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Background: Traumatic brain injury (TBI) is disproportionately prevalent among individuals who intersect or are involved with the criminal justice system (CJS). In the absence of appropriate care, TBI-related impairments, intersecting social determinants of health, and the lack of TBI awareness in CJS settings can lead to lengthened sentences, serious disciplinary charges, and recidivism. However, evidence suggests that most clinical practice guidelines (CPGs) overlook equity and consequently, the needs of disadvantaged groups. As such, this review addressed the research question "To what extent are (1) intersections with the CJS considered in CPGs for TBI, (2) TBI considered in CPGs for CJS, and (3) equity considered in CPGs for CJS?". Methods and findings: CPGs were identified from electronic databases (MEDLINE, Embase, CINAHL, PsycINFO), targeted websites, Google Search, and reference lists of identified CPGs on November 2021 and March 2023 (CPGs for TBI) and May 2022 and March 2023 (CPGs for CJS). Only CPGs for TBI or CPGs for CJS were included. We calculated the proportion of CPGs that included TBI- or CJS-specific content, conducted a qualitative content analysis to understand how evidence regarding TBI and the CJS was integrated in the CPGs, and utilised equity assessment tools to understand if and how equity was considered. Fifty-seven CPGs for TBI and 6 CPGs for CJS were included in this review. Fourteen CPGs for TBI included information relevant to the CJS, but only 1 made a concrete recommendation to consider legal implications during vocational evaluation in the forensic context. Two CPGs for CJS acknowledged the prevalence of TBI among individuals in prison and one specifically recommended considering TBI during health assessments. Both CPGs for TBI and CPGs for CJS provided evidence specific to a single facet of the CJS, predominantly in policing and corrections. The use of equity best practices and the involvement of disadvantaged groups in the development process were lacking among CPGs for CJS. We acknowledge limitations of the review, including that our searches were conducted in English language and thus, we may have missed other non-English language CPGs in this review. We further recognise that we are unable to comment on evidence that is not integrated in the CPGs, as we did not systematically search for research on individuals with TBI who intersect with the CJS, outside of CPGs. Conclusions: Findings from this review provide the foundation to consider CJS involvement in CPGs for TBI and to advance equity in CPGs for CJS. Conducting research, including investigating the process of screening for TBI with individuals who intersect with all facets of the CJS, and utilizing equity assessment tools in guideline development are critical steps to enhance equity in healthcare for this disadvantaged group. Zoe Colclough and co-authors examine how equity is considered in the development of clinical practice guidelines for traumatic brain injury for individuals within the criminal justice system. Author summary: Why was this study done?: Traumatic brain injury (TBI) is more common among individuals involved with the criminal justice system (CJS) than the general population, often resulting in longer prison sentences, serious disciplinary charges, and repeated future conflicts with the CJS. Although individuals with TBI who are involved with the CJS must receive care that meets their needs, studies show that most clinical practice guidelines (CPGs)—designed to guide care—tend to overlook equity and disadvantaged groups, instead focussing on the effectiveness or cost-effectiveness of care. As a first step to improving equitable care, this study assessed existing CPGs for TBI and CPGs for CJS to see if and how (1) evidence regarding individuals who intersect with the CJS is included in CPGs for TBI and evidence regarding TBI is integrated in CPGs for CJS; and (2) equity is considered in CPGs for CJS. What did the researchers do and find?: We used available electronic databases (MEDLINE, Embase, CINAHL, PsycINFO), targeted websites, Google search, and reference lists for CPGs for TBI and CPGs for CJS. We documented their characteristics, reviewed their content, and assessed whether equity was considered using checklists focused on equity and disadvantaged groups. We found that 14 out of 57 CPGs for TBI referenced individuals who are involved with the CJS and 2 out of 6 CPGs for CJS referenced TBI. Practices to ensure that equity is considered, such as the involvement of disadvantaged groups when developing CPGs were lacking in CPGs for CJS. What do these findings mean?: Findings from this review suggest that consideration of equity is lacking in the development of CPGs for TBI for those within the CJS and provide the foundation to consider CJS involvement in CPGs for TBI and to advance equity in CPGs for CJS. There is a critical need for further research into screening processes for TBI with individuals who intersect with all facets of the CJS, and into the benefits of equity assessment tools in guideline development to enhance equity in healthcare for this disadvantaged group Unfortunately, we cannot comment on how much of the existing evidence regarding TBI or individuals who are involved with the CJS remains unintegrated in existing CPGs, as our search did not include research papers on TBI and the CJS, outside of CPGs. [ABSTRACT FROM AUTHOR]

Background: Rapid diagnostic tests (RDTs) for coronavirus disease (COVID) are used in low- and middle-income countries (LMICs) to inform treatment decisions. However, to date, it is unclear when this use is cost-effective. Existing analyses are limited to a narrow set of countries and uses. The aim of this study is to assess the cost-effectiveness of COVID RDTs to inform the treatment of patients with severe illness in LMICs, considering real world practice. Methods and findings: We assessed the cost-effectiveness of COVID testing across LMICs using a decision tree model, differentiating results by country income level, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) prevalence, and testing scenario (none, RDTs, polymerase chain reaction tests—PCRs and combinations). LMIC experts defined realistic care pathways and treatment options. Using a healthcare provider perspective and net monetary benefit approach, we assessed both intended (COVID symptom alleviation) and unintended (treatment side effects) health and economic impacts for each testing scenario. We included the side effects of corticosteroids, which are often the only available treatment for COVID. Because side effects depend both on the treatment and the patient's underlying illness (COVID or COVID-like illnesses, such as influenza), we considered the prevalence of COVID-like illnesses in our analyses. We found that SARS-CoV-2 testing of patients with severe COVID-like illness can be cost-effective in all LMICs, though only in some circumstances. High influenza prevalence among suspected COVID cases improves cost-effectiveness, since incorrectly provided corticosteroids may worsen influenza outcomes. In low- and some lower-middle-income countries, only patients with a high index of suspicion for COVID should be tested with RDTs, while other patients should be presumed to not have COVID. In some lower-middle-income and upper-middle-income countries, suspected severe COVID cases should almost always be tested. Further, in these settings, negative test results in patients with a high initial index of suspicion should be confirmed through PCR and, during influenza outbreaks, positive results in patients with a low initial index of suspicion should also be confirmed with a PCR. The use of interleukin-6 receptor blockers, when supported by testing, may also be cost-effective in higher-income LMICs. The cost at which they would be cost-effective in low-income countries ($162 to $406 per treatment course) is below current prices. The primary limitation of our analysis is substantial uncertainty around some of the parameters in our model due to limited data, most notably on current COVID mortality with standard of care, and insufficient evidence on the impact of corticosteroids on patients with severe influenza. Conclusions: COVID testing can be cost-effective to inform treatment of LMIC patients with severe COVID-like disease. The optimal algorithm is driven by country income level and health budgets, the level of suspicion that the patient may have COVID, and influenza prevalence. Further research to better characterize the unintended effects of corticosteroids, particularly on influenza cases, could improve decision making around the treatment of those with COVID-like symptoms in LMICs. Gabrielle Bonnet and team assess the cost-effectiveness of COVID testing across low-and-middle-income countries, differentiating results by country income level, SARS-CoV-2 prevalence and different testing scenarios. Author summary: Why was this study done?: The main role of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing has evolved from transmission reduction to informing the treatment of patients with most vulnerability or most severe illness. SARS-CoV-2 testing availability and use remains inconsistent in some low- and middle-income countries (LMICs), and understanding the cost-effectiveness of testing in such contexts may help guide priority setting and inform guidelines for health professionals. Research on the cost-effectiveness of SARS-CoV-2 testing in LMICs is limited. To our knowledge, no paper has considered both presumptive and symptomatic coronavirus disease (COVID) treatment as alternatives to testing, or has considered a range of treatment options reflective of LMIC contexts. What did the researchers do and find?: We used a decision tree model, health payer provider perspective and net monetary benefit approach to assess the cost-effectiveness of testing to support treatment for patients with severe/critical COVID-like illness in 129 LMICs, based on treatment pathways reported by experts working in LMICs. In low-income and the poorest of lower-middle-income countries, only patients with a high index of suspicion for COVID should be tested with rapid diagnostic tests. In the wealthiest among lower-middle-income countries and in upper-middle-income countries, testing of suspected severe COVID cases is almost always recommended. Polymerase chain reaction (PCR) confirmation of negative test results in patients with a high index of suspicion and, during influenza epidemics/outbreaks, of positive test results in patients with a low index of suspicion, is recommended. What do these findings mean?: COVID testing of patients with severe, COVID-like symptoms in LMICs can be cost-effective, provided sufficiently specific clinical screening algorithms can be used. Policymakers should consider both our study's results regarding variability between countries at a similar income level and its sensitivity analysis, particularly regarding country-specific factors, alongside other considerations such as local feasibility and equity, to inform national level decision-making. The main limitation of the study is uncertainty on some parameters, including current COVID case fatality risks and the impact of corticosteroids on patients with influenza. [ABSTRACT FROM AUTHOR]

Background: Poor representation of pregnant and lactating women and people in clinical trials has marginalised their health concerns and denied the maternal–fetal/infant dyad benefits of innovation in therapeutic research and development. This mixed-methods systematic review synthesised factors affecting the participation of pregnant and lactating women in clinical trials, across all levels of the research ecosystem. Methods and findings: We searched 8 databases from inception to 14 February 2024 to identify qualitative, quantitative, and mixed-methods studies that described factors affecting participation of pregnant and lactating women in vaccine and therapeutic clinical trials in any setting. We used thematic synthesis to analyse the qualitative literature and assessed confidence in each qualitative review finding using the GRADE-CERQual approach. We compared quantitative data against the thematic synthesis findings to assess areas of convergence or divergence. We mapped review findings to the Theoretical Domains Framework (TDF) and Capability, Opportunity, and Motivation Model of Behaviour (COM-B) to inform future development of behaviour change strategies. We included 60 papers from 27 countries. We grouped 24 review findings under 5 overarching themes: (a) interplay between perceived risks and benefits of participation in women's decision-making; (b) engagement between women and the medical and research ecosystems; (c) gender norms and decision-making autonomy; (d) factors affecting clinical trial recruitment; and (e) upstream factors in the research ecosystem. Women's willingness to participate in trials was affected by: perceived risk of the health condition weighed against an intervention's risks and benefits, therapeutic optimism, intervention acceptability, expectations of receiving higher quality care in a trial, altruistic motivations, intimate relationship dynamics, and power and trust in medicine and research. Health workers supported women's participation in trials when they perceived clinical equipoise, had hope for novel therapeutic applications, and were convinced an intervention was safe. For research staff, developing reciprocal relationships with health workers, having access to resources for trial implementation, ensuring the trial was visible to potential participants and health workers, implementing a woman-centred approach when communicating with potential participants, and emotional orientations towards the trial were factors perceived to affect recruitment. For study investigators and ethics committees, the complexities and subjectivities in risk assessments and trial design, and limited funding of such trials contributed to their reluctance in leading and approving such trials. All included studies focused on factors affecting participation of cisgender pregnant women in clinical trials; future research should consider other pregnancy-capable populations, including transgender and nonbinary people. Conclusions: This systematic review highlights diverse factors across multiple levels and stakeholders affecting the participation of pregnant and lactating women in clinical trials. By linking identified factors to frameworks of behaviour change, we have developed theoretically informed strategies that can help optimise pregnant and lactating women's engagement, participation, and trust in such trials. Using a mixed-methods approach, Mridula Shankar and colleagues investigate the reasons why those who are pregnant and breastfeeding are under-represented in clinical trials. Author summary: Why was this study done?: Pregnant and lactating women and people are routinely excluded from participating in drug and vaccine clinical trials, resulting in limited options for prevention and treatment of medical conditions. Challenges to including pregnant and lactating women and people in clinical research have been identified at multiple levels of the research and health systems, but the full range of barriers and facilitators to participation are not well known. What did the researchers do and find?: We conducted a mixed-methods systematic review and identified 60 research articles from 27 countries on the views and experiences of pregnant and lactating women's participation in clinical research, from the perspectives of cisgender women, family and community members, health workers, and people involved in the conduct of clinical research. Using a thematic synthesis approach, we identified barriers affecting participation including women having a limited appetite for risk during pregnancy and lactation, concerns about women's bodily autonomy during pregnancy, and challenges in obtaining ethical approval for clinical research with pregnant women. We also identified facilitators of participation including the potential for personal health benefits, expectations of higher quality care, trust in the medical and research systems, and strong teamwork between researchers and health workers. What do these findings mean?: Our findings demonstrate the need for multipronged strategies to address barriers and reinforce facilitators across the various levels of the research and health systems. The actions that are needed to overcome these barriers and reinforce facilitators must be discussed, prioritised, and adapted to specific contexts. All included studies focused on factors affecting participation of cisgender pregnant women in clinical trials; future research should consider other pregnancy-capable populations, including transgender and nonbinary people. [ABSTRACT FROM AUTHOR]

Background: India accounts for about one-quarter of people contracting tuberculosis (TB) disease annually and nearly one-third of TB deaths globally. Many Indians do not navigate all care cascade stages to receive TB treatment and achieve recurrence-free survival. Guided by a population/exposure/comparison/outcomes (PECO) framework, we report findings of a systematic review to identify factors contributing to unfavorable outcomes across each care cascade gap for TB disease in India. Methods and findings: We defined care cascade gaps as comprising people with confirmed or presumptive TB who did not: start the TB diagnostic workup (Gap 1), complete the workup (Gap 2), start treatment (Gap 3), achieve treatment success (Gap 4), or achieve TB recurrence-free survival (Gap 5). Three systematic searches of PubMed, Embase, and Web of Science from January 1, 2000 to August 14, 2023 were conducted. We identified articles evaluating factors associated with unfavorable outcomes for each gap (reported as adjusted odds, relative risk, or hazard ratios) and, among people experiencing unfavorable outcomes, reasons for these outcomes (reported as proportions), with specific quality or risk of bias criteria for each gap. Findings were organized into person-, family-, and society-, or health system-related factors, using a social-ecological framework. Factors associated with unfavorable outcomes across multiple cascade stages included: male sex, older age, poverty-related factors, lower symptom severity or duration, undernutrition, alcohol use, smoking, and distrust of (or dissatisfaction with) health services. People previously treated for TB were more likely to seek care and engage in the diagnostic workup (Gaps 1 and 2) but more likely to suffer pretreatment loss to follow-up (Gap 3) and unfavorable treatment outcomes (Gap 4), especially those who were lost to follow-up during their prior treatment. For individual care cascade gaps, multiple studies highlighted lack of TB knowledge and structural barriers (e.g., transportation challenges) as contributing to lack of care-seeking for TB symptoms (Gap 1, 14 studies); lack of access to diagnostics (e.g., X-ray), non-identification of eligible people for testing, and failure of providers to communicate concern for TB as contributing to non-completion of the diagnostic workup (Gap 2, 17 studies); stigma, poor recording of patient contact information by providers, and early death from diagnostic delays as contributing to pretreatment loss to follow-up (Gap 3, 15 studies); and lack of TB knowledge, stigma, depression, and medication adverse effects as contributing to unfavorable treatment outcomes (Gap 4, 86 studies). Medication nonadherence contributed to unfavorable treatment outcomes (Gap 4) and TB recurrence (Gap 5, 14 studies). Limitations include lack of meta-analyses due to the heterogeneity of findings and limited generalizability to some Indian regions, given the country's diverse population. Conclusions: This systematic review illuminates common patterns of risk that shape outcomes for Indians with TB, while highlighting knowledge gaps—particularly regarding TB care for children or in the private sector—to guide future research. Findings may inform targeting of support services to people with TB who have higher risk of poor outcomes and inform multicomponent interventions to close gaps in the care cascade. Tulip A. Jhaveri and team report findings of a systematic review to identify factors contributing to unfavorable outcomes across each care cascade gap for tuberculosis disease in India. Author summary: Why was this study done?: India has the highest tuberculosis (TB) incidence, accounting for about one-quarter of people with TB disease and nearly one-third of TB deaths globally. Many Indians with TB do not traverse all care stages needed to receive treatment and achieve an optimal long-term outcome, with serial losses of people across these stages referred to as the "care cascade." Understanding why losses of people with TB disease occur across the care cascade is crucial to inform interventions to prevent unfavorable outcomes. What did the researchers do and find?: We conducted 3 systematic searches to identify papers published from 2000 to 2023. We extracted information from these studies on risk factors for unfavorable outcomes for each care cascade gap, as well as reasons reported by people with TB who experienced unfavorable outcomes and were surveyed by researchers. Some factors contributed to losses at multiple care cascade stages, including male sex, older age, poverty-related factors, history of prior TB treatment, lower symptom severity or duration, undernutrition, alcohol use, smoking, and dissatisfaction with health services. Other barriers included: lack of TB knowledge and transportation barriers to clinic contributing to lack of care-seeking (Gap 1), poor accessibility of testing and failure to identify people eligible for testing contributing to non-completion of the diagnostic workup (Gap 2), early deaths from diagnostic delays and poor recording of contact information contributing to losses of people before treatment (Gap 3), lack of TB knowledge and depression contributing to unfavorable treatment outcomes (Gap 4), and medication nonadherence contributing to unfavorable treatment outcomes and TB recurrence (Gaps 4 and 5). What do these findings mean?: Reasons for losses of people with TB disease across the care cascade are complex, vary by care cascade gap, and involve patient- and health system-related barriers. India's TB program should target additional services to people with higher risk of poor outcomes and develop multicomponent interventions to address the diverse challenges faced by people with TB. Study limitations include lack of meta-analyses (i.e., estimation of the average effect of each risk factor by combining findings across studies), and caution is required when applying findings across India's diverse population. [ABSTRACT FROM AUTHOR]

Background: When research evidence is limited, inconsistent, or absent, healthcare decisions and policies need to be based on consensus among interested stakeholders. In these processes, the knowledge, experience, and expertise of health professionals, researchers, policymakers, and the public are systematically collected and synthesised to reach agreed clinical recommendations and/or priorities. However, despite the influence of consensus exercises, the methods used to achieve agreement are often poorly reported. The ACCORD (ACcurate COnsensus Reporting Document) guideline was developed to help report any consensus methods used in biomedical research, regardless of the health field, techniques used, or application. This explanatory document facilitates the use of the ACCORD checklist. Methods and findings: This paper was built collaboratively based on classic and contemporary literature on consensus methods and publications reporting their use. For each ACCORD checklist item, this explanation and elaboration document unpacks the pieces of information that should be reported and provides a rationale on why it is essential to describe them in detail. Furthermore, this document offers a glossary of terms used in consensus exercises to clarify the meaning of common terms used across consensus methods, to promote uniformity, and to support understanding for consumers who read consensus statements, position statements, or clinical practice guidelines (CPGs). The items are followed by examples of reporting items from the ACCORD guideline, in text, tables, and figures. Conclusions: The ACCORD materials—including the reporting guideline and this explanation and elaboration document—can be used by anyone reporting a consensus exercise used in the context of health research. As a reporting guideline, ACCORD helps researchers to be transparent about the materials, resources (both human and financial), and procedures used in their investigations so readers can judge the trustworthiness and applicability of their results/recommendations. Patricia Logullo and colleagues created an explanatory document that facilitates the use of the ACCORD checklist. [ABSTRACT FROM AUTHOR]

The editors of I PLOS Medicine i together with Guest Editors Vikram Patel, Daisy Fancourt, Toshi A Furukawa, and Lola Kola are excited to announce a forthcoming special issue devoted to the impact of the COVID-19 pandemic on global mental health. In this forward-looking Special Issue, I PLOS Medicine i and our Guest Editors wish to invite work with the potential to mitigate the mental health consequences of the current pandemic and strengthen the global response to future pandemics. [Extracted from the article]

The PLOS Medicine editors issue a call for papers for translational and clinical cancer research papers with strong potential to advance patient care, public policy, or clinical research agendas. [ABSTRACT FROM AUTHOR]

Background: Antibiotic use during early infancy has been linked to childhood obesity in high-income countries. We evaluated whether a single oral dose of azithromycin administered during infant-well visits led to changes in infant growth outcomes at 6 months of age in a setting with a high prevalence of undernutrition in rural Burkina Faso. Methods and findings: Infants were enrolled from September 25, 2019, until October 22, 2022, in a randomized controlled trial designed to evaluate the efficacy of a single oral dose of azithromycin (20 mg/kg) compared to placebo when administered during well-child visits for prevention of infant mortality. The trial found no evidence of a difference in the primary endpoint. This paper presents prespecified secondary anthropometric endpoints including weight gain (g/day), height change (mm/day), weight-for-age Z-score (WAZ), weight-for-length Z-score (WLZ), length-for-age Z-score (LAZ), and mid-upper arm circumference (MUAC). Infants were eligible for the trial if they were between 5 and 12 weeks of age, able to orally feed, and their families were planning to remain in the study area for the duration of the study. Anthropometric measurements were collected at enrollment (5 to 12 weeks of age) and 6 months of age. Among 32,877 infants enrolled in the trial, 27,298 (83%) were followed and had valid anthropometric measurements at 6 months of age. We found no evidence of a difference in weight gain (mean difference 0.03 g/day, 95% confidence interval (CI) −0.12 to 0.18), height change (mean difference 0.004 mm/day, 95% CI −0.05 to 0.06), WAZ (mean difference −0.004 SD, 95% CI −0.03 to 0.02), WLZ (mean difference 0.001 SD, 95% CI −0.03 to 0.03), LAZ (mean difference −0.005 SD, 95% CI −0.03 to 0.02), or MUAC (mean difference 0.01 cm, 95% CI −0.01 to 0.04). The primary limitation of the trial was that measurements were only collected at enrollment and 6 months of age, precluding assessment of shorter-term or long-term changes in growth. Conclusions: Single-dose azithromycin does not appear to affect weight and height outcomes when administered during early infancy. Trial registration: ClinicalTrials.govNCT03676764 Ali Sié and colleagues present pre-specified anthropometric outcomes from a randomized controlled trial that assessed the impact of a single-dose of oral azithromycin on infant mortality in Burkina Faso. Author summary: Why was this study done?: Antibiotics have been linked to obesity in children in nonrandomized studies in high-income settings. In low-income settings, malnutrition is a strong risk factor for child mortality, and interventions that increase weight gain may be beneficial. Single-dose azithromycin has previously been shown to reduce child mortality in sub-Saharan Africa, and it is possible that some of this effect is via weight gain. Why did the researchers do and find?: We conducted a randomized controlled trial in which infants aged 5 to 12 weeks were randomly assigned to a single dose of azithromycin or a matching placebo. The primary outcome of the parent trial was all-cause mortality, and the trial found no evidence of a benefit of azithromycin for prevention of mortality. Infants were followed until 6 months of age and had anthropometric measurements, including height, weight, and mid-upper arm circumference, collected. We found no evidence of a difference in any anthropometric endpoint in infants randomized to azithromycin compared to placebo. What do these findings mean?: Single-dose azithromycin does not appear to affect growth when administered to healthy infants who are 5 to 12 weeks of age. Growth outcomes were only measured at 6 months of age, and thus, any shorter or longer-term effects of azithromycin would not be detected by this study. This study only considered a single dose of azithromycin, as is used for prevention of child mortality and trachoma, and thus, it is possible that higher doses or longer duration of antibiotics could have a different effects on child growth. [ABSTRACT FROM AUTHOR]

Call for Papers: PLOS Medicine Special Issue on Bacterial Antimicrobial Resistance - Surveillance and Prevention The guest editors and I PLOS Medicine i editors seek high-quality and high-impact research submissions related to the main drivers, surveillance and prevention of bacterial antimicrobial resistance, particularly in low- and middle-income settings. The editors of I PLOS Medicine i , together with guest editors Timothy Walsh, Ramanan Laxminarayan and Ana Cristina Gales, announce a forthcoming Special Issue dedicated to bacterial antimicrobial resistance (AMR). [Extracted from the article]

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]

Nicola Low and colleagues announce a call for research papers on sexually transmitted infections, to accompany a Collection on the topic. [ABSTRACT FROM AUTHOR]

In this months editorial, the PLOS Medicine Editors announce an upcoming Special Issue and call for papers, with Guest Editors Carol Brayne and Bruce Miller, on dementia across the lifespan and around the globe. [ABSTRACT FROM AUTHOR]

Background: In low- and middle-income countries (L&MICs), the biggest contributing factors to the global burden of disease in childhood are deaths due to respiratory illness and diarrhoea, both of which are closely related to use of water, sanitation, and hygiene (WASH) services by households. However, current estimates of the health impacts of WASH interventions use self-reported morbidity, which may fail to capture longer-term or more severe impacts. Reported mortality is thought to be less prone to bias than other reported measures. This study aimed to answer the question: What are the impacts of WASH interventions on reported childhood mortality in L&MICs? Methods and findings: We conducted a systematic review and meta-analysis, using a published protocol. Systematic searches of 11 academic databases and trial registries, plus organisational repositories, were undertaken to locate studies of WASH interventions, which were published in peer review journals or other sources (e.g., organisational reports and working papers). Intervention studies of WASH improvements implemented under endemic disease circumstances in L&MICs were eligible, which reported findings at any time until March 2020. We used the participant flow data supplied in response to journal editors' calls for greater transparency. Data were collected by two authors working independently. We included evidence from 24 randomized and 11 nonrandomized studies of WASH interventions from all global regions, incorporating 2,600 deaths. Effects of 48 WASH treatment arms were included in analysis. We critically appraised and synthesised evidence using meta-analysis to improve statistical power. We found WASH interventions are associated with a significant reduction of 17% in the odds of all-cause mortality in childhood (OR = 0.83, 95% CI = 0.74, 0.92, evidence from 38 interventions), and a significant reduction in diarrhoea mortality of 45% (OR = 0.55, 95% CI = 0.35, 0.84; 10 interventions). Further analysis by WASH technology indicated interventions providing improved water in quantity to households were most consistently associated with reductions in all-cause mortality. Community-wide sanitation was most consistently associated with reductions in diarrhoea mortality. Around one-half of the included studies were assessed as being at "moderate risk of bias" in attributing mortality in childhood to the WASH intervention, and no studies were found to be at "low risk of bias." The review should be updated to incorporate additional published and unpublished participant flow data. Conclusions: The findings are congruent with theories of infectious disease transmission. Washing with water presents a barrier to respiratory illness and diarrhoea, which are the two biggest contributors to all-cause mortality in childhood in L&MICs. Community-wide sanitation halts the spread of diarrhoea. We observed that evidence synthesis can provide new findings, going beyond the underlying data from trials to generate crucial insights for policy. Transparent reporting in trials creates opportunities for research synthesis to answer questions about mortality, which individual studies of interventions cannot be reliably designed to address. Hugh Sharma Waddington and colleagues investigate the impacts of water, sanitation and hygiene interventions on all-cause and diarrhoea-related mortality in low- and middle-income countries. Author summary: Why was this study done?: The biggest contributor to the global burden of infectious disease in childhood in developing countries is mortality due to respiratory and diarrhoeal infections, both of which are closely linked to deficient water, sanitation, and hygiene (WASH) availability and use by households. Multiple systematic reviews and meta-analyses of WASH-related morbidity have been conducted, but there is a shortage of rigorous, systematic evidence on the effectiveness of WASH interventions in reducing mortality. What did the researchers do and find?: We conducted a systematic review and meta-analysis of the impacts of WASH interventions on all-cause and diarrhoea-related mortality in L&MICs, incorporating evidence from 35 studies comprising 48 distinct WASH intervention arms. We found significant effects on all-cause mortality among children aged under 5 of interventions to improve the quantity of water available (34% reduction), hygiene promotion when water supplies were accessible to households (29% reduction), and community-wide sanitation (21% reduction). We also found significant effects of WASH interventions on diarrhoea mortality among under 5s (45% reduction), which were significantly larger when provided to communities that were at the lowest rungs of the sanitation ladder, compared to those that already had improved WASH. What do these findings mean?: Interventions to prevent water-related mortality in childhood in endemic disease circumstances provide adequate water supplies to households, enabling domestic hygiene and safe excreta disposal in the household and community. Systematic reviews can provide new evidence for decision making, but the approach we present is reliant on trial authors and journals adhering to agreed standards of reporting. [ABSTRACT FROM AUTHOR]

Background: Vaccine-preventable diseases (VPDs) remain major causes of morbidity and mortality in low- and middle-income countries (LMICs). Universal access to vaccination, besides improved health outcomes, would substantially reduce VPD-related out-of-pocket (OOP) expenditures and associated financial risks. This paper aims to estimate the extent of OOP expenditures and the magnitude of the associated catastrophic health expenditures (CHEs) for selected VPDs in Ethiopia. Methods and findings: We conducted a cross-sectional costing analysis, from the household (patient) perspective, of care-seeking for VPDs in children aged under 5 years for pneumonia, diarrhea, measles, and pertussis, and in children aged under 15 years for meningitis. Data on OOP direct medical and nonmedical expenditures (2021 USD) and household consumption expenditures were collected from 995 households (1 child per household) in 54 health facilities nationwide between May 1 and July 31, 2021. We used descriptive statistics to measure the main outcomes: magnitude of OOP expenditures, along with the associated CHE within households. Drivers of CHE were assessed using a logistic regression model. The mean OOP expenditures per disease episode for outpatient care for diarrhea, pneumonia, pertussis, and measles were $5·6 (95% confidence interval (CI): $4·3, 6·8), $7·8 ($5·3, 10·3), $9·0 ($6·4, 11·6), and $7·4 ($3·0, 11·9), respectively. The mean OOP expenditures were higher for inpatient care, ranging from $40·6 (95% CI: $12·9, 68·3) for severe measles to $101·7 ($88·5, 114·8) for meningitis. Direct medical expenditures, particularly drug and supply expenses, were the major cost drivers. Among those who sought inpatient care (345 households), about 13·3% suffered CHE, at a 10% threshold of annual consumption expenditures. The type of facility visited, receiving inpatient care, and wealth were significant predictors of CHE (p-value < 0·001) while adjusting for area of residence (urban/rural), diagnosis, age of respondent, and household family size. Limitations include inadequate number of measles and pertussis cases. Conclusions: The OOP expenditures induced by VPDs are substantial in Ethiopia and disproportionately impact those with low income and those requiring inpatient care. Expanding equitable access to vaccines cannot be overemphasized, for both health and economic reasons. Such realization requires the government's commitment toward increasing and sustaining vaccine financing in Ethiopia. In a cross-sectional costing analysis, Solomon Tessema Memirie and colleagues explore out-of-pocket expenditures and financial risks associated with treatment of vaccine-preventable diseases in Ethiopia. Author summary: Why was this study done?: Despite a rapid expansion in access to vaccines in the past 2 decades, vaccine-preventable diseases (VPDs) remain major causes of morbidity and mortality in low- and middle-income countries. Out-of-pocket (OOP) medical expenditures can lead to catastrophic health expenditures and impoverishment. Studies on household healthcare expenditures and associated financial risks for VPDs among children in sub-Saharan African countries are scarce. What did the researchers do and find?: We collected OOP expenditures data from 995 households to estimate medical impoverishment associated with the following vaccine-preventable childhood diseases: measles, pertussis, pneumonia, diarrhea, and meningitis. Households incur substantial OOP expenditures for the treatment of VPDs in Ethiopia. Poor families and those with sick children requiring inpatient care are likely to be impoverished. What do these findings mean?: Expanding access to vaccination has the potential to protect families from OOP expenditures related to the treatment of VPDs and its associated catastrophic and impoverishing financial consequences. The financial risk benefits primarily accrue among the poorest. Universal access to vaccines requires the government's commitment toward increasing and sustaining vaccine financing. [ABSTRACT FROM AUTHOR]

Background: During the Coronavirus Disease 2019 (COVID-19) pandemic, the number of consultations and diagnoses in primary care and referrals to specialist care declined substantially compared to prepandemic levels. Beyond deferral of elective non-COVID-19 care by healthcare providers, it is unclear to what extent healthcare avoidance by community-dwelling individuals contributed to this decline in routine healthcare utilisation. Moreover, it is uncertain which specific symptoms were left unheeded by patients and which determinants predispose to healthcare avoidance in the general population. In this cross-sectional study, we assessed prevalence of healthcare avoidance during the pandemic from a patient perspective, including symptoms that were left unheeded, as well as determinants of healthcare avoidance. Methods and findings: On April 20, 2020, a paper COVID-19 survey addressing healthcare utilisation, socioeconomic factors, mental and physical health, medication use, and COVID-19–specific symptoms was sent out to 8,732 participants from the population-based Rotterdam Study (response rate 73%). All questionnaires were returned before July 10, 2020. By hand, prevalence of healthcare avoidance was subsequently verified through free text analysis of medical records of general practitioners. Odds ratios (ORs) for avoidance were determined using logistic regression models, adjusted for age, sex, and history of chronic diseases. We found that 1,142 of 5,656 included participants (20.2%) reported having avoided healthcare. Of those, 414 participants (36.3%) reported symptoms that potentially warranted urgent evaluation, including limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). Determinants related to avoidance were older age (adjusted OR 1.14 [95% confidence interval (CI) 1.08 to 1.21]), female sex (1.58 [1.38 to 1.82]), low educational level (primary education versus higher vocational/university 1.21 [1.01 to 1.46), poor self-appreciated health (per level decrease 2.00 [1.80 to 2.22]), unemployment (versus employed 2.29 [1.54 to 3.39]), smoking (1.34 [1.08 to 1.65]), concern about contracting COVID-19 (per level increase 1.28 [1.19 to 1.38]) and symptoms of depression (per point increase 1.13 [1.11 to 1.14]) and anxiety (per point increase 1.16 [1.14 to 1.18]). Study limitations included uncertainty about (perceived) severity of the reported symptoms and potentially limited generalisability given the ethnically homogeneous study population. Conclusions: In this population-based cross-sectional study, 1 in 5 individuals avoided healthcare during lockdown in the COVID-19 pandemic, often for potentially urgent symptoms. Healthcare avoidance was strongly associated with female sex, fragile self-appreciated health, and high levels of depression and anxiety. These results emphasise the need for targeted public education urging these vulnerable patients to timely seek medical care for their symptoms to mitigate major health consequences. Marije J. Splinter and colleagues assess the prevalence of healthcare avoidance during the COIVD-19 pandemic and investigate related determinants Author summary: Why was this study done?: ➢ During the Coronavirus Disease 2019 (COVID-19) pandemic, consultation rates in both primary and specialist care declined compared to prepandemic levels, which can partially be attributed to the postponement or cancellation of elective and nonurgent medical care. ➢ It is unclear to what extent these declines in consultation rates could be related to healthcare avoidance by patients in the general population. ➢ To evaluate the collateral health damage of the COVID-19 pandemic, it is important to not only assess the prevalence of healthcare avoidance, but also for what symptoms healthcare was avoided and which determinants are associated with this behaviour. What did the researchers do and find?: ➢ We sent out a paper questionnaire to 8,732 participants of the population-based Rotterdam Study containing several COVID-19–related subjects, such as healthcare utilisation, work status, mental and physical health, and concerns about contracting COVID-19. ➢ About 6,241 participants (73%) returned the questionnaire, of whom 5,656 participants (90.6%) were included in our analyses. We found that 1,142 of them (20.2%) avoided healthcare during the COVID-19 pandemic, often for symptoms that might have needed urgent medical evaluation, such as limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). ➢ Determinants that were most strongly associated with healthcare avoidance were female sex, poor self-appreciated health, and high levels of depression and anxiety. What do these findings mean?: ➢ The results of this population-based study suggest that healthcare avoidance contributed to the decline in consultation rates during the COVID-19 pandemic. Importantly, our findings suggest that this behaviour may be associated with certain vulnerable groups within the population. ➢ These findings should be interpreted in light of the limitations of this study, which include that the actual severity of the symptoms that were reported by participants is unknown, since they were not medically evaluated when they experienced these symptoms. ➢ The findings of this study can be used to develop policy interventions targeted to vulnerable individuals who may be more likely to exhibit healthcare avoiding behaviours. [ABSTRACT FROM AUTHOR]

Background: Evidence regarding the presence and persistence of ethnic inequalities in mental healthcare is well established. The reasons for these inequalities and lack of progress in diminishing them are less understood. This meta-ethnography aims to provide a new conceptual understanding of how ethnic inequalities are created and sustained; this is essential to develop effective interventions. Specifically, we sought to understand why people from ethnic minority groups are underrepresented in primary care mental health service provision and overrepresented in crisis pathways and detention. Methods and findings: Following eMERGe guidelines for meta-ethnographies, we searched OpenGrey, Kings Fund, CINAHL, Medline, PsycINFO, and Social Care Online databases for qualitative articles published from database inception until October 2, 2022, using broad categories of search terms relating to "ethnicity AND (mental illness/mental health/emotional distress) AND (help-seeking/service utilisation/experience/perception/view)." We included all conceptually rich articles that used qualitative methods of data collection and analysis and excluded non-UK studies and those that focused solely on causation of mental illness. Our patient, public, and practitioner lived experience advisory group provided feedback and input on key stages of the project including search terms, research questions, data analysis, and dissemination. A total of 14,142 articles were identified; 66 met the inclusion criteria. We used reciprocal, refutational, and line of argument analytical approaches to identify convergence and divergence between studies. The synthesis showed that current models of statutory mental healthcare are experienced as a major barrier to the delivery of person-centred care to those in ethnic minority groups due to the perceived dominance of monocultural and reductionist frameworks of assessment and treatment (described as "medical" and "Eurocentric") and direct experiences of racist practice. The lack of socially oriented and holistic frameworks of knowledge and understanding in medical training and services is experienced as epistemic injustice, particularly among those who attribute their mental illness to experiences of migration, systemic racism, and complex trauma. Fear of harm, concerns about treatment suitability, and negative experiences with health providers such as racist care and medical neglect/injury contribute to avoidance of, and disengagement from, mainstream healthcare. The lack of progress in tackling ethnic inequalities is attributed to failures in coproduction and insufficient adoption of existing recommendations within services. Study limitations include insufficient recording of participant characteristics relating to generational status and social class in primary studies, which prevented exploration of these intersections. Conclusions: In this study, we found that the delivery of safe and equitable person-centred care requires a model of mental health that is responsive to the lived experiences of people in ethnic minority groups. For the people considered in this review, this requires better alignment of mental health services with social and anti-racist models of care. Our findings suggest that intersections related to experiences of racism, migration, religion, and complex trauma might be more relevant than crude ethnic group classifications. Strategies to tackle ethnic inequalities in mental healthcare require an evaluation of individual, systemic, and structural obstacles to authentic and meaningful coproduction and implementation of existing community recommendations in services. In a meta-ethnography, Dr Narinder Bansal and colleagues report insights into ethnic inequalities in mental healthcare in the UK. Author summary: Why was this study done?: People from ethnic minority groups in the UK have poorer mental health and access to mental healthcare, and more negative experiences and outcomes compared to the majority white British group. These inequalities have been reported for over 50 years. There remains some debate regarding their causes and the interventions required to tackle these. In order to develop effective interventions, we need to consider a wide range of perspectives from communities, service users, carers, and mental health professionals in a way that allows interrogation of commonalities and variations in experience across a diverse range of ethnic and lay/professional backgrounds. What did the researchers do and find?: We conducted a comprehensive literature search and identified 66 relevant studies that explored the experiences and perspectives of people in different ethnic minority groups and mental health professionals in relation to access to and experience of mental healthcare. We identified key themes across papers and explored similarities and differences in experiences across ethnic groups and between communities and mental health professionals. We found that current statutory approaches to the assessment and treatment of mental illness are experienced as a major barrier to the delivery of appropriate and person-centred care to those in ethnic minority groups. These are perceived to exclude the everyday realities of people's lives including racism, migration stress, complex trauma, and spirituality and the ways in which these may contribute to (or mitigate) mental illness. The lack of progress in tackling ethnic inequalities is attributed to superficial attempts at coproduction and inadequate adoption of existing community recommendations within services. What do these findings mean?: The delivery of safe and equitable person-centred care requires a model of mental healthcare that recognises, and is responsive to, the lived experiences of people in ethnic minority groups. This includes paying attention to how experiences of racism and migration affect mental health during assessment and treatment and tackling institutional racism in mental healthcare. Strategies to tackle ethnic inequalities in mental healthcare require an evaluation of existing barriers and obstacles to authentic and meaningful inclusion of people with lived experience from ethnic minority groups in the development and delivery of mental healthcare services. [ABSTRACT FROM AUTHOR]

Background: Surveillance systems are important in detecting changes in disease patterns and can act as early warning systems for emerging disease outbreaks. We hypothesized that analysis of data from existing global influenza surveillance networks early in the COVID-19 pandemic could identify outliers in influenza-negative influenza-like illness (ILI). We used data-driven methods to detect outliers in ILI that preceded the first reported peaks of COVID-19.Methods and Findings: We used data from the World Health Organization's Global Influenza Surveillance and Response System to evaluate time series outliers in influenza-negative ILI. Using automated autoregressive integrated moving average (ARIMA) time series outlier detection models and baseline influenza-negative ILI training data from 2015-2019, we analyzed 8,792 country-weeks across 28 countries to identify the first week in 2020 with a positive outlier in influenza-negative ILI. We present the difference in weeks between identified outliers and the first reported COVID-19 peaks in these 28 countries with high levels of data completeness for influenza surveillance data and the highest number of reported COVID-19 cases globally in 2020. To account for missing data, we also performed a sensitivity analysis using linear interpolation for missing observations of influenza-negative ILI. In 16 of the 28 countries (57%) included in this study, we identified positive outliers in cases of influenza-negative ILI that predated the first reported COVID-19 peak in each country; the average lag between the first positive ILI outlier and the reported COVID-19 peak was 13.3 weeks (standard deviation 6.8). In our primary analysis, the earliest outliers occurred during the week of January 13, 2020, in Peru, the Philippines, Poland, and Spain. Using linear interpolation for missing data, the earliest outliers were detected during the weeks beginning December 30, 2019, and January 20, 2020, in Poland and Peru, respectively. This contrasts with the reported COVID-19 peaks, which occurred on April 6 in Poland and June 1 in Peru. In many low- and middle-income countries in particular, the lag between detected outliers and COVID-19 peaks exceeded 12 weeks. These outliers may represent undetected spread of SARS-CoV-2, although a limitation of this study is that we could not evaluate SARS-CoV-2 positivity.Conclusions: Using an automated system of influenza-negative ILI outlier monitoring may have informed countries of the spread of COVID-19 more than 13 weeks before the first reported COVID-19 peaks. This proof-of-concept paper suggests that a system of influenza-negative ILI outlier monitoring could have informed national and global responses to SARS-CoV-2 during the rapid spread of this novel pathogen in early 2020. [ABSTRACT FROM AUTHOR]

Background: Psychiatric disorders are reported to be present in 80% to 90% of suicide deaths in high-income countries (HIC), but this association is less clear in low- and middle-income countries (LMIC). There has been no previous systematic review of this issue in LMIC. The current study aims to estimate the prevalence of psychiatric morbidity in individuals with suicidal behaviour in LMIC. Methods and findings: PubMed, PsycINFO, and EMBASE searches were conducted to identify quantitative research papers (any language) between 1990 and 2018 from LMIC that reported on the prevalence of psychiatric morbidity in suicidal behaviour. We used meta-analytic techniques to generate pooled estimates for any psychiatric disorder and specific diagnosis based on International classification of disease (ICD-10) criteria. A total of 112 studies (154 papers) from 26 LMIC (India: 25%, China: 15%, and other LMIC: 60%) were identified, including 18 non-English articles. They included 30,030 individuals with nonfatal suicidal behaviour and 4,996 individuals who had died by suicide. Of the 15 studies (5 LMIC) that scored highly on our quality assessment, prevalence estimates for psychiatric disorders ranged between 30% and 80% in suicide deaths and between 3% and 86% in those who engaged in nonfatal suicidal behaviour. There was substantial heterogeneity between study estimates. Fifty-eight percent (95% CI 46%–71%) of those who died by suicide and 45% (95% CI 30%–61%) of those who engaged in nonfatal suicidal behaviour had a psychiatric disorder. The most prevalent disorder in both fatal and nonfatal suicidal behaviour was mood disorder (25% and 21%, respectively). Schizophrenia and related disorders were identified in 8% (4%–12%) of those who died by suicide and 7% (3%–11%) of those who engaged in nonfatal suicidal behaviour. In nonfatal suicidal behaviour, anxiety disorders, and substance misuse were identified in 19% (1%–36%) and 11% (7%–16%) of individuals, respectively. This systematic review was limited by the low number of high-quality studies and restricting our searches to databases that mainly indexed English language journals. Conclusions: Our findings suggest a possible lower prevalence of psychiatric disorders in suicidal behaviour in LMIC. We found very few high-quality studies and high levels of heterogeneity in pooled estimates of psychiatric disorder, which could reflect differing study methods or real differences. There is a clear need for more robust evidence in order for LMIC to strike the right balance between community-based and mental health focussed interventions. Duleeka Knipe and co-workers study associations between psychiatric disorders and suicidal behaviour in low- and middle-income countries. Author summary: Why was the study done?: Approximately 800,000 people die by suicide each year, with 75% of these deaths occurring in low- and middle-income countries (LMIC). Psychiatric disorder is thought to be associated with 80% to 90% of those who engage in suicidal behaviour in high-income countries (HIC), but this association is less clear in LMIC. A better understanding is needed of this association in LMIC to ensure effective and appropriate allocation of limited resources. What did the researchers do and find?: We searched the existing literature for studies conducted in LMIC that estimated the proportion of individuals who engaged in suicidal behaviour with psychiatric disorders and found 112 studies from 26 countries (mainly from China and India). Even in the higher quality studies, there was wide variability in the proportion of psychiatric disorders in fatal (30%–80%) and nonfatal (3%–86%) suicidal behaviour, but on average, 58% of those who died by suicide and 45% of those who engaged in nonfatal suicidal behaviour had a psychiatric disorder. Mood disorders were the most prevalent disorder identified in both fatal and nonfatal suicidal behaviour. What do these findings mean?: There were considerable differences in the estimates of psychiatric disorder between studies. This may reflect differences in the way studies were carried out or real differences, but there were too few high-quality studies to estimate the prevalence by individual country. More high-quality research is needed. Psychiatric disorders may be less common in suicidal behaviour in LMIC than in HIC. Although treating psychiatric illness is important, the treatment and prevention of suicidal behaviour should include a wider range of activities. [ABSTRACT FROM AUTHOR]

Background: Optimizing services to facilitate engagement and retention in care of people living with HIV (PLWH) on antiretroviral therapies (ARTs) is critical to decrease HIV-related morbidity and mortality and HIV transmission. We systematically reviewed the literature for the effectiveness of implementation strategies to reestablish and subsequently retain clinical contact, improve viral load suppression, and reduce mortality among patients who had been lost to follow-up (LTFU) from HIV services.Methods and Findings: We searched 7 databases (PubMed, Cochrane, ERIC, PsycINFO, EMBASE, Web of Science, and the WHO regional databases) and 3 conference abstract archives (CROI, IAC, and IAS) to find randomized trials and observational studies published through 13 April 2020. Eligible studies included those involving children and adults who were diagnosed with HIV, had initiated ART, and were subsequently lost to care and that reported at least one review outcome (return to care, retention, viral suppression, or mortality). Data were extracted by 2 reviewers, with discrepancies resolved by a third. We characterized reengagement strategies according to how, where, and by whom tracing was conducted. We explored effects, first, among all categorized as LTFU from the HIV program (reengagement program effect) and second among those found to be alive and out of care (reengagement contact outcome). We used random-effect models for meta-analysis and conducted subgroup analyses to explore heterogeneity. Searches yielded 4,244 titles, resulting in 37 included studies (6 randomized trials and 31 observational studies). In low- and middle-income countries (LMICs) (N = 16), tracing most frequently involved identification of LTFU from the electronic medical record (EMR) and paper records followed by a combination of telephone calls and field tracing (including home visits), by a team of outreach workers within 3 months of becoming LTFU (N = 7), with few incorporating additional strategies to support reengagement beyond contact (N = 2). In high-income countries (HICs) (N = 21 studies), LTFU were similarly identified through EMR systems, at times matched with other public health records (N = 4), followed by telephone calls and letters sent by mail or email and conducted by outreach specialist teams. Home visits were less common (N = 7) than in LMICs, and additional reengagement support was similarly infrequent (N = 5). Overall, reengagement programs were able to return 39% (95% CI: 31% to 47%) of all patients who were characterized as LTFU (n = 29). Reengagement contact resulted in 58% (95% CI: 51% to 65%) return among those found to be alive and out of care (N = 17). In 9 studies that had a control condition, the return was higher among those in the reengagement intervention group than the standard of care group (RR: 1.20 (95% CI: 1.08 to 1.32, P < 0.001). There were insufficient data to generate pooled estimates of retention, viral suppression, or mortality after the return.Conclusions: While the types of interventions are markedly heterogeneity, reengagement interventions increase return to care. HIV programs should consider investing in systems to better characterize LTFU to identify those who are alive and out of care, and further research on the optimum time to initiate reengagement efforts after missed visits and how to best support sustained reengagement could improve efficiency and effectiveness. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization Model List of Essential Medicines (WHO EML) has played a critical role in guiding the country-level selection and financing of medicines for more than 4 decades. It continues to be a relevant evidence-based policy that can support universal health coverage (UHC) and access to essential medicines. The objective of this review was to identify factors affecting adaptation and implementation of WHO EML at the national level.Methods and Findings: We conducted a qualitative evidence synthesis by searching 10 databases (including CINAHL, Embase, Ovid MEDLINE, Scopus, and Web of Science) through October 2021. Primary qualitative studies focused on country-level implementation of WHO EML were included. The qualitative findings were populated in the Supporting the Use of Research Evidence (SURE) framework, and key themes were identified through an iterative process. We appraised the papers using the Critical Appraisal Skills Programme (CASP) tool and assessed our confidence in the findings using the Grading of Recommendations Assessment, Development and Evaluation working group-Confidence in Evidence from Reviews of Qualitative research (GRADE-CERQual). We screened 1,567 unique citations, reviewed 183 full texts, and included 23 studies, from 30 settings. Non-English studies and experiences and perceptions of stakeholders published in gray literature were not collected. Our findings centered around 3 main ideas pertaining to national adaptation and implementation of WHO EML: (1) the importance of designing institutions, governance, and leadership for national medicines lists (NMLs), particularly the consideration of transparency, coordination capacity, legislative mechanisms, managing regional differences, and clinical guidance; (2) the capacity to manage evidence to inform NML updates, including processes for contextualizing global evidence, utilizing local data and expert knowledge, and assessing budget impact, to which locally relevant cost-effectiveness information plays an important role; and (3) the influence of NML on purchasing and prescribing by altering provider incentives, through linkages to systems for financing and procurement and donor influence.Conclusions: This qualitative evidence synthesis underscores the complexity and interdependencies inherent to implementation of WHO EML. To maximize the value of NMLs, greater investments should be made in processes and institutions that are needed to support various stages of the implementation pathway from global norms to adjusting prescribed behavior. Moreover, further research on linkages between NMLs, procurement, and the availability of medicines will provide additional insight into optimal NML implementation.Protocol Registry: PROSPERO CRD42018104112. [ABSTRACT FROM AUTHOR]

PLOS Medicine editors and guest editors announce a call for papers for submissions for a special issue on diabetes prevention. [ABSTRACT FROM AUTHOR]

Background: Rotavirus vaccination is recommended in all countries to reduce the burden of diarrhea-related morbidity and mortality in children. In resource-limited settings, rotavirus vaccination in the national immunization program has important cost implications, and evidence for protection beyond the first year of life and against the evolving variety of rotavirus strains is important. We assessed the extended and strain-specific vaccine efficacy of a heat-stable, affordable oral rotavirus vaccine (Rotasiil, Serum Institute of India, Pune, India) against severe rotavirus gastroenteritis (SRVGE) among healthy infants in Niger.Methods and Findings: From August 2014 to November 2015, infants were randomized in a 1:1 ratio to receive 3 doses of Rotasiil or placebo at approximately 6, 10, and 14 weeks of age. Episodes of gastroenteritis were assessed through active and passive surveillance and graded using the Vesikari score. The primary endpoint was vaccine efficacy of 3 doses of vaccine versus placebo against a first episode of laboratory-confirmed SRVGE (Vesikari score ≥ 11) from 28 days after dose 3, as previously reported. At the time of the primary analysis, median age was 9.8 months. In the present paper, analyses of extended efficacy were undertaken for 3 periods (28 days after dose 3 to 1 year of age, 1 to 2 years of age, and the combined period 28 days after dose 3 to 2 years of age) and by individual rotavirus G type. Among the 3,508 infants included in the per-protocol efficacy analysis (mean age at first dose 6.5 weeks; 49% male), the vaccine provided significant protection against SRVGE through the first year of life (3.96 and 9.98 cases per 100 person-years for vaccine and placebo, respectively; vaccine efficacy 60.3%, 95% CI 43.6% to 72.1%) and over the entire efficacy follow-up period up to 2 years of age (2.13 and 4.69 cases per 100 person-years for vaccine and placebo, respectively; vaccine efficacy 54.7%, 95% CI 38.1% to 66.8%), but the difference was not statistically significant in the second year of life. Up to 2 years of age, rotavirus vaccination prevented 2.56 episodes of SRVGE per 100 child-years. Estimates of efficacy against SRVGE by individual rotavirus genotype were consistent with the overall protective efficacy. Study limitations include limited generalizability to settings with administration of oral polio virus due to low concomitant administration, limited power to assess vaccine efficacy in the second year of life owing to a low number of events among older children, potential bias due to censoring of placebo children at the time of study vaccine receipt, and suboptimal adapted severity scoring based on the Vesikari score, which was designed for use in settings with high parental literacy.Conclusions: Rotasiil provided protection against SRVGE in infants through an extended follow-up period of approximately 2 years. Protection was significant in the first year of life, when the disease burden and risk of death are highest, and against a changing pattern of rotavirus strains during the 2-year efficacy period. Rotavirus vaccines that are safe, effective, and protective against multiple strains represent the best hope for preventing the severe consequences of rotavirus infection, especially in resource-limited settings, where access to care may be limited. Studies such as this provide valuable information for the planning of national immunization programs and future vaccine development.Trial Registration: ClinicalTrials.gov NCT02145000. [ABSTRACT FROM AUTHOR]

Background: Prospective cohort studies of incident HIV and associated factors among gay, bisexual, and other men who have sex with men (GBMSM) in the United Kingdom are lacking. We report time trends in and factors associated with HIV incidence between 2013 and 2019 among a cohort of GBMSM: the AURAH2 prospective study.Methods and Findings: Participants were recruited through 1 of 3 sexual health clinics in London and Brighton (July 2013 to April 2016) and self-completed a baseline paper questionnaire and subsequent 4-monthly and annual online questionnaires (March 2015 to March 2018), including information on sociodemographics, lifestyle, health and well-being, HIV status, sexual/HIV-related behaviours, and preexposure prophylaxis and postexposure prophylaxis (PrEP/PEP). Incident HIV was ascertained by linkage with national HIV surveillance data from Public Health England (PHE). We investigated the associations of HIV incidence with (1) baseline factors using mixed-effects Weibull proportional hazard models, unadjusted and adjusted for age, country of birth and ethnicity, sexuality, and education level; and (2) time-updated factors, using mixed-effects Poisson regression models. In total, 1,162 men (mean age 34 years, 82% white, 94% gay, 74% university-educated) were enrolled in the study. Thirty-three HIV seroconversions occurred over 4,618.9 person-years (PY) of follow-up: an overall HIV incidence rate (IR) of 0.71 (95% confidence interval (CI) 0.51 to 1.00) per 100 PY. Incidence declined from 1.47 (95% CI 0.48 to 4.57) per 100 PY in 2013/2014 to 0.25 (95% CI 0.08 to 0.78) per 100 PY in 2018/2019; average annual decline was 0.85-fold (p < 0.001). Baseline factors associated with HIV acquisition included the following: injection drug use (6/38 men who reported injection drug-acquired HIV; unadjusted conditional hazard ratio (HR) 27.96, 95% CI 6.99 to 111.85, p < 0.001), noninjection chemsex-related drug use (13/321; HR 6.45, 95% CI 1.84 to 22.64, p < 0.001), condomless anal sex (CLS) (26/741; HR 3.75, 95% CI 1.31 to 10·74, p = 0.014); higher number of CLS partners (HRs >10 partners [7/57]; 5 to 10 partners [5/60]; and 2 to 4 partners [11/293]: 14.04, 95% CI 4.11 to 47.98; 9.60, 95% CI 2.58 to 35.76; and 4.05, 95% CI 1.29 to 12.72, respectively, p < 0.001); CLS with HIV-positive partners (14/147; HR 6.45, 95% CI 3.15 to 13.22, p < 0.001), versatile CLS role (21/362; HR 6.35, 95% CI 2.18 to 18.51, p < 0.001), group sex (64/500; HR 8.81, 95% CI 3.07 to 25.24, p < 0.001), sex for drugs/money (4/55, HR 3.27, 95% CI 1.14 to 9.38, p = 0.027) (all in previous 3 months); previous 12-month report of a bacterial sexually transmitted infection (STI) diagnoses (21/440; HR 3.95, 95% CI 1.81 to 8.63, p < 0.001), and more than 10 new sexual partners (21/471, HRs 11 to 49, 50 to 99, and >100 new partners: 3.17, 95% CI 1.39 to 7.26; 4.40, 95% CI 1.35 to 14.29; and 4.84, 95% CI 1.05 to 22.4, respectively, p < 0.001). Results were broadly consistent for time-updated analysis (n = 622 men). The study's main limitation is that men may not be representative of the broader GBMSM population in England.Conclusions: We observed a substantial decline in HIV incidence from 2013 to 2019 among GBMSM attending sexual health clinics. Injection drug use, chemsex use, and measures of high-risk sexual behaviour were strongly associated with incident HIV. Progress towards zero new infections could be achieved if combination HIV prevention including Test and Treat strategies and routine commissioning of a PrEP programme continues across the UK and reaches all at-risk populations. [ABSTRACT FROM AUTHOR]

Background: Influenza illness burden is substantial, particularly among young children, older adults, and those with underlying conditions. Initiatives are underway to develop better global estimates for influenza-associated hospitalizations and deaths. Knowledge gaps remain regarding the role of influenza viruses in severe respiratory disease and hospitalizations among adults, particularly in lower-income settings.Methods and Findings: We aggregated published data from a systematic review and unpublished data from surveillance platforms to generate global meta-analytic estimates for the proportion of acute respiratory hospitalizations associated with influenza viruses among adults. We searched 9 online databases (Medline, Embase, CINAHL, Cochrane Library, Scopus, Global Health, LILACS, WHOLIS, and CNKI; 1 January 1996-31 December 2016) to identify observational studies of influenza-associated hospitalizations in adults, and assessed eligible papers for bias using a simplified Newcastle-Ottawa scale for observational data. We applied meta-analytic proportions to global estimates of lower respiratory infections (LRIs) and hospitalizations from the Global Burden of Disease study in adults ≥20 years and by age groups (20-64 years and ≥65 years) to obtain the number of influenza-associated LRI episodes and hospitalizations for 2016. Data from 63 sources showed that influenza was associated with 14.1% (95% CI 12.1%-16.5%) of acute respiratory hospitalizations among all adults, with no significant differences by age group. The 63 data sources represent published observational studies (n = 28) and unpublished surveillance data (n = 35), from all World Health Organization regions (Africa, n = 8; Americas, n = 11; Eastern Mediterranean, n = 7; Europe, n = 8; Southeast Asia, n = 11; Western Pacific, n = 18). Data quality for published data sources was predominantly moderate or high (75%, n = 56/75). We estimate 32,126,000 (95% CI 20,484,000-46,129,000) influenza-associated LRI episodes and 5,678,000 (95% CI 3,205,000-9,432,000) LRI hospitalizations occur each year among adults. While adults <65 years contribute most influenza-associated LRI hospitalizations and episodes (3,464,000 [95% CI 1,885,000-5,978,000] LRI hospitalizations and 31,087,000 [95% CI 19,987,000-44,444,000] LRI episodes), hospitalization rates were highest in those ≥65 years (437/100,000 person-years [95% CI 265-612/100,000 person-years]). For this analysis, published articles were limited in their inclusion of stratified testing data by year and age group. Lack of information regarding influenza vaccination of the study population was also a limitation across both types of data sources.Conclusions: In this meta-analysis, we estimated that influenza viruses are associated with over 5 million hospitalizations worldwide per year. Inclusion of both published and unpublished findings allowed for increased power to generate stratified estimates, and improved representation from lower-income countries. Together, the available data demonstrate the importance of influenza viruses as a cause of severe disease and hospitalizations in younger and older adults worldwide. [ABSTRACT FROM AUTHOR]

In this month's editorial, the PLOS Medicine Editors announce an upcoming Special Issue, with Guest Editors Elaine Mardis and Marc Ladanyi, on actionable advances in research on the cancer genome. [ABSTRACT FROM AUTHOR]

Background: While the high prevalence of preterm births and its impact on infant mortality in the US have been widely acknowledged, recent data suggest that even full-term births in the US face substantially higher mortality risks compared to European countries with low infant mortality rates. In this paper, we use the most recent birth records in the US to more closely analyze the primary causes underlying mortality rates among full-term births.Methods and Findings: Linked birth and death records for the period 2010-2012 were used to identify the state- and cause-specific burden of infant mortality among full-term infants (born at 37-42 weeks of gestation). Multivariable logistic models were used to assess the extent to which state-level differences in full-term infant mortality (FTIM) were attributable to observed differences in maternal and birth characteristics. Random effects models were used to assess the relative contribution of state-level variation to FTIM. Hypothetical mortality outcomes were computed under the assumption that all states could achieve the survival rates of the best-performing states. A total of 10,175,481 infants born full-term in the US between January 1, 2010, and December 31, 2012, were analyzed. FTIM rate (FTIMR) was 2.2 per 1,000 live births overall, and ranged between 1.29 (Connecticut, 95% CI 1.08, 1.53) and 3.77 (Mississippi, 95% CI 3.39, 4.19) at the state level. Zero states reached the rates reported in the 6 low-mortality European countries analyzed (FTIMR < 1.25), and 13 states had FTIMR > 2.75. Sudden unexpected death in infancy (SUDI) accounted for 43% of FTIM; congenital malformations and perinatal conditions accounted for 31% and 11.3% of FTIM, respectively. The largest mortality differentials between states with good and states with poor FTIMR were found for SUDI, with particularly large risk differentials for deaths due to sudden infant death syndrome (SIDS) (odds ratio [OR] 2.52, 95% CI 1.86, 3.42) and suffocation (OR 4.40, 95% CI 3.71, 5.21). Even though these mortality differences were partially explained by state-level differences in maternal education, race, and maternal health, substantial state-level variation in infant mortality remained in fully adjusted models (SIDS OR 1.45, suffocation OR 2.92). The extent to which these state differentials are due to differential antenatal care standards as well as differential access to health services could not be determined due to data limitations. Overall, our estimates suggest that infant mortality could be reduced by 4,003 deaths (95% CI 2,284, 5,587) annually if all states were to achieve the mortality levels of the best-performing state in each cause-of-death category. Key limitations of the analysis are that information on termination rates at the state level was not available, and that causes of deaths may have been coded differentially across states.Conclusions: More than 7,000 full-term infants die in the US each year. The results presented in this paper suggest that a substantial share of these deaths may be preventable. Potential improvements seem particularly large for SUDI, where very low rates have been achieved in a few states while average mortality rates remain high in most other areas. Given the high mortality burden due to SIDS and suffocation, policy efforts to promote compliance with recommended sleeping arrangements could be an effective first step in this direction. [ABSTRACT FROM AUTHOR]

Background: Public health evaluation methods have been criticized for being overly reductionist and failing to generate suitable evidence for public health decision-making. A "complex systems approach" has been advocated to account for real world complexity. Qualitative methods may be well suited to understanding change in complex social environments, but guidance on applying a complex systems approach to inform qualitative research remains limited and underdeveloped. This systematic review aims to analyze published examples of process evaluations that utilize qualitative methods that involve a complex systems perspective and proposes a framework for qualitative complex system process evaluations.Methods and Findings: We conducted a systematic search to identify complex system process evaluations that involve qualitative methods by searching electronic databases from January 1, 2014-September 30, 2019 (Scopus, MEDLINE, Web of Science), citation searching, and expert consultations. Process evaluations were included if they self-identified as taking a systems- or complexity-oriented approach, integrated qualitative methods, reported empirical findings, and evaluated public health interventions. Two reviewers independently assessed each study to identify concepts associated with the systems thinking and complexity science traditions. Twenty-one unique studies were identified evaluating a wide range of public health interventions in, for example, urban planning, sexual health, violence prevention, substance use, and community transformation. Evaluations were conducted in settings such as schools, workplaces, and neighborhoods in 13 different countries (9 high-income and 4 middle-income). All reported some utilization of complex systems concepts in the analysis of qualitative data. In 14 evaluations, the consideration of complex systems influenced intervention design, evaluation planning, or fieldwork. The identified studies used systems concepts to depict and describe a system at one point in time. Only 4 evaluations explicitly utilized a range of complexity concepts to assess changes within the system resulting from, or co-occurring with, intervention implementation over time. Limitations to our approach are including only English-language papers, reliance on study authors reporting their utilization of complex systems concepts, and subjective judgment from the reviewers relating to which concepts featured in each study.Conclusion: This study found no consensus on what bringing a complex systems perspective to public health process evaluations with qualitative methods looks like in practice and that many studies of this nature describe static systems at a single time point. We suggest future studies use a 2-phase framework for qualitative process evaluations that seek to assess changes over time from a complex systems perspective. The first phase involves producing a description of the system and identifying hypotheses about how the system may change in response to the intervention. The second phase involves following the pathway of emergent findings in an adaptive evaluation approach. [ABSTRACT FROM AUTHOR]

Background: Following a reduction in global child mortality due to communicable diseases, the relative contribution of congenital anomalies to child mortality is increasing. Although infant survival of children born with congenital anomalies has improved for many anomaly types in recent decades, there is less evidence on survival beyond infancy. We aimed to systematically review, summarise, and quantify the existing population-based data on long-term survival of individuals born with specific major congenital anomalies and examine the factors associated with survival.Methods and Findings: Seven electronic databases (Medline, Embase, Scopus, PsycINFO, CINAHL, ProQuest Natural, and Biological Science Collections), reference lists, and citations of the included articles for studies published 1 January 1995 to 30 April 2020 were searched. Screening for eligibility, data extraction, and quality appraisal were performed in duplicate. We included original population-based studies that reported long-term survival (beyond 1 year of life) of children born with a major congenital anomaly with the follow-up starting from birth that were published in the English language as peer-reviewed papers. Studies on congenital heart defects (CHDs) were excluded because of a recent systematic review of population-based studies of CHD survival. Meta-analysis was performed to pool survival estimates, accounting for trends over time. Of 10,888 identified articles, 55 (n = 367,801 live births) met the inclusion criteria and were summarised narratively, 41 studies (n = 54,676) investigating eight congenital anomaly types (spina bifida [n = 7,422], encephalocele [n = 1,562], oesophageal atresia [n = 6,303], biliary atresia [n = 3,877], diaphragmatic hernia [n = 6,176], gastroschisis [n = 4,845], Down syndrome by presence of CHD [n = 22,317], and trisomy 18 [n = 2,174]) were included in the meta-analysis. These studies covered birth years from 1970 to 2015. Survival for children with spina bifida, oesophageal atresia, biliary atresia, diaphragmatic hernia, gastroschisis, and Down syndrome with an associated CHD has significantly improved over time, with the pooled odds ratios (ORs) of surviving per 10-year increase in birth year being OR = 1.34 (95% confidence interval [95% CI] 1.24-1.46), OR = 1.50 (95% CI 1.38-1.62), OR = 1.62 (95% CI 1.28-2.05), OR = 1.57 (95% CI 1.37-1.81), OR = 1.24 (95% CI 1.02-1.5), and OR = 1.99 (95% CI 1.67-2.37), respectively (p < 0.001 for all, except for gastroschisis [p = 0.029]). There was no observed improvement for children with encephalocele (OR = 0.98, 95% CI 0.95-1.01, p = 0.19) and children with biliary atresia surviving with native liver (OR = 0.96, 95% CI 0.88-1.03, p = 0.26). The presence of additional structural anomalies, low birth weight, and earlier year of birth were the most commonly reported predictors of reduced survival for any congenital anomaly type. The main limitation of the meta-analysis was the small number of studies and the small size of the cohorts, which limited the predictive capabilities of the models resulting in wide confidence intervals.Conclusions: This systematic review and meta-analysis summarises estimates of long-term survival associated with major congenital anomalies. We report a significant improvement in survival of children with specific congenital anomalies over the last few decades and predict survival estimates up to 20 years of age for those born in 2020. This information is important for the planning and delivery of specialised medical, social, and education services and for counselling affected families. This trial was registered on the PROSPERO database (CRD42017074675). [ABSTRACT FROM AUTHOR]

Background: The psychological health of female sex workers (FSWs) has emerged as a major public health concern in many low- and middle-income countries (LMICs). Key risk factors include poverty, low education, violence, alcohol and drug use, human immunodeficiency virus (HIV), and stigma and discrimination. This systematic review and meta-analysis aimed to quantify the prevalence of mental health problems among FSWs in LMICs, and to examine associations with common risk factors.Method and Findings: The review protocol was registered with PROSPERO, number CRD42016049179. We searched 6 electronic databases for peer-reviewed, quantitative studies from inception to 26 April 2020. Study quality was assessed with the Centre for Evidence-Based Management (CEBM) Critical Appraisal Tool. Pooled prevalence estimates were calculated for depression, anxiety, post-traumatic stress disorder (PTSD), and suicidal behaviour. Meta-analyses examined associations between these disorders and violence, alcohol/drug use, condom use, and HIV/sexually transmitted infection (STI). A total of 1,046 studies were identified, and 68 papers reporting on 56 unique studies were eligible for inclusion. These were geographically diverse (26 countries), representing all LMIC regions, and included 24,940 participants. All studies were cross-sectional and used a range of measurement tools; none reported a mental health intervention. Of the 56 studies, 14 scored as strong quality, 34 scored as moderate, and 8 scored as weak. The average age of participants was 28.9 years (age range: 11-64 years), with just under half (46%) having up to primary education or less. The pooled prevalence rates for mental disorders among FSWs in LMICs were as follows: depression 41.8% (95% CI 35.8%-48.0%), anxiety 21.0% (95% CI: 4.8%-58.4%), PTSD 19.7% (95% CI 3.2%-64.6%), psychological distress 40.8% (95% CI 20.7%-64.4%), recent suicide ideation 22.8% (95% CI 13.2%-36.5%), and recent suicide attempt 6.3% (95% CI 3.4%-11.4%). Meta-analyses found significant associations between violence experience and depression, violence experience and recent suicidal behaviour, alcohol use and recent suicidal behaviour, illicit drug use and depression, depression and inconsistent condom use with clients, and depression and HIV infection. Key study limitations include a paucity of longitudinal studies (necessary to assess causality), non-random sampling of participants by many studies, and the use of different measurement tools and cut-off scores to measure mental health problems and other common risk factors.Conclusions: In this study, we found that mental health problems are highly prevalent among FSWs in LMICs and are strongly associated with common risk factors. Study findings support the concept of overlapping vulnerabilities and highlight the urgent need for interventions designed to improve the mental health and well-being of FSWs. [ABSTRACT FROM AUTHOR]

Introduction: Inequalities in maternal and newborn health persist in many high-income countries, including for women of refugee background. The Bridging the Gap partnership programme in Victoria, Australia, was designed to find new ways to improve the responsiveness of universal maternity and early child health services for women and families of refugee background with the codesign and implementation of iterative quality improvement and demonstration initiatives. One goal of this 'whole-of-system' approach was to improve access to antenatal care. The objective of this paper is to report refugee women's access to hospital-based antenatal care over the period of health system reforms. Methods and findings: The study was designed using an interrupted time series analysis using routinely collected data from two hospital networks (four maternity hospitals) at 6-month intervals during reform activity (January 2014 to December 2016). The sample included women of refugee background and a comparison group of Australian-born women giving birth over the 3 years. We describe the proportions of women of refugee background (1) attending seven or more antenatal visits and (2) attending their first hospital visit at less than 16 weeks' gestation compared over time and to Australian-born women using logistic regression analyses. In total, 10% of births at participating hospitals were to women of refugee background. Refugee women were born in over 35 countries, and at one participating hospital, 40% required an interpreter. Compared with Australian-born women, women of refugee background were of similar age at the time of birth and were more likely to be having their second or subsequent baby and have four or more children. At baseline, 60% of refugee-background women and Australian-born women attended seven or more antenatal visits. Similar trends of improvement over the 6-month time intervals were observed for both populations, increasing to 80% of women at one hospital network having seven or more visits at the final data collection period and 73% at the other network. In contrast, there was a steady decrease in the proportion of women having their first hospital visit at less than 16 weeks' gestation, which was most marked for women of refugee background. Using an interrupted time series of observational data over the period of improvement is limited compared with using a randomisation design, which was not feasible in this setting. Conclusions: Accurate ascertainment of 'harder-to-reach' populations and ongoing monitoring of quality improvement initiatives are essential to understand the impact of system reforms. Our findings suggest that improvement in total antenatal visits may have been at the expense of recommended access to public hospital antenatal care within 16 weeks of gestation. Jane Yelland and colleagues report refugee women's access to antenatal services in Australia during a period of health systems reform. Author summary: Why was the study done?: Women of refugee background have rates of stillbirth and perinatal mortality two to three times higher than Australian-born women. Antenatal care is a key preventive strategy for the optimal health of pregnant women and newborn babies and is critical to addressing modifiable factors for poor health outcomes. Refugee women experience barriers in accessing and engaging in antenatal care, and healthcare providers report challenges in responding to the social context and needs of refugee families. What did the researchers do and find?: We codesigned and implemented multiple quality improvement and demonstration initiatives in universal health services, including four maternity hospitals. We used an interrupted time series design to assess the timing and number of antenatal clinical visits for refugee women compared with Australian-born women over 3 years of reform. Applying a method devised by the partnership, we identified from routinely collected data that 10% of all women giving birth at the participating hospitals were of refugee background. There was an increase over time in the proportion of refugee and Australian-born women attending the standard number of visits, with women of refugee background commencing hospital antenatal care well past the recommended gestation. What do these findings mean?: For women of refugee background, delayed access to hospital-based care increases the likelihood of missing out on critical elements of pregnancy care vital to optimising maternal and child outcomes. Accurate ascertainment of this 'harder-to-reach' population is essential to evaluating the impact of quality improvement initiatives on refugee families' access to healthcare. An interrupted time series design with a comparison group is suited to measuring change in number and timing of antenatal visits, although data quality, contextual influences, and qualitative insights into system change are important for interpreting outcomes. Ongoing monitoring of quality improvement initiatives on populations vulnerable to poor health outcomes is essential to understand the impact of system reforms and efforts to reduce inequalities. [ABSTRACT FROM AUTHOR]

Background: The large increase in numbers of refugees and asylum seekers in Germany and most of Europe has put the issue of migration itself, the integration of migrants, and also their health at the top of the political agenda. However, the dynamics of refugee health are not yet well understood. From a life-course perspective, migration experience is associated with various risks and changes, which might differ depending on the socioeconomic status (SES) of refugees in their home country. The aim of this paper was to analyze the relationship between pre-migration SES and self-reported health indicators after migration among Syrian refugees. Specifically, we wanted to find out how their SES affects the change in health satisfaction from pre- to post-migration.Methods and Findings: We used data from the 2016 refugee survey, which was part of the German Socio-Economic Panel (GSOEP). Although cross-sectional by design, this survey collected information referring to the current situation as a refugee in Germany as well as to their situation before migration. Using a sample of 2,209 adult Syrian refugees who had entered Germany between 2013 and 2016, we conducted a cross-sectional and a quasi-longitudinal (retrospective) analysis. The mean ± SD age was 35 ± 11 years, with 64% of the participants being male. Our results showed a positive association between pre-migration self-reported SES and several subjective health indicators (e.g., health satisfaction, self-reported health, mental health) in the cross-sectional analysis. However, the quasi-longitudinal analysis revealed that the socioeconomic gradient in health satisfaction before migration was strongly attenuated after migration (SES-by-time interaction: -0.48, 95% CI -0.61 to -0.35, p < 0.001; unstandardized regression coefficients, 5-point SES scale and 11-point health outcome scale). Similar results were produced after controlling for sociodemographic characteristics, experiences during the migration passage, and the current situation in Germany. A sex-stratified analysis showed that while there was some improvement in health satisfaction among men from the lowest SES over time, no improvement was found among women. A limitation of this study is that it considers only the first months or years after migration. Thus, we cannot preclude that the socioeconomic gradient regains importance in the longer run.Conclusions: Our findings suggest that the pre-migration socioeconomic gradient in health satisfaction is strongly attenuated in the first years after migration among Syrian refugees. Hence, a high SES before crisis and migration provides limited protection against the adverse health effects of migration passage. [ABSTRACT FROM AUTHOR]

Background: Strengthening Evidence base on scHool-based intErventions for pRomoting adolescent health (SEHER) is a multicomponent, whole-school health promotion intervention delivered by a lay counsellor or a teacher in government-run secondary schools in Bihar, India. The objective of this study is to examine the effects of the intervention after two years of follow-up and to evaluate the consistency of the findings observed over time.Methods and Findings: We conducted a cluster randomised trial in which 75 schools were randomised (1:1:1) to receive the SEHER intervention delivered by a lay counsellor (SEHER Mitra [SM]) or a teacher (Teacher as SEHER Mitra [TSM]), respectively, alongside a standardised, classroom-based life skills Adolescence Education Program (AEP), compared to AEP alone (control group). The trial design was a repeat cross-sectional study. Students enrolled in grade 9 (aged 13-15 years) in the 2015-2016 academic year were exposed to the intervention for two years and the outcome assessment was conducted at three time points─at baseline in June 2015; 8-months follow-up in March 2016, when the students were still in grade 9; and endpoint at 17-months follow-up in December 2016 (when the students were in grade 10), the results of which are presented in this paper. The primary outcome, school climate, was measured with the Beyond Blue School Climate Questionnaire (BBSCQ). Intervention effects were estimated using mixed-effects linear or logistic regression, including a random effect to adjust for within-school clustering, minimisation variables, baseline cluster-level score of the outcome, and sociodemographic characteristics. In total, 15,232 students participated in the 17-month survey. Compared with the control group, the participants in the SM intervention group reported improvements in school climate (adjusted mean difference [aMD] = 7.33; 95% CI: 6.60-8.06; p < 0.001) and most secondary outcomes (depression: aMD = -4.64; 95% CI: -5.83-3.45; p < 0.001; attitude towards gender equity: aMD = 1.02; 95% CI: 0.65-1.40; p < 0.001; frequency of bullying: aMD = -2.77; 95% CI: -3.40 to -2.14; p < 0.001; violence victimisation: odds ratio [OR] = 0.08; 95% CI: 0.04-0.14; p < 0.001; and violence perpetration: OR = 0.16; 95% CI: 0.09-0.29; p < 0.001). There was no evidence of an intervention effect in the TSM group compared with control group. The effects of the lay counsellor-delivered intervention were larger for most outcomes at 17-months follow-up compared with those at 8 months: school climate (effect size [ES; 95% CI] = 2.23 [1.97-2.50] versus 1.88 [1.44-2.32], p < 0.001); depression (ES [95% CI] = -1.19 [-1.56 to -0.82] versus -0.27 [-0.44 to -0.11], p < 0.001); attitude towards gender equity (ES [95% CI] = 0.53 [0.27-0.79] versus 0.23 [0.10-0.36], p < 0.001); bullying (ES [95% CI] = -2.22 [-2.84 to -1.60] versus -0.47 [-0.61 to -0.33], p < 0.001); violence victimisation (OR [95% CI] = 0.08 [0.04-0.14] versus 0.62 [0.46-0.84], p < 0.001); and violence perpetration (OR [95% CI] = 0.16 [0.09-0.29] versus 0.68 [0.48-0.96], p < 0.001), suggesting incremental benefits with an extended intervention. A limitation of the study is that 27% of baseline participants did not complete the 17-month outcome assessment.Conclusions: The trial showed that the second-year outcomes were similar to the first-year outcomes, with no effect of the teacher-led intervention and larger benefits on school climate and adolescent health accruing from extending lay counsellor-delivered intervention.Trial Registration: ClinicalTrials.gov NCT02907125. [ABSTRACT FROM AUTHOR]

Background: In low-resource settings where disease burdens remain high and many health facilities lack essentials such as drugs or commodities, functional equipment, and trained personnel, poor quality of care often results and the impact can be profound. In this paper, we systematically quantify the potential gain of addressing quality of care globally using country-level data about antenatal, childbirth, and postnatal care interventions.Methods and Findings: In this study, we created deterministic models to project health outcomes if quality of care was addressed in a representative sample of 81 low- and middle-income countries (LMICs). First, available data from health facility surveys (e.g., Service Provision Assessment [SPA] and Service Availability and Readiness Assessment [SARA]) conducted 2007-2016 were linked to household surveys (e.g., Demographic and Health Surveys [DHS] and Multiple Indicator Cluster Surveys [MICS]) to estimate baseline coverage for a core subset of 19 maternal and newborn health interventions. Next, models were constructed with the Lives Saved Tool (LiST) using country-specific baseline levels in countries with a linked dataset (n = 17) and sample medians applied as a proxy in countries without linked data. Lastly, these 2016 starting baseline levels were raised to reach targets in 2020 as endline based upon country-specific utilization (e.g., proportion of women who attended 4+ antenatal visits, percentage of births delivered in a health facility) from the latest DHS or MICS population-based reports. Our findings indicate that if high-quality health systems could effectively deliver this subset of evidence-based interventions to mothers and their newborns who are already seeking care, there would be an estimated 28% decrease in maternal deaths, 28% decrease in neonatal deaths, and 22% fewer stillbirths compared to a scenario without any change or improvement in quality of care. Totals of 86,000 (range, 77,800-92,400) maternal and 0.67 million (range, 0.59 million-0.75 million) neonatal lives could be saved, and 0.52 million (range, 0.48 million-0.55 million) stillbirths could be prevented across the 81 countries in the calendar year 2020 when adequate quality care is provided at current levels of utilization. Limitations include the paucity of data to individually assess quality of care for each intervention in all LMICs and the necessary assumption that quality of care being provided among the subset of countries with linked datasets is comparable or representative of LMICs overall.Conclusions: Our findings suggest that efforts to close the quality gap would still produce substantial benefits at current levels of access or utilization. With estimated mortality rate declines of 21%-32% on average, gains from this first step would be significant if quality was improved for selected antenatal, intrapartum, and postnatal interventions to benefit pregnant women and newborns seeking care. Interventions provided at or around the time of childbirth are most critical and accounted for 64% of the impact overall estimated in this quality improvement analysis. [ABSTRACT FROM AUTHOR]

Background: Improving oxygen systems may improve clinical outcomes for hospitalised children with acute lower respiratory infection (ALRI). This paper reports the effects of an improved oxygen system on mortality and clinical practices in 12 general, paediatric, and maternity hospitals in southwest Nigeria.Methods and Findings: We conducted an unblinded stepped-wedge cluster-randomised trial comparing three study periods: baseline (usual care), pulse oximetry introduction, and stepped introduction of a multifaceted oxygen system. We collected data from clinical records of all admitted neonates (<28 days old) and children (28 days to 14 years old). Primary analysis compared the full oxygen system period to the pulse oximetry period and evaluated odds of death for children, children with ALRI, neonates, and preterm neonates using mixed-effects logistic regression. Secondary analyses included the baseline period (enabling evaluation of pulse oximetry introduction) and evaluated mortality and practice outcomes on additional subgroups. Three hospitals received the oxygen system intervention at 4-month intervals. Primary analysis included 7,716 neonates and 17,143 children admitted during the 2-year stepped crossover period (November 2015 to October 2017). Compared to the pulse oximetry period, the full oxygen system had no association with death for children (adjusted odds ratio [aOR] 1.06; 95% confidence interval [CI] 0.77-1.46; p = 0.721) or children with ALRI (aOR 1.09; 95% CI 0.50-2.41; p = 0.824) and was associated with an increased risk of death for neonates overall (aOR 1.45; 95% CI 1.04-2.00; p = 0.026) but not preterm/low-birth-weight neonates (aOR 1.30; 95% CI 0.76-2.23; p = 0.366). Secondary analyses suggested that the introduction of pulse oximetry improved oxygen practices prior to implementation of the full oxygen system and was associated with lower odds of death for children with ALRI (aOR 0.33; 95% CI 0.12-0.92; p = 0.035) but not for children, preterm neonates, or neonates overall (aOR 0.97, 95% CI 0.60-1.58, p = 0.913; aOR 1.12, 95% CI 0.56-2.26, p = 0.762; aOR 0.90, 95% CI 0.57-1.43, p = 0.651). Limitations of our study are a lower-than-anticipated power to detect change in mortality outcomes (low event rates, low participant numbers, high intracluster correlation) and major contextual changes related to the 2016-2017 Nigerian economic recession that influenced care-seeking and hospital function during the study period, potentially confounding mortality outcomes.Conclusions: We observed no mortality benefit for children and a possible higher risk of neonatal death following the introduction of a multifaceted oxygen system compared to introducing pulse oximetry alone. Where some oxygen is available, pulse oximetry may improve oxygen usage and clinical outcomes for children with ALRI.Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12617000341325. [ABSTRACT FROM AUTHOR]

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

Background: Globally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved infant and young child feeding (IYCF) on early child development (ECD) among children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe.Methods and Findings: SHINE was a cluster-randomized community-based 2×2 factorial trial. A total of 5,280 pregnant women were enrolled from 211 clusters (defined as the catchment area of 1-4 village health workers [VHWs] employed by the Zimbabwean Ministry of Health and Child Care). Clusters were randomly allocated to standard of care, IYCF (20 g of small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counseling), WASH (ventilated improved pit latrine, handwashing stations, chlorine, liquid soap, and play yard), and WASH + IYCF. Primary outcomes were child length-for-age Z-score and hemoglobin concentration at 18 months of age. Children who completed the 18-month visit and turned 2 years (102-112 weeks) between March 1, 2016, and April 30, 2017, were eligible for the ECD substudy. We prespecified that primary inferences would be drawn from findings of children born to HIV-negative mothers; these results are presented in this paper. A total of 1,655 HIV-unexposed children (64% of those eligible) were recruited into the ECD substudy from 206 clusters and evaluated for ECD at 2 years of age using the Malawi Developmental Assessment Tool (MDAT) to assess gross motor, fine motor, language, and social skills; the MacArthur-Bates Communicative Development Inventories (CDI) to assess vocabulary and grammar; the A-not-B test to assess object permanence; and a self-control task. Outcomes were analyzed in the intention-to-treat population. For all ECD outcomes, there was not a statistical interaction between the IYCF and WASH interventions, so we estimated the effects of the interventions by comparing the 2 IYCF groups with the 2 non-IYCF groups and the 2 WASH groups with the 2 non-WASH groups. The mean (95% CI) total MDAT score was modestly higher in the IYCF groups compared to the non-IYCF groups in unadjusted analysis: 1.35 (0.24, 2.46; p = 0.017); this difference did not persist in adjusted analysis: 0.79 (-0.22, 1.68; p = 0.057). There was no evidence of impact of the IYCF intervention on the CDI, A-not-B, or self-control tests. Among children in the WASH groups compared to those in the non-WASH groups, mean scores were not different for the MDAT, A-not-B, or self-control tests; mean CDI score was not different in unadjusted analysis (0.99 [95% CI -1.18, 3.17]) but was higher in children in the WASH groups in adjusted analysis (1.81 [0.01, 3.61]). The main limitation of the study was the specific time window for substudy recruitment, meaning not all children from the main trial were enrolled.Conclusions: We found little evidence that the IYCF and WASH interventions implemented in SHINE caused clinically important improvements in child development at 2 years of age. Interventions that directly target neurodevelopment (e.g., early stimulation) or that more comprehensively address the multifactorial nature of neurodevelopment may be required to support healthy development of vulnerable children.Trial Registration: ClinicalTrials.gov NCT01824940. [ABSTRACT FROM AUTHOR]

Background: Globally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved infant and young child feeding (IYCF) on early child development (ECD) among children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. Methods and findings: SHINE was a cluster-randomized community-based 2×2 factorial trial. A total of 5,280 pregnant women were enrolled from 211 clusters (defined as the catchment area of 1–4 village health workers [VHWs] employed by the Zimbabwean Ministry of Health and Child Care). Clusters were randomly allocated to standard of care, IYCF (20 g of small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counseling), WASH (ventilated improved pit latrine, handwashing stations, chlorine, liquid soap, and play yard), and WASH + IYCF. Primary outcomes were child length-for-age Z-score and hemoglobin concentration at 18 months of age. Children who completed the 18-month visit and turned 2 years (102–112 weeks) between March 1, 2016, and April 30, 2017, were eligible for the ECD substudy. We prespecified that primary inferences would be drawn from findings of children born to HIV-negative mothers; these results are presented in this paper. A total of 1,655 HIV-unexposed children (64% of those eligible) were recruited into the ECD substudy from 206 clusters and evaluated for ECD at 2 years of age using the Malawi Developmental Assessment Tool (MDAT) to assess gross motor, fine motor, language, and social skills; the MacArthur–Bates Communicative Development Inventories (CDI) to assess vocabulary and grammar; the A-not-B test to assess object permanence; and a self-control task. Outcomes were analyzed in the intention-to-treat population. For all ECD outcomes, there was not a statistical interaction between the IYCF and WASH interventions, so we estimated the effects of the interventions by comparing the 2 IYCF groups with the 2 non-IYCF groups and the 2 WASH groups with the 2 non-WASH groups. The mean (95% CI) total MDAT score was modestly higher in the IYCF groups compared to the non-IYCF groups in unadjusted analysis: 1.35 (0.24, 2.46; p = 0.017); this difference did not persist in adjusted analysis: 0.79 (−0.22, 1.68; p = 0.057). There was no evidence of impact of the IYCF intervention on the CDI, A-not-B, or self-control tests. Among children in the WASH groups compared to those in the non-WASH groups, mean scores were not different for the MDAT, A-not-B, or self-control tests; mean CDI score was not different in unadjusted analysis (0.99 [95% CI −1.18, 3.17]) but was higher in children in the WASH groups in adjusted analysis (1.81 [0.01, 3.61]). The main limitation of the study was the specific time window for substudy recruitment, meaning not all children from the main trial were enrolled. Conclusions: We found little evidence that the IYCF and WASH interventions implemented in SHINE caused clinically important improvements in child development at 2 years of age. Interventions that directly target neurodevelopment (e.g., early stimulation) or that more comprehensively address the multifactorial nature of neurodevelopment may be required to support healthy development of vulnerable children. Trial registration: ClinicalTrials.gov NCT01824940 In this substudy from a 2x2 factorial cluster-randomized trial, Melissa Gladstone and colleagues assess whether improved WASH and/or feeding provide a benefit to early child development. Author summary: Why was this study done?: Some 43% of children globally fail to reach their full developmental potential due to stunting and poverty. Current evidence shows that improved nutrition has a modest effect on early child development. Improving water, sanitation, and hygiene (WASH) may plausibly benefit neurodevelopment through reduced illness and improved gut health (through improving nutrient absorption and optimizing gut–brain communication). What did the researchers do and find?: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial tested the individual and combined effects of improved complementary feeding (provision of a small quantity of lipid-based nutrient supplement from 6 to 18 months of age, with complementary feeding counseling) and improved household WASH (provision of a pit latrine, handwashing stations, soap, chlorine, and hygiene counseling) on early child development at 24 months. In all, 1,655 children born to HIV-negative women were assessed for gross motor, fine motor, language, cognitive, and social development using tools that were designed and adapted for rural Zimbabwe. We found little evidence that the complementary feeding or WASH interventions tested improved child neurodevelopment at 2 years of age. What do these findings mean?: Complementary feeding and WASH interventions (as described above) may not have a clinically significant impact on child neurodevelopment. More holistic approaches and interventions that explicitly target early child development may be needed to substantially impact child neurodevelopment. [ABSTRACT FROM AUTHOR]

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

Background: Tobacco industry interference has been identified as the greatest obstacle to the implementation of evidence-based measures to reduce tobacco use. Understanding and addressing industry interference in public health policy-making is therefore crucial. Existing conceptualisations of corporate political activity (CPA) are embedded in a business perspective and do not attend to CPA's social and public health costs; most have not drawn on the unique resource represented by internal tobacco industry documents. Building on this literature, including systematic reviews, we develop a critically informed conceptual model of tobacco industry political activity.Methods and Findings: We thematically analysed published papers included in two systematic reviews examining tobacco industry influence on taxation and marketing of tobacco; we included 45 of 46 papers in the former category and 20 of 48 papers in the latter (n = 65). We used a grounded theory approach to build taxonomies of "discursive" (argument-based) and "instrumental" (action-based) industry strategies and from these devised the Policy Dystopia Model, which shows that the industry, working through different constituencies, constructs a metanarrative to argue that proposed policies will lead to a dysfunctional future of policy failure and widely dispersed adverse social and economic consequences. Simultaneously, it uses diverse, interlocking insider and outsider instrumental strategies to disseminate this narrative and enhance its persuasiveness in order to secure its preferred policy outcomes. Limitations are that many papers were historical (some dating back to the 1970s) and focused on high-income regions.Conclusions: The model provides an evidence-based, accessible way of understanding diverse corporate political strategies. It should enable public health actors and officials to preempt these strategies and develop realistic assessments of the industry's claims. [ABSTRACT FROM AUTHOR]

Background: 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: Type 2 diabetes (T2D) is a heterogeneous disease for which (1) disease-causing pathways are incompletely understood and (2) subclassification may improve patient management. Unlike other biomarkers, germline genetic markers do not change with disease progression or treatment. In this paper, we test whether a germline genetic approach informed by physiology can be used to deconstruct T2D heterogeneity. First, we aimed to categorize genetic loci into groups representing likely disease mechanistic pathways. Second, we asked whether the novel clusters of genetic loci we identified have any broad clinical consequence, as assessed in four separate subsets of individuals with T2D.Methods and Findings: In an effort to identify mechanistic pathways driven by established T2D genetic loci, we applied Bayesian nonnegative matrix factorization (bNMF) clustering to genome-wide association study (GWAS) results for 94 independent T2D genetic variants and 47 diabetes-related traits. We identified five robust clusters of T2D loci and traits, each with distinct tissue-specific enhancer enrichment based on analysis of epigenomic data from 28 cell types. Two clusters contained variant-trait associations indicative of reduced beta cell function, differing from each other by high versus low proinsulin levels. The three other clusters displayed features of insulin resistance: obesity mediated (high body mass index [BMI] and waist circumference [WC]), "lipodystrophy-like" fat distribution (low BMI, adiponectin, and high-density lipoprotein [HDL] cholesterol, and high triglycerides), and disrupted liver lipid metabolism (low triglycerides). Increased cluster genetic risk scores were associated with distinct clinical outcomes, including increased blood pressure, coronary artery disease (CAD), and stroke. We evaluated the potential for clinical impact of these clusters in four studies containing individuals with T2D (Metabolic Syndrome in Men Study [METSIM], N = 487; Ashkenazi, N = 509; Partners Biobank, N = 2,065; UK Biobank [UKBB], N = 14,813). Individuals with T2D in the top genetic risk score decile for each cluster reproducibly exhibited the predicted cluster-associated phenotypes, with approximately 30% of all individuals assigned to just one cluster top decile. Limitations of this study include that the genetic variants used in the cluster analysis were restricted to those associated with T2D in populations of European ancestry.Conclusion: Our approach identifies salient T2D genetically anchored and physiologically informed pathways, and supports the use of genetics to deconstruct T2D heterogeneity. Classification of patients by these genetic pathways may offer a step toward genetically informed T2D patient management. [ABSTRACT FROM AUTHOR]

This paper summarises key advances in defining the infectious reservoir for malaria and the measurement of transmission for research and programmatic use since the Malaria Eradication Research Agenda (malERA) publication in 2011. Rapid and effective progress towards elimination requires an improved understanding of the sources of transmission as well as those at risk of infection. Characterising the transmission reservoir in different settings will enable the most appropriate choice, delivery, and evaluation of interventions. Since 2011, progress has been made in a number of areas. The extent of submicroscopic and asymptomatic infections is better understood, as are the biological parameters governing transmission of sexual stage parasites. Limitations of existing transmission measures have been documented, and proof-of-concept has been established for new innovative serological and molecular methods to better characterise transmission. Finally, there now exists a concerted effort towards the use of ensemble datasets across the spectrum of metrics, from passive and active sources, to develop more accurate risk maps of transmission. These can be used to better target interventions and effectively monitor progress toward elimination. The success of interventions depends not only on the level of endemicity but also on how rapidly or recently an area has undergone changes in transmission. Improved understanding of the biology of mosquito-human and human-mosquito transmission is needed particularly in low-endemic settings, where heterogeneity of infection is pronounced and local vector ecology is variable. New and improved measures of transmission need to be operationally feasible for the malaria programmes. Outputs from these research priorities should allow the development of a set of approaches (applicable to both research and control programmes) that address the unique challenges of measuring and monitoring transmission in near-elimination settings and defining the absence of transmission. [ABSTRACT FROM AUTHOR]

Resistance to first-line treatments for Plasmodium falciparum malaria and the insecticides used for Anopheles vector control are threatening malaria elimination efforts. Suboptimal responses to drugs and insecticides are both spreading geographically and emerging independently and are being seen at increasing intensities. Whilst resistance is unavoidable, its effects can be mitigated through resistance management practices, such as exposing the parasite or vector to more than one selective agent. Resistance contributed to the failure of the 20th century Global Malaria Eradication Programme, and yet the global response to this issue continues to be slow and poorly coordinated-too often, too little, too late. The Malaria Eradication Research Agenda (malERA) Refresh process convened a panel on resistance of both insecticides and antimalarial drugs. This paper outlines developments in the field over the past 5 years, highlights gaps in knowledge, and proposes a research agenda focused on managing resistance. A deeper understanding of the complex biological processes involved and how resistance is selected is needed, together with evidence of its public health impact. Resistance management will require improved use of entomological and parasitological data in decision making, and optimisation of the useful life of new and existing products through careful implementation, combination, and evaluation. A proactive, collaborative approach is needed from basic science and the development of new tools to programme and policy interventions that will ensure that the armamentarium of drugs and insecticides is sufficient to deal with the challenges of malaria control and its elimination. [ABSTRACT FROM AUTHOR]

This paper summarises key advances and priorities since the 2011 presentation of the Malaria Eradication Research Agenda (malERA), with a focus on the combinations of intervention tools and strategies for elimination and their evaluation using modelling approaches. With an increasing number of countries embarking on malaria elimination programmes, national and local decisions to select combinations of tools and deployment strategies directed at malaria elimination must address rapidly changing transmission patterns across diverse geographic areas. However, not all of these approaches can be systematically evaluated in the field. Thus, there is potential for modelling to investigate appropriate 'packages' of combined interventions that include various forms of vector control, case management, surveillance, and population-based approaches for different settings, particularly at lower transmission levels. Modelling can help prioritise which intervention packages should be tested in field studies, suggest which intervention package should be used at a particular level or stratum of transmission intensity, estimate the risk of resurgence when scaling down specific interventions after local transmission is interrupted, and evaluate the risk and impact of parasite drug resistance and vector insecticide resistance. However, modelling intervention package deployment against a heterogeneous transmission background is a challenge. Further validation of malaria models should be pursued through an iterative process, whereby field data collected with the deployment of intervention packages is used to refine models and make them progressively more relevant for assessing and predicting elimination outcomes. [ABSTRACT FROM AUTHOR]

Health systems underpin disease elimination and eradication programmes. In an elimination and eradication context, innovative research approaches are needed across health systems to assess readiness for programme reorientation, mitigate any decreases in effectiveness of interventions ('effectiveness decay'), and respond to dynamic and changing needs. The malaria eradication research agenda (malERA) Refresh consultative process for the Panel on Health Systems and Policy Research identifies opportunities to build health systems evidence and the tools needed to eliminate malaria from different zones, countries, and regions and to eradicate it globally. The research questions are organised as a portfolio that global health practitioners, researchers, and funders can identify with and support. This supports the promotion of an actionable and more cohesive approach to building the evidence base for scaled-up implementation of findings. Gaps and opportunities discussed in the paper include delivery strategies to meet the changing dynamics of needs of individuals, environments, and malaria programme successes; mechanisms and approaches to best support accelerated policy and financial responsiveness at national and global level to ensure timely response to evidence and needs, including in crisis situations; and systems' readiness tools and decision-support systems. [ABSTRACT FROM AUTHOR]

Since the turn of the century, a remarkable expansion has been achieved in the range and effectiveness of products and strategies available to prevent, treat, and control malaria, including advances in diagnostics, drugs, vaccines, and vector control. These advances have once again put malaria elimination on the agenda. However, it is clear that even with the means available today, malaria control and elimination pose a formidable challenge in many settings. Thus, currently available resources must be used more effectively, and new products and approaches likely to achieve these goals must be developed. This paper considers tools (both those available and others that may be required) to achieve and maintain malaria elimination. New diagnostics are needed to direct treatment and detect transmission potential; new drugs and vaccines to overcome existing resistance and protect against clinical and severe disease, as well as block transmission and prevent relapses; and new vector control measures to overcome insecticide resistance and more powerfully interrupt transmission. It is also essential that strategies for combining new and existing approaches are developed for different settings to maximise their longevity and effectiveness in areas with continuing transmission and receptivity. For areas where local elimination has been recently achieved, understanding which measures are needed to maintain elimination is necessary to prevent rebound and the reestablishment of transmission. This becomes increasingly important as more countries move towards elimination. [ABSTRACT FROM AUTHOR]

Background: Operational research is required to design delivery of pre-exposure prophylaxis (PrEP) and early antiretroviral treatment (ART). This paper presents the primary analysis of programmatic data, as well as demographic, behavioural, and clinical data, from the TAPS Demonstration Project, which offered both interventions to female sex workers (FSWs) at 2 urban clinic sites in South Africa.Methods and Findings: The TAPS study was conducted between 30 March 2015 and 30 June 2017, with the enrolment period ending on 31 July 2016. TAPS was a prospective observational cohort study with 2 groups receiving interventions delivered in existing service settings: (1) PrEP as part of combination prevention for HIV-negative FSWs and (2) early ART for HIV-positive FSWs. The main outcome was programme retention at 12 months of follow-up. Of the 947 FSWs initially seen in clinic, 692 were HIV tested. HIV prevalence was 49%. Among those returning to clinic after HIV testing and clinical screening, 93% of the women who were HIV-negative were confirmed as clinically eligible for PrEP (n = 224/241), and 41% (n = 110/270) of the women who were HIV-positive had CD4 counts within National Department of Health ART initiation guidelines at assessment. Of the remaining women who were HIV-positive, 93% were eligible for early ART (n = 148/160). From those eligible, 98% (n = 219/224) and 94% (n = 139/148) took up PrEP and early ART, respectively. At baseline, a substantial fraction of women had a steady partner, worked in brothels, and were born in Zimbabwe. Of those enrolled, 22% on PrEP (n = 49/219) and 60% on early ART (n = 83/139) were seen at 12 months; we observed high rates of loss to follow-up: 71% (n = 156/219) and 30% (n = 42/139) in the PrEP and early ART groups, respectively. Little change over time was reported in consistent condom use or the number of sexual partners in the last 7 days, with high levels of consistent condom use with clients and low use with steady partners in both study groups. There were no seroconversions on PrEP and 7 virological failures on early ART among women remaining in the study. Reported adherence to PrEP varied over time between 70% and 85%, whereas over 90% of participants reported taking pills daily while on early ART. Data on provider-side costs were also collected and analysed. The total cost of service delivery was approximately US$126 for PrEP and US$406 for early ART per person-year. The main limitations of this study include the lack of a control group, which was not included due to ethical considerations; clinical study requirements imposed when PrEP was not approved through the regulatory system, which could have affected uptake; and the timing of the implementation of a national sex worker HIV programme, which could have also affected uptake and retention.Conclusions: PrEP and early ART services can be implemented within FSW routine services in high prevalence, urban settings. We observed good uptake for both PrEP and early ART; however, retention rates for PrEP were low. Retention rates for early ART were similar to retention rates for the current standard of care. While the cost of the interventions was higher than previously published, there is potential for cost reduction at scale. The TAPS Demonstration Project results provided the basis for the first government PrEP and early ART guidelines and the rollout of the national sex worker HIV programme in South Africa. [ABSTRACT FROM AUTHOR]

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

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

Background: Reductions in smoking in Arizona and California have been shown to be associated with reduced per capita healthcare expenditures in these states compared to control populations in the rest of the US. This paper extends that analysis to all states and estimates changes in healthcare expenditure attributable to changes in aggregate measures of smoking behavior in all states.Methods and Findings: State per capita healthcare expenditure is modeled as a function of current smoking prevalence, mean cigarette consumption per smoker, other demographic and economic factors, and cross-sectional time trends using a fixed effects panel data regression on annual time series data for each the 50 states and the District of Columbia for the years 1992 through 2009. We found that 1% relative reductions in current smoking prevalence and mean packs smoked per current smoker are associated with 0.118% (standard error [SE] 0.0259%, p < 0.001) and 0.108% (SE 0.0253%, p < 0.001) reductions in per capita healthcare expenditure (elasticities). The results of this study are subject to the limitations of analysis of aggregate observational data, particularly that a study of this nature that uses aggregate data and a relatively small sample size cannot, by itself, establish a causal connection between smoking behavior and healthcare costs. Historical regional variations in smoking behavior (including those due to the effects of state tobacco control programs, smoking restrictions, and differences in taxation) are associated with substantial differences in per capita healthcare expenditures across the United States. Those regions (and the states in them) that have lower smoking have substantially lower medical costs. Likewise, those that have higher smoking have higher medical costs. Sensitivity analysis confirmed that these results are robust.Conclusions: Changes in healthcare expenditure appear quickly after changes in smoking behavior. A 10% relative drop in smoking in every state is predicted to be followed by an expected $63 billion reduction (in 2012 US dollars) in healthcare expenditure the next year. State and national policies that reduce smoking should be part of short term healthcare cost containment. [ABSTRACT FROM AUTHOR]