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Background: Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials.Methods and Findings: We received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report. None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were "bothersome," a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that "all adverse events were recorded." For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student's t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper. Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs.Conclusions: In the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles. [ABSTRACT FROM AUTHOR]

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

Background: The development of cognitive and socioemotional skills early in life influences later health and well-being. Existing estimates of unmet developmental potential in low- and middle-income countries (LMICs) are based on either measures of physical growth or proxy measures such as poverty. In this paper we aim to directly estimate the number of children in LMICs who would be reported by their caregivers to show low cognitive and/or socioemotional development.Methods and Findings: The present paper uses Early Childhood Development Index (ECDI) data collected between 2005 and 2015 from 99,222 3- and 4-y-old children living in 35 LMICs as part of the Multiple Indicator Cluster Survey (MICS) and Demographic and Health Surveys (DHS) programs. First, we estimate the prevalence of low cognitive and/or socioemotional ECDI scores within our MICS/DHS sample. Next, we test a series of ordinary least squares regression models predicting low ECDI scores across our MICS/DHS sample countries based on country-level data from the Human Development Index (HDI) and the Nutrition Impact Model Study. We use cross-validation to select the model with the best predictive validity. We then apply this model to all LMICs to generate country-level estimates of the prevalence of low ECDI scores globally, as well as confidence intervals around these estimates. In the pooled MICS and DHS sample, 14.6% of children had low ECDI scores in the cognitive domain, 26.2% had low socioemotional scores, and 36.8% performed poorly in either or both domains. Country-level prevalence of low cognitive and/or socioemotional scores on the ECDI was best represented by a model using the HDI as a predictor. Applying this model to all LMICs, we estimate that 80.8 million children ages 3 and 4 y (95% CI 48.1 million, 113.6 million) in LMICs experienced low cognitive and/or socioemotional development in 2010, with the largest number of affected children in sub-Saharan Africa (29.4.1 million; 43.8% of children ages 3 and 4 y), followed by South Asia (27.7 million; 37.7%) and the East Asia and Pacific region (15.1 million; 25.9%). Positive associations were found between low development scores and stunting, poverty, male sex, rural residence, and lack of cognitive stimulation. Additional research using more detailed developmental assessments across a larger number of LMICs is needed to address the limitations of the present study.Conclusions: The number of children globally failing to reach their developmental potential remains large. Additional research is needed to identify the specific causes of poor developmental outcomes in diverse settings, as well as potential context-specific interventions that might promote children's early cognitive and socioemotional well-being. [ABSTRACT FROM AUTHOR]

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

Jean-Paul Chretien and colleagues argue that recent Ebola and Zika virus outbreaks highlight the importance of data sharing in scientific research. [ABSTRACT FROM AUTHOR]

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

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

Christian Lienhardt and colleagues discuss the importance of communication and coordination between regulators, researchers, and policy makers to ensure tuberculosis trials provide high-quality evidence for policy decisions. [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: 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]

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

Background: Differentiated antiretroviral therapy (ART) delivery models, in which patients are provided with care relevant to their current status (e.g., newly initiating, stable on treatment, or unstable on treatment) has become an essential part of patient-centered health systems. In 2015, the South African government implemented Chronic Disease Adherence Guidelines (AGLs), which involved five interventions: Fast Track Initiation Counseling for newly initiating patients, Enhanced Adherence Counseling for patients with an unsuppressed viral load, Early Tracing of patients who miss visits, and Adherence Clubs (ACs) and Decentralized Medication Delivery (DMD) for stable patients. We evaluated two of these interventions in 24 South African facilities: ACs, in which patients meet in groups outside usual clinic procedures and receive medication; and DMD, in which patients pick up their medication outside usual pharmacy queues.Methods and Findings: We compared those participating in ACs or receiving DMD at intervention sites to those eligible for ACs or DMD at control sites. Outcomes were retention and sustained viral suppression (<400 copies/mL) 12 months after AC or DMD enrollment (or comparable time for controls). 12 facilities were randomly allocated to intervention and 12 to control arms in four provinces (Gauteng, North West, Limpopo, and KwaZulu Natal). We calculated adjusted risk differences (aRDs) with cluster adjustment using generalized estimating equations (GEEs) using difference in differences (DiD) with patients eligible for ACs/DMD prior to implementation (Jan 1, 2015) for comparison. For DMD, randomization was not preserved, and the analysis was treated as observational. For ACs, 275 intervention and 294 control patients were enrolled; 72% of patients were female, 61% were aged 30-49 years, and median CD4 count at ART initiation was 268 cells/μL. AC patients had higher 1-year retention (89.5% versus 81.6%, aRD: 8.3%; 95% CI: 1.1% to 15.6%) and comparable sustained 1-year viral suppression (<400 copies/mL any time ≤ 18 months) (80.0% versus 79.6%, aRD: 3.8%; 95% CI: -6.9% to 14.4%). Retention associations were apparently stronger for men than women (men RD: 13.1%, 95% CI: 0.3% to 23.5%; women RD: 6.0%, 95% CI: -0.9% to 12.9%). For DMD, 232 intervention and 346 control patients were enrolled; 71% of patients were female, 65% were aged 30-49 years, and median CD4 count at ART initiation was 270 cells/μL. DMD patients had apparently lower retention (81.5% versus 87.2%, aRD: -5.9%; 95% CI: -12.5% to 0.8%) and comparable viral suppression versus standard of care (77.2% versus 74.3%, aRD: -1.0%; 95% CI: -12.2% to 10.1%), though in both cases, our findings were imprecise. We also noted apparently increased viral suppression among men (RD: 11.1%; 95% CI: -3.4% to 25.5%). The main study limitations were missing data and lack of randomization in the DMD analysis.Conclusions: In this study, we found comparable DMD outcomes versus standard of care at facilities, a benefit for retention of patients in care with ACs, and apparent benefits in terms of retention (for AC patients) and sustained viral suppression (for DMD patients) among men. This suggests the importance of alternative service delivery models for men and of community-based strategies to decongest primary healthcare facilities. Because these strategies also reduce patient inconvenience and decongest clinics, comparable outcomes are a potential success. The cost of all five AGL interventions and possible effects on reducing clinic congestion should be investigated.Clinical Trial Registration: NCT02536768. [ABSTRACT FROM AUTHOR]

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

In this Collection Review for the Novel Treatments for Tuberculosis Collection, Piero Olliaro and Michael Vaillant discuss the considerations when choosing a non-inferiority margin that is meaningful from statistical, ethical, clinical, and health standpoint. [ABSTRACT FROM AUTHOR]

Geraint Davies and colleagues discuss the potential for innovative early-phase clinical trial methods and technologies to reduce risk and speed up drug development for tuberculosis. [ABSTRACT FROM AUTHOR]

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

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

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

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

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

Background: Magnetic resonance imaging (MRI) combined with targeted biopsy (TB) is increasingly used in men with clinically suspected prostate cancer (PCa), but the long acquisition times, high costs, and inter-center/reader variability of routine multiparametric prostate MRI limit its wider adoption.Methods and Findings: The aim was to validate a previously developed unique MRI acquisition and reporting protocol, IMPROD biparametric MRI (bpMRI) (NCT01864135), in men with a clinical suspicion of PCa in a multi-institutional trial (NCT02241122). IMPROD bpMRI has average acquisition time of 15 minutes (no endorectal coil, no intravenous contrast use) and consists of T2-weighted imaging and 3 separate diffusion-weighed imaging acquisitions. Between February 1, 2015, and March 31, 2017, 364 men with a clinical suspicion of PCa were enrolled at 4 institutions in Finland. Men with an equivocal to high suspicion (IMPROD bpMRI Likert score 3-5) of PCa had 2 TBs of up to 2 lesions followed by a systematic biopsy (SB). Men with a low to very low suspicion (IMPROD bpMRI Likert score 1-2) had only SB. All data and protocols are freely available. The primary outcome of the trial was diagnostic accuracy-including overall accuracy, sensitivity, specificity, negative predictive value (NPV), and positive predictive value-of IMPROD bpMRI for clinically significant PCa (SPCa), which was defined as a Gleason score ≥ 3 + 4 (Gleason grade group 2 or higher). In total, 338 (338/364, 93%) prospectively enrolled men completed the trial. The accuracy and NPV of IMPROD bpMRI for SPCa were 70% (113/161) and 95% (71/75) (95% CI 87%-98%), respectively. Restricting the biopsy to men with equivocal to highly suspicious IMPROD bpMRI findings would have resulted in a 22% (75/338) reduction in the number of men undergoing biopsy while missing 4 (3%, 4/146) men with SPCa. The main limitation is uncertainty about the true PCa prevalence in the study cohort, since some of the men may have PCa despite having negative biopsy findings.Conclusions: IMPROD bpMRI demonstrated a high NPV for SPCa in men with a clinical suspicion of PCa in this prospective multi-institutional clinical trial.Trial Registration: ClinicalTrials.gov NCT02241122. [ABSTRACT FROM AUTHOR]

Background: Although the success of HIV treatment programs depends on retention and viral suppression, routine program monitoring of these outcomes may be incomplete. We used data from the national electronic medical record (EMR) system in Zambia to enumerate a large and regionally representative cohort of patients on treatment. We traced a random sample with unknown outcomes (lost to follow-up) to document true care status and HIV RNA levels.Methods and Findings: On 31 July 2015, we selected facilities from 4 provinces in 12 joint strata defined by facility type and province with probability proportional to size. In each facility, we enumerated adults with at least 1 clinical encounter after treatment initiation in the previous 24 months. From this cohort, we identified lost-to-follow-up patients (defined as 90 or more days late for their last appointment), selected a random sample, and intensively reviewed their records and traced them via phone calls and in-person visits in the community. In 1 of 4 provinces, we also collected dried blood spots (DBSs) for plasma HIV RNA testing. We used inverse probability weights to incorporate sampling outcomes into Aalen-Johansen and Cox proportional hazards regression to estimate retention and viremia. We used a bias analysis approach to correct for the known inaccuracy of plasma HIV RNA levels obtained from DBSs. From a total of 64 facilities with 165,464 adults on ART, we selected 32 facilities with 104,966 patients, of whom 17,602 (17%) were lost to follow-up: Those lost to follow-up had median age 36 years, 60% were female (N = 11,241), they had median enrollment CD4 count of 220 cells/μl, and 38% had WHO stage 1 clinical disease (N = 10,690). We traced 2,892 (16%) and found updated outcomes for 2,163 (75%): 412 (19%) had died, 836 (39%) were alive and in care at their original clinic, 457 (21%) had transferred to a new clinic, 255 (12%) were alive and out of care, and 203 (9%) were alive but we were unable to determine care status. Estimates using data from the EMR only suggested that 42.7% (95% CI 38.0%-47.1%) of new ART starters and 72.3% (95% CI 71.8%-73.0%) of all ART users were retained at 2 years. After incorporating updated data through tracing, we found that 77.3% (95% CI 70.5%-84.0%) of new initiates and 91.2% (95% CI 90.5%-91.8%) of all ART users were retained (at original clinic or transferred), indicating that routine program data underestimated retention in care markedly. In Lusaka Province, HIV RNA levels greater than or equal to 1,000 copies/ml were present in 18.1% (95% CI 14.0%-22.3%) of patients in care, 71.3% (95% CI 58.2%-84.4%) of lost patients, and 24.7% (95% CI 21.0%-29.3%). The main study limitations were imperfect response rates and the use of self-reported care status.Conclusions: In this region of Zambia, routine program data underestimated retention, and the point prevalence of unsuppressed HIV RNA was high when lost patients were accounted for. Viremia was prevalent among patients who unofficially transferred: Sustained engagement remains a challenge among HIV patients in Zambia, and targeted sampling is an effective strategy to identify such gaps in the care cascade and monitor programmatic progress. [ABSTRACT FROM AUTHOR]

In a Policy Forum, Peter Ehrenkranz and colleagues discuss the contribution of CD4 and viral load testing to outcomes for people with HIV in low- and middle-income countries. [ABSTRACT FROM AUTHOR]

Background: Low-grade gliomas cause significant neurological morbidity by brain invasion. There is no universally accepted objective technique available for detection of enlargement of low-grade gliomas in the clinical setting; subjective evaluation by clinicians using visual comparison of longitudinal radiological studies is the gold standard. The aim of this study is to determine whether a computer-assisted diagnosis (CAD) method helps physicians detect earlier growth of low-grade gliomas.Methods and Findings: We reviewed 165 patients diagnosed with grade 2 gliomas, seen at the University of Alabama at Birmingham clinics from 1 July 2017 to 14 May 2018. MRI scans were collected during the spring and summer of 2018. Fifty-six gliomas met the inclusion criteria, including 19 oligodendrogliomas, 26 astrocytomas, and 11 mixed gliomas in 30 males and 26 females with a mean age of 48 years and a range of follow-up of 150.2 months (difference between highest and lowest values). None received radiation therapy. We also studied 7 patients with an imaging abnormality without pathological diagnosis, who were clinically stable at the time of retrospective review (14 May 2018). This study compared growth detection by 7 physicians aided by the CAD method with retrospective clinical reports. The tumors of 63 patients (56 + 7) in 627 MRI scans were digitized, including 34 grade 2 gliomas with radiological progression and 22 radiologically stable grade 2 gliomas. The CAD method consisted of tumor segmentation, computing volumes, and pointing to growth by the online abrupt change-of-point method, which considers only past measurements. Independent scientists have evaluated the segmentation method. In 29 of the 34 patients with progression, the median time to growth detection was only 14 months for CAD compared to 44 months for current standard of care radiological evaluation (p < 0.001). Using CAD, accurate detection of tumor enlargement was possible with a median of only 57% change in the tumor volume as compared to a median of 174% change of volume necessary to diagnose tumor growth using standard of care clinical methods (p < 0.001). In the radiologically stable group, CAD facilitated growth detection in 13 out of 22 patients. CAD did not detect growth in the imaging abnormality group. The main limitation of this study was its retrospective design; nevertheless, the results depict the current state of a gold standard in clinical practice that allowed a significant increase in tumor volumes from baseline before detection. Such large increases in tumor volume would not be permitted in a prospective design. The number of glioma patients (n = 56) is a limitation; however, it is equivalent to the number of patients in phase II clinical trials.Conclusions: The current practice of visual comparison of longitudinal MRI scans is associated with significant delays in detecting growth of low-grade gliomas. Our findings support the idea that physicians aided by CAD detect growth at significantly smaller volumes than physicians using visual comparison alone. This study does not answer the questions whether to treat or not and which treatment modality is optimal. Nonetheless, early growth detection sets the stage for future clinical studies that address these questions and whether early therapeutic interventions prolong survival and improve quality of life. [ABSTRACT FROM AUTHOR]

Background: In Vietnam, the importance of vivax malaria relative to falciparum during the past decade has steadily increased to 50%. This, together with the spread of multidrug-resistant Plasmodium falciparum, is a major challenge for malaria elimination. A 2-year prospective cohort study to assess P. vivax morbidity after radical cure treatment and related risk factors was conducted in Central Vietnam.Methods and Findings: The study was implemented between April 2009 and December 2011 in four neighboring villages in a remote forested area of Quang Nam province. P. vivax-infected patients were treated radically with chloroquine (CQ; 25 mg/kg over 3 days) and primaquine (PQ; 0.5 mg/kg/day for 10 days) and visited monthly (malaria symptoms and blood sampling) for up to 2 years. Time to first vivax recurrence was estimated by Kaplan-Meier survival analysis, and risk factors for first and recurrent infections were identified by Cox regression models. Among the 260 P. vivax patients (61% males [159/260]; age range 3-60) recruited, 240 completed the 10-day treatment, 223 entered the second month of follow-up, and 219 were followed for at least 12 months. Most individuals (76.78%, 171/223) had recurrent vivax infections identified by molecular methods (polymerase chain reaction [PCR]); in about half of them (55.61%, 124/223), infection was detected by microscopy, and 84 individuals (37.67%) had symptomatic recurrences. Median time to first recurrence by PCR was 118 days (IQR 59-208). The estimated probability of remaining free of recurrence by month 24 was 20.40% (95% CI [14.42; 27.13]) by PCR, 42.52% (95% CI [35.41; 49.44]) by microscopy, and 60.69% (95% CI [53.51; 67.11]) for symptomatic recurrences. The main risk factor for recurrence (first or recurrent) was prior P. falciparum infection. The main limitations of this study are the age of the results and the absence of a comparator arm, which does not allow estimating the proportion of vivax relapses among recurrent infections.Conclusion: A substantial number of P. vivax recurrences, mainly submicroscopic (SM) and asymptomatic, were observed after high-dose PQ treatment (5.0 mg/kg). Prior P. falciparum infection was an important risk factor for all types of vivax recurrences. Malaria elimination efforts need to address this largely undetected P. vivax transmission by simultaneously tackling the reservoir of P. falciparum and P. vivax infections. [ABSTRACT FROM AUTHOR]

Background: Attention to women's and girls' menstrual needs is critical for global health and gender equality. The importance of this neglected experience has been elucidated by a growing body of qualitative research, which we systematically reviewed and synthesised.Methods and Findings: We undertook systematic searching to identify qualitative studies of women's and girls' experiences of menstruation in low- and middle-income countries (LMICs). Of 6,892 citations screened, 76 studies reported in 87 citations were included. Studies captured the experiences of over 6,000 participants from 35 countries. This included 45 studies from sub-Saharan Africa (with the greatest number of studies from Kenya [n = 7], Uganda [n = 6], and Ethiopia [n = 5]), 21 from South Asia (including India [n = 12] and Nepal [n = 5]), 8 from East Asia and the Pacific, 5 from Latin America and the Caribbean, 5 from the Middle East and North Africa, and 1 study from Europe and Central Asia. Through synthesis, we identified overarching themes and their relationships to develop a directional model of menstrual experience. This model maps distal and proximal antecedents of menstrual experience through to the impacts of this experience on health and well-being. The sociocultural context, including menstrual stigma and gender norms, influenced experiences by limiting knowledge about menstruation, limiting social support, and shaping internalised and externally enforced behavioural expectations. Resource limitations underlay inadequate physical infrastructure to support menstruation, as well as an economic environment restricting access to affordable menstrual materials. Menstrual experience included multiple themes: menstrual practices, perceptions of practices and environments, confidence, shame and distress, and containment of bleeding and odour. These components of experience were interlinked and contributed to negative impacts on women's and girls' lives. Impacts included harms to physical and psychological health as well as education and social engagement. Our review is limited by the available studies. Study quality was varied, with 18 studies rated as high, 35 medium, and 23 low trustworthiness. Sampling and analysis tended to be untrustworthy in lower-quality studies. Studies focused on the experiences of adolescent girls were most strongly represented, and we achieved early saturation for this group. Reflecting the focus of menstrual health research globally, there was an absence of studies focused on adult women and those from certain geographical areas.Conclusions: Through synthesis of extant qualitative studies of menstrual experience, we highlight consistent challenges and developed an integrated model of menstrual experience. This model hypothesises directional pathways that could be tested by future studies and may serve as a framework for program and policy development by highlighting critical antecedents and pathways through which interventions could improve women's and girls' health and well-being.Review Protocol Registration: The review protocol registration is PROSPERO: CRD42018089581. [ABSTRACT FROM AUTHOR]

Background: Seizures are the main cause of maternal death in women with epilepsy, but there are no tools for predicting seizures in pregnancy. We set out to develop and validate a prognostic model, using information collected during the antenatal booking visit, to predict seizure risk at any time in pregnancy and until 6 weeks postpartum in women with epilepsy on antiepileptic drugs.Methods and Findings: We used datasets of a prospective cohort study (EMPiRE) of 527 pregnant women with epilepsy on medication recruited from 50 hospitals in the UK (4 November 2011-17 August 2014). The model development cohort comprised 399 women whose antiepileptic drug doses were adjusted based on clinical features only; the validation cohort comprised 128 women whose drug dose adjustments were informed by serum drug levels. The outcome was epileptic (non-eclamptic) seizure captured using diary records. We fitted the model using LASSO (least absolute shrinkage and selection operator) regression, and reported the performance using C-statistic (scale 0-1, values > 0.5 show discrimination) and calibration slope (scale 0-1, values near 1 show accuracy) with 95% confidence intervals (CIs). We determined the net benefit (a weighted sum of true positive and false positive classifications) of using the model, with various probability thresholds, to aid clinicians in making individualised decisions regarding, for example, referral to tertiary care, frequency and intensity of monitoring, and changes in antiepileptic medication. Seizures occurred in 183 women (46%, 183/399) in the model development cohort and in 57 women (45%, 57/128) in the validation cohort. The model included age at first seizure, baseline seizure classification, history of mental health disorder or learning difficulty, occurrence of tonic-clonic and non-tonic-clonic seizures in the 3 months before pregnancy, previous admission to hospital for seizures during pregnancy, and baseline dose of lamotrigine and levetiracetam. The C-statistic was 0.79 (95% CI 0.75, 0.84). On external validation, the model showed good performance (C-statistic 0.76, 95% CI 0.66, 0.85; calibration slope 0.93, 95% CI 0.44, 1.41) but with imprecise estimates. The EMPiRE model showed the highest net proportional benefit for predicted probability thresholds between 12% and 99%. Limitations of this study include the varied gestational ages of women at recruitment, retrospective patient recall of seizure history, potential variations in seizure classification, the small number of events in the validation cohort, and the clinical utility restricted to decision-making thresholds above 12%. The model findings may not be generalisable to low- and middle-income countries, or when information on all predictors is not available.Conclusions: The EMPiRE model showed good performance in predicting the risk of seizures in pregnant women with epilepsy who are prescribed antiepileptic drugs. Integration of the tool within the antenatal booking visit, deployed as a simple nomogram, can help to optimise care in women with epilepsy. [ABSTRACT FROM AUTHOR]

Background: Evidence on where in the hypertension care process individuals are lost to care, and how this varies among states and population groups in a country as large as India, is essential for the design of targeted interventions and to monitor progress. Yet, to our knowledge, there has not yet been a nationally representative analysis of the proportion of adults who reach each step of the hypertension care process in India. This study aimed to determine (i) the proportion of adults with hypertension who have been screened, are aware of their diagnosis, take antihypertensive treatment, and have achieved control and (ii) the variation of these care indicators among states and sociodemographic groups.Methods and Findings: We used data from a nationally representative household survey carried out from 20 January 2015 to 4 December 2016 among individuals aged 15-49 years in all states and union territories (hereafter "states") of the country. The stages of the care process-computed among those with hypertension at the time of the survey-were (i) having ever had one's blood pressure (BP) measured before the survey ("screened"), (ii) having been diagnosed ("aware"), (iii) currently taking BP-lowering medication ("treated"), and (iv) reporting being treated and not having a raised BP ("controlled"). We disaggregated these stages by state, rural-urban residence, sex, age group, body mass index, tobacco consumption, household wealth quintile, education, and marital status. In total, 731,864 participants were included in the analysis. Hypertension prevalence was 18.1% (95% CI 17.8%-18.4%). Among those with hypertension, 76.1% (95% CI 75.3%-76.8%) had ever received a BP measurement, 44.7% (95% CI 43.6%-45.8%) were aware of their diagnosis, 13.3% (95% CI 12.9%-13.8%) were treated, and 7.9% (95% CI 7.6%-8.3%) had achieved control. Male sex, rural location, lower household wealth, and not being married were associated with greater losses at each step of the care process. Between states, control among individuals with hypertension varied from 2.4% (95% CI 1.7%-3.3%) in Nagaland to 21.0% (95% CI 9.8%-39.6%) in Daman and Diu. At 38.0% (95% CI 36.3%-39.0%), 28.8% (95% CI 28.5%-29.2%), 28.4% (95% CI 27.7%-29.0%), and 28.4% (95% CI 27.8%-29.0%), respectively, Puducherry, Tamil Nadu, Sikkim, and Haryana had the highest proportion of all adults (irrespective of hypertension status) in the sampled age range who had hypertension but did not achieve control. The main limitation of this study is that its results cannot be generalized to adults aged 50 years and older-the population group in which hypertension is most common.Conclusions: Hypertension prevalence in India is high, but the proportion of adults with hypertension who are aware of their diagnosis, are treated, and achieve control is low. Even after adjusting for states' economic development, there is large variation among states in health system performance in the management of hypertension. Improvements in access to hypertension diagnosis and treatment are especially important among men, in rural areas, and in populations with lower household wealth. [ABSTRACT FROM AUTHOR]

Background: Despite the relative ease with which breech presentation can be identified through ultrasound screening, the assessment of foetal presentation at term is often based on clinical examination only. Due to limitations in this approach, many women present in labour with an undiagnosed breech presentation, with increased risk of foetal morbidity and mortality. This study sought to determine the cost effectiveness of universal ultrasound scanning for breech presentation near term (36 weeks of gestational age [wkGA]) in nulliparous women.Methods and Findings: The Pregnancy Outcome Prediction (POP) study was a prospective cohort study between January 14, 2008 and July 31, 2012, including 3,879 nulliparous women who attended for a research screening ultrasound examination at 36 wkGA. Foetal presentation was assessed and compared for the groups with and without a clinically indicated ultrasound. Where breech presentation was detected, an external cephalic version (ECV) was routinely offered. If the ECV was unsuccessful or not performed, the women were offered either planned cesarean section at 39 weeks or attempted vaginal breech delivery. To compare the likelihood of different mode of deliveries and associated long-term health outcomes for universal ultrasound to current practice, a probabilistic economic simulation model was constructed. Parameter values were obtained from the POP study, and costs were mainly obtained from the English National Health Service (NHS). One hundred seventy-nine out of 3,879 women (4.6%) were diagnosed with breech presentation at 36 weeks. For most women (96), there had been no prior suspicion of noncephalic presentation. ECV was attempted for 84 (46.9%) women and was successful in 12 (success rate: 14.3%). Overall, 19 of the 179 women delivered vaginally (10.6%), 110 delivered by elective cesarean section (ELCS) (61.5%) and 50 delivered by emergency cesarean section (EMCS) (27.9%). There were no women with undiagnosed breech presentation in labour in the entire cohort. On average, 40 scans were needed per detection of a previously undiagnosed breech presentation. The economic analysis indicated that, compared to current practice, universal late-pregnancy ultrasound would identify around 14,826 otherwise undiagnosed breech presentations across England annually. It would also reduce EMCS and vaginal breech deliveries by 0.7 and 1.0 percentage points, respectively: around 4,196 and 6,061 deliveries across England annually. Universal ultrasound would also prevent 7.89 neonatal mortalities annually. The strategy would be cost effective if foetal presentation could be assessed for £19.80 or less per woman. Limitations to this study included that foetal presentation was revealed to all women and that the health economic analysis may be altered by parity.Conclusions: According to our estimates, universal late pregnancy ultrasound in nulliparous women (1) would virtually eliminate undiagnosed breech presentation, (2) would be expected to reduce foetal mortality in breech presentation, and (3) would be cost effective if foetal presentation could be assessed for less than £19.80 per woman. [ABSTRACT FROM AUTHOR]

In a Collection Review, Patrick Phillips and colleagues discuss developments in clinical trial design for the evaluation of TB therapeutics. [ABSTRACT FROM AUTHOR]

Christian Lienhardt and Payam Nahid launch the Collection on Advances in Clinical Trial Design for Development of New Tuberculosis Treatments. [ABSTRACT FROM AUTHOR]

Background: Despite the sharp decline in global under-5 deaths since 1990, uneven progress has been achieved across and within countries. In sub-Saharan Africa (SSA), the Millennium Development Goals (MDGs) for child mortality were met only by a few countries. Valid concerns exist as to whether the region would meet new Sustainable Development Goals (SDGs) for under-5 mortality. We therefore examine further sources of variation by assessing age patterns, trends, and forecasts of mortality rates.Methods and Findings: Data came from 106 nationally representative Demographic and Health Surveys (DHSs) with full birth histories from 31 SSA countries from 1990 to 2017 (a total of 524 country-years of data). We assessed the distribution of age at death through the following new demographic analyses. First, we used a direct method and full birth histories to estimate under-5 mortality rates (U5MRs) on a monthly basis. Second, we smoothed raw estimates of death rates by age and time by using a two-dimensional P-Spline approach. Third, a variant of the Lee-Carter (LC) model, designed for populations with limited data, was used to fit and forecast age profiles of mortality. We used mortality estimates from the United Nations Inter-agency Group for Child Mortality Estimation (UN IGME) to adjust, validate, and minimize the risk of bias in survival, truncation, and recall in mortality estimation. Our mortality model revealed substantive declines of death rates at every age in most countries but with notable differences in the age patterns over time. U5MRs declined from 3.3% (annual rate of reduction [ARR] 0.1%) in Lesotho to 76.4% (ARR 5.2%) in Malawi, and the pace of decline was faster on average (ARR 3.2%) than that observed for infant (IMRs) (ARR 2.7%) and neonatal (NMRs) (ARR 2.0%) mortality rates. We predict that 5 countries (Kenya, Rwanda, Senegal, Tanzania, and Uganda) are on track to achieve the under-5 sustainable development target by 2030 (25 deaths per 1,000 live births), but only Rwanda and Tanzania would meet both the neonatal (12 deaths per 1,000 live births) and under-5 targets simultaneously. Our predicted NMRs and U5MRs were in line with those estimated by the UN IGME by 2030 and 2050 (they overlapped in 27/31 countries for NMRs and 22 for U5MRs) and by the Institute for Health Metrics and Evaluation (IHME) by 2030 (26/31 and 23/31, respectively). This study has a number of limitations, including poor data quality issues that reflected bias in the report of births and deaths, preventing reliable estimates and predictions from a few countries.Conclusions: To our knowledge, this study is the first to combine full birth histories and mortality estimates from external reliable sources to model age patterns of under-5 mortality across time in SSA. We demonstrate that countries with a rapid pace of mortality reduction (ARR ≥ 3.2%) across ages would be more likely to achieve the SDG mortality targets. However, the lower pace of neonatal mortality reduction would prevent most countries from achieving those targets: 2 countries would reach them by 2030, 13 between 2030 and 2050, and 13 after 2050. [ABSTRACT FROM AUTHOR]

Background: The prevalence of diabetes is increasing rapidly in low- and middle-income countries (LMICs), urgently requiring detailed evidence to guide the response of health systems to this epidemic. In an effort to understand at what step in the diabetes care continuum individuals are lost to care, and how this varies between countries and population groups, this study examined health system performance for diabetes among adults in 28 LMICs using a cascade of care approach.Methods and Findings: We pooled individual participant data from nationally representative surveys done between 2008 and 2016 in 28 LMICs. Diabetes was defined as fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl), random plasma glucose ≥ 11.1 mmol/l (200 mg/dl), HbA1c ≥ 6.5%, or reporting to be taking medication for diabetes. Stages of the care cascade were as follows: tested, diagnosed, lifestyle advice and/or medication given ("treated"), and controlled (HbA1c < 8.0% or equivalent). We stratified cascades of care by country, geographic region, World Bank income group, and individual-level characteristics (age, sex, educational attainment, household wealth quintile, and body mass index [BMI]). We then used logistic regression models with country-level fixed effects to evaluate predictors of (1) testing, (2) treatment, and (3) control. The final sample included 847,413 adults in 28 LMICs (8 low income, 9 lower-middle income, 11 upper-middle income). Survey sample size ranged from 824 in Guyana to 750,451 in India. The prevalence of diabetes was 8.8% (95% CI: 8.2%-9.5%), and the prevalence of undiagnosed diabetes was 4.8% (95% CI: 4.5%-5.2%). Health system performance for management of diabetes showed large losses to care at the stage of being tested, and low rates of diabetes control. Total unmet need for diabetes care (defined as the sum of those not tested, tested but undiagnosed, diagnosed but untreated, and treated but with diabetes not controlled) was 77.0% (95% CI: 74.9%-78.9%). Performance along the care cascade was significantly better in upper-middle income countries, but across all World Bank income groups, only half of participants with diabetes who were tested achieved diabetes control. Greater age, educational attainment, and BMI were associated with higher odds of being tested, being treated, and achieving control. The limitations of this study included the use of a single glucose measurement to assess diabetes, differences in the approach to wealth measurement across surveys, and variation in the date of the surveys.Conclusions: The study uncovered poor management of diabetes along the care cascade, indicating large unmet need for diabetes care across 28 LMICs. Performance across the care cascade varied by World Bank income group and individual-level characteristics, particularly age, educational attainment, and BMI. This policy-relevant analysis can inform country-specific interventions and offers a baseline by which future progress can be measured. [ABSTRACT FROM AUTHOR]

Background: To our knowledge, no publication providing overarching guidance on the conduct of systematic reviews of observational studies of etiology exists.Methods and Findings: Conducting Systematic Reviews and Meta-Analyses of Observational Studies of Etiology (COSMOS-E) provides guidance on all steps in systematic reviews of observational studies of etiology, from shaping the research question, defining exposure and outcomes, to assessing the risk of bias and statistical analysis. The writing group included researchers experienced in meta-analyses and observational studies of etiology. Standard peer-review was performed. While the structure of systematic reviews of observational studies on etiology may be similar to that for systematic reviews of randomised controlled trials, there are specific tasks within each component that differ. Examples include assessment for confounding, selection bias, and information bias. In systematic reviews of observational studies of etiology, combining studies in meta-analysis may lead to more precise estimates, but such greater precision does not automatically remedy potential bias. Thorough exploration of sources of heterogeneity is key when assessing the validity of estimates and causality.Conclusion: As many reviews of observational studies on etiology are being performed, this document may provide researchers with guidance on how to conduct and analyse such reviews. [ABSTRACT FROM AUTHOR]

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

Background: Inappropriate antibiotic prescribing causes widespread serious health problems. To reduce prescribing of antibiotics in Chinese primary care to children with upper respiratory tract infections (URTIs), we developed an intervention comprising clinical guidelines, monthly prescribing review meetings, doctor-patient communication skills training, and education materials for caregivers. We previously evaluated our intervention using an unblinded cluster-randomised controlled trial (cRCT) in 25 primary care facilities across two rural counties. When our trial ended at the 6-month follow-up period, we found that the intervention had reduced antibiotic prescribing for childhood URTIs by 29 percentage points (pp) (95% CI -42 to -16).Methods and Findings: In this long-term follow-up study, we collected our trial outcomes from the one county (14 facilities and 1:1 cluster randomisation ratio) that had electronic records available 12 months after the trial ended, at the 18-month follow-up period. Our primary outcome was the antibiotic prescription rate (APR)-the percentage of outpatient prescriptions containing any antibiotic(s) for children aged 2 to 14 years who had a primary diagnosis of a URTI and had no other illness requiring antibiotics. We also conducted 15 in-depth interviews to understand how interventions were sustained. In intervention facilities, the APR was 84% (1,171 out of 1,400) at baseline, 37% (515 out of 1,380) at 6 months, and 54% (2,748 out of 5,084) at 18 months, and in control facilities, it was 76% (1,063 out of 1,400), 77% (1,084 out of 1,400), and 75% (2,772 out of 3,685), respectively. After adjusting for patient and prescribing doctor covariates, compared to the baseline intervention-control difference, the difference at 6 months represented a 6-month intervention-arm reduction in the APR of -49 pp (95% CI -63 to -35; P < 0.0001), and compared to the baseline difference, the difference at 18 months represented an 18-month intervention-arm reduction in the APR of -36 pp (95% CI -55 to -17; P < 0.0001). Compared to the 6-month intervention-control difference, the difference at 18 months represented no change in the APR: 13 pp (95% CI -7 to 33; P = 0.21). Factors reported to sustain reductions in antibiotic prescribing included doctors' improved knowledge and communication skills and focused prescription review meetings, whereas lack of supervision and monitoring may be associated with relapse. Key limitations were not including all clusters from the trial and not collecting returned visits or sepsis cases.Conclusions: Our intervention was associated with sustained and substantial reductions in antibiotic prescribing at the end of the intervention period and 12 months later. Our intervention may be adapted to similar resource-poor settings.Trial Registration: ISRCTN registry ISRCTN14340536. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a common inflammatory skin disease that has been reported to be associated with obesity. We aimed to investigate a possible causal relationship between body mass index (BMI) and psoriasis.Methods and Findings: Following a review of published epidemiological evidence of the association between obesity and psoriasis, mendelian randomization (MR) was used to test for a causal relationship with BMI. We used a genetic instrument comprising 97 single-nucleotide polymorphisms (SNPs) associated with BMI as a proxy for BMI (expected to be much less confounded than measured BMI). One-sample MR was conducted using individual-level data (396,495 individuals) from the UK Biobank and the Nord-Trøndelag Health Study (HUNT), Norway. Two-sample MR was performed with summary-level data (356,926 individuals) from published BMI and psoriasis genome-wide association studies (GWASs). The one-sample and two-sample MR estimates were meta-analysed using a fixed-effect model. To test for a potential reverse causal effect, MR analysis with genetic instruments comprising variants from recent genome-wide analyses for psoriasis were used to test whether genetic risk for this skin disease has a causal effect on BMI. Published observational data showed an association of higher BMI with psoriasis. A mean difference in BMI of 1.26 kg/m2 (95% CI 1.02-1.51) between psoriasis cases and controls was observed in adults, while a 1.55 kg/m2 mean difference (95% CI 1.13-1.98) was observed in children. The observational association was confirmed in UK Biobank and HUNT data sets. Overall, a 1 kg/m2 increase in BMI was associated with 4% higher odds of psoriasis (meta-analysis odds ratio [OR] = 1.04; 95% CI 1.03-1.04; P = 1.73 × 10(-60)). MR analyses provided evidence that higher BMI causally increases the odds of psoriasis (by 9% per 1 unit increase in BMI; OR = 1.09 (1.06-1.12) per 1 kg/m2; P = 4.67 × 10(-9)). In contrast, MR estimates gave little support to a possible causal effect of psoriasis genetic risk on BMI (0.004 kg/m2 change in BMI per doubling odds of psoriasis (-0.003 to 0.011). Limitations of our study include possible misreporting of psoriasis by patients, as well as potential misdiagnosis by clinicians. In addition, there is also limited ethnic variation in the cohorts studied.Conclusions: Our study, using genetic variants as instrumental variables for BMI, provides evidence that higher BMI leads to a higher risk of psoriasis. This supports the prioritization of therapies and lifestyle interventions aimed at controlling weight for the prevention or treatment of this common skin disease. Mechanistic studies are required to improve understanding of this relationship. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that airway obstruction and increased bronchial reactivity are present in early life in children developing asthma, which challenges the dogma that airway inflammation leads to low lung function. Further studies are needed to explore whether low lung function and bronchial hyperreactivity are inherent traits increasing the risk of developing airway inflammation and asthmatic symptoms in order to establish timely primary preventive initiatives.Methods and Findings: We investigated 367 (89%) of the 411 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort born to mothers with asthma, who were assessed by spirometry and bronchial reactivity to methacholine from age 1 month, plethysmography and bronchial reversibility from age 3 years, cold dry air hyperventilation from age 4 years, and exercise challenge at age 7 years. The COPSAC pediatricians diagnosed and treated asthma based on symptom load, response to inhaled corticosteroid, and relapse after treatment withdrawal according to a standardized algorithm. Repeated measures mixed models were applied to analyze lung function trajectories in children with asthma ever or never at age 1 month to 13 years. The number of children ever versus never developing asthma in their first 13 years of life was 97 (27%) versus 270 (73%), respectively. Median age at diagnosis was 2.0 years (IQR 1.2-5.7), and median remission age was 6.2 years (IQR 4.2-7.8). Children with versus without asthma had reduced lung function (z-score difference, forced expiratory volume, -0.31 [95% CI -0.47; -0.15], p < 0.001), increased airway resistance (z-score difference, specific airway resistance, +0.40 [95% CI +0.24; +0.56], p < 0.001), increased bronchial reversibility (difference in change in forced expiratory volume in the first second [ΔFEV1], +3% [95% CI +2%; +4%], p < 0.001), increased reactivity to methacholine (z-score difference for provocative dose, -0.40 [95% CI -0.58; -0.22], p < 0.001), decreased forced expiratory volume at cold dry air challenge (ΔFEV1, -4% [95% CI -7%; -1%], p < 0.01), and decreased forced expiratory volume after exercise (ΔFEV1, -4% [95% CI -7%; -1%], p = 0.02). Both airway obstruction and bronchial hyperreactivity were present before symptom debut, independent of disease duration, and did not improve with symptom remission. The generalizability of these findings may be limited by the high-risk nature of the cohort (all mothers had a diagnosis of asthma), the modest study size, and limited ethnic variation.Conclusions: Children with asthma at some point at age 1 month to 13 years had airway obstruction and bronchial hyperreactivity before symptom debut, which did not worsen with increased asthma symptom duration or attenuate with remission. This suggests that airway obstruction and bronchial hyperreactivity are stable traits of childhood asthma since neonatal life, implying that symptomatic disease may in part be a consequence of these traits but not their cause. [ABSTRACT FROM AUTHOR]

Background: A person's rate of aging has important implications for his/her risk of death and disease; thus, quantifying aging using observable characteristics has important applications for clinical, basic, and observational research. Based on routine clinical chemistry biomarkers, we previously developed a novel aging measure, Phenotypic Age, representing the expected age within the population that corresponds to a person's estimated mortality risk. The aim of this study was to assess its applicability for differentiating risk for a variety of health outcomes within diverse subpopulations that include healthy and unhealthy groups, distinct age groups, and persons with various race/ethnic, socioeconomic, and health behavior characteristics.Methods and Findings: Phenotypic Age was calculated based on a linear combination of chronological age and 9 multi-system clinical chemistry biomarkers in accordance with our previously established method. We also estimated Phenotypic Age Acceleration (PhenoAgeAccel), which represents Phenotypic Age after accounting for chronological age (i.e., whether a person appears older [positive value] or younger [negative value] than expected, physiologically). All analyses were conducted using NHANES IV (1999-2010, an independent sample from that originally used to develop the measure). Our analytic sample consisted of 11,432 adults aged 20-84 years and 185 oldest-old adults top-coded at age 85 years. We observed a total of 1,012 deaths, ascertained over 12.6 years of follow-up (based on National Death Index data through December 31, 2011). Proportional hazard models and receiver operating characteristic curves were used to evaluate all-cause and cause-specific mortality predictions. Overall, participants with more diseases had older Phenotypic Age. For instance, among young adults, those with 1 disease were 0.2 years older phenotypically than disease-free persons, and those with 2 or 3 diseases were about 0.6 years older phenotypically. After adjusting for chronological age and sex, Phenotypic Age was significantly associated with all-cause mortality and cause-specific mortality (with the exception of cerebrovascular disease mortality). Results for all-cause mortality were robust to stratifications by age, race/ethnicity, education, disease count, and health behaviors. Further, Phenotypic Age was associated with mortality among seemingly healthy participants-defined as those who reported being disease-free and who had normal BMI-as well as among oldest-old adults, even after adjustment for disease prevalence. The main limitation of this study was the lack of longitudinal data on Phenotypic Age and disease incidence.Conclusions: In a nationally representative US adult population, Phenotypic Age was associated with mortality even after adjusting for chronological age. Overall, this association was robust across different stratifications, particularly by age, disease count, health behaviors, and cause of death. We also observed a strong association between Phenotypic Age and the disease count an individual had. These findings suggest that this new aging measure may serve as a useful tool to facilitate identification of at-risk individuals and evaluation of the efficacy of interventions, and may also facilitate investigation into potential biological mechanisms of aging. Nevertheless, further evaluation in other cohorts is needed. [ABSTRACT FROM AUTHOR]

Background: China has the highest global prevalence of cigarette smokers, accounting for more than 40% of the total cigarette consumption in the world. Considering the shortage of smoking cessation services in China, and the acceptability, feasibility, and efficacy of mobile-phone-based text messaging interventions for quitting smoking in other countries, we conducted a mobile-phone-based smoking cessation study in China.Methods and Findings: We conducted a randomized controlled trial in China across 30 cities and provinces from August 17, 2016, to May 27, 2017. Adult smokers aged 18 years and older with the intention to quit smoking were recruited and randomized to a 12-week high-frequency messaging (HFM) or low-frequency messaging (LFM) intervention ("Happy Quit") or to a control group in a 5:2:3 ratio. The control group received only text messages unrelated to quitting. The primary outcome was biochemically verified continuous smoking abstinence at 24 weeks. Secondary outcomes included (1) self-reported 7-day point prevalence of abstinence (i.e., not even a puff of smoke, for the last 7 days) at 1, 4, 8, 12, 16, 20, and 24 weeks; (2) self-reported continuous abstinence at 4, 12, and 24 weeks; and (3) self-reported average number of cigarettes smoked per day. A total of 1,369 participants received 12 weeks of intervention or control text messages with continued follow-up for 12 weeks. The baseline characteristics of participants among the HFM (n = 674), LFM (n = 284), and control (n = 411) groups were similar. The study sample included 1,295 (94.6%) men; participants had a mean age of 38.1 (SD 9.79) years and smoked an average of 20.1 (SD 9.19) cigarettes per day. We included the participants in an intention-to-treat analysis. Biochemically verified continuous smoking abstinence at 24 weeks occurred in 44/674 participants in the HFM group (6.5%), 17/284 participants in the LFM group (6.0%), and 8/411 participants (1.9%) in the control group; participants in both the HFM (odds ratio [OR] = 3.51, 95% CI 1.64-7.55, p < 0.001) and the LFM (OR = 3.21, 95% CI 1.36-7.54], p = 0.002) intervention groups were more likely to quit smoking than those in the control group. However, there was no difference in quit rate between the HFM and LFM interventions. We also found that the 7-day point quit rate from week 1 to week 24 ranged from approximately 10% to more than 26% with the intervention and from less than 4% to nearly 12% without the intervention. Those who continued as smokers in the HFM group smoked 1 to 3 fewer cigarettes per day than those in the LFM group over the 24 weeks of trial. Among study limitations, the participants were able to use other smoking cessation services (although very few participants reported using them), cotinine tests can only detect smoking status for a few days, and the proportion of quitters was small.Conclusions: Our findings demonstrate that a mobile-phone-based text messaging intervention (Happy Quit), with either high- or low-frequency messaging, led to smoking cessation in the present study, albeit in a low proportion of smokers, and can therefore be considered for use in large-scale intervention efforts in China. Mobile-phone-based interventions could be paired with other smoking cessation services for treatment-seeking smokers in China.Trial Registration: ClinicalTrials.gov NCT02693626. [ABSTRACT FROM AUTHOR]