PLOS Medicine

BackgroundChlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis are curable sexually transmitted infections (STIs) associated with adverse birth outcomes. Most infections are asymptomatic. Whether antenatal STI screening improves birth outcomes remains uncertain. MethodsIn a randomized three-group trial in South Africa, pregnant women aged 18 years or older were assigned before 27 weeks gestation to: (1) screening and treatment for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis at enrollment, with tests-of-cure (One-Time Screening); (2) screening and treatment at enrollment, repeated at 30 to 34 weeks (Two-Time Screening); or (3) Standard-of-Care (Syndromic management). The primary outcome was a composite of preterm birth (<37 weeks gestation) or low birthweight (<2500 g), analyzed in the modified intention-to-treat population of participants with live births. Components of the composite outcome were evaluated individually as the main secondary outcomes. The study was registered with ClinicalTrials.gov, NCT04446611. FindingsOf 2247 enrolled participants, 1910 had live births. The composite outcome occurred in 22{middle dot}9% of the One-Time Screening group (risk ratio [RR] 0{middle dot}99; 95% confidence interval [CI] 0{middle dot}81-1{middle dot}21), 20{middle dot}6% of the Two-Time Screening group (RR 0{middle dot}89; 95% CI 0{middle dot}72-1{middle dot}09), compared with 23{middle dot}2% of the Standard-of-Care group. Preterm birth occurred in 18{middle dot}9% of the One-Time Screening group (RR 1{middle dot}00; 95% CI 0{middle dot}80-1{middle dot}26), 14{middle dot}5% of the Two-Time Screening group (RR 0{middle dot}77; 95% CI 0{middle dot}60-0{middle dot}99), and 18{middle dot}8% of the Standard-of-Care group. Low birthweight occurred in 14{middle dot}1% of the One-Time Screening group (RR 1{middle dot}10; 95% CI 0{middle dot}83-1{middle dot}46), 12{middle dot}9% of the Two-Time Screening group (RR 1{middle dot}01; 95% CI 0{middle dot}76-1{middle dot}35), and 12{middle dot}8% of the Standard-of-Care group. InterpretationNeither screening strategy for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis reduced the primary composite outcome of preterm birth or low birthweight, or low birthweight alone. The Two-Time antenatal STI screening strategy, however, reduced preterm birth by 23%.

ImportanceDrug-related pregnancy-associated mortality is a leading contributor to the US maternal mortality crisis, yet whether it follows the persistent rural disadvantage documented for all-cause maternal mortality--or is restructured by the geographic dynamics of drug markets--has not been established. ObjectiveTo characterize geographic variation in pregnancy-associated overdose (OD) and substance use disorder (SUD) mortality across the rural-urban continuum and by US Census region from 2016 through 2022. Design, Setting, and ParticipantsNational population-based surveillance study using individual-level National Vital Statistics System (NVSS) mortality and natality records. Pregnancy-associated deaths (occurring during pregnancy or within one year of the end of pregnancy) were ascertained among 25,007,723 live births during 2016-2022 using the NVSS 2018 algorithm. ExposuresRural-urban classification cross-classified by four US Census regions. Main Outcomes and MeasuresRates of pregnancy-associated OD mortality and SUD mortality per 100,000 live births. Post-COVID excess OD mortality was estimated using a Bayesian hierarchical Poisson model. ResultsThere were 516 OD deaths (2.06 per 100,000 live births) and 1,080 SUD deaths (4.32 per 100,000) nationally; SUD exceeded OD mortality more than two-to-one in all strata, and both outcomes were concentrated in the late postpartum period (43 days to 1 year). OD mortality converged across the rural-urban gradient during the COVID era (2020-2022)--the inverse of the persistent rural disadvantage in all-cause maternal mortality--with metropolitan areas falling below pre-pandemic trajectory expectations while non-metropolitan areas exceeded theirs. Credible excess OD mortality was identified in non-metropolitan Southern and Northeastern counties. SUD rates were non-monotonic across urbanicity, with metro-adjacent counties carrying elevated rates in all regions. Conclusions and RelevanceDrug-related pregnancy-associated mortality follows a distinct geographic logic from all-cause maternal mortality, shaped by drug supply dynamics and harm reduction geography rather than obstetric care infrastructure alone. The convergence of OD mortality across the rural-urban gradient, the dominance of SUD over acute overdose, and the concentration of deaths in the late postpartum year point to care and surveillance gaps requiring integrated obstetric and addiction treatment, extended postpartum insurance coverage, and rural harm reduction capacity.

Previous research links Adverse Childhood Experiences (ACEs) with problem gambling, but most studies rely on retrospective reporting and focus narrowly on maltreatment, overlooking adversities such as parental mental health issues. Using data on 3794 young adults in the Avon Longitudinal Study of Parents and Children, we examined longitudinal associations between 10 prospectively measured ACEs (individually and cumulatively), and moderate-risk/problem gambling (Problem Gambling Severity Index >=3) at ages 17, 20 and 24, adjusted for socioeconomic and other background factors. Population attributable fractions (PAFs) estimated proportions of cases potentially attributable to ACEs. Most ACEs were associated with higher odds of moderate-risk/problem gambling across ages (24/30 estimates) after adjustment, though effect sizes were generally small (median adjusted odds ratio [aOR] 1.31, interquartile range 1.24-1.59), and confidence intervals (CIs) wide. Sexual abuse showed the strongest association (aORs 2.4-4.2, CIs 0.5-10.5), while bullying and parental conviction were associated at ages 17 and 20 only, parental separation age 24 only. Evidence for a dose-response relationship was weak. PAFs suggested ACEs accounted for up to 12% of moderate-risk/problem gambling cases. These findings highlight potential impacts of ACEs on later gambling behaviour, but imprecise estimates suggest findings should be interpreted cautiously and strengthened through larger datasets and meta-analyses.

ImportanceSemaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is a highly effective medication to treat type 2 diabetes and obesity. However, concerns about potential suicidality persist, creating clinical uncertainty about its neuropsychiatric safety. ObjectiveTo assess risks of suicidality after initiating semaglutide compared to initiating SGLT2i and by duration of continuous semaglutide treatment. DesignActive-comparator, new-user target trial emulation to estimate inverse probability-weighted marginal cause-specific hazard ratios (HRs). For duration-of-treatment analyses, we used clone-censor-weight methods to estimate exposure-adjusted effects. SettingVeterans Health Administration. ParticipantsU.S. Veterans with type 2 diabetes receiving care from March 1, 2018 to September 1, 2025. ExposureInitiation of semaglutide vs SGLT2i; duration of semaglutide use ([&le;]6, 7-12, >12 months). OutcomesIncident suicidal ideation; suicide attempt or death; and a composite outcome. ResultsA total of 102,361 Veterans met inclusion criteria, including 11,478 new initiators of semaglutide and 90,883 new initiators of an SGLT2i. After overlap weighting, baseline characteristics were well balanced between treatment groups (mean [SD] age, 60.1 [11.7] years; BMI, 37.8 [6.8] kg/m2; hemoglobin A1c, 7.0% [1.4]; 85.5% male; 61.9% non-Hispanic White). During a median follow-up of 2.2 years, 9077 incident suicidal ideation events and 696 suicide attempts or deaths occurred. The incidence rate of suicidal ideation was 56.3 and 37.7 per 1000 person-years among semaglutide initiators and SGLT2i initiators, respectively (hazard ratio [HR], 0.99; 95% CI, 0.93-1.06; P = 0.86). For suicide attempts or deaths, the incidence rates were 4.30 and 2.64 per 1000 person-years, respectively (HR, 1.05; 95% CI, 0.84-1.31; P = .86). In adherence-adjusted analyses, sustained semaglutide treatment for more than 12 months, compared with 6 or fewer months, was associated with a 74% lower risk of suicide attempts or deaths (HR, 0.27; 95% CI, 0.14-0.54; P<.001). ConclusionAmong U.S. Veterans with type 2 diabetes, initiators of semaglutide were not observed to have an increased risk of suicidality compared with initiators of SGLT2i. Those with longer semaglutide treatment (beyond 12 months) had decreased risk of suicide attempt or death, suggesting longer term treatment is safe and may protect against for those outcomes.

ObjectiveDetermine acceptability and feasibility of loop electrosurgical excision procedure (LEEP) combined with adjuvant intravaginal 5-fluorouracil (5FU) for treatment of cervical intraepithelial neoplasia grade 2/3 (CIN2/3) in women living with HIV (WLWH). DesignDouble-blind, randomized, placebo-controlled Phase 2b feasibility trial. SettingPublic-sector hospital in Johannesburg, South Africa. Population180 WLWH aged 18+ years with CIN2/3 confirmed by LEEP and on antiretroviral therapy for [&ge;]60 days. MethodsParticipants underwent LEEP and were randomly assigned (1:1) to receive 8 doses of adjuvant 5FU or placebo cream every other week and followed for 24 weeks. Main Outcome MeasuresThe primary outcomes were acceptability and feasibility (adherence, retention, safety, tolerability). ResultsBetween March 2023 and January 2025, we randomized 180 WLWH. Median age was 41 years (interquartile range [IQR]: 35-45), median CD4+ count was 636 cells/mm3 (IQR: 376-873), and 98.9% were virologically suppressed. Acceptability (>94%) and adherence (>91%) were high and comparable between arms. Retention exceeded 92% in both arms, although Week 24 attendance was lower in the 5FU arm (92.2% vs. 98.9%, probability difference [PD] -6.7%, 95% confidence interval [CI] -14.4%, -0.5%). Safety events were mild, more common with 5FU, and primarily reported as Grade 1 or 2 cervical inflammation (49.2% vs. 26.7%, risk difference [RD] 22.5%, 95% CI 8.6%, 36.4%). One Grade 3 adverse event (an allergic reaction to 5FU) resulted in treatment discontinuation. ConclusionsLEEP plus adjuvant intravaginal 5FU is acceptable and feasible among WLWH in South Africa, supporting progression to a Phase 3 trial. Clinical Trial RegistrationNCT05413811. FundingUnited States National Institutes of Health (R01CA250850).

BackgroundLong-acting injectable HIV pre-exposure prophylaxis (PrEP), including Lenacapavir, has the potential to accelerate HIV incidence declines in eastern and southern Africa (ESA). However, high product and delivery costs and constrained budgets necessitate efficient prioritization strategies to maximize impact and achieve cost-effectiveness. MethodsWe used district-level HIV incidence estimates published by UNAIDS to estimate the direct health and economic impact of prioritizing Lenacapavir delivery according to geography, age, and sex across 837 districts in 11 high-burden ESA countries. Infections and disability-adjusted life years (DALY) averted, number needed to treat (NNT), cost per DALY averted, and price thresholds to achieve cost-effectiveness were estimated across geographic prioritization scenarios. Cost-effectiveness was assessed against a $500 per DALY averted threshold, assuming $5,000 discounted lifetime HIV treatment costs and 10 DALYs per HIV infection. Sensitivity analyses varied Lenacapavir costs (commodities + delivery) per person per year (pppy) ($125 versus $55), DALYs per HIV infection (7.5), and the risk differentiation among those who uptake long-acting PrEP. ResultsHIV incidence varied substantially across ESA, with 50% of new infections in districts containing less than 20% of at-risk adults. Lenacapavir cost-effectiveness varied accordingly, with high-incidence districts exhibiting substantially lower NNT and higher price thresholds for cost-effective delivery. In high-incidence districts, [>5/1,000 person-years (py)], of South Africa, Mozambique, Lesotho, and eSwatini, Lenacapavir would be cost-effective at $50-100 pppy. In South Africa, at annual cost $55 pppy, Lenacapavir was cost-effective in all 52 districts when provided to women aged 15-24 years with incidence exceeding twice the district average and could reach approximately 18-20% of new infections while covering 4% of the full HIV-negative adult population aged 15-49 years. Geographically optimized prioritization in South Africa with minimal age and risk-group stratification achieved efficiency comparable to country-level prioritization to high-risk groups and key populations ([~]20% incidence reduction with 3-5% coverage). Impact and cost-effectiveness were sensitive to assumptions about risk heterogeneity. ConclusionsLenacapavir impact and cost-effectiveness varies substantially across geographic settings, driven primarily by variation in HIV incidence. Simple incidence-based models can identify where universal provision to certain demographic groups is both impactful and cost-effective, particularly in high-incidence districts and age groups.

BackgroundSyphilis screening and treatment coverage remain lower than recommended among pregnant women in the US. ObjectiveWe estimated the prevalence and incidence of syphilis among pregnant women, incidence of congenital syphilis and the impact of improved prenatal care cascade by race and ethnicity. DesignCompartmental mathematical model of syphilis natural history, prenatal care, and syphilis screening and testing SettingUnited States ParticipantsPregnant women MeasurementsWomen were stratified by race and ethnicity and whether they received any prenatal care. The model was calibrated to epidemiological data for 2019. InterventionsWe evaluated improvements among women with any prenatal care and in all pregnant women, and we examined 100% treatment completion, first-trimester testing, first-trimester testing with 100% treatment, testing twice and testing twice with 100% treatment. ResultsWe estimated that, per 100,000 pregnant women, 110 (95% uncertainty interval [UI] 110-120) had syphilis at pregnancy onset, 13 (95% UI 10-15) acquired syphilis during pregnancy, and 13 (95% UI 12-14) had a syphilis-attributable stillbirth (95% UI 12-14). We estimated a 61% (95% UI 60-62) reduction in non-stillbirth-related congenital syphilis outcomes when at least two syphilis tests were provided and treatment was completed among women who receive prenatal care, and a 98% (95%UI 98- 99%) reduction if two tests were provided and treatment was completed for all pregnant women. The largest benefit of expanding testing and treatment to all pregnant women was seen in non-Hispanic Black and Hispanic populations. LimitationsResults represent national averages and do not account regional variation. ConclusionReaching women without prenatal care would substantially reduce congenital syphilis and racial and ethnic differences in congenital syphilis burden. Primary Funding sourceCenters for Disease Control and Prevention.

Background: Previous recommendations on screening for prostate cancer relied on ongoing trials of screening with prostate-specific antigen (PSA), which may have lacked sufficient follow-up duration to fully examine effects on mortality and overdiagnosis. Findings which consider absolute effects by age and screening intensity, along with newer guidance for assessing evidence certainty, may lead to different interpretations. Adding magnetic resonance imaging (MRI) to PSA-based screening has been raised as a way to reduce false positives (FPs) and overdiagnosis. Methods: We systematically searched MEDLINE, Embase, and Central from 2014 to January 28, 2026, for randomized controlled trials (RCTs) and prospective observational studies of: (i) screening versus no screening and (ii) sequential screening with MRI for those with a positive PSA test versus PSA alone among men not known to be at high risk for prostate cancer. Studies on screening with PSA or digital rectal examination (DRE) published pre-2014 were identified from existing systematic reviews and reference lists. Studies on FPs and complications from biopsies after PSA screening did not require a control group. Paired reviewers screened titles/abstracts (assisted with artificial intelligence) and full texts, assessed risk of bias, and extracted data, by age when available. We pooled data when suitable using random-effects models, investigated heterogeneity, and assessed the certainty of evidence using GRADE with conclusions of effects based on decision thresholds based on absolute effect sizes. Results: Across both questions, we included 15 RCTs (N=856,000; 8 sites of ERSPC considered separate trials) and 8 observational studies (N=56,122). At 20 years, among 1000 men who underwent repeated PSA-based screening every 2-4 years starting from age 55-69 (mean 62), there is likely a reduction in prostate-cancer mortality ([&ge;]2 fewer) and metastatic cancer incidence ([&ge;]6 fewer), at the expense of prostate-cancer overdiagnosis ([&ge;]24 cases) and FPs ([&ge;]150 cases) (all moderate certainty). If screening starts at age 50-54 or age 55, the benefits are probably smaller (e.g., 1 vs. 2 fewer prostate-cancer related deaths) with similar harms. Adding DRE or screening with PSA annually does not add benefit. One round of PSA screening or starting screening later at age 70-74 may not offer any important benefit or harm (low to moderate certainty), and any benefit from screening primarily with DRE was not shown. Compared with PSA alone, sequential screening with PSA followed by MRI reduces FPs ([&ge;]33 fewer) and overdiagnosis (via [&ge;]10 fewer diagnoses of clinically insignificant [e.g., Gleason 6] cancers without impacting detection of clinically significant cancers) (moderate to high certainty), though findings were limited to one round of screening without long-term follow-up or measurement of mortality. Interpretation: This review provides clinicians and other interest holders with anticipated absolute effects by age, and assessments of certainty across critical and important outcomes and with approximately two decades of follow-up. Findings apply to a general population and may differ for specific groups. Results for most critical outcomes, both benefits and harms, exceeded thresholds for clinically important effect sizes, thereby demonstrating the complexity of guideline developers' and patients' decision-making regarding screening trade-offs. Findings about adding MRI for those with a positive PSA test were limited and would require additional consideration of costs, infrastructure, expertise, and equity. Protocol registration: PROSPERO - CRD420250651056.

ABSTRACT Objective To estimate the benefit and risk of replacing regular salt with potassium-enriched salt. Design Comparative risk assessment modelling. Setting Worldwide Participants Adult populations aged 25 and above. Intervention (1) worldwide replacement of all salt (discretionary salt used for seasoning or cooking in the home, and non-discretionary salt used in processed and restaurant foods); (2) worldwide replacement of just discretionary salt; (3) worldwide replacement of just non-discretionary salt; (4) replacement of discretionary salt just for people with diagnosed hypertension; and (5) replacement of discretionary salt just for people with treated hypertension. Main outcome measures For scenarios 1-3, we estimated benefits including deaths, new cases and disability-adjusted-life-years (DALYs) from cardiovascular disease and chronic kidney disease (CKD), from blood pressure-lowering as well as harms (CVD deaths) caused by hyperkalaemia among people with CKD stages G3-G5. Results Replacement of all salt worldwide could prevent 2.96 (95% uncertainty interval 2.81-3.12) million deaths, 10.17 (9.59-10.70) million new cases of disease and 69.43 (65.61-72.92) million disability-adjusted life years (DALYs) each year. These figures represent 14.6%, 13.1% and 16.5% of the annual global disease burden attributable to CVD and CKD. Replacement of all discretionary salt (1.85, 1.74-1.97 million deaths) would have a greater impact on mortality than replacement of all non-discretionary salt (1.56, 1.46-1.67 million deaths). In people with CKD Stage G3-G5, there would be a net benefit - replacement of all salt would prevent 0.75 (0.71-0.80) million deaths but might cause 0.10 (0.09-0.11) million deaths from hyperkalaemia. Discretionary salt replacement only among diagnosed or treated hypertensives would prevent 0.59 (0.55-0.63) million and 0.48 (0.45-0.52) million deaths, respectively. Conclusion Switching regular salt to potassium-enriched salt appears to offer large potential for health gains under diverse scenarios, including for people with CKD.

BackgroundHIV incidence in sub-Saharan Africa has declined substantially since 2000 according to epidemic estimates published by UNAIDS. These estimates, derived by fitting mathematical models to national surveillance data, guide HIV programmes and epidemic response strategies. We assessed whether the level and age distribution of HIV incidence from modelled estimates were consistent with empirical HIV incidence observations, and whether incidence levels and trends were systematically different between study types, populations, and age groups. MethodsWe conducted an updated systematic review of adult HIV incidence data from sub-Saharan Africa published July 2019-February 2024 by searching Scopus, PubMed, Embase, and OVID databases, and combined with earlier systematic review data. We matched empirical incidence measurements between 1990-2023 to UNAIDS HIV incidence estimates by study area, sex, age group, and year. We used Bayesian mixed-effect Poisson regression to estimate (1) incidence rate ratios (IRR) between empirical observations and matched modelled incidence estimates adjusted for sex, year and study type/population; and (2) time trends in age-specific incidence from population-based cohort studies and household surveys. Results3560 HIV empirical incidence measurements were included from 179 studies conducted in 21 countries, comprising 23,000 new infections and 3.1 million person-years. Incidence observations from nationally-representative household surveys (IRR 1.07 95%CI 0.68, 1.67) and population-representative study populations (IRR 0.98 95%CI 0.51, 1.89) were not significantly different from matched modelled estimates, and declined at the same rate as modelled estimates (annual aRR 0.99 95%CI 0.98, 1.01). Studies among pregnant women (IRR 2.60 95%CI 1.58, 4.28), control arms of clinical trials (IRR 3.01 95%CI 1.90, 4.77) and key populations (FSW IRR: 6.46 95%CI 4.18, 10.00; MSM 44.02 95%CI 27.35, 70.87) had significantly higher incidence than modelled total population incidence estimates. Across population cohorts in Eastern and Southern Africa, HIV incidence among adults aged 15-49 declined by 75-90% between 2010-2023, and declined 7% (95%CI 4-10%) faster per year among young adults 15-24 compared to age 25+ years. Modelled incidence declined similarly to cohort data, but did not reflect the aging of the epidemic. ConclusionObserved incidence in population-representative studies in sub-Saharan Africa has declined steeply. Mathematical models that infer incidence from cross-sectional HIV surveillance data estimated the same incidence level and decline over time as population-representative studies. Studies with non-representative inclusion criteria had significantly higher incidence, including those among pregnant women and most HIV prevention/vaccine efficacy trials. The age pattern of incidence in modelled estimates should be reconsidered to capture the aging of the epidemic indicated by cohort studies.

BackgroundEvidence on how leisure-time physical activity (LTPA) improves lifetime body mass index (BMI) remains fragmented and prone to confounding. MethodsWe pooled 14,993 adults (30-90 y; 52.7% women; cohorts: REGICOR-ACRISC, ILERVAS, ARTPER) with baseline estimated LTPA (moderate-to-vigorous LTPA [MVLTPA] in REGICOR-ACRISC), genotype, and repeated BMI values from electronic health records (1990-2024, 36,157 measures). LTPA was categorized into cohort-specific quartiles; MVLTPA in 0, <100, <200, and [&ge;]200 METs-min/day. In one-sample Mendelian randomization analyses, we categorized participants in quartiles of a cardiorespiratory fitness polygenic risk score derived from a large GWAS in UK Biobank. Group-dependent BMI trajectories were modeled using spline mixed-effects models. Obesity onset (first BMI [&ge;]30 kg/m2) was analyzed with IPW-weighted Kaplan-Meier curves and Cox models. ResultsHigher LTPA was associated with slower BMI increases in ages 30-60 (Q1: +0.120 vs Q4: +0.075 kg/m2{middle dot}year), slower declines in ages 70-90 (Q1: -0.143 vs Q4: -0.123 kg/m2{middle dot}year), and lower obesity risk (Q4 vs Q1: HR 0.83, 95% CI 0.72-0.96). Similar trends were observed for MVLTPA. Higher genetically determined cardiorespiratory fitness showed parallel gradients (ages 30-60, Q1: +0.109 vs Q4: +0.101 kg/m2{middle dot}year; ages 70-90, Q1: -0.130 vs Q4: -0.102 kg/m2{middle dot}year) and lower obesity risk (Q4 vs Q1: HR 0.66, 0.56-0.78). Associations were present for women and men separately, but were stronger in men. ConclusionsHigher LTPA and MVLTPA were associated with more favorable lifelong BMI trajectories, delayed obesity risk, and convergent support from Mendelian randomization analyses, supporting a causal protective role of physical activity (in both sexes but stronger in men).

BackgroundSkin disease affects 4.7-4.9 billion individuals globally; however, little is known about access to dermatological care. MethodsWe conducted a multinational, cross-sectional survey of dermatological care across 194 WHO member states and three additional geographic areas in 2024-2025. Primary outcomes included dermatologist density per 100,000 population and number of dermatologists globally. Secondary outcomes included training programme density, workforce distribution, perceived access to care, and health system characteristics. Descriptive statistics and nonparametric tests compared outcomes across World Bank Income (WBI) levels and WHO regions. FindingsResponses were obtained from 158 countries. Mean dermatologist density was 2.66 per 100,000, ranging from 0.37 in low-income (LICs) to 5.05 in high-income countries (HICs). There are estimated 175,633 dermatologists globally (95% CI: 173,598-177,668). Forty-two percent of countries reported inadequate or extremely poor access to dermatological care. There was significant variation (p < 0.001) in access to all types of subspecialty care (paediatric, surgical, dermatopathology) across WBI levels, with consistently worse access in lower-income countries. Dermatologists are primarily based in urban centres (79%). Twenty-one percent of countries lack dermatology training programs, with training varying by WBI level (p < 0.001). Non-dermatologist healthcare workers bear a substantial responsibility for management of skin disease. InterpretationSignificant global disparities exist in access to dermatological care, particularly in lower resource settings. Achieving skin health equity will require global commitment to expanding/funding training programmes, incentivizing decentralization of dermatology practice, and optimizing alternative care delivery including upskilling front-line healthcare workers. FundingInternational League of Dermatological Societies and LOreal Dermatological Beauty.

BackgroundSustained retention in care supports continuous access to antiretroviral therapy, routine clinical monitoring, and long-term viral suppression. ObjectiveTo compare the effectiveness of interventions for improving retention in care among people living with HIV (PLHIV). DesignSystematic review and network meta-analysis Data sourcesPubMed, Embase, CINAHL, PsycINFO, Web of Science, and the Cochrane Library from 1995 to December 2024. Eligibility criteriaRandomised controlled trials (RCTs) evaluating interventions to improve retention in care, viral load suppression, or quality of life (QoL) among PLHIV, compared with standard of care (SoC) or other interventions. Data extraction and synthesisPairs of reviewers independently screened studies, extracted data, and assessed risk of bias using ROBUST-RCT. We conducted a fixed-effect frequentist network meta-analysis and rated interventions categories relative to SoC based on effect estimates effects and the certainty of evidence.. Dichotomous outcomes were summarized as odds ratios (ORs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with 95% CI. ResultsEighty-four trials enrolling 107 137 PLHIV evaluated 13 intervention categories. For retention in care, five interventions supported by moderate or high certainty evidence proved superior to SoC: multi-month dispensing (OR 2.02, 95% CI 1.32 to 3.09), task shifting (OR 1.94, 95% CI 1.42 to 2.66), differentiated service delivery (OR 1.47, 95% CI 1.22 to 1.76), behavioural counselling (OR 1.36, 95% CI 1.21 to 1.54), and supportive interventions (OR 1.31, 95% CI 1.11 to 1.55). For viral load suppression, two interventions supported by moderate or high certainty evidence proved superior to SoC: task shifting (OR 2.07, 95% CI 1.25 to 3.43) and behavioural counselling (OR 1.34, 95% CI 1.11 to 1.67). Across outcomes, no intervention demonstrated convincing superiority over other active interventions. ConclusionsAmong 13 intervention categories, only a subset provided moderate or high-certainty evidence of superiority to the standard of care, and no superiority to other interventions. Persistent evidence gaps for key populations, diverse settings, and long-term outcomes support the need for context-sensitive and patient-centred interventions. RegistrationPROSPERO CRD42024589177 Strengths and limitations of this study[tpltrtarr] This systematic review followed Cochrane methods and was reported in accordance with PRISMA-NMA guidelines. [tpltrtarr]The network meta-analysis integrated direct and indirect evidence to compare multiple intervention categories within a single framework. [tpltrtarr]Risk of bias and certainty of evidence were assessed using ROBUST-RCT and the GRADE approach for network meta-analysis, respectively. [tpltrtarr]Some networks were sparse, and limited representation of key populations and long-term follow-up constrained the strength and generalisability of inferences.

Key PointsO_LIIn a randomized trial, an educational booklet and video did not increase evaluation completion or living donor kidney transplant receipt. C_LIO_LIFor patients who received the booklet and video intervention, experiencing discrimination in healthcare reduced evaluation completion. C_LIO_LILong-term follow-up and a large sample size yielded sufficient power to validate a true null effect of the intervention on key outcomes. C_LI BackgroundKidney transplantation (KT) evaluation is a complex, lengthy process; and living donor KT (LDKT) is the optimal treatment for kidney failure. Interventions at the start of evaluation may improve evaluation completion and LDKT rates. This study tested whether (a) an educational booklet and video (the "Talking About Living Kidney donation" [TALK] intervention) increased evaluation completion and LDKT when delivered under a streamlined KT evaluation program; and (b) if no effects found, explore differential effects by psychosocial/sociocultural factors (e.g., healthcare-related discrimination). MethodsWe conducted a randomized-controlled trial of the TALK intervention using permuted block randomization at an urban transplant center. Participants were enrolled 05/2015-06/2018; follow-up through 08/2022. Staff were blinded to block size, not allocation. Fine-Gray proportional hazards models examined intent-to-treat and per-protocol approaches. Primary outcomes were the cumulative incidence of evaluation completion and LDKT receipt. We explored interaction analyses by psychosocial/sociocultural factors and TALK-assignment. ResultsAmong 1108 participants (574 [52%] TALK, 534 [48%] No-TALK; median age: 59.13 [IQR: 48.92-67.10]; 243 [22%] Black, 783 [71%] White, 82 [7%] Other; 695 [63%] male), TALK did not significantly improve evaluation completion (sub-distribution hazard [SHR]=1.06; 95% CI: 0.92-1.22) or LDKT receipt (SHR=0.83; 95% CI: 0.55-1.25) in intent-to-treat and per-protocol analyses. In exploratory per-protocol analyses, discrimination significantly modified the effect of TALK on evaluation completion (SHR=0.42; 95% CI: 0.29-0.61). The "No-Discrimination" TALK participants had greater evaluation completion than No-TALK (SHR=1.32; 95% CI: 1.10-1.58), but the "Discrimination" TALK participants had lower evaluation completion than No-TALK (SHR=0.56; 95% CI: 0.41-0.77). ConclusionsDespite streamlined care, TALK did not improve evaluation completion or LDKT rates. A significant interaction in the per-protocol analyses for evaluation completion suggests prior healthcare-related discrimination may limit educational intervention effectiveness. Future studies should explore approaches that address systemic barriers and complement, rather than rely on, educational strategies to promote LDKT (ClinicalTrials.gov Identifier: NCT02342119).

ObjectiveWe report secondary histologic and high-risk HPV (hrHPV) outcomes from the Acceptability and Feasibility of Combination Treatment for Cervical Precancer Among South African Women Living with HIV (ACT 2) Trial. MethodsWe conducted a double-blind Phase 2b feasibility trial of loop electrosurgical excision procedure (LEEP) combined with adjuvant intravaginal 5-fluorouracil (5FU) cream. Women living with HIV (WLWH) and cervical intraepithelial neoplasia (CIN) 2/3 underwent LEEP and were randomly assigned (1:1) to receive 8 doses of 5FU or placebo cream. Our secondary outcomes were (a) regression of cervical disease and (b) clearance of hrHPV. ResultsFrom March 2023 to January 2025, 180 participants underwent LEEP and were randomized to 5FU or placebo cream. Median age was 41 years (IOR: 35-45), 29% had HPV16, 18% had HPV18/45; 99% of women were virologically suppressed (<200 copies/mL) and median CD4 count was 636 cells/uL (IOR: 376-873). 172 participants (95.6%) completed follow-up. At week 24, 96.3% (78/81) in the 5FU group and 82.0% (73/89) in the placebo group regressed to CIN1 or normal histology (PD 14.3%, CI 5.3%, 23.3%). Among participants with positive LEEP margins at week 0, 88.0% (22/25) in the 5FU versus 61.3% (19/31) in the placebo group regressed to CIN1 or normal (PD 26.7%, CI 5.4%, 48.1%). Genotype-specific hrHPV clearance was similar in both groups (5FU: 58.0%, 40/69; Placebo: 53.8%, 43/80; PD 4.2%, CI -11.7%, 20.2%). ConclusionClinical outcomes from our Phase 2b trial demonstrates that intravaginal 5FU post-LEEP may be a beneficial adjuvant treatment for CIN2/3. Clinical Trial RegistrationNCT05413811

ObjectivesTo determine temporal trends in the rates of preterm birth and its sub-types in Sweden and assess the contribution of known-risk factors. DesignA population-based register study. SettingSweden. Participants (Instead of patients or subjects)3,264,146 pregnancies registered in the Swedish Medical Birth Registry with information on pregnancy duration and onset of labour (1991 - 2021). Main outcome measuresThe primary outcomes were the overall, spontaneous and iatrogenic preterm birth rates between 1991 - 2021, stratified on singleton and multiple births, as well as for extremely preterm (<28 weeks, <196 days), very preterm (28-31 weeks, 196 - 224 days), moderately preterm (32 - 33 weeks, 224 - 238 days), and late preterm (34 - 36 weeks, 238 - 259 days) births. Using logistic regression models, we investigated whether maternal age at conception, use of artificial reproductive technologies, smoking, parity, and maternal continent of birth were associated with the observed trends. ResultsThe overall preterm birth rate was stable between 1991 - 2005 at 5.50% (95% CI: 5.37%, 5.63% in 1991) but decreased thereafter to 4.78% (95% CI: 4.66%, 4.91%) in 2021, a finding confined to spontaneous preterm births. The largest decline was observed in late preterm births, from 3.92% (95% CI: 3.80%, 4.05%) in 2005 to 3.52% (95% CI: 3.41%, 3.63%) in 2021. Moderately preterm birth also declined (0.70%, 95% CI: 0.65%, 0.76% in 2005 to 0.53%; 95% CI: 0.49%, 0.58% in 2021), whereas very-extremely preterm birth did not. Decreased spontaneous preterm birth rates were observed in women born in European, Asian and African countries, with largest decline observed in the latter (rate in 1991 = 2.65%, 95% CI: 1.74%, 3.86%; rate in 2021 = 1.72%, 95% CI: 1.42%, 2.07%). Adjusting for maternal and obstetric risk factors didnt alter these associations. ConclusionsWhile rates of preterm birth have been stable or increased globally, they have decreased in Sweden from 2006 - 2021, despite the lack of any nation-wide preventive strategy during this period. Understanding the reasons for this decline will provide useful strategies to make the decline a rule, rather than an exception.

BackgroundDeath certificates record both an underlying cause and contributing conditions, yet mortality statistics predominantly report only the underlying cause. We quantify this "hidden burden" across all ICD-10 conditions in Australian mortality data using the multiple-to-underlying ratio (MUR): total death certificate mentions divided by underlying cause deaths. MethodsWe analysed Australian Bureau of Statistics Causes of Death 2023 data (N = 187,268 registered deaths) to compute the ratio for all ICD-10 conditions. Three pre-registered confirmatory hypotheses tested sex differences in hypertension and mental health ratios, and geographic variation by preventability, with Holm-Bonferroni correction. ResultsDeath certificates recorded an average of 3.5 causes per decedent, meaning the underlying cause captures only [~]29% of recorded morbidity. Of 663 conditions with [&ge;]10 underlying cause deaths, the ratio ranged from 1.0 (external causes) to 281.1, with a median of 2.5. Among conditions with stable estimates ([&ge;]50 underlying deaths), the highest ratio was 94.3 (complications of medical care). Age explained only 10.9% of ratio variation (R2 = 0.109), and no top-ranked conditions were identified as primarily age-driven, suggesting the ratio ranking is robust to age confounding. However, external validation using US CDC data showed age standardisation materially changed absolute ratio values for 6 of 8 cause groups (divergence 16-34%), with the direction varying by condition rather than following a simple age-concentration pattern. Males showed consistently higher ratios, most strikingly for mental health disorders (62% higher); a counterfactual analysis estimated suicide coding rules explain only 6-15% of this sex difference. Three pre-registered hypotheses were null after correction; H1 and H3 (sex differences) were underpowered (n = 4, n = 8 pairs) with large effect sizes (r = 0.77-0.80), while H2 (geographic variation) showed a clear null. ConclusionsThe hidden burden of mortality in Australia is substantial and unevenly distributed, with symptom codes, mental health conditions, and hypertension most undercounted. The ratio provides a transparent framework for identifying conditions whose health impact is systematically understated by conventional mortality reporting.

Background and AimsThe glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide has demonstrated efficacy for the secondary prevention of cardiovascular disease among patients with overweight/obesity without diabetes mellitus. However, the comparative effectiveness of GLP-1 RA versus other antiobesity medications (e.g. phentermine-topiramate) not been evaluated. MethodsThis was a retrospective, observational, cohort study using target trial emulation methodology using the Truveta electronic health record database of more than 120 million patients. Adult patients with a body mass index (BMI) >=27 kg/m2, a history of cardiovascular disease (prior ischemic stroke, transient ischemic attack, or myocardial infarction, or known coronary artery disease, heart failure, or peripheral artery disease) without diabetes mellitus were included in the study. The primary endpoint was time to first major adverse cardiovascular or cerebrovascular event (MACCE, defined as stroke or myocardial infarction). ResultsIn total, 35,240 were included in the bupropion-naltrexone versus GLP-1 RA comparison, and 27,051 were included in the phentermine-topiramate versus GLP-1 RA comparison. In the pre-weighting cohort, GLP-1 RA use was associated with decreased hazard of MACCE compared to bupropion-naltrexone (HR 0.50 [95% confidence interval (CI) 0.36-0.69]) and phentermine-topiramate (HR 0.43 [95% CI 0.30-0.60]). In the propensity score-overlap weighted cohort, GLP-1 RA prescription was not associated with a lower hazard of MACCE than bupropion-naltrexone (aHR 0.69 [95% CI 0.47-1.00]) but was associated with a lower hazard compared to phentermine-topiramate (aHR 0.61 [95% CI 0.41-0.91]; adjusted absolute rate difference 0.98 per 1000 person-years). ConclusionsPrescription of a GLP-1 RA was associated with a lower risk of subsequent MACCE than phentermine-topiramate.

Background India represents 18% of the global population yet remains underrepresented in health research. Moreover, existing national surveys miss critical variation across its 4,600 ethnolinguistic groups. We present a comprehensive phenotypic characterisation of 81 populations from the GenomeIndia project. Methods We analysed 67 sociodemographic, anthropometric, and blood biochemistry variables from 17,777 individuals sampled across 81 ethnolinguistic populations from India, examining population-level variation, disease reporting fractions, and age- and sex-specific life-course trends. Findings Ethnolinguistic identity predicted health outcomes independently of administrative state, improving phenotypic variance explained by an average of 7.4%. 95% of participants had at least one abnormal biochemical or anthropometric marker, driven by low HDL (52.2%) and elevated triglycerides (43.6%). Metabolic risk, however, was highly stratified: adjusted prevalence for low HDL ranged four-fold across ancestry groups from 17.2% to 67.7%. We also identified an "awareness gap"; only 17.6% of people with hypertension and 2.2% of people with dyslipidemia were aware of their condition. This awareness gap was higher in tribal populations, in which women did not show the higher HDL levels typically seen compared to men, pointing to distinct metabolic profiles and healthcare access barriers across India. Interpretation The Indian phenotypic landscape is highly structured along ethnolinguistic lines, where ancestry and environment both influence risk. The high systemic burden of abnormalities necessitates population-specific reference intervals. GenomeIndia provides a foundational map for precision public health, shifting the focus from state-level averages to population-specific risk profiles. Funding This work was funded by the Department of Biotechnology, Ministry of Science and Technology, Government of India.

BackgroundBladder cancer imposes substantial clinical and economic burden, yet key natural-history quantities that determine the potential effectiveness of screening--such as the size of the screen-detectable preclinical reservoir and the preclinical sojourn time--are largely unobservable. The Cancer Intervention and Surveillance Modeling Network (CISNET) uses standardized stress tests to compare independently developed microsimulation models and to clarify how differences in model structure translate into differences in intervention impact. The Maximum Clinical Incidence Reduction (MCLIR) framework estimates the maximum achievable reduction in clinically detected incidence following a one-time, perfect screening intervention, while Realistic Clinical Incidence Reduction (RCLIR) relaxes the perfect-test and/or perfect-treatment assumptions. MethodsWe applied the CISNET MCLIR/RCLIR protocol to three independently developed bladder cancer microsimulation models (COBRAS, Kystis, and SCOUT), each calibrated to common U.S. epidemiologic targets. We simulated a U.S. birth cohort born in 1950 and compared: (1) no-screening baseline; (2) one-time perfect screening with universally curative treatment (MCLIR) at ages 60, 65, 70, and 75; and (3) one-time realistic screening with cystoscopy sensitivity of 80% and perfect treatment (RCLIR-1) or usual-care treatment effectiveness (RCLIR-2). Outcomes included age-specific clinical incidence and incidence-reduction curves relative to baseline, as well as cumulative reductions over follow-up. ResultsAcross models, median ages at first lesion emergence, clinical diagnosis, and onset of muscle-invasive disease were similar, but preclinical sojourn time differed meaningfully: COBRAS produced the shortest median sojourn time (2.1 years) compared with Kystis (3.3 years) and SCOUT (3.1 years). Under MCLIR, all models predicted an immediate drop in clinical incidence followed by attenuation toward zero as new lesions emerged after the screening age. Peak MCLIR at age 65 among White men ranged from 20% (COBRAS) to 21% (Kystis) and 32% (SCOUT), with reductions dissipating within [~]8 years in COBRAS and persisting [~]10 years in Kystis and SCOUT. In COBRAS and Kystis, incidence reductions later became negative, consistent with rebound emergence of new lesions among individuals whose first lesions were removed by screening. Under RCLIR-1, peak reductions were smaller and varied substantially across models (13%, 4%, and 37% for COBRAS, Kystis, and SCOUT, respectively). RCLIR-2 further reduced gains and produced more gradual decay, reflecting incomplete prevention under usual-care treatment. Across models, most residual post-screening incidence was attributable to new lesion emergence rather than missed detection or incomplete treatment. ConclusionsIn a standardized CISNET stress test, three bladder cancer microsimulation models imply a relatively short detectable preclinical phase, placing a modest upper bound on the effectiveness of one-time screening in the general population. Differences in MCLIR/RCLIR magnitude and persistence are explained by differences in implied sojourn time and detectable reservoir size. These findings motivate evaluation of risk-targeted and repeated early-detection strategies and highlight key empirical priorities for improving inference on bladder cancer natural history.