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Author(s): The PLOS Medicine Editors * The editors of PLOS Medicine together with Guest Editors Vikram Patel, Daisy Fancourt, Toshi A Furukawa, and Lola Kola are excited to announce a [...]

Author(s): The PLOS Medicine Editors * The editors of PLOS Medicine , together with guest editors Timothy Walsh, Ramanan Laxminarayan and Ana Cristina Gales, announce a forthcoming Special Issue dedicated [...]

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: 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: 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: The consumption of sugar-sweetened beverages (SSBs) is associated with obesity, metabolic diseases, and incremental healthcare costs. Given their health consequences, the World Health Organization (WHO) recommended that countries implement taxes on SSB. Over the last 10 years, obesity prevalence has almost doubled in Brazil, yet, in 2016, the Brazilian government cut the existing federal SSB taxes to their current 4%. Since 2022, a bill to impose a 20% tax on SSB has been under discussion in the Brazilian Senate. To simulate the potential impact of increasing taxes on SSB in Brazil, we aimed to estimate the price-elasticity of SSB and the potential impact of a new 20% or 30% excise SSB tax on consumption, obesity prevalence, and cost savings. Methods and findings: Using household purchases data from the Brazilian Household Budget Survey (POF) from 2017/2018, we estimated constant elasticity regressions. We used a log-log specification by income level for all beverage categories: (1) sugar-sweetened beverages; (2) alcoholic beverages; (3) unsweetened beverages; and (4) low-calorie or artificially sweetened beverages. We estimated the adult nationwide baseline intake for each beverage category using 24-h dietary recall data collected in 2017/2018. Taking group one as the taxed beverages, we applied the price and cross-price elasticities to the baseline intake data, we obtained changes in caloric intake. The caloric reduction was introduced into an individual dynamic model to estimate changes in weight and obesity prevalence. No benefits on cost savings were modeled during the first 3 years of intervention to account for the time lag in obesity cases to reduce costs. We multiplied the reduction in obesity cases during 7 years by the obesity costs per capita to predict the costs savings attributable to the sweetened beverage tax. SSB price elasticities were higher among the lowest tertile of income (−1.24) than in the highest income tertile (−1.13), and cross-price elasticities suggest SSB were weakly substituted by milk, water, and 100% fruit juices. We estimated a caloric change of −17.3 kcal/day/person under a 20% excise tax and −25.9 kcal/day/person under a 30% tax. Ten years after implementation, a 20% tax is expected to reduce obesity prevalence by 6.7%; 9.1% for a 30% tax. These reductions translate into a −2.8 million and −3.8 million obesity cases for a 20% and 30% tax, respectively, and a reduction of $US 13.3 billion and $US 17.9 billion in obesity costs over 10 years for a 20% and 30% tax, respectively. Study limitations include using a quantile distribution method to adjust self-reported baseline weight and height, which could be insufficient to correct for reporting bias; also, weight, height, and physical activity were assumed to be steady over time. Conclusions: Adding a 20% to 30% excise tax on top of Brazil's current federal tax could help to reduce the consumption of ultra-processed beverages, empty calories, and body weight while avoiding large health-related costs. Given the recent cuts to SSB taxes in Brazil, a program to revise and implement excise taxes could prove beneficial for the Brazilian population. Using the context of the proposed Sugar-Sweetened-Beverages tax in Brazil, Ana Basto-Abreu and colleagues model the estimated reduction in obesity prevalence and savings in health-related costs. Author summary: Why was this study done?: The consumption of sugar-sweetened beverages (SSBs) is associated with obesity, metabolic diseases, and incremental healthcare costs. The World Health Organization (WHO) recommends governments to tax SSB to improve diet and reduce chronic diseases. Since 2022, a bill to impose a 20% tax on SSB is under discussion in the Brazilian Senate. What did the researchers do and find?: We estimated SSB own- and cross-price elasticities by socioeconomic status and simulated the potential effects of introducing a 20% excise tax to SSB in consumption. If a 20% tax is introduced, we would expect a 16.9 kcal/day/person caloric reduction among Brazilian adults. We used an individual dynamic weight change model to translate caloric reductions into obesity reductions. We estimated an expected 6.7% reduction in obesity, which could lead to USD 13.3 billion healthcare cost savings over 10 years. Larger benefits of the tax are expected to be experienced by younger adults and by people from high-income groups. What do these findings mean?: The implementation of the SSB tax is expected to produce important reductions in population weight and obesity prevalence, while saving health-related costs. Limitations of our analysis include assuming no change in weight under the no-intervention scenario and using a quantile distribution method to adjust self-reported baseline weight and height. [ABSTRACT FROM AUTHOR]

Background: The Danish cardiovascular screening (DANCAVAS) trial, a nationwide trial designed to investigate the impact of cardiovascular screening in men, did not decrease all-cause mortality, an outcome decided by the investigators. However, the target group may have varied preferences. In this study, we aimed to evaluate whether men aged 65 to 74 years requested a CT-based cardiovascular screening examination and to assess its impact on outcomes determined by their preferences. Methods and findings: This is a post hoc study of the randomised DANCAVAS trial. All men 65 to 74 years of age residing in specific areas of Denmark were randomised (1:2) to invitation-to-screening (16,736 men, of which 10,471 underwent screening) or usual-care (29,790 men). The examination included among others a non-contrast CT scan (to assess the coronary artery calcium score and aortic aneurysms). Positive findings prompted preventive treatment with atorvastatin, aspirin, and surveillance/surgical evaluation. The usual-care group remained unaware of the trial and the assignments. The user-defined outcome was based on patient preferences and determined through a survey sent in January 2023 to a random sample of 9,095 men from the target group, with a 68.0% response rate (6,182 respondents). Safety outcomes included severe bleeding and mortality within 30 days after cardiovascular surgery. Analyses were performed on an intention-to-screen basis. Prevention of stroke and myocardial infarction was the primary motivation for participating in the screening examination. After a median follow-up of 6.4 years, 1,800 of 16,736 men (10.8%) in the invited-to-screening group and 3,420 of 29,790 (11.5%) in the usual-care group experienced an event (hazard ratio (HR), 0.93 (95% confidence interval (CI), 0.88 to 0.98; p = 0.010); number needed to invite at 6 years, 148 (95% CI, 80 to 986)). A total of 324 men (1.9%) in the invited-to-screening group and 491 (1.7%) in the usual-care group had an intracranial bleeding (HR, 1.17; 95% CI, 1.02 to 1.35; p = 0.029). Additionally, 994 (5.9%) in the invited-to-screening group and 1,722 (5.8%) in the usual-care group experienced severe gastrointestinal bleeding (HR, 1.02; 95% CI, 0.95 to 1.11; p = 0.583). No differences were found in mortality after cardiovascular surgery. The primary limitation of the study is that exclusive enrolment of men aged 65 to 74 renders the findings non-generalisable to women or men of other age groups. Conclusion: In this comprehensive population-based cardiovascular screening and intervention program, we observed a reduction in the user-defined outcome, stroke and myocardial infarction, but entail a small increased risk of intracranial bleeding. Trial registration: ISRCTN Registry number, ISRCTN12157806https://www.isrctn.com/ISRCTN12157806. In this post-hoc analysis of the DANCAVAS trial, Axel Diederichsen and colleagues explore how cardiovascular screening impacts on outcomes as defined by patients themselves. Author summary: Why was this study done?: Stroke and heart attack remain a prevalent cause of decreased quality of life and premature death. Coronary atherosclerosis serves as an important risk modifier and is easily identifiable by cardiac imaging. Despite this, screening for cardiovascular disease by cardiac CT in the Danish cardiovascular screening (DANCAVAS) trial did not lead to a decrease in death from cardiovascular causes. However, it is essential to recognise that patients may have preferences other than death, and these preferences play a critically important role in informed and shared decision-making between caregivers and patients. What did the researchers do and find?: The DANCAVAS trial included men aged 65 to 74 from specific areas of Denmark, with some receiving invitations to screening (16,736 men) and others receiving usual care (29,790 men). Patients with significant atherosclerosis were treated with atorvastatin, aspirin, and underwent surveillance or surgery in case of aneurysms. Here, the study outcomes were determined based on patient preferences, which were assessed through a survey of a random sample of 9,095 men aged 65 to 74. The surveyed men expressed a preference for preventing stroke and heart attack over death. Screening reduced the absolute risk of stroke and heart attack by 0.7%, but it also increased the risk of intracranial haemorrhage by 0.2%. What do these findings mean?: The DANCAVAS trial met patient preferences, but the benefits were modest and accompanied by a slight increase in the risk of intracranial haemorrhage. These data suggest that there is limited benefit to the widespread implementation of cardiovascular screening programmes. The trial specifically targeted men aged 65 to 74, meaning the findings cannot be generalised to women or men outside this age group. Future cardiovascular screening programs should encompass both sexes and accommodate patient preferences. Additionally, they might consider excluding aspirin from the intervention arm. [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]

Background: Women with mental illness experience an increased risk of cervical cancer. The excess risk is partly due to low participation in cervical screening; however, it remains unknown whether it is also attributable to an increased risk of infection with human papillomavirus (HPV). We aimed to examine whether women with mental illness had an increased infection rate of HPV compared to women without mental illness. Methods and findings: Using a cohort design, we analyzed all 337,116 women aged 30 to 64 and living in Stockholm, who had a negative test result of 14 high-risk HPV subtypes in HPV-based screening, during August 2014 to December 2019. We defined women as exposed to mental illness if they had a specialist diagnosis of mental disorder or had a filled prescription of psychotropic medication. We identified incident infection of any high-risk HPV during follow-up and fitted multivariable Cox models to estimate hazard ratios (HR) with 95% confidence intervals (CI) for HPV infection. A total of 3,263 women were tested positive for high-risk HPV during follow-up (median: 2.21 years; range: 0 to 5.42 years). The absolute infection rate of HPV was higher among women with a specialist diagnosis of mental disorder (HR = 1.45; 95% CI [1.34, 1.57]; p < 0.001) or a filled prescription of psychotropic medication (HR = 1.67; 95% CI [1.55, 1.79]; p < 0.001), compared to women without such. The increment in absolute infection rate was noted for depression, anxiety, stress-related disorder, substance-related disorder, and ADHD, and for use of antidepressants, anxiolytics, sedatives, and hypnotics, and was consistent across age groups. The main limitations included selection of the female population in Stockholm as they must have at least 1 negative test result of HPV, and relatively short follow-up as HPV-based screening was only introduced in 2014 in Stockholm. Conclusions: Mental illness is associated with an increased infection rate of high-risk HPV in women. Our findings motivate refined approaches to facilitate the WHO elimination agenda of cervical cancer among these marginalized women worldwide. Author summary: Why was this study done?: Mental illness has been associated with a higher risk of cervical cancer and precancerous lesions as well as a lower degree of participation in cervical screening. Little is known, however, regarding disparities in HPV infection between women with and without mental illness. What did the researchers do and find?: In a cohort study, we followed all 337,116 women who were at age 30 to 64, living in Stockholm, and had a negative test result of high-risk HPV during August 2014 to December 2019, to assess the link between mental illness and risk of infection with high-risk HPV. The absolute infection rate of HPV was 45% higher among women with a specialist diagnosis of mental disorder and 67% higher among women with a filled prescription of psychotropic medications, compared to women without such. What do these findings mean?: Mental illness is associated with an increased infection rate of oncogenic HPV in women. Refined approaches are needed to facilitate the elimination agenda of cervical cancer among women with mental illness. [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]

Background: Despite universal healthcare, socioeconomic differences in healthcare utilization (HCU) persist in modern welfare states. However, little is known of how HCU inequalities has developed over time. The aim of this study is to assess time trends of differences in utilization of primary and specialized care for the lowest (Q1) and highest (Q5) income quantiles and compare these to mortality. Methods and findings: Using a repeated cross-sectional register-based study design, data on utilization of (i) primary; (ii) specialized outpatient; and (iii) inpatient care, as well as (iv) cause of death, were linked to family income and sociodemographic control variables (for instance, country of origin and marital status). The study sample comprised all individuals 16 years or older residing in Sweden any year during the study period and ranged from 7.1 million in year 2004 to 8.0 million year 2017. HCU and mortality for all disease as well as for the 5 disease groups causing most deaths were compared for the Q1 and Q5 using logistic regression, adjusting for sex, age, marital status, and birth country. The primary outcome measures were adjusted odds ratios (ORs), and regression coefficients of annual changes in these ORs log-transformed. Additionally, we conducted negative binominal regression to calculate adjusted rate ratios (RRs) comparing Q1 and Q5 with regard to number of disease specific healthcare encounters ≤5 years prior to death. In 2017, for all diseases combined, Q1 utilized marginally more primary and specialized outpatient care than Q5 (OR 1.07, 95% CI [1.07, 1.08]; p < 0.001, and OR 1.04, 95% CI [1.04, 1.05]; p < 0.001, respectively), and considerably more inpatient care (OR 1.44, 95% CI [1.43, 1.45]; p < 0.001). The largest relative inequality was observed for mortality (OR 1.78, 95% CI [1.74, 1.82]; p < 0.001). This pattern was broadly reproduced for each of the 5 disease groups. Time trends in HCU inequality varied by level of care. Each year, Q1 (versus Q5) used more inpatient care and suffered increasing mortality rates. However, utilization of primary and specialized outpatient care increased more among Q5 than in Q1. Finally, group differences in number of healthcare encounters ≤5 years prior to death demonstrated a similar pattern. For each disease group, primary and outpatient care encounters were fewer in Q1 than in Q5, while inpatient encounters were similar or higher in Q1. A main limitation of this study is the absence of data on self-reported need for care, which impedes quantifications of HCU inequalities each year. Conclusions: Income-related differences in the utilization of primary and specialized outpatient care were considerably smaller than for mortality, and this discrepancy widened with time. Facilitating motivated use of primary and outpatient care among low-income groups could help mitigate the growing health inequalities. In this cohort study conducted in Sweden, Pär Flodin and colleagues, investigate how income influences healthcare utilisation and mortality. Author summary: Why was this study done?: In recent decades, Sweden has witnessed a rise in income inequalities, accompanied by shifts in the sociodemographic composition of the population and transformations of the healthcare system. Previous studies show that high-income groups utilize specialized outpatient care more than low-income groups (after adjusting for need), yet little is known about the development of inequalities in the utilization of primary, outpatient, and inpatient care over time. What did the researchers do and find?: We linked income and sociodemographic data to data on utilization of primary, outpatient, and inpatient care, as well as to mortality, to track differences in care utilization between the lowest and the highest income quintile in the Swedish adult population for more than a decade. We found that the lowest income quintile utilized a decreasing proportion of primary and outpatient care, despite having increasing mortality rates. The disparities between inequalities in healthcare utilization (HCU) and mortality were most pronounced for neoplasms and chronic respiratory diseases, while being less prominent for neurological disorders. What do these findings mean?: By comparing the trends in income-related differences in HCU with trends in mortality inequalities, we here provide evidence of increasing inequalities in utilization of primary and outpatient care over time. To deliver healthcare in proportion to needs and to ensure efficient use of healthcare resources, the health sector should promote motivated utilization of primary and specialized care among low-income groups. A main limitation of this study is the absence of self-reported healthcare needs, restricting our ability to quantify inequalities in HCU. Future studies should assess to what extent group differences in care utilization explains inequalities in mortality. [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: Cervical cerclage, cervical pessary, and vaginal progesterone have each been shown to reduce preterm birth (PTB) in high-risk women, but to our knowledge, there has been no randomised comparison of the 3 interventions. The SuPPoRT "Stitch, Pessary, or Progesterone Randomised Trial" was designed to compare the rate of PTB <37 weeks between each intervention in women who develop a short cervix in pregnancy. Methods and findings: SuPPoRT was a multicentre, open label 3-arm randomised controlled trial designed to demonstrate equivalence (equivalence margin 20%) conducted from 1 July 2015 to 1 July 2021 in 19 obstetric units in the United Kingdom. Asymptomatic women with singleton pregnancies with transvaginal ultrasound cervical lengths measuring <25 mm between 14+0 and 23+6 weeks' gestation were eligible for randomisation (1:1:1) to receive either vaginal cervical cerclage (n = 128), cervical pessary (n = 126), or vaginal progesterone (n = 132). Minimisation variables were gestation at recruitment, body mass index (BMI), and risk factor for PTB. The primary outcome was PTB <37 weeks' gestation. Secondary outcomes included PTB <34 weeks', <30 weeks', and adverse perinatal outcome. Analysis was by intention to treat. A total of 386 pregnant women between 14+0 and 23+6 weeks' gestation with a cervical length <25 mm were randomised to one of the 3 interventions. About 67% were of white ethnicity, 18% black ethnicity, and 7.5% Asian ethnicity. Mean BMI was 25.6. Around 85% of women had prior risk factors for PTB; 39.1% had experienced a spontaneous PTB or midtrimester loss (>14 weeks gestation); and 45.8% had prior cervical surgery. Data from 381 women were available for outcome analysis. Using binary regression, randomised therapies (cerclage versus pessary versus vaginal progesterone) were found to have similar effects on the primary outcome PTB <37 weeks (39/127 versus 38/122 versus 32/132, p = 0.4, cerclage versus pessary risk difference (RD) −0.7% [−12.1 to 10.7], cerclage versus progesterone RD 6.2% [−5.0 to 17.0], and progesterone versus pessary RD −6.9% [−17.9 to 4.1]). Similarly, no difference was seen for PTB <34 and 30 weeks, nor adverse perinatal outcome. There were some differences in the mild side effect profile between interventions (vaginal discharge and bleeding) and women randomised to progesterone reported more severe abdominal pain. A small proportion of women did not receive the intervention as per protocol; however, per-protocol and as-treated analyses showed similar results. The main study limitation was that the trial was underpowered for neonatal outcomes and was stopped early due to the COVID-19 pandemic. Conclusions: In this study, we found that for women who develop a short cervix, cerclage, pessary, and vaginal progesterone were equally efficacious at preventing PTB, as judged with a 20% equivalence margin. Commencing with any of the therapies would be reasonable clinical management. These results can be used as a counselling tool for clinicians when managing women with a short cervix. Trial registration: EU Clinical Trials register. EudraCT Number: 2015-000456-15, clinicaltrialsregister.eu., ISRCTN Registry: ISRCTN13364447, isrctn.com. In a randomised controlled trial, Natasha Hezelgrave and co-workers compare therapies for prevention of preterm birth in women with a short cervix. Author summary: Why was this study done?: We evaluated whether commonly used treatments (cervical cerclage, cervical pessary, and vaginal progesterone) are equally effective for preventing preterm birth (PTB) before 37 weeks' gestation in women who are found to have a short cervix on ultrasound scan What did the researchers do and find?: We randomised 386 at-risk women with a short cervix to one of 3 treatments (cervical cerclage, cervical pessary, and vaginal progesterone). Each group had a similar rate of PTB before 37 weeks of gestation. What do these findings mean?: For women with a short cervix, commencing any of the 3 therapies would be reasonable management for PTB prevention. However, as a small number of women received alternative or additional therapies to the randomised treatment, continued monitoring of the cervix is advised. Further research should evaluate the benefit of combination therapies. [ABSTRACT FROM AUTHOR]

Background: The World Health Organisation (WHO) 2013 diagnostic criteria for gestational diabetes mellitus (GDM) has been criticised due to the limited evidence of benefits on pregnancy outcomes in different populations when switching from previously higher glycemic thresholds to the lower WHO-2013 diagnostic criteria. The aim of this study was to determine whether the switch from previous Swedish (SWE-GDM) to the WHO-2013 GDM criteria in Sweden following risk factor-based screening improves pregnancy outcomes. Methods and findings: A stepped wedge cluster randomised trial was performed between January 1 and December 31, 2018 in 11 clusters (17 delivery units) across Sweden, including all pregnancies under care and excluding preexisting diabetes, gastric bypass surgery, or multifetal pregnancies from the analysis. After implementation of uniform clinical and laboratory guidelines, a number of clusters were randomised to intervention (switch to WHO-2013 GDM criteria) each month from February to November 2018. The primary outcome was large for gestational age (LGA, defined as birth weight >90th percentile). Other secondary and prespecified outcomes included maternal and neonatal birth complications. Primary analysis was by modified intention to treat (mITT), excluding 3 clusters that were randomised before study start but were unable to implement the intervention. Prespecified subgroup analysis was undertaken among those discordant for the definition of GDM. Multilevel mixed regression models were used to compare outcome LGA between WHO-2013 and SWE-GDM groups adjusted for clusters, time periods, and potential confounders. Multiple imputation was used for missing potential confounding variables. In the mITT analysis, 47 080 pregnancies were included with 6 882 (14.6%) oral glucose tolerance tests (OGTTs) performed. The GDM prevalence increased from 595/22 797 (2.6%) to 1 591/24 283 (6.6%) after the intervention. In the mITT population, the switch was associated with no change in primary outcome LGA (2 790/24 209 (11.5%) versus 2 584/22 707 (11.4%)) producing an adjusted risk ratio (aRR) of 0.97 (95% confidence interval 0.91 to 1.02, p = 0.26). In the subgroup, the prevalence of LGA was 273/956 (28.8%) before and 278/1 239 (22.5%) after the switch, aRR 0.87 (95% CI 0.75 to 1.01, p = 0.076). No serious events were reported. Potential limitations of this trial are mainly due to the trial design, including failure to adhere to guidelines within and between the clusters and influences of unidentified temporal variations. Conclusions: In this study, implementing the WHO-2013 criteria in Sweden with risk factor-based screening did not significantly reduce LGA prevalence defined as birth weight >90th percentile, in the total population, or in the subgroup discordant for the definition of GDM. Future studies are needed to evaluate the effects of treating different glucose thresholds during pregnancy in different populations, with different screening strategies and clinical management guidelines, to optimise women's and children's health in the short and long term. Trial registration: The trial is registered with ISRCTN (41918550). Maryam de Brun and colleagues assess whether implementation of the WHO-2013 diagnostic criteria for gestational diabetes with risk factor based screening affects pregnancy outcomes in Sweden. Author summary: Why was this study done?: The implementation of the World Health Organisation (WHO)-2013 diagnostic criteria for gestational diabetes mellitus (GDM) have been challenged due to the limited evidence of benefits on pregnancy outcomes in different populations by switching from former higher plasma glucose diagnostic cutoffs to the lower plasma glucose WHO-2013 diagnostic criteria. Screening, laboratory methods, and diagnostic criteria for GDM vary throughout the world and there is limited randomised controlled trial (RCT) evidence on the effects of switching to WHO 2013 diagnostic criteria for GDM. The Swedish National Board of Health and Welfare introduced new guidelines for GDM in 2015 and the aim was to evaluate if the switch in a real-world setting improved pregnancy outcomes. What did the researchers do and find?: A stepped wedge randomised trial was performed during 2018 which included nearly half of all pregnancies in Sweden that year (n = 47 080). Since risk factor screening was used, analysis was conducted in all pregnancies (modified intention to treat (mITT)) as well as in a subgroup affected by the switch. There was no reduction in the main outcome large for gestational age (LGA) (>90th birth weight percentile) in the mITT population or in the subgroup of women affected by the switch. What do these findings mean?: These findings indicate that the effect of treatment may differ using lower compared to higher plasma glucose diagnostic cutoffs for GDM depending on whether risk factor based screening or universal screening is used. The study findings highlight the importance of also reporting treatment effects on high absolute birth weight besides the LGA 90th percentile, since absolute high birth weight most likely results in associated adverse pregnancy outcomes. Limitations of this trial are mainly due to the trial design, including failure to adhere to guidelines within and between the clusters and influences of unidentified temporal variations. Future studies need to evaluate long-term effects on women's and children's health after diagnosing and treating lower levels of hyperglycemia during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Preclinical animal studies have suggested that myeloid cell–synthesized coagulation factor X dampens antitumor immunity and that rivaroxaban, a direct factor Xa inhibitor, can be used to promote tumor immunity. This study was aimed at assessing whether patients with atrial fibrillation taking direct factor Xa inhibitors have lower risk of cancer and cancer-related mortality than patients taking the direct thrombin inhibitor dabigatran. Methods and findings: This nationwide population-based cohort study in Denmark included adult patients with atrial fibrillation and without a history of cancer, who started taking a factor Xa inhibitor or dabigatran between 2011 and 2015. Data on medical history, outcomes, and drug use were acquired through Danish healthcare registries. The primary outcome was any cancer. Secondary outcomes were cancer-related mortality and all-cause mortality. Outcome events were assessed during 5 years of follow-up in an intention-to-treat analysis. The propensity score-based inverse probability of treatment weighting was used to compute cumulative incidence and subdistribution hazard ratios (SHRs) and corresponding 95% confidence intervals (CIs), with death as a competing event. Propensity scores were estimated using logistic regression and including in the model sex, age group at index date, comorbidities, and use of comedications. A total of 11,742 patients with atrial fibrillation starting a factor Xa inhibitor and 11,970 patients starting dabigatran were included. Mean age was 75.2 years (standard deviation [SD] 11.2) in the factor Xa cohort and 71.7 years (SD 11.1) in the dabigatran cohort. On the basis of the propensity score-weighted models, after 5 years of follow-up, no substantial difference in the cumulative incidence of cancer was observed between the factor Xa inhibitor (2,157/23,711; 9.11%, 95% CI [8.61%,9.63%]) and dabigatran (2,294/23,715; 9.68%, 95% CI [9.14%,10.25%]) groups (SHR 0.94, 95% CI [0.89,1.00], P value 0.0357). We observed no difference in cancer-related mortality (factor Xa inhibitors cohort 1,028/23,711; 4.33%, 95% CI [4.02%,4.68%]. Dabigatran cohort 1,001/23,715; 4.22%, 95% CI [3.83%,4.66%]; SHR 1.03, 95% CI [0.94,1.12]), but all-cause mortality was higher in the factor Xa inhibitor cohort (factor Xa inhibitors cohort 7,416/23,711; 31.31%, 95% CI [30.37%,32.29%]. Dabigatran cohort 6,531/23,715; 27.56%, 95% CI [26.69%,28.45%]; HR 1.17, 95% CI [1.13,1.21]). The main limitations of the study were the possibility of residual confounding and the short follow-up period. Conclusions: In this population based cohort study, factor Xa inhibitor use was not associated with an overall lower incidence of cancer or cancer-related mortality when compared to dabigatran. We did observe an increase in all-cause mortality in the factor Xa inhibitor cohort. Floris Bosch and colleagues investigate whether patients with atrial fibrillation taking direct Factor Xa inhibitors have a lower risk of cancer and cancer-related mortality than patients taking dabigatran. Author summary: Why was this study done?: A preclinical study in mice with breast cancer and fibrosarcoma showed that factor X dampens antitumor immunity and that factor Xa inhibitor promote tumor immunity. Whether factor Xa inhibition is associated with decreased cancer incidence and cancer-related mortality in humans is unknown. What did the researchers do and find?: We assessed cancer incidence during 5 years of follow-up in patients with atrial fibrillation in Denmark using a factor Xa inhibitor (n = 11,742) or a thrombin inhibitor (dabigatran) (n = 11,970) for stroke prevention. No substantial difference in the cumulative incidence of cancer was observed between the factor Xa inhibitor (9.11%, 95% CI [8.61%,9.63%]) and dabigatran (9.68%, 95% CI [9.14%,10.25%]) groups (SHR 0.94, 95% CI [0.89,1.00]. No difference in cancer-related mortality (SHR 1.03, 95% CI [0.94,1.12]) was observed, but all-cause mortality was higher in the factor Xa inhibitor cohort (HR 1.17, 95% CI [1.13,1.21]). What do these findings mean?: Factor Xa inhibitor use for atrial fibrillation did not appear to significantly reduce cancer risk compared to dabigatran use. The main limitations of the study were the possibility of residual confounding and the short follow-up period. [ABSTRACT FROM AUTHOR]

Background: Obesity and rapid weight gain are established risk factors for noncommunicable diseases and have emerged as independent risk factors for severe disease following Coronavirus Disease 2019 (COVID-19) infection. Restrictions imposed to reduce COVID-19 transmission resulted in profound societal changes that impacted many health behaviours, including physical activity and nutrition, associated with rate of weight gain. We investigated which clinical and sociodemographic characteristics were associated with rapid weight gain and the greatest acceleration in rate of weight gain during the pandemic among adults registered with an English National Health Service (NHS) general practitioner (GP) during the COVID-19 pandemic. Methods and findings: With the approval of NHS England, we used the OpenSAFELY platform inside TPP to conduct an observational cohort study of routinely collected electronic healthcare records. We investigated changes in body mass index (BMI) values recorded in English primary care between March 2015 and March 2022. We extracted data on 17,742,365 adults aged 18 to 90 years old (50.1% female, 76.1% white British) registered with an English primary care practice. We estimated individual rates of weight gain before (δ-prepandemic) and during (δ-pandemic) the pandemic and identified individuals with rapid weight gain (>0.5 kg/m2/year) in each period. We also estimated the change in rate of weight gain between the prepandemic and pandemic period (δ-change = δ-pandemic—δ-prepandemic) and defined extreme accelerators as the 10% of individuals with the greatest increase in their rate of weight gain (δ-change ≥1.84 kg/m2/year) between these periods. We estimated associations with these outcomes using multivariable logistic regression adjusted for age, sex, index of multiple deprivation (IMD), and ethnicity. P-values were generated in regression models. The median BMI of our study population was 27.8 kg/m2, interquartile range (IQR) [24.3, 32.1] in 2019 (March 2019 to February 2020) and 28.0 kg/m2, IQR [24.4, 32.6] in 2021. Rapid pandemic weight gain was associated with sex, age, and IMD. Male sex (male versus female: adjusted odds ratio (aOR) 0.76, 95% confidence interval (95% CI) [0.76, 0.76], p < 0.001), older age (e.g., 50 to 59 years versus 18 to 29 years: aOR 0.60, 95% CI [0.60, 0.61], p < 0.001]); and living in less deprived areas (least-deprived-IMD-quintile versus most-deprived: aOR 0.77, 95% CI [0.77, 0.78] p < 0.001) reduced the odds of rapid weight gain. Compared to white British individuals, all other ethnicities had lower odds of rapid pandemic weight gain (e.g., Indian versus white British: aOR 0.69, 95% CI [0.68, 0.70], p < 0.001). Long-term conditions (LTCs) increased the odds, with mental health conditions having the greatest effect (e.g., depression (aOR 1.18, 95% CI [1.17, 1.18], p < 0.001)). Similar characteristics increased odds of extreme acceleration in the rate of weight gain between the prepandemic and pandemic periods. However, changes in healthcare activity during the pandemic may have introduced new bias to the data. Conclusions: We found female sex, younger age, deprivation, white British ethnicity, and mental health conditions were associated with rapid pandemic weight gain and extreme acceleration in rate of weight gain between the prepandemic and pandemic periods. Our findings highlight the need to incorporate sociodemographic, physical, and mental health characteristics when formulating research, policies, and interventions targeting BMI in the period of post pandemic service restoration and in future pandemic planning. Miriam Samuel and team analyzed health records of 17 million adults in England, examining patterns of weight change before and during COVID-19 and identifying groups most prone to rapid weight gain. Author summary: Why was this study done?: Restrictions imposed during the Coronavirus Disease 2019 (COVID-19) pandemic may have led to lifestyle changes that are associated with weight gain. Some studies have suggested that women, younger adults (18 to 29 years), and those living in more deprived areas were at greatest risk of weight gain during the pandemic, but these were limited by small sample size. There are currently no large-scale analyses of how the pandemic impacted preexisting patterns of weight gain, and how this varied by sociodemographic and clinical characteristics. What did the researchers do and find?: We used data from the routinely collected health records of 17 million adults living in England to investigate patterns of weight change before and during the pandemic and describe which groups were most likely to have experienced unhealthy patterns of weight gain. We found that, among adults with measures of weight recorded in their healthcare records, women, younger adults (18 to 29 years), those living in the most deprived areas, and those of white British ethnicity were most likely to have gained weight rapidly before and during the pandemic. The same groups were also most likely to have experienced extreme acceleration in their rate of weight gain during the pandemic. Almost all the long-term conditions (LTCs) increased the risk of unhealthy patterns of weight gain, with mental health conditions, such as depression, having the greatest estimated effect. What do these findings mean?: The COVID-19 pandemic appears to have had the greatest impact on women, young adults, and those living in the most deprived areas in terms of unhealthy patterns of weight gain. We present, to our knowledge, new evidence that people with mental health conditions were more likely to have unhealthy patterns of weight gain during the pandemic, highlighting the need to consider sociodemographic, physical, and mental health characteristics in research, policies, and interventions around weight. We recommend that future pandemic planning should consider how to mitigate the unequal indirect impact of a pandemic on patterns of weight gain to prevent preexisting health inequalities being further exacerbated. Changes in healthcare activity during the pandemic affected patterns of weight monitoring in primary care, which may have introduced new bias to the analyses. [ABSTRACT FROM AUTHOR]

Background: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. Methods and findings: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). Conclusions Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. Trial registration: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p). https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371998&isReview=true. Just one registry (as above). Gladymar Pérez Chacón and colleagues report the safety and immunogenicity of a mixed whole-cell and acellular pertussis vaccine in Australian infants in stage 1 of the two-stage OPTIMUM trial. Author summary: Why was this study done?: Evidence-based strategies to lower the risk of food allergies developing in young children are limited. A previous observational study suggested that food allergies appear to be less common among Australian-born children vaccinated with a first dose of whole-cell whooping cough (wP) vaccine before 4 months old versus those receiving a first dose of acellular whooping cough (aP) vaccine at the same age. Why did the researchers do and find?: In the first stage of a 2-stage, double-blind, noninferiority trial, Australian-born infants were randomised to receive a first dose of wP versus aP at approximately 6 weeks old; in both study groups, aP vaccine is given at 4 and 6 months old. Stage (phase) one examined the immunogenicity, reactogenicity, and IgE-mediated immune responses of the mixed vaccine schedule (wP/aP/aP) versus the standard aP-only vaccination strategy (aP/aP/aP) in a cohort of 150 infants; stage two is ongoing and was designed to ascertain the development of food allergy by 12 months old (primary outcome) in a cohort of up to 3,000 infants. At 7 months old, the mixed schedule was noninferior to the standard aP-only strategy with respect to pertussis toxin IgG responses; at the same age, we observed no difference across the study groups in IgE responses to hen's egg and tetanus toxoid antigens. The mixed schedule was more reactogenic but well accepted by parents. What do these findings mean?: These findings support the acceptable immunogenicity and reactogenicity of the mixed schedule and are relevant for countries in which wP and aP vaccines are licensed and readily available. While the reported IgE responses are not conclusive, further studies of CD4+ T cell polarisation in response to pertussis antigens, along with primary outcome data will provide a comprehensive picture of the atopic immunophenotypic responses across the study groups. Additional evidence is required to understand the population-level acceptability of the mixed vaccination strategy. [ABSTRACT FROM AUTHOR]

Background: Diabetes control is poor globally and leads to burdensome microvascular and macrovascular complications. We aimed to assess post hoc between-group differences in sustained risk factor control and macrovascular and microvascular endpoints at 6.5 years in the Center for cArdiovascular Risk Reduction in South Asia (CARRS) randomized trial. Methods and findings: This parallel group individual randomized clinical trial was performed at 10 outpatient diabetes clinics in India and Pakistan from January 2011 through September 2019. A total of 1,146 patients with poorly controlled type 2 diabetes (HbA1c ≥8% and systolic BP ≥140 mm Hg and/or LDL-cholesterol ≥130 mg/dl) were randomized to a multicomponent quality improvement (QI) strategy (trained nonphysician care coordinator to facilitate care for patients and clinical decision support system for physicians) or usual care. At 2.5 years, compared to usual care, those receiving the QI strategy were significantly more likely to achieve multiple risk factor control. Six clinics continued, while 4 clinics discontinued implementing the QI strategy for an additional 4-year follow-up (overall median 6.5 years follow-up). In this post hoc analysis, using intention-to-treat, we examined between-group differences in multiple risk factor control (HbA1c <7% plus systolic BP <130 mm Hg and/or LDL-cholesterol <100 mg/dl) and first macrovascular endpoints (nonfatal myocardial infarction, nonfatal stroke, death, revascularization [angioplasty or coronary artery bypass graft]), which were coprimary outcomes. We also examined secondary outcomes, namely, single risk factor control, first microvascular endpoints (retinopathy, nephropathy, neuropathy), and composite first macrovascular plus microvascular events (which also included amputation and all-cause mortality) by treatment group and whether QI strategy implementation was continued over 6.5 years. At 6.5 years, assessment data were available for 854 participants (74.5%; n = 417 [intervention]; n = 437 [usual care]). In terms of sociodemographic and clinical characteristics, participants in the intervention and usual care groups were similar and participants at sites that continued were no different to participants at sites that discontinued intervention implementation. Patients in the intervention arm were more likely to exhibit sustained multiple risk factor control than usual care (relative risk: 1.79; 95% confidence interval [CI], 1.45, 2.20), p < 0.001. Cumulatively, there were 233 (40.5%) first microvascular and macrovascular events in intervention and 274 (48.0%) in usual care patients (absolute risk reduction: 7.5% [95% CI: −13.2, −1.7], p = 0.01; hazard ratio [HR] = 0.72 [95% CI: 0.61, 0.86]), p < 0.001. Patients in the intervention arm experienced lower incidence of first microvascular endpoints (HR = 0.68 [95% CI: 0.56, 0.83), p < 0.001, but there was no evidence of between-group differences in first macrovascular events. Beneficial effects on microvascular and composite vascular outcomes were observed in sites that continued, but not sites that discontinued the intervention. Conclusions: In urban South Asian clinics, a multicomponent QI strategy led to sustained multiple risk factor control and between-group differences in microvascular, but not macrovascular, endpoints. Between-group reductions in vascular outcomes at 6.5 years were observed only at sites that continued the QI intervention, suggesting that practice change needs to be maintained for better population health of people with diabetes. Trial registration: ClinicalTrials.govNCT01212328. Nikhil Tandon and colleagues explore the impact of a quality improvement strategy for patients with type 2 diabetes 6.5 years after its implementation for the CARRS randomised trial. Author summary: Why was this study done?: Data on whether improvements in diabetes care goal achievement can be sustained (>5 years) with quality improvement (QI) strategies are lacking from low- and middle-income countries (LMICs). Prior studies of QI strategies to improve care goal achievement among people with diabetes from high-income countries reported modest benefits in blood glucose, blood pressure, and lipids, but the effects of these improvements on reducing vascular complications and deaths related to diabetes are unknown. What did the researchers do and find?: In the Center for cArdiovascular Risk Reduction in South Asia (CARRS) randomised trial of 1,146 patients with type 2 diabetes attending 10 diverse diabetes clinics in India and Pakistan, the QI strategy was associated with benefits on diabetes care goals (HbA1c <7% plus systolic BP <130 mm Hg and/or LDL-cholesterol <100 mg/dl) at 2.5 years after randomization. Four clinics discontinued implementation, while 6 clinics continued to implement the QI strategy for an additional 4 years. This report assesses whether benefits were sustained and reduced vascular complications and deaths associated with diabetes at 6.5 years. Patients receiving the QI strategy, compared to those receiving usual care, experienced sustained benefits on diabetes care goals and less microvascular endpoints (eye, kidney, and nerve diseases) at 6.5 years after randomization. Total macrovascular and microvascular events were also lower in those receiving the QI strategy, and this was only observed at sites that continued implementation of the QI strategy for 6.5 years. What do these findings mean?: These findings add to our knowledge of the long-term effects of multicomponent QI strategies in sustaining multiple risk factor control and reducing combined vascular events compared to usual care in resource-limited settings. In view of these findings, clinical decision support and trained nonphysician health workers may be important QI strategies to consider integrating into India's healthcare system to improve diabetes care quality and reduce morbidity and mortality. One limitation of the study is that the tertiary care facilities included in the CARRS trial may not be generalizable across LMICs. [ABSTRACT FROM AUTHOR]

Background: Syndromic management is widely used to treat symptomatic sexually transmitted infections in settings without aetiologic diagnostics. However, underlying aetiologies and consequent treatment suitability are uncertain without regular assessment. This systematic review estimated the distribution, trends, and determinants of aetiologies for vaginal discharge, urethral discharge, and genital ulcer in sub-Saharan Africa (SSA). Methods and findings: We searched Embase, MEDLINE, Global Health, Web of Science, and grey literature from inception until December 20, 2023, for observational studies reporting aetiologic diagnoses among symptomatic populations in SSA. We adjusted observations for diagnostic test performance, used generalised linear mixed-effects meta-regressions to generate estimates, and critically appraised studies using an adapted Joanna Briggs Institute checklist. Of 4,418 identified records, 206 reports were included from 190 studies in 32 countries conducted between 1969 and 2022. In 2015, estimated primary aetiologies for vaginal discharge were candidiasis (69.4% [95% confidence interval (CI): 44.3% to 86.6%], n = 50), bacterial vaginosis (50.0% [95% CI: 32.3% to 67.8%], n = 39), chlamydia (16.2% [95% CI: 8.6% to 28.5%], n = 50), and trichomoniasis (12.9% [95% CI: 7.7% to 20.7%], n = 80); for urethral discharge were gonorrhoea (77.1% [95% CI: 68.1% to 84.1%], n = 68) and chlamydia (21.9% [95% CI: 15.4% to 30.3%], n = 48); and for genital ulcer were herpes simplex virus type 2 (HSV-2) (48.3% [95% CI: 32.9% to 64.1%], n = 47) and syphilis (9.3% [95% CI: 6.4% to 13.4%], n = 117). Temporal variation was substantial, particularly for genital ulcer where HSV-2 replaced chancroid as the primary cause. Aetiologic distributions for each symptom were largely the same across regions and population strata, despite HIV status and age being significantly associated with several infection diagnoses. Limitations of the review include the absence of studies in 16 of 48 SSA countries, substantial heterogeneity in study observations, and impeded assessment of this variability due to incomplete or inconsistent reporting across studies. Conclusions: In our study, syndrome aetiologies in SSA aligned with World Health Organization guidelines without strong evidence of geographic or demographic variation, supporting broad guideline applicability. Temporal changes underscore the importance of regular aetiologic re-assessment for effective syndromic management. PROSPERO number: CRD42022348045. Julia Michalow and colleagues estimate the aetiologies and aetiologic distributions of vaginal discharge, urethral discharge, and genital ulcer in sub-Saharan Africa. Author summary: Why was this study done?: Symptom-based case management is common for treating sexually transmitted infections (STIs) in sub-Saharan Africa (SSA). Characterising the infectious aetiologies (causes) of each syndrome is crucial to ensure adequate choice of treatment. Recent comprehensive assessments on the aetiologies for vaginal discharge, urethral discharge, and genital ulcer are lacking in SSA. What did the researchers do and find?: We conducted a systematic review that included 190 studies in 32 SSA countries spanning 1969 and 2022. We accounted for the sensitivity and specificity of different diagnostic tests used across studies and used meta-regression models to estimate the distribution of infections causing each symptom. We determined that the main aetiologies for vaginal discharge were candidiasis (69% of cases in 2015), bacterial vaginosis (50%), chlamydia (16%), and trichomoniasis (13%); for urethral discharge were gonorrhoea (77%) and chlamydia (22%); and for genital ulcer were herpes simplex virus type 2 (HSV-2) (48%) and syphilis (9%). Distributions of infectious aetiologies were similar across regions and population subgroups but changed over time. What do these findings mean?: The findings support the applicability and continued use of World Health Organization guidelines for symptomatic STI management across SSA settings. National STI programmes should re-assess aetiologies regularly due to changes over time. Limitations of the review include that no data were available in 16 of 48 SSA countries, there was large variability in results across studies identified in the review, and certain information of interest was missing or inconsistently reported across studies. [ABSTRACT FROM AUTHOR]

Background: Micronutrient deficiencies are widespread in India. Soil-transmitted helminth (STH) infections are acquired by interaction with soil and water contaminated by human feces and lead to blood loss and poor micronutrient absorption. The current recommendation for control of STH-related morbidity is targeted deworming, yet little is known about the effectiveness of deworming on micronutrient status in varying sanitation contexts. Ranging between 1% and 40% prevalence across Indian states, open defecation (OD) remains high despite India's investments at elimination by promoting community-wide sanitation. This variation provides an opportunity to study the relationship between deworming, micronutrient status, and OD at-scale. Methods and findings: Cross-sectional datasets that were representative for India were obtained the Comprehensive National Nutrition Survey in 2016 to 2018 (n = 105,060 individuals aged 1 to 19 years). Consumption of deworming medication was described by age and community OD level. Logistic regression models were used to examine the relationship between deworming, cluster OD, and their interactions, with anemia and micronutrient deficiencies (iron, zinc, vitamin A, folate, and vitamin B12), controlling for age, sex, wealth, diet, and seasonality. These regression models further allowed us to identify a minimum OD rate after which deworming becomes ineffective. In sensitivity analyses, the association between deworming and deficiencies were tested in subsamples of communities classified into 3 OD levels based on statistical tertiles: OD free (0% of households in the community practicing OD), moderate OD (>0% and <30%), or high OD (at least 30%). Average deworming coverage and OD prevalence in the sample were 43.4% [IQR 26.0, 59.0] and 19.1% [IQR 0, 28.5], respectively. Controlling for other determinants of nutritional status, adolescents living in communities with higher OD levels had lower coverage of deworming and higher prevalence of anemia, zinc, vitamin A, and B12 deficiencies. Compared to those who were not dewormed, dewormed children and adolescents had lower odds of anemia (adjusted odds ratio 0.72, (95% CI [0.67, 0.78], p < 0.001) and deficiencies of iron 0.78, (95% CI [0.74, 0.82], p < 0.001) and folate 0.69, (95% CI [0.64,0.74], p<0.001)) in OD free communities. These protective effects remained significant for anemia but diminished for other micronutrient deficiencies in communities with moderate or high OD. Analysis of community OD indicated a threshold range of 30% to 60%, above which targeted deworming was no longer significantly associated with lower anemia, iron, and folate deficiency. The primary limitations of the study included potential for omitted variables bias and inability to capture longitudinal effects. Conclusions: Moderate to high rates of OD significantly modify the association between deworming and micronutrient status in India. Public health policy could involve sequencing interventions, with focus on improving deworming coverage in communities that have achieved minimum thresholds of OD and re- triggering sanitation interventions in high OD communities prior to deworming days, ensuring high coverage for both. The efficacy of micronutrient supplementation as a complementary strategy to improve nutritional outcomes alongside deworming and OD elimination in this age group needs further study. Using data from India, Chakrabarti and colleagues evaluate whether higher open defecation levels diminished the protection provided by deworming against anaemia or micronutrient deficiencies. Author summary: Why was this study done?: Deworming is recommended to tackle soil-transmitted worm infections in low- and middle-income countries (LMICs), but the effectiveness of deworming provided on a large scale varies significantly. Sanitation levels across communities are likely to influence the impact of deworming in populations due to high rates of reinfection, but no studies have investigated these links. Despite well-intended programs intended to eliminate open defecation in India, this behavior persists in certain communities. This study was done to test whether higher open defecation levels diminished the protection provided by deworming against anemia or micronutrient deficiencies among Indian children and adolescents. What did the researchers do and find?: We used a cross-sectional dataset (sample size 105,060 individuals) representative of Indian children and adolescents to look at links between open defecation, deworming, anemia, and micronutrient deficiencies. We found that deworming coverage remains low in India, especially among young children and adolescents out of school, indicating the need for enhanced and expanded deworming interventions. After accounting for the influence of age, sex, wealth, education, diet, and season, dewormed children in areas without open defecation had lower rates of anemia (28% lower), iron deficiency (22% lower), and folate deficiency (31% lower); however, in communities with open defecation, dewormed children showed similar deficiency levels as those not dewormed. What do these findings mean?: Our findings suggest that open defecation diminishes the protection provided by deworming medication against anemia and micronutrient deficiencies in India. The findings highlight the importance of sequencing sanitation interventions such as behavior change campaigns before deworming initiatives in high open defecation communities. This study cannot establish causation because the statistical models were based on observing associations at a single point in time rather than tracking changes over time. [ABSTRACT FROM AUTHOR]

Background: Childhood obesity is a growing concern worldwide. School-based interventions have been proposed as effective means to improve nutritional knowledge and prevent obesity. In 2023, Mexico approved a reform to the General Education Law to strengthen the ban of sales and advertising of nonessential energy-dense food and beverages (NEDFBs) in schools and surroundings. We aimed to predict the expected one-year change in total caloric intake and obesity prevalence by introducing the ban of NEDFBs sales in schools, among school-aged children and adolescents (6 to 17 years old) in Mexico. Methods and findings: We used age-specific equations to predict baseline fat-free mass (FFM) and fat mass (FM) and then estimated total energy intake (TEI) per day. The TEI after the intervention was estimated under 4 scenarios: (1) using national data to inform the intervention effect; (2) varying law compliance; (3) using meta-analytic data to inform the intervention effect size on calories; and (4) using national data to inform the intervention effect by sex and socioeconomic status (SES). We used Hall's microsimulation model to estimate the potential impact on body weight and obesity prevalence of children and adolescents 1 year after implementing the intervention in Mexican schools. We found that children could reduce their daily energy intake by 33 kcal/day/person (uncertainty interval, UI, [25, 42] kcal/day/person), reducing on average 0.8 kg/person (UI [0.6, 1.0] kg/person) and 1.5 percentage points (pp) in obesity (UI [1.1, 1.9] pp) 1 year after implementing the law. We showed that compliance will be key to the success of this intervention: considering a 50% compliance the intervention effect could reduce 0.4 kg/person (UI [0.3, 0.5] kg/person). Our sensitivity analysis showed that the ban could reduce body weight by 1.3 kg/person (UI [0.8, 1.8] kg/person) and up to 5.4 kg/person (UI [3.4, 7.5] kg/person) in the best-case scenario. Study limitations include assuming that obesity and the contribution of NEDFBs consumed at school remain constant over time, assuming full compliance, and not considering the potential effect of banning NEDFBs in stores near schools. Conclusions: Even in the most conservative scenario, banning sales of NEDFBs in schools is expected to significantly reduce obesity, but achieving high compliance will be key to its success. Why was this study done?: - School-based interventions have been recognized as effective means to improve nutritional knowledge and prevent obesity-related diseases. - In December 2023, the Chamber of Representatives of Mexico approved an amendment that strengthens and updates the General Education Law (Article 75) and nutritional guidelines to ban the sales and advertising of nonessential energy-dense food and beverages (NEDFBs) in schools. What did the researchers do and find?: - We used age-specific equations to predict baseline fat-free mass (FFM) and fat mass (FM) and total energy intake (TEI) per day. - We used microsimulation modeling to predict body weight and obesity prevalence of children and adolescents 1 year after implementing the intervention in Mexican schools. - Our modeling study suggests that an important impact on obesity prevalence can be expected if the law is implemented and enforced as intended. What do these findings mean?: - If successful, this law could serve as an example beyond Mexico on how to achieve changes in body weight through school food regulation. - An important limitation of our main scenario is that we assumed full compliance of schools with the law, yet lower compliance will reduce its impact. We also did not consider historical trends on obesity or NEDFBs consumed in schools during our 1 year simulation, and we considered only the ban impact inside schools, excluding effects near and outside schools. [ABSTRACT FROM AUTHOR]

Background: An increasing number of countries are currently implementing or scaling-up HIV pre-exposure prophylaxis (PrEP) care. With the introduction of PrEP, there was apprehension that condom use would decline and sexually transmitted infections (STIs) would increase. To inform sexual health counselling and STI screening programmes, we aimed to study sexual behaviour and STI incidence among men who have sex with men (MSM) and transgender women who use long-term daily or event-driven PrEP. Methods and findings: The Amsterdam PrEP demonstration project (AMPrEP) was a prospective, closed cohort study, providing oral daily PrEP and event-driven PrEP to MSM and transgender women from 2015 to 2020. Participants could choose their PrEP regimen and could switch at each three-monthly visit. STI testing occurred at and, upon request, in-between 3-monthly study visits. We assessed changes in numbers of sex partners and condomless anal sex (CAS) acts with casual partners over time using negative binomial regression, adjusted for age. We assessed HIV incidence and changes in incidence rates (IRs) of any STI (i.e., chlamydia, gonorrhoea, or infectious syphilis) and individual STIs over time using Poisson regression, adjusted for age and testing frequency. A total of 367 participants (365 MSM) commenced PrEP and were followed for a median 3.9 years (interquartile range [IQR] = 3.4–4.0). Median age was 40 years (IQR = 32–48), 315 participants (85.8%) self-declared ethnicity as white and 280 (76.3%) had a university or university of applied sciences degree. Overall median number of sex partners (past 3 months) was 13 (IQR = 6–26) and decreased per additional year on PrEP (adjusted rate ratio [aRR] = 0.86/year, 95% confidence interval [CI] = 0.83–0.88). Overall median number of CAS acts with casual partners (past 3 months) was 10 (IQR = 3–20.5) and also decreased (aRR = 0.92/year, 95% CI = 0.88–0.97). We diagnosed any STI in 1,092 consultations during 1,258 person years, resulting in an IR of 87/100 person years (95% CI = 82–92). IRs of any STI did not increase over time for daily PrEP or event-driven PrEP users. Two daily PrEP users, and no event-driven PrEP users, were diagnosed with HIV during their first year on PrEP. Study limitations include censoring follow-up due to COVID-19 measures and an underrepresentation of younger, non-white, practically educated, and transgender individuals. Conclusions: In this prospective cohort with a comparatively long follow-up period of 4 years, we observed very low HIV incidence and decreases in the numbers of casual sex partners and CAS acts over time. Although the STI incidence was high, it did not increase over time. Trial registration: The study was registered at the Netherlands Trial Register (NL5413) https://www.onderzoekmetmensen.nl/en/trial/22706 Mark A. M. van den Elshout, Eline S. Wijstma and colleagues assess sexual behaviour and incidence of sexually transmitted infections among men who have sex with men using long-term daily and event-driven pre-exposure prophylaxis (PrEP) over a four-year period. Author summary: Why was this study done?: Oral pre-exposure prophylaxis (PrEP) is medication that almost 100% effectively prevents HIV when taken as prescribed: daily or before and after sex. Information on how people use PrEP, their sexual behaviour, and how often they acquire sexually transmitted infections (STI), can be used to tailor PrEP care to the needs of PrEP users. Since people can benefit from PrEP for several years (i.e., for as long as they are vulnerable to HIV), it is important to study the outcomes of PrEP use over longer periods of time. What did the researchers do and find?: Between 2015 and 2020, 365 men who have sex with men and 2 transgender women who were at risk for HIV in the Netherlands were provided oral PrEP and followed up every 3 months. We examined how participants use PrEP (daily or before and after sex), participants' sexual behaviour, and how often they tested positive for STIs or HIV, and whether these outcomes changed over 4 years of PrEP use. Over 4 years, most participants used PrEP correctly, and only 2 acquired HIV. The numbers of sex partners and anal sex acts without a condom with casual partners decreased over time, and STIs occurred frequently, but did not increase over time. What do these findings mean?: Our findings indicate that PrEP effectively prevents HIV over longer time periods and support structural implementation of PrEP with easy access. Our findings support regular counselling and STI testing as part of PrEP care. Young, non-white, practically educated, and transgender individuals were underrepresented in the study population; this should be considered when applying these findings to broader populations of PrEP users. [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: Coronavirus Disease 2019 (COVID-19) continues to cause significant hospitalizations and deaths in the United States. Its continued burden and the impact of annually reformulated vaccines remain unclear. Here, we present projections of COVID-19 hospitalizations and deaths in the United States for the next 2 years under 2 plausible assumptions about immune escape (20% per year and 50% per year) and 3 possible CDC recommendations for the use of annually reformulated vaccines (no recommendation, vaccination for those aged 65 years and over, vaccination for all eligible age groups based on FDA approval). Methods and findings: The COVID-19 Scenario Modeling Hub solicited projections of COVID-19 hospitalization and deaths between April 15, 2023 and April 15, 2025 under 6 scenarios representing the intersection of considered levels of immune escape and vaccination. Annually reformulated vaccines are assumed to be 65% effective against symptomatic infection with strains circulating on June 15 of each year and to become available on September 1. Age- and state-specific coverage in recommended groups was assumed to match that seen for the first (fall 2021) COVID-19 booster. State and national projections from 8 modeling teams were ensembled to produce projections for each scenario and expected reductions in disease outcomes due to vaccination over the projection period. From April 15, 2023 to April 15, 2025, COVID-19 is projected to cause annual epidemics peaking November to January. In the most pessimistic scenario (high immune escape, no vaccination recommendation), we project 2.1 million (90% projection interval (PI) [1,438,000, 4,270,000]) hospitalizations and 209,000 (90% PI [139,000, 461,000]) deaths, exceeding pre-pandemic mortality of influenza and pneumonia. In high immune escape scenarios, vaccination of those aged 65+ results in 230,000 (95% confidence interval (CI) [104,000, 355,000]) fewer hospitalizations and 33,000 (95% CI [12,000, 54,000]) fewer deaths, while vaccination of all eligible individuals results in 431,000 (95% CI: 264,000–598,000) fewer hospitalizations and 49,000 (95% CI [29,000, 69,000]) fewer deaths. Conclusions: COVID-19 is projected to be a significant public health threat over the coming 2 years. Broad vaccination has the potential to substantially reduce the burden of this disease, saving tens of thousands of lives each year. Using the Scenario Modeling Hub approach, Jung and colleagues project the potential impact of COVID-19 and assess the extent to which vaccinations may reduce hospitalizations and deaths. Author summary: Why was this study done?: While Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is likely to pose a persistent threat to public health for the foreseeable future, regular revaccination with reformulated vaccines is considered a prominent mitigation tool. Questions exist regarding the effectiveness of annual vaccination campaigns and the optimal target age ranges, given the concentration of severe Coronavirus Disease 2019 (COVID-19) outcomes in older populations. The US COVID-19 Scenario Modeling Hub (SMH) has provided projections on the unfolding of the COVID-19 epidemic under various conditions, summarizing the results of multiple teams working on the same set of scenarios. Informed decisions on future vaccination policy need to be made with well-grounded projections of the likely course of COVID-19 epidemics and its impact under different vaccination scenarios. What did the researchers do and find?: Applying the SMH approach, we projected the potential impact of COVID-19 from April 2023 to April 2025 and assessed the extent to which vaccination can reduce hospitalizations and deaths. Under plausible assumptions about viral evolution and waning immunity, COVID-19 will likely cause annual epidemics peaking in November to January over the two-year projection period. Though significant, hospitalizations and deaths are unlikely to reach levels seen in previous winters. The projected health impacts of COVID-19 are reduced by 10% to 20% through moderate use of reformulated vaccines. What do these findings mean?: COVID-19 is projected to remain a significant public health threat in the coming years, exceeding the pre-pandemic mortality of influenza and pneumonia. Annual vaccination can reduce morbidity, mortality, and strain on health systems. While the projected impact of annual vaccination is significant, it is conditional on scenario assumptions including vaccine coverage and effectiveness. [ABSTRACT FROM AUTHOR]

Background: Acute neurological manifestation is a common complication of acute Coronavirus Disease 2019 (COVID-19) disease. This retrospective cohort study investigated the 3-year outcomes of patients with and without significant neurological manifestations during initial COVID-19 hospitalization. Methods and findings: Patients hospitalized for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection between 03/01/2020 and 4/16/2020 in the Montefiore Health System in the Bronx, an epicenter of the early pandemic, were included. Follow-up data was captured up to 01/23/2023 (3 years post-COVID-19). This cohort consisted of 414 patients with COVID-19 with significant neurological manifestations and 1,199 propensity-matched patients (for age and COVID-19 severity score) with COVID-19 without neurological manifestations. Neurological involvement during the acute phase included acute stroke, new or recrudescent seizures, anatomic brain lesions, presence of altered mentation with evidence for impaired cognition or arousal, and neuro-COVID-19 complex (headache, anosmia, ageusia, chemesthesis, vertigo, presyncope, paresthesias, cranial nerve abnormalities, ataxia, dysautonomia, and skeletal muscle injury with normal orientation and arousal signs). There were no significant group differences in female sex composition (44.93% versus 48.21%, p = 0.249), ICU and IMV status, white, not Hispanic (6.52% versus 7.84%, p = 0.380), and Hispanic (33.57% versus 38.20%, p = 0.093), except black non-Hispanic (42.51% versus 36.03%, p = 0.019). Primary outcomes were mortality, stroke, heart attack, major adverse cardiovascular events (MACE), reinfection, and hospital readmission post-discharge. Secondary outcomes were neuroimaging findings (hemorrhage, active and prior stroke, mass effect, microhemorrhages, white matter changes, microvascular disease (MVD), and volume loss). More patients in the neurological cohort were discharged to acute rehabilitation (10.39% versus 3.34%, p < 0.001) or skilled nursing facilities (35.75% versus 25.35%, p < 0.001) and fewer to home (50.24% versus 66.64%, p < 0.001) than matched controls. Incidence of readmission for any reason (65.70% versus 60.72%, p = 0.036), stroke (6.28% versus 2.34%, p < 0.001), and MACE (20.53% versus 16.51%, p = 0.032) was higher in the neurological cohort post-discharge. Per Kaplan–Meier univariate survival curve analysis, such patients in the neurological cohort were more likely to die post-discharge compared to controls (hazard ratio: 2.346, (95% confidence interval (CI) [1.586, 3.470]; p < 0.001)). Across both cohorts, the major causes of death post-discharge were heart disease (13.79% neurological, 15.38% control), sepsis (8.63%, 17.58%), influenza and pneumonia (13.79%, 9.89%), COVID-19 (10.34%, 7.69%), and acute respiratory distress syndrome (ARDS) (10.34%, 6.59%). Factors associated with mortality after leaving the hospital involved the neurological cohort (odds ratio (OR): 1.802 (95% CI [1.237, 2.608]; p = 0.002)), discharge disposition (OR: 1.508 (95% CI [1.276, 1.775]; p < 0.001)), congestive heart failure (OR: 2.281 (95% CI [1.429, 3.593]; p < 0.001)), higher COVID-19 severity score (OR: 1.177 (95% CI [1.062, 1.304]; p = 0.002)), and older age (OR: 1.027 (95% CI [1.010, 1.044]; p = 0.002)). There were no group differences in radiological findings, except that the neurological cohort showed significantly more age-adjusted brain volume loss (p = 0.045) than controls. The study's patient cohort was limited to patients infected with COVID-19 during the first wave of the pandemic, when hospitals were overburdened, vaccines were not yet available, and treatments were limited. Patient profiles might differ when interrogating subsequent waves. Conclusions: Patients with COVID-19 with neurological manifestations had worse long-term outcomes compared to matched controls. These findings raise awareness and the need for closer monitoring and timely interventions for patients with COVID-19 with neurological manifestations, as their disease course involving initial neurological manifestations is associated with enhanced morbidity and mortality. Tim Q Duong and colleagues investigate the 3-year outcomes of patients with and without significant neurological manifestations during initial COVID-19 hospitalization. Author summary: Why was this study done?: Neurological symptoms are present in both acute and long-term manifestations of Coronavirus Disease 2019 (COVID-19). Patients with acute neurological syndromes during COVID-19 hospitalization are known to have higher short-term mortality rates. Although acute outcomes of patients with COVID-19 and neurological manifestations are understood, the long-term sequelae of COVID-19 survivors who suffered acute neurological manifestations are unknown. What did the researchers do and find?: We used 2 cohorts, a neurological group and control group (propensity-matched) both of which were hospitalized for COVID-19, to evaluate long-term outcomes after discharge, up to 3 years later. A Kaplan–Meier survival analysis curve was built to analyze the different time-to-death in neurological and control cohorts, revealing that patients in the neurological cohort have shorter time-to-death than patients in the control cohort. Brain magnetic resonance imaging (MRI) and computed tomography (CT) studies were scored by radiologists and compared between neurological and control groups, although few group differences in structural abnormalities were observed. What do these findings mean?: Patients who suffer from neurological manifestations during COVID-19 hospitalization have worse long-term outcomes than controls. Patients who experienced neurological symptoms during acute COVID-19 infection need to be closely monitored at subsequent follow-up. This study came from a single health system with limited sample size. [ABSTRACT FROM AUTHOR]

Background: Alcohol consumption contributes to excess morbidity and mortality in part through the development of alcohol-related medical conditions (AMCs, including alcoholic cardiomyopathy, hepatitis, cirrhosis, etc.). The current study aimed to clarify the extent to which risk for these outcomes differs as a function of socioeconomic position (SEP), as discrepancies could lead to exacerbated health disparities. Methods and findings: We used longitudinal Swedish national registries to estimate the individual and joint associations between 2 SEP indicators, educational attainment and income level, and risk of AMC based on International Classification of Diseases codes, while controlling for other sociodemographic covariates and psychiatric illness. We conducted Cox proportional hazards models in sex-stratified analyses (N = 1,162,679 females and N = 1,196,659 males), beginning observation at age 40 with follow-up through December 2018, death, or emigration. By the end of follow-up, 4,253 (0.37%) females and 11,183 (0.93%) males had received an AMC registration, corresponding to overall AMC incidence rates among females and males of 2.01 and 5.20, respectively. In sex-stratified models adjusted for birth year, marital status, region of origin, internalizing and externalizing disorder registrations, and alcohol use disorder (AUD) registration, lower educational attainment was associated with higher risk of AMC in both females (hazard ratios [HRs] = 1.40 to 2.46 for low- and mid-level educational attainment across 0 to 15 years of observation) and males (HRs = 1.13 to 1.48). Likewise, risk of AMC was increased for those with lower income levels (females: HRs = 1.10 to 5.86; males: HRs = 1.07 to 6.41). In secondary analyses, we further adjusted for aggregate familial risk of AUD by including family genetic risk scores for AUD (FGRSAUD), estimated using medical, pharmacy, and criminal registries in extended families, as covariates. While FGRSAUD were associated with risk of AMC in adjusted models (HR = 1.17 for females and HR = 1.21 for males), estimates for education and income level remained largely unchanged. Furthermore, FGRSAUD interacted with income level, but not education level, such that those at higher familial liability to AUD were more susceptible to the adverse effect of low income. Limitations of these analyses include the possibility of false negatives for psychiatric illness registrations, changes in income after age 40 that were not accounted for due to modeling restrictions, restriction to residents of a high-income country, and the inability to account for individual-level alcohol consumption using registry data. Conclusions: Using comprehensive national registry data, these analyses demonstrate that individuals with lower levels of education and/or income are at higher risk of developing AMC. These associations persist even when accounting for a range of sociodemographic, psychiatric, and familial risk factors. Differences in risk could contribute to further health disparities, potentially warranting increased screening and prevention efforts in clinical and public health settings. Alexis Edwards and colleagues explore how educational attainment and income level correlate with the risk of developing medical conditions directly related to alcohol consumption. Author summary: Why was this study done?: Alcohol consumption contributes to worldwide excess morbidity and mortality, including conditions directly related to alcohol (alcohol-related medical conditions, AMCs) such as alcoholic liver disease. The extent to which socioeconomic position (SEP) is longitudinally associated with AMC risk is unclear, but important to understand as it may contribute to health disparities. What did the researchers do and find?: We employed a model that follows people over time to estimate their risk of AMC as a function of 2 SEP indicators: educational attainment and income. The model adjusted for other factors that might also be related to risk of AMC, such as marital status, history of psychiatric illness, and aggregate genetic liability to alcohol use disorder (AUD). We found that lower educational attainment and lower income were both associated with higher risk of AMC, even after accounting for other predictors. Individuals with higher genetic liability to AUD were at increased risk for AMC; these individuals were also more vulnerable to the negative effects of low income. What do these findings mean?: These results indicate that individuals with lower levels of educational attainment or lower incomes might warrant particular clinical attention with respect to screening or evaluation of alcohol consumption, as their risk of AMC is elevated. These differences in risk could exacerbate poor health outcomes among people with lower SEP. Clinicians should also be aware that individuals with a family history of AUD are at higher risk of alcohol-related medical morbidities. Limitations include the inability to account for individual differences in alcohol consumption, potential for excluding less severe AUD cases, and inability to extend findings to less wealthy countries. [ABSTRACT FROM AUTHOR]

Background: Adjuvants are widely used to enhance and/or direct vaccine-induced immune responses yet rarely evaluated head-to-head. Our trial directly compared immune responses elicited by MF59 versus alum adjuvants in the RV144-like HIV vaccine regimen modified for the Southern African region. The RV144 trial of a recombinant canarypox vaccine vector expressing HIV env subtype B (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost adjuvanted with alum is the only trial to have shown modest HIV vaccine efficacy. Data generated after RV144 suggested that use of MF59 adjuvant might allow lower protein doses to be used while maintaining robust immune responses. We evaluated safety and immunogenicity of an HIV recombinant canarypox vaccine vector expressing HIV env subtype C (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost (gp120) adjuvanted with alum (ALVAC-HIV+gp120/alum) or MF59 (ALVAC-HIV+gp120/MF59) or unadjuvanted (ALVAC-HIV+gp120/no-adjuvant) and a regimen where ALVAC-HIV+gp120 adjuvanted with MF59 was used for the prime and boost (ALVAC-HIV+gp120/MF59 coadministration). Methods and findings: Between June 19, 2017 and June 14, 2018, 132 healthy adults without HIV in South Africa, Zimbabwe, and Mozambique were randomized to receive intramuscularly: (1) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/MF59 (months 3, 6, and 12), n = 36; (2) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/alum (months 3, 6, and 12), n = 36; (3) 4 doses of ALVAC-HIV+gp120/MF59 coadministered (months 0, 1, 6, and 12), n = 36; or (4) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/no adjuvant (months 3, 6, and 12), n = 24. Primary outcomes were safety and occurrence and mean fluorescence intensity (MFI) of vaccine-induced gp120-specific IgG and IgA binding antibodies at month 6.5. All vaccinations were safe and well-tolerated; increased alanine aminotransferase was the most frequent related adverse event, occurring in 2 (1.5%) participants (1 severe, 1 mild). At month 6.5, vaccine-specific gp120 IgG binding antibodies were detected in 100% of vaccinees for all 4 vaccine groups. No significant differences were seen in the occurrence and net MFI of vaccine-specific IgA responses between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/alum-prime-boost groups or between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/MF59 coadministration groups. Limitations were the relatively small sample size per group and lack of evaluation of higher gp120 doses. Conclusions: Although MF59 was expected to enhance immune responses, alum induced similar responses to MF59, suggesting that the choice between these adjuvants may not be critical for the ALVAC+gp120 regimen. Trial registration: HVTN 107 was registered with the South African National Clinical Trials Registry (DOH-27-0715-4894) and ClinicalTrials.gov (NCT03284710). Zoe Moodie and colleagues investigate the safety and immunogenicity of a subtype C ALVAC-HIV vaccine prime plus bivalent subtype C gp120 vaccine boost adjuvanted with MF59 or alum in healthy adults without HIV. Author summary: Why was this study done?: Vaccines may use an adjuvant to help the body produce a stronger immune response. Results from animal studies suggested that the MF59 adjuvant generates better immunogenicity than the alum adjuvant when given as part of an HIV vaccine and could also allow a lower dose of protein to be used. Our clinical trial was done to directly assess in humans whether MF59 leads to better immune responses than alum when given with protein in a subtype C canarypox vaccine (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost (gp120). What did the researchers do and find?: Vaccines were safe and well-tolerated over the 18 months of follow-up. 100% of vaccinees had vaccine-specific gp120 IgG binding antibodies at month 6.5. Immune responses for the ALVAC-HIV+gp120/MF59 group and the ALVAC-HIV+gp120/alum group were similar. What do these findings mean?: Contrary to expectation, the choice between MF59 and alum does not seem critical to the immune responses assessed in the peripheral blood for this subtype C ALVAC-HIV+gp120 prime-boost regimen. The main limitations of our study were the small vaccine group sample sizes and that higher doses of gp120 protein were not evaluated. [ABSTRACT FROM AUTHOR]

Background: While national adoption of universal HIV treatment guidelines has led to improved, timely uptake of antiretroviral therapy (ART), longer-term care outcomes are understudied. There is little data from real-world service delivery settings on patient attrition, viral load (VL) monitoring, and viral suppression (VS) at 24 and 36 months after HIV treatment initiation. Methods and findings: For this retrospective cohort analysis, we used observational data from 25 countries in the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium's Asia-Pacific, Central Africa, East Africa, Central/South America, and North America regions for patients who were ART naïve and aged ≥15 years at care enrollment between 24 months before and 12 months after national adoption of universal treatment guidelines, occurring 2012 to 2018. We estimated crude cumulative incidence of loss-to-clinic (CI-LTC) at 12, 24, and 36 months after enrollment among patients enrolling in care before and after guideline adoption using competing risks regression. Guideline change–associated hazard ratios of LTC at each time point after enrollment were estimated via cause-specific Cox proportional hazards regression models. Modified Poisson regression was used to estimate relative risks of retention, VL monitoring, and VS at 12, 24, and 36 months after ART initiation. There were 66,963 patients enrolling in HIV care at 109 clinics with ≥12 months of follow-up time after enrollment (46,484 [69.4%] enrolling before guideline adoption and 20,479 [30.6%] enrolling afterwards). More than half (54.9%) were females, and median age was 34 years (interquartile range [IQR]: 27 to 43). Mean follow-up time was 51 months (standard deviation: 17 months; range: 12, 110 months). Among patients enrolling before guideline adoption, crude CI-LTC was 23.8% (95% confidence interval [95% CI] 23.4, 24.2) at 12 months, 31.0% (95% CI [30.6, 31.5]) at 24 months, and 37.2% (95% [CI 36.8, 37.7]) at 36 months after enrollment. Adjusting for sex, age group, enrollment CD4, clinic location and type, and country income level, enrolling in care and initiating ART after guideline adoption was associated with increased hazard of LTC at 12 months (adjusted hazard ratio [aHR] 1.25 [95% CI 1.08, 1.44]; p = 0.003); 24 months (aHR 1.38 [95% CI 1.19, 1.59]; p <.001); and 36 months (aHR 1.34 [95% CI 1.18, 1.53], p <.001) compared with enrollment before guideline adoption, with no before–after differences among patients with no record of ART initiation by end of follow-up. Among patients retained after ART initiation, VL monitoring was low, with marginal improvements associated with guideline adoption only at 12 months after ART initiation. Among those with VL monitoring, VS was high at each time point among patients enrolling before guideline adoption (86.0% to 88.8%) and afterwards (86.2% to 90.3%), with no substantive difference associated with guideline adoption. Study limitations include lags in and potential underascertainment of care outcomes in real-world service delivery data and potential lack of generalizability beyond IeDEA sites and regions included in this analysis. Conclusions: In this study, adoption of universal HIV treatment guidelines was associated with lower retention after ART initiation out to 36 months of follow-up, with little change in VL monitoring or VS among retained patients. Monitoring long-term HIV care outcomes remains critical to identify and address causes of attrition and gaps in HIV care quality. Using real-world service delivery data, Ellen Brazier and team examine long-term HIV care outcomes under universal HIV treatment guidelines across 25 countries. Author summary: Why was this study done?: Although universal HIV treatment recommendations have been adopted in national HIV treatment guidelines, longer-term HIV care outcomes under such guidelines are poorly documented and largely limited to single-country studies with short follow-up times. No multicountry studies using real-world service delivery data have examined long-term HIV care outcomes associated under universal HIV treatment guidelines. What did the researchers do and find?: With data on 66,963 patients enrolling in HIV care at 109 clinics participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) research consortium across 25 countries where universal HIV treatment guidelines were adopted, we estimated the hazard ratios of loss-to-clinic (LTC) at 12, 24, and 36 months after enrollment, comparing those enrolling in HIV care after guideline adoption to those enrolling before guideline adoption. Among 57,615 patients with documented initiation of antiretroviral therapy (ART), we also estimated the relative risks of clinic retention, viral load (VL) monitoring, and viral suppression (VS) at 12, 24, and 36 months after ART initiation, comparing those enrolling after versus before national adoption of universal treatment guidelines. Compared with patients enrolling in HIV care and initiating HIV treatment before national adoption of universal treatment guidelines, those enrolling and initiating treatment after guideline adoption had higher risk of being LTC at 12 months, 24 months, and 36 months after enrollment. Among patients retained in care after ART initiation, those enrolling in HIV care after the adoption of universal HIV treatment guidelines were more likely to have VL monitoring at 12 months after ART initiation and less likely at 36 months, with no difference at 24 months. VS was high at each time point among patients enrolling before and after the adoption of universal HIV treatment guidelines, with no substantive change associated with guideline adoption. What do these findings mean?: Our results raise concerns about long-term retention of patients after ART initiation, as well as the capacity of HIV programs to provide essential aspects of HIV care, including annual VL monitoring for timely identification of adherence problems and treatment failure. Our findings that patient retention in care at the clinic where ART was initiated decreased after the adoption of universal HIV treatment guidelines and that there has been no improvement in annual VL monitoring among patients retained in care should motivate efforts to identify and address factors associated with attrition among patients enrolling in HIV care, as well as barriers to routine VL testing in the era of universal treatment of all people living with HIV. Study limitations include potential underascertainment of patient outcomes in real-world service delivery data, lags in the availability of real-world service delivery data, and the nonrepresentativeness of the clinics and countries reflected in IeDEA datasets available for analysis. [ABSTRACT FROM AUTHOR]

Background: The incidence of prostate cancer is increasing in older males globally. Age, ethnicity, and family history are identified as the well-known risk factors for prostate cancer, but few modifiable factors have been firmly established. The objective of this study was to identify and evaluate various factors modifying the risk of prostate cancer reported in meta-analyses of prospective observational studies and mendelian randomization (MR) analyses. Methods and findings: We searched PubMed, Embase, and Web of Science from the inception to January 10, 2022, updated on September 9, 2023, to identify meta-analyses and MR studies on prostate cancer. Eligibility criteria for meta-analyses were (1) meta-analyses including prospective observational studies or studies that declared outcome-free at baseline; (2) evaluating the factors of any category associated with prostate cancer incidence; and (3) providing effect estimates for further data synthesis. Similar criteria were applied to MR studies. Meta-analysis was repeated using the random-effects inverse-variance model with DerSimonian—Laird method. Quality assessment was then conducted for included meta-analyses using AMSTAR-2 tool and for MR studies using STROBE-MR and assumption evaluation. Subsequent evidence grading criteria for significant associations in meta-analyses contained sample size, P values and 95% confidence intervals, 95% prediction intervals, heterogeneity, and publication bias, assigning 4 evidence grades (convincing, highly suggestive, suggestive, or weak). Significant associations in MR studies were graded as robust, probable, suggestive, or insufficient considering P values and concordance of effect directions. Finally, 92 selected from 411 meta-analyses and 64 selected from 118 MR studies were included after excluding the overlapping and outdated studies which were published earlier and contained fewer participants or fewer instrument variables for the same exposure. In total, 123 observational associations (45 significant and 78 null) and 145 causal associations (55 significant and 90 null) were categorized into lifestyle; diet and nutrition; anthropometric indices; biomarkers; clinical variables, diseases, and treatments; and environmental factors. Concerning evidence grading on significant associations, there were 5 highly suggestive, 36 suggestive, and 4 weak associations in meta-analyses, and 10 robust, 24 probable, 4 suggestive, and 17 insufficient causal associations in MR studies. Twenty-six overlapping factors between meta-analyses and MR studies were identified, with consistent significant effects found for physical activity (PA) (occupational PA in meta: OR = 0.87, 95% CI: 0.80, 0.94; accelerator-measured PA in MR: OR = 0.49, 95% CI: 0.33, 0.72), height (meta: OR = 1.09, 95% CI: 1.06, 1.12; MR: OR = 1.07, 95% CI: 1.01, 1.15, for aggressive prostate cancer), and smoking (current smoking in meta: OR = 0.74, 95% CI: 0.68, 0.80; smoking initiation in MR: OR = 0.91, 95% CI: 0.86, 0.97). Methodological limitation is that the evidence grading criteria could be expanded by considering more indices. Conclusions: In this large-scale study, we summarized the associations of various factors with prostate cancer risk and provided comparisons between observational associations by meta-analysis and genetically estimated causality by MR analyses. In the absence of convincing overlapping evidence based on the existing literature, no robust associations were identified, but some effects were observed for height, physical activity, and smoking. Huijie Cui and team identify and evaluate various risk factors of prostate cancer reported in meta-analyses of prospective observational studies and Mendelian randomization analyses. Author summary: Why was this study done?: The incidence of prostate cancer is increasing with the growing trend of aging globally. Effective preventions and interventions for prostate cancer require better understandings of its etiology. The well-known risk factors for prostate cancer are age, ethnicity, and family history, but few modifiable factors have been firmly established. What did the researchers do and find?: Our study extensively collected, evaluated, and compared the current observational and genetic evidence for various factors modifying the risk of prostate cancer based on meta-analyses and Mendelian randomization (MR) studies. Totally 123 observational associations (45 significant and 78 null) from 92 meta-analyses and 145 causal associations (55 significant and 90 null) from 64 MR studies were identified and categorized into lifestyle; diet and nutrition; anthropometric indices; biomarkers; clinical variables, diseases, and treatments; and environmental factors. Concerning evidence grading on significant associations, there were 5 highly suggestive, 36 suggestive, and 4 weak associations in meta-analyses, and 10 robust, 24 probable, 4 suggestive, and 17 insufficient causal associations in MR studies. Consistent significant associations between meta-analysis and MR studies were found for physical activity, height, and smoking, which however were not robust. What do these findings mean?: Most included cohort studies were conducted in developed western countries, and hence the findings in this study are limited for mainly European descendants. The comparison between observational associations by meta-analysis and genetically estimated causality by MR analyses does not provide robust evidence due to the lack of overlapping associations and high-quality evidence, especially in MR studies. Evidence grading criteria for meta-analyses could be further improved by adding more indices such as magnitude of effect size and different levels of sample size. [ABSTRACT FROM AUTHOR]

Background: Antibiotic usage, contact with high transmission healthcare settings as well as changes in immune system function all vary by a patient's age and sex. Yet, most analyses of antimicrobial resistance (AMR) ignore demographic indicators and provide only country-level resistance prevalence values. This study aimed to address this knowledge gap by quantifying how resistance prevalence and incidence of bloodstream infection (BSI) varied by age and sex across bacteria and antibiotics in Europe. Methods and findings: We used patient-level data collected as part of routine surveillance between 2015 and 2019 on BSIs in 29 European countries from the European Antimicrobial Resistance Surveillance Network (EARS-Net). A total of 6,862,577 susceptibility results from isolates with age, sex, and spatial information from 944,520 individuals were used to characterise resistance prevalence patterns for 38 different bacterial species and antibiotic combinations, and 47% of these susceptibility results were from females, with a similar age distribution in both sexes (mean of 66 years old). A total of 349,448 isolates from 2019 with age and sex metadata were used to calculate incidence. We fit Bayesian multilevel regression models by country, laboratory code, sex, age, and year of sample to quantify resistant prevalence and provide estimates of country-, bacteria-, and drug-family effect variation. We explore our results in greater depths for 2 of the most clinically important bacteria–antibiotic combinations (aminopenicillin resistance in Escherichia coli and methicillin resistance in Staphylococcus aureus) and present a simplifying indicative index of the difference in predicted resistance between old (aged 100) and young (aged 1). At the European level, we find distinct patterns in resistance prevalence by age. Trends often vary more within an antibiotic family, such as fluroquinolones, than within a bacterial species, such as Pseudomonas aeruginosa. Clear resistance increases by age for methicillin-resistant Staphylococcus aureus (MRSA) contrast with a peak in resistance to several antibiotics at approximately 30 years of age for P. aeruginosa. For most bacterial species, there was a u-shaped pattern of infection incidence with age, which was higher in males. An important exception was E. coli, for which there was an elevated incidence in females between the ages of 15 and 40. At the country-level, subnational differences account for a large amount of resistance variation (approximately 38%), and there are a range of functional forms for the associations between age and resistance prevalence. For MRSA, age trends were mostly positive, with 72% (n = 21) of countries seeing an increased resistance between males aged 1 and 100 years and a greater change in resistance in males. This compares to age trends for aminopenicillin resistance in E. coli which were mostly negative (males: 93% (n = 27) of countries see decreased resistance between those aged 1 and 100 years) with a smaller change in resistance in females. A change in resistance prevalence between those aged 1 and 100 years ranged up to 0.51 (median, 95% quantile of model simulated prevalence using posterior parameter ranges 0.48, 0.55 in males) for MRSA in one country but varied between 0.16 (95% quantile 0.12, 0.21 in females) to −0.27 (95% quantile −0.4, −0.15 in males) across individual countries for aminopenicillin resistance in E. coli. Limitations include potential bias due to the nature of routine surveillance and dependency of results on model structure. Conclusions: In this study, we found that the prevalence of resistance in BSIs in Europe varies substantially by bacteria and antibiotic over the age and sex of the patient shedding new light on gaps in our understanding of AMR epidemiology. Future work is needed to determine the drivers of these associations in order to more effectively target transmission and antibiotic stewardship interventions. Naomi R Waterlow and colleagues leverage data from 29 countries across Europe to determine how antimicrobial resistance varies by age and sex. Author summary: Why was this study done?: Antimicrobial resistance (AMR) is a major global public health threat, but little is known about how the prevalence of resistance varies with age and sex. What did the researchers do and find?: We explored patterns of resistance prevalence and incidence by age and sex in routinely collected data from bloodstream infections (BSIs) across Europe for 8 bacterial species. We fitted a Bayesian multilevel regression model to quantify the variation nationally and subnationally. Distinct patterns in resistance prevalence by age were observed across Europe for different bacteria. Sex was often only weakly associated with resistance, except across ages in Escherichia coli and Klebsiella pneumoniae, and at younger ages for Acinetobacter species, where it was higher in males. What do these findings mean?: These findings highlight important gaps in our knowledge of the epidemiology of AMR that are difficult to explain through known patterns of antibiotic exposure and healthcare contact. Differences in AMR burden by age and sex may be explained by cultural differences between countries as well as variation in pathways to infection between bacteria. Our findings suggest that there may be value in considering interventions to reduce AMR burden that take into account important variations in AMR prevalence with age and sex. This study is limited by the nature of routine surveillance, the lack of open availability of disaggregated data, and the model structures explored. [ABSTRACT FROM AUTHOR]

Background: Population mental health in the United Kingdom (UK) has deteriorated, alongside worsening socioeconomic conditions, over the last decade. Policies such as Universal Basic Income (UBI) have been suggested as an alternative economic approach to improve population mental health and reduce health inequalities. UBI may improve mental health (MH), but to our knowledge, no studies have trialled or modelled UBI in whole populations. We aimed to estimate the short-term effects of introducing UBI on mental health in the UK working-age population. Methods and findings: Adults aged 25 to 64 years were simulated across a 4-year period from 2022 to 2026 with the SimPaths microsimulation model, which models the effects of UK tax/benefit policies on mental health via income, poverty, and employment transitions. Data from the nationally representative UK Household Longitudinal Study were used to generate the simulated population (n = 25,000) and causal effect estimates. Three counterfactual UBI scenarios were modelled from 2023: "Partial" (value equivalent to existing benefits), "Full" (equivalent to the UK Minimum Income Standard), and "Full+" (retaining means-tested benefits for disability, housing, and childcare). Likely common mental disorder (CMD) was measured using the General Health Questionnaire (GHQ-12, score ≥4). Relative and slope indices of inequality were calculated, and outcomes stratified by gender, age, education, and household structure. Simulations were run 1,000 times to generate 95% uncertainty intervals (UIs). Sensitivity analyses relaxed SimPaths assumptions about reduced employment resulting from Full/Full+ UBI. Partial UBI had little impact on poverty, employment, or mental health. Full UBI scenarios practically eradicated poverty but decreased employment (for Full+ from 78.9% [95% UI 77.9, 79.9] to 74.1% [95% UI 72.6, 75.4]). Full+ UBI increased absolute CMD prevalence by 0.38% (percentage points; 95% UI 0.13, 0.69) in 2023, equivalent to 157,951 additional CMD cases (95% UI 54,036, 286,805); effects were largest for men (0.63% [95% UI 0.31, 1.01]) and those with children (0.64% [95% UI 0.18, 1.14]). In our sensitivity analysis assuming minimal UBI-related employment impacts, CMD prevalence instead fell by 0.27% (95% UI −0.49, −0.05), a reduction of 112,228 cases (95% UI 20,783, 203,673); effects were largest for women (−0.32% [95% UI −0.65, 0.00]), those without children (−0.40% [95% UI −0.68, −0.15]), and those with least education (−0.42% [95% UI −0.97, 0.15]). There was no effect on educational mental health inequalities in any scenario, and effects waned by 2026. The main limitations of our methods are the model's short time horizon and focus on pathways from UBI to mental health solely via income, poverty, and employment, as well as the inability to integrate macroeconomic consequences of UBI; future iterations of the model will address these limitations. Conclusions: UBI has potential to improve short-term population mental health by reducing poverty, particularly for women, but impacts are highly dependent on whether individuals choose to remain in employment following its introduction. Future research modelling additional causal pathways between UBI and mental health would be beneficial. Rachel M Thomson and colleagues used a policy model to simulate how a Universal Basic Income might influence mental health for working-age adults in the UK. Author summary: Why was this study done?: Universal Basic Income (UBI) is a radical social security policy proposal where everyone in a society would receive a regular, unconditional cash payment. It has been suggested that UBI might be beneficial for mental health. However, there has never been a trial of a true UBI in a high-income country to know what its potential mental health impacts might be. What did the researchers do and find?: We used a policy model to simulate how a UBI might influence mental health for working-age adults in the United Kingdom. We found that the effects of UBI were very sensitive to assumptions we made about how people's employment choices might respond to receiving the money—if people choose to stay in work, UBI may have small benefits for population mental health, but if people are more likely to leave work, population mental health may actually worsen. The groups most likely to experience positive mental health effects of UBI were women and those with the lowest educational qualifications. What do these findings mean?: UBI may have potential to improve population mental health in high-income countries, but only if people do not choose to leave work in response to the policy. More real-world research is needed to know how people are likely to respond to receiving a UBI in reality. The main limitation of our modelling study is that it looks at how UBI would influence mental health only through income and employment, and other pathways might also be important to include in future research. [ABSTRACT FROM AUTHOR]

Background: Endometrial hyperplasia (EH) is a precusor lesion for endometrial cancer (EC), the commonest gynaecological malignancy in high-income countries. EH is a proliferation of glandular tissue, classified as either non-atypical endometrial hyperplasia (NEH) or, if the cytological features are abnormal, atypical endometrial hyperplasia (AEH). The clinical significance of AEH is that patients face both a high risk of having occult EC and a high risk of progression to EC if untreated. Recommendations on the care of women with EH were introduced by United Kingdom–wide guidance (Green-top Guide No. 67, 2016). National adherence to guidance is unknown. We aimed to describe the care of patients with EH; to compare the patterns of care for those with EH with national guidance to identify opportunities for quality improvement; and to compare patterns of care prior to and following the introduction of national guidance to understand its impact. Methods and findings: In this UK-wide patient-level clinical audit, we included 3,307 women who received a new histological diagnosis of EH through a gynaecology service between 1 January 2012 and 30 June 2020. We described first-line management, management at 2 years, and surgical characteristics prior to and following national guidance for EH using proportions and 95% confidence intervals (CIs) and compared process measures between time periods using multilevel Poisson regression. Of the 3,307 patients, 1,570 had NEH and 1,511 had AEH between 2012 and 2019. An additional 85 patients had NEH and 141 had AEH during 2020. Prior to national guidance, 9% (95% CI [6%, 15%]) received no initial treatment for NEH compared with 3% (95% CI [1%, 5%]) post-guidance; 31% (95% CI [26%, 36%]) and 48% (95% CI [43% 53%]) received an intrauterine progestogen, respectively, in the same periods. The predominant management of women with AEH did not differ, with 68% (95% CI [61%, 74%]) and 67% (95 CI [63%, 71%]) receiving first-line hysterectomy, respectively. By 2 years, follow-up to histological regression without hysterectomy increased from 38% (95% CI [33%, 43%]) to 52% (95% CI [47%, 58%]) for those with NEH (rate ratio (RR) 1.38, 95% CI [1.18, 1.63] p < 0.001). We observed an increase in the use of total laparoscopic hysterectomy among those with AEH (RR 1.26, 95% CI [1.04, 1.52]). In the later period, 37% (95% CI [29%, 44%]) of women initially diagnosed with AEH who underwent a first-line hysterectomy, received an upgraded diagnosis of EC. Study limitations included retrospective data collection from routine clinical documentation and the inability to comprehensively understand the shared decision-making process where care differed from guidance. Conclusions: The care of patients with EH has changed in accordance with national guidance. More women received first-line medical management of NEH and were followed up to histological regression. The follow-up of those with AEH who do not undergo hysterectomy must be improved, given their very high risk of coexistent cancer and high risk of developing cancer. Author summary: Why was this study done?: New national guidance was introduced in the United Kingdom with recommendations for the care and surveillance of people with endometrial hyperplasia (EH). Comparing patterns of care with these recommendations has identified opportunities for improvement. What did the researchers do and find?: After the guidance, medical treatment of non-atypical hyperplasia increased and more patients achieved histological regression, avoiding hysterectomy. Surveillance of hyperplasia for those who do not undergo hysterectomy could be improved. A greater proportion of women with atypia diagnosed in 2020 commenced medical management and fewer underwent hysterectomy; the impact of the pandemic on care must be considered as a contributory factor towards this. What do these findings mean?: This work has identified where the care of patients with EH diverged from recommended guidance. Clinicians may use these findings to review their local care pathways and quality assurance processes so that they can improve the care of women with EH. The main limitation was the retrospective collection of data from routine clinical documentation. [ABSTRACT FROM AUTHOR]

Background: Expanding access to shorter regimens for tuberculosis (TB) prevention, such as once-weekly isoniazid and rifapentine taken for 3 months (3HP), is critical for reducing global TB burden among people living with HIV (PLHIV). Our coprimary hypotheses were that high levels of acceptance and completion of 3HP could be achieved with delivery strategies optimized to overcome well-contextualized barriers and that 3HP acceptance and completion would be highest when PLHIV were provided an informed choice between delivery strategies. Methods and findings: In a pragmatic, single-center, 3-arm, parallel-group randomized trial, PLHIV receiving care at a large urban HIV clinic in Kampala, Uganda, were randomly assigned (1:1:1) to receive 3HP by facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid. We assessed the primary outcome of acceptance and completion (≥11 of 12 doses of 3HP) within 16 weeks of treatment initiation using proportions with exact binomial confidence intervals (CIs). We compared proportions between arms using Fisher's exact test (two-sided α = 0.025). Trial investigators were blinded to primary and secondary outcomes by study arm. Between July 13, 2020, and July 8, 2022, 1,656 PLHIV underwent randomization, with equal numbers allocated to each study arm. One participant was erroneously enrolled a second time and was excluded in the primary intention-to-treat analysis. Among the remaining 1,655 participants, the proportion who accepted and completed 3HP exceeded the prespecified 80% target in the DOT (0.94; 97.5% CI [0.91, 0.96] p < 0.001), SAT (0.92; 97.5% CI [0.89, 0.94] p < 0.001), and Choice (0.93; 97.5% CI [0.91, 0.96] p < 0.001) arms. There was no difference in acceptance and completion between any 2 arms overall or in prespecified subgroup analyses based on sex, age, time on antiretroviral therapy, and history of prior treatment for TB or TB infection. Only 14 (0.8%) participants experienced an adverse event prompting discontinuation of 3HP. The main limitation of the study is that it was conducted in a single center. Multicenter studies are now needed to confirm the feasibility and generalizability of the facilitated 3HP delivery strategies in other settings. Conclusions: Short-course TB preventive treatment was widely accepted by PLHIV in Uganda, and very high levels of treatment completion were achieved in a programmatic setting with delivery strategies tailored to address known barriers. Trial Registration: ClinicalTrials.govNCT03934931. Fred C. Semitala and colleagues compared three delivery strategies for the completion of Isoniazid-Rifapentine for tuberculosis prevention among people living with HIV in Uganda. Author summary: Why was this study done?: There is limited evidence on strategies that achieve high acceptance and completion of tuberculosis (TB) preventive therapy in the context of routine HIV/AIDS care, despite recommendations from the World Health Organization for its scale-up in high-burden HIV/TB settings. Two previous implementation trials have assessed delivery of 12 weeks of isoniazid and rifapentine (3HP) by self-administered therapy (SAT) in high-burden settings and found variable completion rates. In both studies, 3HP dosing and treatment supervision were conducted by research staff rather than by routine health workers. What did the researchers do and find?: In a pragmatic trial,1,655 people living with HIV (PLHIV) at a high-volume clinic in Kampala, Uganda, received 3HP either by facilitated directly observed therapy (DOT) involving a pharmacy technician, facilitated SAT, or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid. We found high levels of 3HP completion in the context of routine HIV/AIDS care. The high treatment completion rates were independent of 3HP delivery strategy. What do these findings mean?: High levels of 3HP treatment completion are achievable in routine programmatic settings when delivery strategies are optimized to overcome known barriers. A limitation of the study is that it was conducted at a single center. Further studies are needed to confirm the findings and the feasibility of the facilitation strategies in other settings. [ABSTRACT FROM AUTHOR]

Background: Ethnic minorities living in high-income countries have been disproportionately affected by Coronavirus Disease 2019 (COVID-19) in terms of infection rates, hospitalisations, and deaths; however, less is known about long COVID in these populations. Our aim was to examine the risk of long COVID and associated symptoms among ethnic minorities. Methods and findings: We used nationwide register-based cohort data on individuals diagnosed with COVID-19 aged ≥18 years (n = 2,286,955) between January 2020 and August 2022 in Denmark. We calculated the risk of long COVID diagnosis and long COVID symptoms among ethnic minorities compared with native Danes using multivariable Cox proportional hazard regression and logistic regression, respectively. Among individuals who were first time diagnosed with COVID-19 during the study period, 39,876 (1.7%) were hospitalised and 2,247,079 (98.3%) were nonhospitalised individuals. Of the diagnosed COVID-19 cases, 1,952,021 (85.3%) were native Danes and 334,934 (14.7%) were ethnic minorities. After adjustment for age, sex, civil status, education, family income, and Charlson comorbidity index, ethnic minorities from North Africa (adjusted hazard ratio [aHR] 1.41, 95% confidence interval [CI] [1.12,1.79], p = 0.003), Middle East (aHR 1.38, 95% CI [1.24,1.55], p < 0.001), Eastern Europe (aHR 1.35, 95% CI [1.22,1.49], p < 0.001), and Asia (aHR 1.23, 95% CI [1.09,1.40], p = 0.001) had significantly greater risk of long COVID diagnosis than native Danes. In the analysis by largest countries of origin, the greater risks of long COVID diagnosis were found in people of Iraqi origin (aHR 1.56, 95% CI [1.30,1.88], p < 0.001), people of Turkish origin (aHR 1.42, 95% CI [1.24,1.63], p < 0.001), and people of Somali origin (aHR 1.42, 95% CI [1.07,1.91], p = 0.016). A significant factor associated with an increased risk of long COVID diagnosis was COVID-19 hospitalisation. The risk of long COVID diagnosis among ethnic minorities was more pronounced between January 2020 and June 2021. Furthermore, the odds of reporting cardiopulmonary symptoms (including dyspnoea, cough, and chest pain) and any long COVID symptoms were higher among people of North African, Middle Eastern, Eastern European, and Asian origins than among native Danes in both unadjusted and adjusted models. Despite including the nationwide sample of individuals diagnosed with COVID-19, the precision of our estimates on long COVID was limited to the sample of patients with symptoms who had contacted the hospital. Conclusions: Belonging to an ethnic minority group was significantly associated with an increased risk of long COVID, indicating the need to better understand long COVID drivers and address care and treatment strategies in these populations. George F. Mkoma and colleagues examine the risk of long COVID and associated symptoms among ethnic minorities in Denmark. Author summary: Why was this study done?: Evidence indicates overrepresentation of ethnic minorities among those tested positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), hospitalised for Coronavirus Disease 2019 (COVID-19), and died from COVID-19. After acute COVID-19 infection, many COVID-19 survivors experience a range of symptoms persisting beyond weeks or months, the condition known as long COVID. However, little is known about the risk of long COVID among ethnic minorities, and no existing studies had compared symptoms distribution before and after COVID-19 diagnosis in these populations. What did the researchers do and find?: A nationwide register-based cohort study was performed on individuals diagnosed with COVID-19 between January 2020 and August 2022 in Denmark. We found that people of North African, Middle Eastern, Eastern European, and Asian origins had a higher risk of long COVID diagnosis than native Danes, with the greatest ethnic disparities being observed in the early phase of COVID-19 pandemic (January 2020 to June 2021). People of North African, Middle Eastern, Eastern European, and Asian origins were more likely to report cardiopulmonary symptoms (including dyspnoea, cough, and chest pain) and any long COVID symptoms than native Danes, especially beyond 4 weeks to 6 months after COVID-19 diagnosis. What do these findings mean?: These findings indicate the need to understand the drivers of long COVID in ethnic minorities and tailor preventive policies to their contexts. Efforts addressing disparities in socioeconomic conditions, advocacy activities for COVID-19 vaccines, and continuation of preventive measures may help reduce the burden of long COVID in ethnic minorities. The diagnosis of long COVID was limited to the sample of patients with symptoms who had contacted the hospital after acute COVID-19 infection. [ABSTRACT FROM AUTHOR]

Background: World Health Organization (WHO) guidelines recommend cotrimoxazole prophylaxis for children who are HIV-exposed until infection is excluded and vertical transmission risk has ended. While cotrimoxazole has benefits for children with HIV, there is no mortality benefit for children who are HIV-exposed but uninfected, prompting a review of global guidelines. Here, we model the potential impact of alternative cotrimoxazole strategies on mortality in children who are HIV-exposed. Methods and findings: Using a deterministic compartmental model, we estimated mortality in children who are HIV-exposed from 6 weeks to 2 years of age in 4 high-burden countries: Côte d'Ivoire, Mozambique, Uganda, and Zimbabwe. Vertical transmission rates, testing rates, and antiretroviral therapy (ART) uptake were derived from UNAIDS data, trial evidence, and meta-analyses. We explored 6 programmatic strategies: maintaining current recommendations; shorter cotrimoxazole provision for 3, 6, 9, or 12 months; and starting cotrimoxazole only for children diagnosed with HIV. Modelled alternatives to the current strategy increased mortality to varying degrees; countries with high vertical transmission had the greatest mortality. Compared to current recommendations, starting cotrimoxazole only after a positive HIV test had the greatest predicted increase in mortality: Mozambique (961 excess annual deaths; excess mortality 339 per 100,000 HIV-exposed children; risk ratio (RR) 1.06), Uganda (491; 221; RR 1.04), Zimbabwe (352; 260; RR 1.05), and Côte d'Ivoire (125; 322; RR 1.06). Similar effects were observed for 3-, 6-, 9-, and 12-month strategies. Increased mortality persisted but was attenuated when modelling lower cotrimoxazole uptake, smaller mortality benefits, higher testing coverage, and lower vertical transmission rates. The study is limited by uncertain estimates of cotrimoxazole coverage in programmatic settings; an inability to model increases in mortality arising from antimicrobial resistance due to limited surveillance data in sub-Saharan Africa; and lack of a formal health economic analysis. Conclusions: Changing current guidelines from universal cotrimoxazole provision for children who are HIV-exposed increased predicted mortality across the 4 modelled high-burden countries, depending on test-to-treat cascade coverage and vertical transmission rates. These findings can help inform policymaker deliberations on cotrimoxazole strategies, recognising that the risks and benefits differ across settings. Mathur and colleagues estimate the potential impact of alternative cotrimoxazole strategies on mortality in children born to mothers with HIV in Côte d'Ivoire, Mozambique, Uganda, and Zimbabwe. Author summary: Why was this study done?: Cotrimoxazole prophylaxis is recommended in World Health Organization (WHO) guidelines for all children born to mothers with HIV until HIV infection has been excluded by an age-appropriate HIV test to establish the final diagnosis after complete cessation of breastfeeding. Though there is a proven mortality benefit for children who acquire HIV, recent trial evidence has shown that cotrimoxazole does not reduce mortality for majority of children who are HIV-exposed uninfected (HEU), which has led to countries considering changing their guidelines. In many resource-limited settings, however, it is difficult to reliably distinguish children with HIV from children who are HEU, due to incomplete coverage of early infant diagnosis (EID) of HIV. There is a need to model to what extent alternative cotrimoxazole strategies, which either do not provide universal cotrimoxazole for all infants who are HIV-exposed, or provide it for a shorter duration, would be predicted to increase mortality in different settings among infants who acquire HIV but are undiagnosed. What did the researchers do and find?: This study uses mathematical modelling based on epidemiological data from 4 high-burden settings (Côte d'Ivoire, Mozambique, Uganda, and Zimbabwe) to estimate the effect on mortality of alternative programmatic cotrimoxazole strategies. The model incorporates the HIV status of the infant, perinatal and postnatal transmission rates, testing rates, and mortality benefits from trial evidence for cotrimoxazole and antiretroviral therapy (ART) across 6 different programmatic strategies: maintaining current recommendations; reducing the duration of cotrimoxazole provision to 3, 6, 9, or 12 months; or starting cotrimoxazole only once a child tests positive for HIV. We demonstrate that changing the current strategy is predicted to increase mortality in all 4 settings, with the greatest increase in mortality in countries with the highest vertical transmission rates. Increased predicted mortality persisted in sensitivity analyses considering conservative model estimates, although cotrimoxazole had fewer predicted benefits when vertical transmission rates were lowered, testing coverage improved or uptake of cotrimoxazole was reduced. What do these findings mean?: Changing the current strategy of cotrimoxazole provision for all children born to mothers with HIV is estimated to increase mortality in these 4 high-burden settings to varying degrees as countries continue to scale up prevention of mother-to-child transmission (PMTCT) of HIV and EID coverage. Cotrimoxazole continues to provide important protection to children who acquire HIV and are missed by gaps in the test-to-treatment cascade, but does not replace the importance of timely testing and treatment. Our study is limited by lack of cost-effectiveness analysis, lack of data on cotrimoxazole uptake, and limited antimicrobial resistance surveillance data in sub-Saharan Africa. Policymakers need to weigh the risks and benefits of cotrimoxazole prophylaxis through any change to current recommendations, noting that these differ across settings: where lower vertical transmission rates and improved testing and treatment uptake occurs, the estimated mortality benefits of cotrimoxazole are attenuated. [ABSTRACT FROM AUTHOR]

Background: The occurrence of a range of health outcomes following myocardial infarction (MI) is unknown. Therefore, this study aimed to determine the long-term risk of major health outcomes following MI and generate sociodemographic stratified risk charts in order to inform care recommendations in the post-MI period and underpin shared decision making. Methods and findings: This nationwide cohort study includes all individuals aged ≥18 years admitted to one of 229 National Health Service (NHS) Trusts in England between 1 January 2008 and 31 January 2017 (final follow-up 27 March 2017). We analysed 11 non-fatal health outcomes (subsequent MI and first hospitalisation for heart failure, atrial fibrillation, cerebrovascular disease, peripheral arterial disease, severe bleeding, renal failure, diabetes mellitus, dementia, depression, and cancer) and all-cause mortality. Of the 55,619,430 population of England, 34,116,257 individuals contributing to 145,912,852 hospitalisations were included (mean age 41.7 years (standard deviation [SD 26.1]); n = 14,747,198 (44.2%) male). There were 433,361 individuals with MI (mean age 67.4 years [SD 14.4)]; n = 283,742 (65.5%) male). Following MI, all-cause mortality was the most frequent event (adjusted cumulative incidence at 9 years 37.8% (95% confidence interval [CI] [37.6,37.9]), followed by heart failure (29.6%; 95% CI [29.4,29.7]), renal failure (27.2%; 95% CI [27.0,27.4]), atrial fibrillation (22.3%; 95% CI [22.2,22.5]), severe bleeding (19.0%; 95% CI [18.8,19.1]), diabetes (17.0%; 95% CI [16.9,17.1]), cancer (13.5%; 95% CI [13.3,13.6]), cerebrovascular disease (12.5%; 95% CI [12.4,12.7]), depression (8.9%; 95% CI [8.7,9.0]), dementia (7.8%; 95% CI [7.7,7.9]), subsequent MI (7.1%; 95% CI [7.0,7.2]), and peripheral arterial disease (6.5%; 95% CI [6.4,6.6]). Compared with a risk-set matched population of 2,001,310 individuals, first hospitalisation of all non-fatal health outcomes were increased after MI, except for dementia (adjusted hazard ratio [aHR] 1.01; 95% CI [0.99,1.02];p = 0.468) and cancer (aHR 0.56; 95% CI [0.56,0.57];p < 0.001). The study includes data from secondary care only—as such diagnoses made outside of secondary care may have been missed leading to the potential underestimation of the total burden of disease following MI. Conclusions: In this study, up to a third of patients with MI developed heart failure or renal failure, 7% had another MI, and 38% died within 9 years (compared with 35% deaths among matched individuals). The incidence of all health outcomes, except dementia and cancer, was higher than expected during the normal life course without MI following adjustment for age, sex, year, and socioeconomic deprivation. Efforts targeted to prevent or limit the accrual of chronic, multisystem disease states following MI are needed and should be guided by the demographic-specific risk charts derived in this study. Using hospital records of 34 million adults admitted to hospitals in England, Marlous Hall and team examine the long-term risk of major health outcomes following myocardial infarction. Author summary: Why was this study done?: Myocardial infarction (MI; heart attack) can have major long-term impact on individuals and result in a wide range of further health conditions. Existing studies have focussed on determining the short-term risk of a second heart attack, stroke, or major bleeding, but research describing the long-term risk of major health outcomes for specific age, sex, and deprivation groups was lacking. Nationally representative and robust information of a wide range of long-term health outcomes following a heart attack is critical for the development of treatment recommendations, which take account of an individuals' specific risk. What did the researchers do and find?: From the population of 56 million adults in England, we analysed hospital records for 34 million adults admitted to hospital (constituting 145 million admission records) to investigate the long-term health outcomes following a heart attack compared with individuals without a heart attack. Of 433,361 individuals with a heart attack, up to a third developed heart failure or renal failure, 7% had further heart attacks, and 38% died within the 9-year study period. Heart failure, atrial fibrillation, stroke, peripheral arterial disease, severe bleeding, renal failure, diabetes, and depression occurred more frequently for people who had a heart attack compared with those who did not, but the risk of cancer was lower overall and the risk of dementia did not differ overall. What do these findings mean?: Efforts should be made to prevent or limit the development of long-term health outcomes that follow a heart attack—the likelihood of which differ depending on the age, sex, and deprivation of an individual. These findings are based on the full population of adults admitted to hospital in England, address limitations of previous studies, and can be used to inform preventative strategies tailored to specific individuals surviving a heart attack. The study was limited to hospitalisation data only—therefore, some diagnoses made outside of hospital may have been missed. [ABSTRACT FROM AUTHOR]

Background: Emulsifiers are widely used food additives in industrially processed foods to improve texture and enhance shelf-life. Experimental research suggests deleterious effects of emulsifiers on the intestinal microbiota and the metabolome, leading to chronic inflammation and increasing susceptibility to carcinogenesis. However, human epidemiological evidence investigating their association with cancer is nonexistent. This study aimed to assess associations between food additive emulsifiers and cancer risk in a large population-based prospective cohort. Methods and findings: This study included 92,000 adults of the French NutriNet-Santé cohort without prevalent cancer at enrolment (44.5 y [SD: 14.5], 78.8% female, 2009 to 2021). They were followed for an average of 6.7 years [SD: 2.2]. Food additive emulsifier intakes were estimated for participants who provided at least 3 repeated 24-h dietary records linked to comprehensive, brand-specific food composition databases on food additives. Multivariable Cox regressions were conducted to estimate associations between emulsifiers and cancer incidence. Overall, 2,604 incident cancer cases were diagnosed during follow-up (including 750 breast, 322 prostate, and 207 colorectal cancers). Higher intakes of mono- and diglycerides of fatty acids (FAs) (E471) were associated with higher risks of overall cancer (HR high vs. low category = 1.15; 95% CI [1.04, 1.27], p-trend = 0.01), breast cancer (HR = 1.24; 95% CI [1.03, 1.51], p-trend = 0.04), and prostate cancer (HR = 1.46; 95% CI [1.09, 1.97], p-trend = 0.02). In addition, associations with breast cancer risk were observed for higher intakes of total carrageenans (E407 and E407a) (HR = 1.32; 95% CI [1.09, 1.60], p-trend = 0.009) and carrageenan (E407) (HR = 1.28; 95% CI [1.06, 1.56], p-trend = 0.01). No association was detected between any of the emulsifiers and colorectal cancer risk. Several associations with other emulsifiers were observed but were not robust throughout sensitivity analyses. Main limitations include possible exposure measurement errors in emulsifiers intake and potential residual confounding linked to the observational design. Conclusions: In this large prospective cohort, we observed associations between higher intakes of carrageenans and mono- and diglycerides of fatty acids with overall, breast and prostate cancer risk. These results need replication in other populations. They provide new epidemiological evidence on the role of emulsifiers in cancer risk. Trial registration: ClinicalTrials.gov NCT03335644. Author summary: Why was this study done?: Emulsifiers are widely used food additives in industrially processed foods to improve texture and enhance shelf-life. Experimental in vivo/in vitro research as well as a pilot clinical trial on healthy individuals suggests deleterious effects of food additive emulsifier intake on the intestinal microbiota, metabolome, host inflammation, and susceptibility to carcinogenesis. To our knowledge, due to challenges to accurately estimate the exposure to food additive emulsifiers through diet, so far there was no available epidemiological evidence from prospective cohorts on food additive emulsifier intakes in relation to cancer risk. What did the researchers do and find?: This study assessed quantitative exposures to a wide range of food additive emulsifiers in a large prospective cohort of adults. Higher intakes of mono- and diglycerides of fatty acids (FAs) (E471), total carrageenans (E407, E407a), and carrageenan (E407) were associated with higher risks of overall, breast, and/or prostate cancers. What do these findings mean?: These results provide important epidemiological insights into the role of emulsifiers on cancer risks, and need to be confirmed in further epidemiological and experimental research. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests common pathways between pregnancy losses and subsequent long-term maternal morbidity, rendering pregnancy complications an early chronic disease marker. There is a plethora of studies exploring associations between miscarriage and stillbirth with long-term adverse maternal health; however, these data are inconclusive. Methods and findings: We systematically searched MEDLINE, EMBASE, AMED, BNI, CINAHL, and the Cochrane Library with relevant keywords and MeSH terms from inception to June 2023 (no language restrictions). We included studies exploring associations between stillbirth or miscarriage and incidence of cardiovascular, malignancy, mental health, other morbidities, and all-cause mortality in women without previous pregnancy loss. Studies reporting short-term morbidity (within a year of loss), case reports, letters, and animal studies were excluded. Study selection and data extraction were performed by 2 independent reviewers. Risk of bias was assessed using the Newcastle Ottawa Scale (NOS) and publication bias with funnel plots. Subgroup analysis explored the effect of recurrent losses on adverse outcomes. Statistical analysis was performed using an inverse variance random effects model and results are reported as risk ratios (RRs) with 95% confidence intervals (CIs) and prediction intervals (PIs) by combining the most adjusted RR, odds ratios (ORs) and hazard ratios (HRs) under the rare outcome assumption. We included 56 observational studies, including 45 in meta-analysis. There were 1,119,815 women who experienced pregnancy loss of whom 951,258 had a miscarriage and 168,557 stillbirth, compared with 11,965,574 women without previous loss. Women with a history of stillbirth had a greater risk of ischaemic heart disease (IHD) RR 1.56, 95% CI [1.30, 1.88]; p < 0.001, 95% PI [0.49 to 5.15]), cerebrovascular (RR 1.71, 95% CI [1.44, 2.03], p < 0.001, 95% PI [1.92, 2.42]), and any circulatory/cardiovascular disease (RR 1.86, 95% CI [1.01, 3.45], p = 0.05, 95% PI [0.74, 4.10]) compared with women without pregnancy loss. There was no evidence of increased risk of cardiovascular disease (IHD: RR 1.11, 95% CI [0.98, 1.27], 95% PI [0.46, 2.76] or cerebrovascular: RR 1.01, 95% CI [0.85, 1.21]) in women experiencing a miscarriage. Only women with a previous stillbirth were more likely to develop type 2 diabetes mellitus (T2DM) (RR: 1.16, 95% CI [1.07 to 2.26]; p < 0.001, 95% PI [1.05, 1.35]). Women with a stillbirth history had an increased risk of developing renal morbidities (RR 1.97, 95% CI [1.51, 2.57], p < 0.001, 95% [1.06, 4.72]) compared with controls. Women with a history of stillbirth had lower risk of breast cancer (RR: 0.80, 95% CI [0.67, 0.96], p-0.02, 95% PI [0.72, 0.93]). There was no evidence of altered risk of other malignancies in women experiencing pregnancy loss compared to controls. There was no evidence of long-term mental illness risk in women with previous pregnancy losses (stillbirth: RR 1.90, 95% CI [0.93, 3.88], 95% PI [0.34, 9.51], miscarriage: RR 1.78, 95% CI [0.88, 3.63], 95% PI [1.13, 4.16]). The main limitations include the potential for confounding due to use of aggregated data with variable degrees of adjustment. Conclusions: Our results suggest that women with a history of stillbirth have a greater risk of future cardiovascular disease, T2DM, and renal morbidities. Women experiencing miscarriages, single or multiple, do not seem to have an altered risk. In this systematic review and meta-analysis, Florentia Vlachou and team explore the associations between miscarriage and stillbirth with long-term adverse maternal health outcomes. Author summary: Why was this study done?: Fetal loss is one of the most serious complications of pregnancy, with approximately 23,000,000 miscarriages and 2,000,000 stillbirths reported globally per annum. Emerging data suggest a relationship between pregnancy loss and subsequent development of maternal long-term illness. We conducted a systematic review and meta-analysis on the clinical evidence available to better understand the effect of pregnancy loss on the long-term maternal morbidity and mortality. What did the researchers do and find?: Our systematic review included a total of 56 observational studies, with a total of 1,119,815 women who experienced pregnancy loss (those experiencing a miscarriage: 951,258; those experiencing a stillbirth: 168,557) and 11,965,574 controls. Women with a history of stillbirth were found to have an increased risk of developing ischaemic heart, cerebrovascular, circulatory, and renal disease, and type 2 diabetes mellitus (T2DM) as well as a slight decrease in the risk of breast cancer. There was no evidence of increased risk of developing these conditions in women with a history of miscarriage. What do these findings mean?: Our results show a possible association of stillbirth with future cardiovascular disease, T2DM, and renal disease, suggesting that pregnancy loss could be an indicator for future risk. Our work suggests future research focussing on long-term maternal health outcomes related to pregnancy loss is necessary. Our work uses aggregated data with variable degrees of adjustment. As a consequence, the potential for confounding variables with well-known risk factors for metabolic diseases such as gestational diabetes affecting the results is considerable. [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: Exposure to isotretinoin during pregnancy must be avoided due to its teratogenicity, but real-world data on its use are scarce. We aimed to describe (i) isotretinoin use in women of childbearing age in Germany; (ii) the occurrence of isotretinoin-exposed pregnancies; and (iii) malformations among children exposed in utero. Methods and findings: Using observational data from the German Pharmacoepidemiological Research Database (GePaRD, claims data from approximately 20% of the German population), we conducted annual cross-sectional analyses to determine age-standardized prevalence of isotretinoin use between 2004 and 2019 among girls and women aged 13 to 49 years. In cohort analyses, we estimated the number of exposed pregnancies by assessing whether there was prescription supply overlapping the beginning of pregnancy (estimated supply was varied in sensitivity analyses) or a dispensation within the first 8 weeks of pregnancy. Data of live-born children classified as exposed in a critical period according to these criteria were reviewed to assess the presence of congenital malformations. The age-standardized prevalence of isotretinoin use per 1,000 girls and women increased from 1.20 (95% confidence interval [CI]: 1.16, 1.24) in 2004 to 1.96 (95% CI: 1.92, 2.01) in 2019. In the base case analysis, we identified 178 pregnancies exposed to isotretinoin, with the number per year doubling during the study period, and at least 45% of exposed pregnancies ended in an induced abortion. In sensitivity analyses, the number of exposed pregnancies ranged between 172 and 375. Among live-born children, 6 had major congenital malformations. The main limitation of this study was the lack of information on the prescribed dose, i.e., the supply had to be estimated based on the dispensed amount of isotretinoin. Conclusions: Isotretinoin use among girls and women of childbearing age increased in Germany between 2004 and 2019, and there was a considerable number of pregnancies likely exposed to isotretinoin in a critical period. This highlights the importance of monitoring compliance with the existing risk minimization measures for isotretinoin in Germany. Jonas Reinold and colleagues investigate how isotretinoin use has changed over a 15 year period in Germany and the potential for in-utero exposure. Author summary: Why was this study done?: Systemic (oral) isotretinoin is used in the treatment of moderate to severe acne. Given that isotretinoin is one of the strongest human teratogens known today, it is important to monitor the use of isotretinoin in girls and women of childbearing age as well as the occurrence of pregnancies exposed to this drug. There is a lack of population-based studies addressing these research questions. What did the researchers do and find?: Using a database covering 20% of the German population, we conducted cross-sectional analyses to assess the prevalence of isotretinoin use between 2004 and 2019 in girls and women of childbearing age. We found that the age-standardized prevalence of isotretinoin use increased from 1.20 to 1.96 per 1,000 girls/women during this period. In cohort analyses, we estimated the number of pregnancies likely exposed to isotretinoin in a critical period. In the base case analysis, we identified 178 of such pregnancies. Sensitivity analyses considering the recommended one-month washout period suggested that there could have been additional pregnancies exposed to isotretinoin because they started before the end of the washout period. What do these findings mean?: Isotretinoin use among girls and women of childbearing age increased in Germany between 2004 and 2019, and there were a considerable number of pregnancies likely exposed to isotretinoin in a critical period. This highlights the importance of monitoring compliance with the existing risk minimization measures for isotretinoin in Germany. It also seems important to increase awareness regarding the component of the pregnancy prevention program that recommends contraception also in the month after treatment cessation. The main limitation of this study was the lack of information on the prescribed dose of isotretinoin. We therefore estimated the dose based on the dispensed amount of isotretinoin and varied the underlying assumptions. [ABSTRACT FROM AUTHOR]

Background: Despite the substantial evidence of the relationship between diet and mortality, the role of beverage consumption patterns is not well known. The aim of this study was to assess the association of the adherence to a Healthy Beverage Score (HBS) and all-cause mortality in a representative sample of the Spanish adult population. Methods and findings: We conducted an observational cohort study using data from the Study on Nutrition and Cardiovascular Risk in Spain (ENRICA), which included 12,161 community-dwelling individuals aged ≥18 years recruited in 2008 to 2010 and followed until January 2022. At baseline, food consumption was collected using a validated diet history. The HBS consists of 7 items, each of which is scored from 1 to 4 (highest adherence). The HBS ranges from 7 to 28 points with a higher score representing a healthier pattern. Adherence was assigned as a higher consumption of low-fat milk, and coffee and tea, a lower consumption of whole-fat milk, no consumption of fruit juice, artificially sweetened beverages, or sugar-sweetened beverages, and no or moderate consumption of alcohol. Total mortality was ascertained by linkage to the Spanish National Death Index. Statistical analyses were performed with Cox models and adjusted for the main confounders, including sociodemographic, lifestyle, dietary variables, and morbidity. After a mean follow-up of 12.5 years (SD: 1.7; range: 0.5 to 12.9), a total of 967 deaths occurred. For all-cause mortality, the fully adjusted hazard ratio (HR) for the highest versus lowest sex-specific quartiles of HBS was 0.72 (95% confidence interval [0.57, 0.91], p linear-trend = 0.015), corresponding to an 8.3% reduction in the absolute risk of death. A linear relationship between the risk of death and the adherence to the HBS was observed using restricted cubic splines. The results were robust to sensitivity analyses. The main limitation was that repeated measurements on beverage consumption were not available and beverage consumption could have changed during follow-up. Conclusions: In this study, we observed that higher adherence to the HBS was associated with lower total mortality. Adherence to a healthy beverage pattern could play a role in the prevention of premature mortality. Montserrat Rodríguez-Ayala and coworkers assess the relationship between a Healthy Beverage Score (HBS) and mortality in a representative sample of >12,000 individuals from Spain. Author summary: Why was this study done?: Most dietary patterns focus solely on solid foods, and the role of beverages as a whole has received little attention. Our aim was to assess the relationship between a Healthy Beverage Score (HBS) and mortality in a representative sample of community-dwelling individuals from Spain. Our hypothesis was that high adherence to the HBS would be associated with lower mortality. What did the researchers do and find?: We included a representative sample of 12,161 adults (18 years and older) from Spain who were recruited in 2008 to 2010 and followed up until 2022. A total of 967 deaths occurred. Participants were categorized according to their adherence to the HBS. A higher total score was achieved with a higher consumption of low-fat milk, and coffee and tea, no consumption of whole-fat milk, fruit juice, artificially sweetened beverages, sugar-sweetened beverages, and no consumption or moderate consumption of alcohol. Each HBS item scored from 1 (minimum adherence) to 4 points (maximum adherence) and the HBS ranged from 7 to 28 points. The higher the HBS, the healthier. When comparing extreme categories, higher adherence to the HBS was associated with lower all-cause mortality in the Spanish adult population, with an 8.3% reduction in the absolute risk of death. What do these findings mean?: The adherence to the HBS could serve as a potential diet-based strategy to prevent premature mortality. The quality of beverage patterns could influence health outcomes in the general population. [ABSTRACT FROM AUTHOR]

Background: Injuries represent a vast and relatively neglected burden of disease affecting low- and middle-income countries (LMICs). While many health systems underperform in treating injured patients, most assessments have not considered the whole system. We integrated findings from 9 methods using a 3 delays approach (delays in seeking, reaching, or receiving care) to prioritise important trauma care health system barriers in Karonga, Northern Malawi, and exemplify a holistic health system assessment approach applicable in comparable settings. Methods and findings: To provide multiple perspectives on each conceptual delay and include data from community-based and facility-based sources, we used 9 methods to examine the injury care health system. The methods were (1) household survey; (2) verbal autopsy analysis; (3) community focus group discussions (FGDs); (4) community photovoice; (5) facility care-pathway process mapping and elucidation of barriers following injury; (6) facility healthcare worker survey; (7) facility assessment survey; (8) clinical vignettes for care process quality assessment of facility-based healthcare workers; and (9) geographic information system (GIS) analysis. Empirical data collection took place in Karonga, Northern Malawi, between July 2019 and February 2020. We used a convergent parallel study design concurrently conducting all data collection before subsequently integrating results for interpretation. For each delay, a matrix was created to juxtapose method-specific data relevant to each barrier identified as driving delays to injury care. Using a consensus approach, we graded the evidence from each method as to whether an identified barrier was important within the health system. We identified 26 barriers to access timely quality injury care evidenced by at least 3 of the 9 study methods. There were 10 barriers at delay 1, 6 at delay 2, and 10 at delay 3. We found that the barriers "cost," "transport," and "physical resources" had the most methods providing strong evidence they were important health system barriers within delays 1 (seeking care), 2 (reaching care), and 3 (receiving care), respectively. Facility process mapping provided evidence for the greatest number of barriers—25 of 26 within the integrated analysis. There were some barriers with notable divergent findings between the community- and facility-based methods, as well as among different community- and facility-based methods, which are discussed. The main limitation of our study is that the framework for grading evidence strength for important health system barriers across the 9 studies was done by author-derived consensus; other researchers might have created a different framework. Conclusions: By integrating 9 different methods, including qualitative, quantitative, community-, patient-, and healthcare worker-derived data sources, we gained a rich insight into the functioning of this health system's ability to provide injury care. This approach allowed more holistic appraisal of this health system's issues by establishing convergence of evidence across the diverse methods used that the barriers of cost, transport, and physical resources were the most important health system barriers driving delays to seeking, reaching, and receiving injury care, respectively. This offers direction and confidence, over and above that derived from single methodology studies, for prioritising barriers to address through health service development and policy. Using a mixed-methods approach, John Whitaker and colleagues examine barriers to seeking, reaching, or receiving care in the injury care health system in Karonga, Northern Malawi. Author summary: Why was this study done?: Injuries represent a vast and relatively neglected burden of disease affecting low- and middle-income countries (LMICs). While evidence suggests that many health systems underperform in treating injured patients in LMICs, most assessments have not considered all elements of the healthcare system for injured people. Innovative mixed methods approaches to holistic health system assessment including community and facility perspectives are therefore needed. What did the researchers do and find?: To examine the injury care health system in Karonga, Northern Malawi, we integrated the findings from 9 different methods: (1) household survey; (2) verbal autopsy analysis; (3) community focus group discussions (FGDs); (4) community photovoice; (5) facility care-pathway process mapping and elucidation of barriers following injury; (6) facility healthcare worker surveys; (7) facility assessment surveys; (8) clinical vignettes for care quality assessment of facility-based healthcare workers; and (9) geographic information system (GIS) analysis. We graded the strength of evidence each method provided as to whether a given barrier was important in inhibiting access to timely quality injury care. We found 26 barriers evidenced by at least 3 of the 9 methods with the barriers "cost," "transport," and "physical resources" having the strongest evidence that they were important barriers delaying seeking, reaching, and receiving care, respectively. What do these findings mean?: By comparing the findings from the perspectives of 9 different methods, we were able to gain an in-depth understanding of the health system for trauma care. This approach can allows researchers and planners to know the barriers consistently shown to be important and prioritise health service development and policy interventions accordingly. This study, to our knowledge, represents a novel and innovative approach in terms of both the number and types of methods mixed, serving as an example other researchers could use in similar contexts. The way we graded evidence strength for comparison across methods was somewhat subjective and other researchers may have made different judgements. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholestasis of pregnancy (ICP) is the most common obstetric liver disorder and is associated with an increased risk of iatrogenic preterm birth and adverse infant outcomes. Hence, there are several plausible pathways through which ICP could affect offspring neurodevelopment. However, to the best of our knowledge, no studies have investigated these associations. Thus, we aimed to determine whether ICP is associated with offspring neurodevelopmental conditions. Methods and findings: In this Swedish register-based cohort study, we included singleton non-adopted children born in Sweden between the 1st of January 1987 and the 31st of December 2010, who were resident in Sweden >5 years, with no missing covariate information, which we followed until the 31st of December 2016. Maternal ICP diagnosis and the date of the initial diagnosis during pregnancy were obtained from the National Patient Register. Offspring diagnoses of attention deficit/hyperactivity disorder (ADHD), autism, or intellectual disability were obtained from the National Patient Register, and the dispensation of ADHD medications were obtained from the Prescribed Drug Register. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression while controlling for observed confounders and unobserved confounders shared among full siblings and maternal full cousins. A total of 2,375,856 children were included in the study; 81.6% of them were of Nordic origin, and 51.4% were male. Of these, 10,378 (0.44%) were exposed to ICP. During a median of 18 years follow-up (interquartile range 11 to 24), 143,746 (6.05%) of children were diagnosed with a neurodevelopmental condition. After adjusting for child's sex, birth year, birth month, maternal age, highest parental education level, maternal birth country, birth order, maternal psychiatric history, ICP was associated with increased odds of offspring neurodevelopmental conditions (OR 1.22, 95% CI 1.13 to 1.31), particularly among those exposed to early-onset ICP (OR 2.38, 95% CI 1.71 to 3.30) as compared to ICP diagnosed after reaching term (≥37 weeks of gestation) (OR 1.08, 95% CI 0.97 to 1.20). The findings of early-onset ICP were consistent in family-based analyses. Within-family comparisons of full maternal cousins yielded an OR of 2.99 (95% CI 1.48 to 6.04), and comparisons of full siblings showed an OR of 1.92 (95% CI 0.92 to 4.02), though the latter was less precise. The findings were consistent across specific neurodevelopmental conditions and different analytical approaches. The primary limitations of this study included its observational design, the absence of data on ICP therapeutics, and the lack of bile acid measures. Conclusions: In this study, we observed that exposure to ICP during gestation is associated with an increased likelihood of neurodevelopmental conditions in offspring, particularly in cases of early-onset ICP. Further studies are warranted to better understand the role of early-ICP in offspring neurodevelopment. In this Swedish register-based cohort study, Shuyun Chen, Viktor H. Ahlqvist and colleagues assess the association between maternal intrahepatic cholestasis of pregnancy and neurodevelopmental disorders in children exposed during gestation. Author summary: Why was this study done?: Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder during pregnancy characterized by rising bile acid levels, and it is associated with early delivery and adverse infant outcomes. Less is known about the long-term outcomes of children exposed to ICP. Because ICP may plausibly affect the development of the fetus either directly or via its association with adverse pregnancy outcomes, this study examined the hypothesis that ICP would be associated with an increased likelihood of neurodevelopmental conditions in children exposed during gestation. What did the researchers do and find?: The study analyzed data from the Swedish registers including children born between 1987 and 2010, with follow-up for neurodevelopmental outcomes until the end of 2016. The study recorded cases of mothers diagnosed with ICP and documented the timing of these diagnoses during pregnancy using patient registries. Associations between these diagnoses and neurodevelopmental conditions, including attention deficit/hyperactivity disorder (ADHD), autism, or intellectual disability in children, were estimated using multiple analytical approaches. The results suggested that children exposed to ICP during pregnancy were more likely to receive diagnoses of neurodevelopmental conditions, particularly when ICP was diagnosed early in pregnancy (before 28 weeks of gestation). Because the associations were similar when children were compared to their maternal cousins and to their siblings, these findings do not appear to be explained by factors shared within families, such as genetics and some aspects of the early life environment, that can also influence the likelihood of neurodevelopmental conditions. What do these findings mean?: Diagnosis of ICP during pregnancy, especially early in pregnancy, is associated with an increased likelihood of neurodevelopmental disorders in the children exposed during gestation. Because this study is observational, it is not possible to determine whether ICP is a causative factor in the development of neurodevelopmental conditions in children born to affected mothers. This study did not include information on bile acid concentrations among the pregnant women, and this study was conducted before treatment (using ursodeoxycholic acid) was widely used in Sweden. It will be important for future studies to consider if therapeutic modulation of bile acid levels in pregnant women affected by ICP can mitigate the associations we observe. [ABSTRACT FROM AUTHOR]

Background: The psychological toll on parents of a child receiving a cancer diagnosis is known to be high, but there is a knowledge gap regarding suicidal behavior among these parents. The aim of this study was to investigate the risk of suicide attempt and death by suicide in relation to having a child with cancer. Methods and findings: We performed a binational population-based and sibling-controlled cohort study, including all parents with a child diagnosed with cancer in Denmark (1978 to 2016) or Sweden (1973 to 2014), 10 matched unexposed parents per exposed parent (population comparison), and unaffected full siblings of the exposed parents (sibling comparison). Suicide attempt was identified through the Patient Register and the Psychiatric Central Register in Denmark and the Patient Register in Sweden, whereas death by suicide was identified through the Danish Causes of Death Register and the Swedish Causes of Death Register. In population comparison, we used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of suicide attempt and death by suicide associated with cancer diagnosis of a child, adjusting for sex, age, country of residence, calendar year, marital status, highest attained educational level, household income, history of cancer, history of psychiatric disorder, and family history of psychiatric disorder. The sibling comparison was performed to assess the role of familial confounding in the studied associations. The population comparison consisted of 106,005 exposed parents and 1,060,050 matched unexposed parents, with a median age of 56 at cohort entry and 46.9% male. During the median follow-up of 7.3 and 7.2 years, we observed 613 (incidence rate [IR], 58.8 per 100,000 person-years) and 5,888 (IR, 57.1 per 100,000 person-years) cases of first-onset suicide attempt among the exposed and unexposed parents, respectively. There was an increased risk of parental suicide attempt during the first years after a child's cancer diagnosis (HR, 1.15; 95% CI, [1.03, 1.28]; p = 0.01), particularly when the child was 18 or younger at diagnosis (HR, 1.25; 95% CI, [1.08, 1.46]; p = 0.004), when the child was diagnosed with a highly aggressive cancer (HR, 1.60; 95% CI, [1.05, 2.43]; p = 0.03), or when the child died due to cancer (HR, 1.63; 95% CI, [1.29, 2.06]; p < 0.001). The increased risk did not, however, maintain thereafter (HR, 0.86; 95% CI: [0.75, 0.98]; p = 0.03), and there was no altered risk of parental death by suicide any time after the child's cancer diagnosis. Sibling comparison corroborated these findings. The main limitation of the study is the potential residual confounding by factors not shared between full siblings. Conclusions: In this study, we observed an increased risk of parental suicide attempt during the first years after a child's cancer diagnosis, especially when the child was diagnosed during childhood, or with an aggressive or fatal form of cancer. There was, however, no altered risk of parental death by suicide at any time after a child's cancer diagnosis. Our findings suggest extended clinical awareness of suicide attempt among parents of children with cancer, especially during the first few years after cancer diagnosis. In this large population based cohort study, Qianwei Liu and co-workers explore how a diagnosis of cancer in children influences suicide risk in parents. Author summary: Why was this study done?: Having a child with a cancer diagnosis is highly stressful for parents. Little is known about risk of parental suicidal behavior in relation to cancer diagnosis of a child. What did the researchers do and find?: We performed a binational population-based and sibling-controlled cohort study to investigate the association between cancer diagnosis of a child and the subsequent risk of suicide attempt or death by suicide among the parents. We observed an increased risk of parental suicide attempt during the first years after a child's cancer diagnosis, especially when the child was diagnosed during childhood, or with an aggressive or fatal form of cancer, in both the population-based comparison and the sibling comparison. What do these findings mean?: Our findings call for clinical awareness of the risk of suicide attempt among parents of children with cancer, primarily within the first years after cancer diagnosis of the child. Future studies are needed to examine the generalizability of our findings to other countries with different healthcare system, sociocultural context, and prevalence of cancer and suicidal behavior as Denmark and Sweden. [ABSTRACT FROM AUTHOR]

Background: Estimating the medical complexity of people aging with HIV can inform clinical programs and policy to meet future healthcare needs. The objective of our study was to forecast the prevalence of comorbidities and multimorbidity among people with HIV (PWH) using antiretroviral therapy (ART) in the United States (US) through 2030. Methods and findings: Using the PEARL model—an agent-based simulation of PWH who have initiated ART in the US—the prevalence of anxiety, depression, stage ≥3 chronic kidney disease (CKD), dyslipidemia, diabetes, hypertension, cancer, end-stage liver disease (ESLD), myocardial infarction (MI), and multimorbidity (≥2 mental or physical comorbidities, other than HIV) were forecasted through 2030. Simulations were informed by the US CDC HIV surveillance data of new HIV diagnosis and the longitudinal North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) data on risk of comorbidities from 2009 to 2017. The simulated population represented 15 subgroups of PWH including Hispanic, non-Hispanic White (White), and non-Hispanic Black/African American (Black/AA) men who have sex with men (MSM), men and women with history of injection drug use and heterosexual men and women. Simulations were replicated for 200 runs and forecasted outcomes are presented as median values (95% uncertainty ranges are presented in the Supporting information). In 2020, PEARL forecasted a median population of 670,000 individuals receiving ART in the US, of whom 9% men and 4% women with history of injection drug use, 60% MSM, 8% heterosexual men, and 19% heterosexual women. Additionally, 44% were Black/AA, 32% White, and 23% Hispanic. Along with a gradual rise in population size of PWH receiving ART—reaching 908,000 individuals by 2030—PEARL forecasted a surge in prevalence of most comorbidities to 2030. Depression and/or anxiety was high and increased from 60% in 2020 to 64% in 2030. Hypertension decreased while dyslipidemia, diabetes, CKD, and MI increased. There was little change in prevalence of cancer and ESLD. The forecasted multimorbidity among PWH receiving ART increased from 63% in 2020 to 70% in 2030. There was heterogeneity in trends across subgroups. Among Black women with history of injection drug use in 2030 (oldest demographic subgroup with median age of 66 year), dyslipidemia, CKD, hypertension, diabetes, anxiety, and depression were most prevalent, with 92% experiencing multimorbidity. Among Black MSM in 2030 (youngest demographic subgroup with median age of 42 year), depression and CKD were highly prevalent, with 57% experiencing multimorbidity. These results are limited by the assumption that trends in new HIV diagnoses, mortality, and comorbidity risk observed in 2009 to 2017 will persist through 2030; influences occurring outside this period are not accounted for in the forecasts. Conclusions: The PEARL forecasts suggest a continued rise in comorbidity and multimorbidity prevalence to 2030, marked by heterogeneities across race/ethnicity, gender, and HIV acquisition risk subgroups. HIV clinicians must stay current on the ever-changing comorbidities-specific guidelines to provide guideline-recommended care. HIV clinical directors should ensure linkages to subspecialty care within the clinic or by referral. HIV policy decision-makers must allocate resources and support extended clinical capacity to meet the healthcare needs of people aging with HIV. In this modelling study, Keri N Althoff and colleagues employ an agent-based simulation model to forecast the burden of comorbidity and multimorbidity in individuals who have initiated ART in the US. Author summary: Why was this study done?: Individuals with HIV are aging and are experiencing an increased risk of comorbidities and multimorbidity. Anticipating the healthcare needs of an aging population with HIV is crucial for healthcare providers, policymakers, and public health officials to plan for medical and support services tailored to the unique needs of aging people with HIV. In response to the increasing medical complexity among aging adults with HIV, we employed an agent-based simulation model to forecast the potential burden of comorbidity and multimorbidity in individuals who have initiated antiretroviral therapy (ART) in the US. What did the researchers do and find?: PEARL is an agent-based simulation of persons with HIV who have initiated ART in the US, utilizing data from the CDC HIV surveillance system and comorbidity risk functions derived from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), the largest longitudinal cohort of people with HIV who have linked into care in the US. Following a gradual increase in number of people with HIV receiving ART from 2020 to 2030, PEARL forecasted a population of 908,504 in the US in 2030, and an increase in multimorbidity burden from 63% in 2020 to 70% in 2030 among people with HIV. Although mental health conditions had the highest burden, the mix of physical comorbidities of greatest burden was different by demographic and HIV acquisition risk subgroups. What do these findings mean?: HIV clinicians can use these findings to identify the comorbidity-specific screening, diagnoses, and treatment guidelines and tools that will be necessary to care for their panel of patients. HIV care program decision-makers can use these findings to predict the subspecialities that will be in highest demand by their clinical population and make the connections to subspecialists (bringing them into the HIV clinic or by referral) needed meet the healthcare needs of people with HIV. HIV policy decision-makers can use these findings to guide expansion in subspecialty care capacity (particularly for mental health conditions) and the resources needed for expansion. [ABSTRACT FROM AUTHOR]

Background: Malaria transmission modelling has demonstrated the potential impact of semiquantitative glucose-6-phosphate dehydrogenase (G6PD) testing and treatment with single-dose tafenoquine for Plasmodium vivax radical cure but has not investigated the associated costs. This study evaluated the cost-effectiveness of P. vivax treatment with tafenoquine after G6PD testing using a transmission model. Methods and findings: We explored the cost-effectiveness of using tafenoquine after G6PD screening as compared to usual practice (7-day low-dose primaquine (0.5 mg/kg/day) without G6PD screening) in Brazil using a 10-year time horizon with 5% discounting considering 4 scenarios: (1) tafenoquine for adults only assuming 66.7% primaquine treatment adherence; (2) tafenoquine for adults and children aged >2 years assuming 66.7% primaquine adherence; (3) tafenoquine for adults only assuming 90% primaquine adherence; and (4) tafenoquine for adults only assuming 30% primaquine adherence. The incremental cost-effectiveness ratios (ICERs) were estimated by dividing the incremental costs by the disability-adjusted life years (DALYs) averted. These were compared to a willingness to pay (WTP) threshold of US$7,800 for Brazil, and one-way and probabilistic sensitivity analyses were performed. All 4 scenarios were cost-effective in the base case analysis using this WTP threshold with ICERs ranging from US$154 to US$1,836. One-way sensitivity analyses showed that the results were most sensitive to severity and mortality due to vivax malaria, the lifetime and number of semiquantitative G6PD analysers needed, cost per malaria episode and per G6PD test strips, and life expectancy. All scenarios had a 100% likelihood of being cost-effective at the WTP threshold. The main limitations of this study are due to parameter uncertainty around our cost estimates for low transmission settings, the costs of G6PD screening, and the severity of vivax malaria Conclusions: In our modelling study that incorporated impact on transmission, tafenoquine prescribed after a semiquantitative G6PD testing was highly likely to be cost-effective in Brazil. These results demonstrate the potential health and economic importance of ensuring safe and effective radical cure. Author summary: Why was this study done?: Radical cure with primaquine or recently approved tafenoquine is required to clear the dormant liver parasites of vivax malaria. While single-dose tafenoquine overcomes the barrier of patient adherence to the current 7-day primaquine treatment, it costs more and requires screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency. While the impact of changing policies to tafenoquine after G6PD screening on transmission has been evaluated, the associated costs and cost-effectiveness will be important considerations for policymakers. What did the researchers find?: Using an economic evaluation model coupled with a transmission model, we found that prescribing tafenoquine to vivax malaria patients without G6PD deficiency would be highly likely to be cost-effective in Brazil. Tafenoquine will be particularly cost-effective in settings where patient adherence to the current 7-day treatment is low and when paediatric tafenoquine is available to treat children as well as adults. What do these findings mean?: To our knowledge, this is the first study that has looked at the cost-effectiveness of tafenoquine when including the impact on disease transmission. The high probability of cost-effectiveness across a wide range of scenarios and municipalities should reassure decision-makers in Brazil, where tafenoquine has recently been adopted into national policy, and aid other countries considering the implementation of tafenoquine after G6PD screening. [ABSTRACT FROM AUTHOR]