on the primary outcome (adjusted mean RMDQ score difference 0.57, 95% CI -0.64 to 1.78; p = 0.354) or secondary patient outcomes. The RMDQ difference met the predefined criterion to indicate noninferiority. One control group participant experienced an activity-related gluteal tear, with no other adverse events recorded. Intervention group GPs had improvements in attitudes, knowledge, and confidence compared with control group GPs. Intervention group GP LBP management behaviour became more guideline concordant than the control group. In cost-effectiveness, the intervention dominated control with lower costs and higher Quality-Adjusted Life Year (QALY) gains. Limitations of this study were that although adequately powered for primary outcome assessment, the study was not powered for evaluating some employment, healthcare use, and economic outcomes. It was also not possible for research nurses (responsible for patient recruitment) to be masked on group allocation for practices.Conclusions: Findings from this study suggest that the FREE approach improves GP concordance with LBP guideline recommendations but does not improve patient recovery outcomes compared with usual care. The FREE approach may reduce unnecessary healthcare use and produce economic benefits. Work participation or health resource use should be considered for primary outcome assessment in future trials of undifferentiated LBP.Trial Registration: ACTRN12616000888460. [ABSTRACT FROM AUTHOR]

Background: Global data indicate that women with a history of hyperglycemia first detected in pregnancy (HFDP) are at up to 7 times risk of progressing to type 2 diabetes mellitus (T2DM) compared with their counterparts who have pregnancies that are not complicated by hyperglycemia. However, there are no data from the sub-Saharan African region, which has the highest projected rise in diabetes prevalence globally. The aim of this study was to determine the proportion of women who progress to T2DM and associated risk factors 5 to 6 years after HFDP in Cape Town, South Africa.Methods and Findings: All women with HFDP, at a major referral hospital in Cape Town, were followed up 5 to 6 years later using a cross-sectional study. Each participant had a 75 g oral glucose tolerance test; anthropometric measurements and a survey were administered. A total of 220 participants were followed up. At this time, their mean age was 37.2 years (SD 6.0). Forty-eight percent (95% CI 41.2-54.4) progressed to T2DM, 5.5% (95% CI 3.1-9.4) had impaired fasting glucose, and 10.5% (95% CI 7.0-15.3) had impaired glucose tolerance. Of the participants who progressed to T2DM, 47% were unaware of their diabetes status. When HFDP was categorized post hoc according to WHO 2013 guidelines, progression in the diabetes in pregnancy (DIP) group was 81% (95% CI 70.2-89.0) and 31.3% (95% CI 24.4-39.3) in the gestational diabetes mellitus (GDM) category. Factors associated with risk of progression to T2DM were; at follow-up: waist circumference (odds ratios [OR] 1.1, 95% CI 1.0-1.1, p = 0.007), hip circumference (OR 0.9, 95% CI 0.8-1.0, p = 0.001), and BMI (OR 1.1, 95% CI 1.0-1.3, p = 0.001), and at baseline: insulin (OR 25.8, 95% CI 3.9-171.4, p = 0.001) and oral hypoglycaemic treatment during HFDP (OR 4.1, 95% CI 1.3-12.9, p = 0.018), fasting (OR 2.7, 95% CI 1.5-4.8, p = 0.001), and oral glucose tolerance test 2-hour glucose concentration at HFDP diagnosis (OR 4.3, 95% CI 2.4-7.7, p < 0.001). Our findings have limitations in that we did not include a control group of women without a history of HFDP.Conclusions: The progression to T2DM in women with previous HFDP found in this study highlights the need for interventions to delay or prevent progression to T2DM after HFDP. In addition, interventions to prevent HFDP may also contribute to reducing the risk of T2DM. [ABSTRACT FROM AUTHOR]

Background: Young women account for a disproportionate fraction of new HIV infections in Africa and are a priority population for HIV prevention, including implementation of preexposure prophylaxis (PrEP). The overarching goal of this project was to demonstrate the feasibility of integrating PrEP delivery within routine family planning (FP) clinics to serve as a platform to efficiently reach at-risk adolescent girls and young women (AGYW) for PrEP in HIV high-burden settings.Methods and Findings: The PrEP Implementation in Young Women and Adolescents (PrIYA) program is a real-world implementation program to demonstrate integration of PrEP delivery for at-risk AGYW in FP clinics in Kisumu, Kenya. Between November 2017 and June 2018, women aged 15 to 45 from the general population seeking FP services at 8 public health clinics were universally screened for HIV behavioral risk factors and offered PrEP following national PrEP guidelines. We evaluated PrEP uptake and continuation, and robust Poisson regression methods were used to identify correlates of uptake and early continuation of PrEP, with age included as a one-knot linear spline. Overall, 1,271 HIV-uninfected women accessing routine FP clinics were screened for PrEP; the median age was 25 years (interquartile range [IQR]: 22-29), 627 (49%) were <24 years old, 1,026 (82%) were married, more than one-third (34%) had partners of unknown HIV status, and the vast majority (n = 1,200 [94%]) reported recent condom-less sex. Of 1,271 women screened, 278 (22%) initiated PrEP, and 114 (41%) returned for at least one refill visit after initiation. PrEP uptake was independently associated with reported male-partner HIV status (HIV-positive 94%, unknown 35%, HIV-negative 8%; p < 0.001) and marital status (28% unmarried versus married 21%; p = 0.04), and a higher proportion of women ≥24 years (26%; 191/740) initiated PrEP compared to 16% (87/531) of young women <24 years (p < 0.001). There was a moderate and statistically non-significant unadjusted increase in PrEP uptake among women using oral contraception pills (OCPs) compared to women using injectable or long-acting reversible contraception methods (OCP 28% versus injectable/implants/intrauterine devices [IUDs] 18%; p = 0.06). Among women with at least one post-PrEP initiation follow-up visit (n = 278), no HIV infection was documented during the project period. Overall, continuation of PrEP use at 1, 3, and 6 months post initiation was 41%, 24%, and 15%, respectively. The likelihood for early continuation of PrEP use (i.e., return for at least one PrEP refill within 45 days post initiation) was strongly associated with reported male-partner HIV status (HIV-positive 67%, -negative 39%, unknown 31%; overall effect p = 0.001), and a higher proportion of women ≥24 years old continued PrEP at 1 month compared with young women <24 years old (47% versus 29%; p = 0.002). For women ≥24 years old, the likelihood to continue PrEP use at 1 month post initiation increased by 3% for each additional year of a woman's age (adjusted prevalence ratio [PR]: 1.03; 95% confidence interval [CI]: 1.01-1.05; p = 0.01). In contrast, for women <24 years old, the likelihood of continuing PrEP for each additional year of a woman's age was high in magnitude (approximately 6%) but statistically non-significant (adjusted PR: 1.06; 95% CI: 0.97-1.16; p = 0.18). Frequently reported reasons for discontinuing PrEP were low perceived risk of HIV (25%), knowledge that partner was HIV negative (24%), experiencing side effects (20%), and pill burden (17%). Study limitations include lack of qualitative work to provide insights into women's decision-making on PrEP uptake and continuation, the small number of measured covariates imposed by the program data, and a nonrandomized design limiting definitive ascertainment of the robustness of a PrEP-dedicated nurse-led implementation strategy.Conclusions: In this real-world PrEP implementation program in Kenya, integration of universal screening and counseling for PrEP in FP clinics was feasible, making this platform a potential "one-stop" location for FP and PrEP. There was a high drop-off in PrEP continuation, but a subset of women continued PrEP use at least through 1 month, possibly indicating further reflection or decision-making on PrEP use. Greater efforts to support PrEP normalization and persistence for African women are needed to help women navigate their decisions about HIV prevention preferences as their reproductive goals and HIV vulnerability evolve. [ABSTRACT FROM AUTHOR]

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

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

Background: Children with uncomplicated severe acute malnutrition (SAM) are treated at home with ready-to-use therapeutic foods (RUTFs). The current RUTF dose is prescribed according to the weight of the child to fulfil 100% of their nutritional needs until discharge. However, there is doubt concerning the dose, as it seems to be shared, resulting in suboptimal cost-efficiency of SAM treatment. We investigated the efficacy of a reduced RUTF dose in community-based treatment of uncomplicated SAM.Methods and Findings: We undertook a randomised trial testing the non-inferiority of weight gain velocity of children with SAM receiving (a) a standard RUTF dose for two weeks, followed by a reduced dose thereafter (reduced), compared with (b) a standard RUTF dose throughout the treatment (standard). A mean difference of 0.0 g/kg/day was expected, with a non-inferiority margin fixed at -0.5 g/kg/day. Linear and logistic mixed regression analyses were performed, with study site and team as random effects. Between October 2016 and July 2018, 801 children with uncomplicated SAM aged 6-59 months were enrolled from 10 community health centres in Burkina Faso. At admission, the mean age (± standard deviation [SD]) was 13.4 months (±8.7), 49% were male, and the mean weight was 6.2 kg (±1.3). The mean weight gain velocity from admission to discharge was 3.4 g/kg/day and did not differ between study arms (Δ 0.0 g/kg/day; 95% CI -0.4 to 0.4; p = 0.92) confirming non-inferiority (p = 0.013). However, after two weeks, the weight gain velocity was significantly lower in the reduced dose with a mean of 2.3 g/kg/day compared with 2.7 g/kg/day in the standard dose (Δ -0.4 g/kg/day; 95% CI -0.8 to -0.02; p = 0.041). The length of stay (LoS) was not different (p = 0.73) between groups with a median of 56 days (interquartile range [IQR] 35-91) in both arms. No differences were found between reduced and standard arm in recovery (52.7% and 55.4%; p = 0.45), referral (19.2% and 20.1%; p = 0.80), defaulter (12.2% and 8.5%; p = 0.088), non-response (12.7% and 12.5%; p = 0.95), and relapse (2.4% and 1.8%; p = 0.69) rates, respectively. However, the reduced RUTF dose had a small 0.2 mm/week (95% CI 0.04 to 0.4; p = 0.015) negative effect on height gain velocity with a mean height gain of 2.6 mm/week with reduced and 2.8 mm/week with standard RUTF dose. The impact was more pronounced in children under 12 months of age (interaction, p = 0.019) who gained 2.8 mm/week with reduced and 3.1 mm/week with standard dose (Δ -0.4 mm/week; 95% CI -0.6 to -0.2; p < 0.001). Limitations include not blinding participants to the RUTF dose received and excluding all children with negative appetite test. The results are generalisable for relatively food secure contexts with a young SAM population.Conclusions: Reducing the RUTF dose provided to children with SAM after two weeks of treatment did not reduce overall weight or mid-upper arm circumference (MUAC) gain velocity nor affect recovery or lengthen treatment time. However, it led to a small but significant negative effect on linear growth, especially among the youngest. The potential effect of reducing the RUTF dose in a routine program on treatment outcomes should be evaluated before scaling up.Trial Registration: ISRCTN registry ISRCTN50039021. [ABSTRACT FROM AUTHOR]

Background: Evidence on the association between breastfeeding and later childhood obesity and blood pressure (BP) is inconsistent, especially in HIV-prevalent areas where, until recently, HIV-infected women were discouraged from breastfeeding, but obesity is increasingly prevalent.Methods and Findings: The Siyakhula cohort (2012-2014), a population-based prospective cohort study, collected data over 3 visits on HIV-negative children ages 7 to 11 years in rural South Africa. We used weight (body mass index [BMI]), fat, and BP as outcome variables and incorporated early life (including mother's age at delivery and HIV status) and current life factors (including maternal education and current BMI). Our primary exposure was breastfeeding duration. We dichotomized 3 outcome measures using pre-established thresholds for clinical interpretability: (1) overfat: ≥85th percentile of body fat; (2) overweight: >1 SD BMI z score; and (3) prehypertension: ≥90th percentile for systolic BP (SBP) or diastolic BP (DBP). We modelled each outcome using multivariable logistic regression, including stopping breastfeeding, then early life, and finally current life factors. Of 1,536 children (mean age = 9.3 years; 872 girls; 664 boys), 7% were overfat, 13.2% overweight, and 9.1% prehypertensive. Over half (60%) of the mothers reported continued breastfeeding for 12+ months. In multivariable analyses, continued breastfeeding between 6 and 11 months was associated with approximately halved odds of both being overfat (adjusted odds ratio [aOR] = 0.43, 95% confidence interval [CI] 0.21-0.91, P = 0.027) and overweight (aOR = 0.46, CI 0.26-0.82, P = 0.0083), but the association with prehypertension did not reach statistical significance (aOR = 0.72, CI 0.38-1.37, P = 0.32). Children with a mother who was currently obese were 5 times more likely (aOR = 5.02, CI 2.47-10.20, P < 0.001) to be overfat and over 4 times more likely to be overweight (aOR = 4.33, CI 2.65-7.09, P < 0.001) than children with normal weight mothers. Differences between HIV-exposed and unexposed children on any of the outcomes were minimal and not significant. The main study limitation was that duration of breastfeeding was based on maternal recall.Conclusions: To our knowledge, this is the first study examining and quantifying the association between breastfeeding and childhood obesity in an African setting with high HIV prevalence. We observed that breastfeeding was independently associated with reduced childhood obesity for both HIV-exposed and unexposed children, suggesting that promoting optimal nutrition throughout the life course, starting with continued breastfeeding, may be critical to tackling the growing obesity epidemic. In the era of widespread effective antiretroviral treatment for HIV-infected women for life, these data further support the recommendation of breastfeeding for all women. [ABSTRACT FROM AUTHOR]

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

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

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

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

Background: Accelerated growth in early childhood is an established risk factor for later obesity and cardiometabolic disease, but the relative importance of fat mass (FM) and fat-free mass (FFM) accretion is not well understood. We aimed to study how FM and FFM at birth and their accretion during infancy were associated with body composition and cardiometabolic risk markers at 5 years.Methods and Findings: Healthy children born at term were enrolled in the Infant Anthropometry and Body Composition (iABC) birth cohort between December 2008 and October 2012 at Jimma University Specialized Hospital in the city of Jimma, Ethiopia. FM and FFM were assessed using air displacement plethysmography a median of 6 times between birth and 6 months of age. In 507 children, we estimated individual FM and FFM at birth and their accretion over 0-3 and 3-6 months of age using linear-spline mixed-effects modelling. We analysed associations of FM and FFM at birth and their accretion in infancy with height, waist circumference, FM, FFM, and cardiometabolic risk markers at 5 years using multiple linear regression analysis. A total of 340 children were studied at the 5-year follow-up (mean age: 60.0 months; girls: 50.3%; mean wealth index: 45.5 out of 100; breastfeeding status at 4.5 to 6 months post-partum: 12.5% exclusive, 21.4% almost exclusive, 60.6% predominant, 5.5% partial/none). Higher FM accretion in infancy was associated with higher FM and waist circumference at 5 years. For instance, 100-g/month higher FM accretion in the periods 0-3 and 3-6 months was associated with 339 g (95% CI: 243-435 g, p < 0.001) and 367 g (95% CI: 250-484 g, p < 0.001) greater FM at 5 years, respectively. Higher FM at birth and FM accretion from 0 to 3 months were associated with higher FFM and cholesterol concentrations at 5 years. Associations for cholesterol were strongest for low-density lipoprotein (LDL)-cholesterol, and remained significant after adjusting for current FM. A 100-g higher FM at birth and 100-g/month higher FM accretion from 0 to 3 months were associated with 0.16 mmol/l (95% CI: 0.05-0.26 mmol/l, p = 0.005) and 0.06 mmol/l (95% CI: 0.01-0.12 mmol/l, p = 0.016) higher LDL-cholesterol at 5 years, respectively. Higher FFM at birth and FFM accretion in infancy were associated with higher FM, FFM, waist circumference, and height at 5 years. For instance, 100-g/month higher FFM accretion in the periods 0-3 and 3-6 months was associated with 1,002 g (95% CI: 815-1,189 g, p < 0.001) and 624 g (95% CI: 419-829 g, p < 0.001) greater FFM at 5 years, respectively. We found no associations of FM and FFM growth with any of the other studied cardiometabolic markers including glucose, HbA1c, insulin, C-peptide, HOMA-IR, triglycerides, and blood pressure. Non-attendance at the 5-year follow-up visit was the main limitation of this study, which may have introduced selection bias and limited the power of the regression analyses.Conclusions: FM accretion in early life was positively associated with markers of adiposity and lipid metabolism, but not with blood pressure and cardiometabolic markers related to glucose homeostasis. FFM accretion was primarily related to linear growth and FFM at 5 years. [ABSTRACT FROM AUTHOR]

Background: Weight-control interventions in pregnant women with overweight or obesity have limited effectiveness for fetal growth and birth outcomes. Interventions or prevention programs aiming at the pre-pregnancy period should be considered. However, how the woman's weight change before pregnancy affects fetal growth is not known. We investigated the association between weight change over the year before pregnancy and birth weight.Methods and Findings: We used the inclusion data of 16,395 women from the ELFE French national birth cohort, a nationally representative cohort in which infants were enrolled at birth with their families in 2011. Maternal weight change was self-reported and classified into 3 groups: moderate weight variation or stable weight, weight loss > 5 kg, and weight gain > 5 kg or both weight loss and gain > 5 kg. Multiple linear regression models were used to investigate the association between pre-pregnancy weight change and a birth weight z-score calculated according to the French Audipog reference, adjusted for a large set of maternal characteristics. The analyses were stratified by maternal body mass index (BMI) at conception (<25 versus ≥25 kg/m2) and adjusted for BMI within these categories. We used the MacKinnon method to test the mediating effect of gestational weight gain (GWG) on these associations. Mother's mean age was 30.5 years, 87% were born in France, and 26% had overweight or obesity. For women in either BMI category at conception, GWG was more than 2 kg higher, on average, for women with weight loss before pregnancy than for women with stable weight or moderate weight variation. For women with BMI < 25 kg/m2 at conception, birth weight was significantly higher with weight loss than stable weight before pregnancy (β = 0.08 [95% CI 0.02; 0.14], p = 0.01), and this total effect was explained by a significant mediating effect through GWG. For women with BMI ≥ 25 kg/m2 at conception, birth weight was not associated with pre-pregnancy weight loss during the year before pregnancy. Mediation analysis revealed that in these women, the direct effect of pre-pregnancy weight loss that would have resulted in a smaller birth weight z-score (β = -0.11 [95% CI -0.19; -0.03], p = 0.01) was cancelled out by the GWG. The mediating effect of GWG was even higher when weight loss resulted from a restrictive diet in the year before pregnancy. Weight gain before pregnancy was not associated with birth weight. Although we included a large number of women and had extensive data, the only potential cause of pre-pregnancy weight loss that was investigated was dieting for intentional weight loss. We have no information on other potential causes but did however exclude women with a history of pre-pregnancy chronic disease. Another limitation is declaration bias due to self-reported data.Conclusions: Health professionals should be aware that GWG may offset the expected effect of weight loss before conception on fetal growth in overweight and obese women. Further studies are required to understand the underlying mechanisms in order to develop weight-control interventions and improve maternal periconceptional health and developmental conditions for the fetus. [ABSTRACT FROM AUTHOR]

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

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

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

Background: High body mass index (BMI) is associated with mortality, but the pervasive problem of confounding and reverse causality in observational studies limits inference about the direction and magnitude of causal effects. We aimed to obtain estimates of the causal association of BMI with all-cause and cause-specific mortality.Methods and Findings: In a record-linked, intergenerational prospective study from the general population of Sweden, we used two-sample instrumental variable (IV) analysis with data from 996,898 fathers (282,407 deaths) and 1,013,083 mothers (153,043 deaths) and their sons followed up from January 1, 1961, until December 31, 2004. Sons' BMI was used as the instrument for parents' BMI to compute hazard ratios (HRs) for risk of mortality per standard deviation (SD) higher parents' BMI. Using offspring exposure as an instrument for parents' exposure is unlikely to be affected by reverse causality (an important source of bias in this context) and reduces confounding. IV analyses supported causal associations between higher BMI and greater risk of all-cause mortality (HR [95% confidence interval (CI)] per SD higher fathers' BMI: 1.29 [1.26-1.31] and mothers' BMI: 1.39 [1.35-1.42]) and overall cancer mortality (HR per SD higher fathers' BMI: 1.20 [1.16-1.24] and mothers' BMI: 1.29 [1.24-1.34]), including 9 site-specific cancers in men (bladder, colorectum, gallbladder, kidney, liver, lung, lymphatic system, pancreas, and stomach) and 11 site-specific cancers in women (gallbladder, kidney, liver, lung, lymphatic system, ovaries, pancreas, stomach, uterus, cervix, and endometrium). There was evidence supporting causal associations between higher BMI in mothers and greater risk of mortality from kidney disease (HR: 2.17 [1.68-2.81]) and lower risk of mortality from suicide (HR: 0.77 [0.65-0.90]). In both sexes, there was evidence supporting causal associations between higher BMI and mortality from cardiovascular diseases (CVDs), stroke, diabetes, and respiratory diseases. We were unable to test the association between sons' and mothers' BMIs (as mothers' data were unavailable) or whether the instrument was independent of unmeasured or residual confounding; however, the associations between parents' mortality and sons' BMI were negligibly influenced by adjustment for available confounders.Conclusions: Consistent with previous large-scale meta-analyses and reviews, results supported the causal role of higher BMI in increasing the risk of several common causes of death, including cancers with increasing global incidence. We also found positive effects of BMI on mortality from respiratory disease, prostate cancer, and lung cancer, which has been inconsistently reported in the literature, suggesting that the causal role of higher BMI in mortality from these diseases may be underestimated. Furthermore, we expect different patterns of bias in the current observational and IV analyses; therefore, the similarities between our findings from both methods increases confidence in the results. These findings support efforts to understand the mechanisms underpinning these effects to inform targeted interventions and develop population-based strategies to reduce rising obesity levels for disease prevention. [ABSTRACT FROM AUTHOR]

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

Background: High satisfaction with healthcare is common in low- and middle-income countries (LMICs), despite widespread quality deficits. This may be due to low expectations because people lack knowledge about what constitutes good quality or are resigned about the quality of available services.Methods and Findings: We fielded an internet survey in Argentina, China, Ghana, India, Indonesia, Kenya, Lebanon, Mexico, Morocco, Nigeria, Senegal, and South Africa in 2017 (N = 17,996). It included vignettes describing poor-quality services-inadequate technical or interpersonal care-for 2 conditions. After applying population weights, most of our respondents lived in urban areas (59%), had finished primary school (55%), and were under the age of 50 (75%). Just over half were men (51%), and the vast majority reported that they were in good health (73%). Over half (53%) of our study population rated the quality of vignettes describing poor-quality services as good or better. We used multilevel logistic regression and found that good ratings were associated with less education (no formal schooling versus university education; adjusted odds ratio [AOR] 2.22, 95% CI 1.90-2.59, P < 0.001), better self-reported health (excellent versus poor health; AOR 5.19, 95% CI 4.33-6.21, P < 0.001), history of discrimination in healthcare (AOR 1.47, 95% CI 1.36-1.57, P < 0.001), and male gender (AOR 1.32, 95% CI 1.23-1.41, P < 0.001). The survey did not reach nonusers of the internet thus only representing the internet-using population.Conclusions: Majorities of the internet-using public in 12 LMICs have low expectations of healthcare quality as evidenced by high ratings given to poor-quality care. Low expectations of health services likely dampen demand for quality, reduce pressure on systems to deliver quality care, and inflate satisfaction ratings. Policies and interventions to raise people's expectations of the quality of healthcare they receive should be considered in health system quality reforms. [ABSTRACT FROM AUTHOR]