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%.

BackgroundThe multicentre WOMAN trial showed that tranexamic acid reduces postpartum haemorrhage (PPH) deaths. Several studies have recommended adjusting for clustering at the country and centre level to improve power and reduce bias in the standard errors. We reanalysed data from the WOMAN trial, adjusting for these centre effects. MethodsThe WOMAN trial recruited 20,060 women with clinically diagnosed PPH from 193 centres in 21 countries. The intervention was intravenous tranexamic acid versus matching placebo and the outcome was death from bleeding within 42 days of randomisation. We reanalysed data for the 14,928 women treated within 3 hours of birth for whom tranexamic acid provided the most benefit. We used random effects logistic regression to calculate the effect of tranexamic acid taking into account variation in risk of death and treatment effectiveness by country and centre. We calculated intraclass correlations (ICCs) to quantify between country and between centre within country variation. Results216 (1.4%) women died from bleeding. Using a univariable analysis without adjusting for centre effects, we found tranexamic acid reduced the odds of death from bleeding by 31% (OR=0.69 95% CI: 0.52-0.90, p=0.007). Adjusting for baseline covariates (age, systolic blood pressure (SBP) and SBP2) but not country or centre yielded a 36% odds reduction (OR=0.64 95% CI: 0.48-0.85 p=0.002). Adjustment for baseline covariates, country and centre yielded a 37% odds reduction (OR=0.63 95% CI: 0.48-0.85 p=0.002). We found substantial between country and centre variation in outcomes but not treatment effectiveness. The ICC for outcome was 14% for country and 19% for centre within country. ConclusionsAdjusting for country and centre effects made negligible differences to the magnitude of the treatment effect estimate or its associated p-value. Consistent with other studies of large clinical trials for medicines with binary outcomes, we found considerable between country and centre variation in outcomes but not in relative treatment effectiveness. Despite substantial ICCs for the outcome, adjusting for country and centre effects had minimal impact on our results. Trial registrationclinicalTrials.gov:NCT00872469 (March 2009)

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.

Niger has the worlds highest adolescent fertility rate. Social network (SN) approaches to family planning may improve intervention impact through diffusion beyond direct beneficiaries. We tested a social network modification of a community-based family planning intervention to increase contraceptive use compared to standard implementation and control.Three-arm cluster-randomized trial in 56 rural villages in Maradi, Niger. Eligible participants were adolescent wives (AW) aged 15-19 with 0-1 children and their husbands. Villages were randomized using covariate-constrained randomization (Minirand): standard Kulawa (100% coverage), SN modification (50% coverage pairing AW-mother-in-law dyads with adopt-a-friend diffusion), or control. Interventions were delivered over 12 months. Blinding of participants and implementers was infeasible; analysts were blinded. Primary outcome was current contraceptive use assessed at endline and analyzed using intention-to-treat difference-in-differences logistic regression adjusting for clustering; no missing data were imputed. ClinicalTrials.gov NCT05777473; trial closed to enrollment.From May 1 to September 30, 2022, 1,538 female AW were enrolled (517 control, 532 Kulawa, 489 Kulawa SN); 1,396 (90.8%) completed endline (May-August 2024). Compared to control, the SN arm significantly increased contraceptive use (AOR 2.36, 95% CI 1.27-4.44); the standard arm showed no significant effect (AOR 1.36, 95% CI 0.76-2.41). Within SN villages, both non-participants (AOR 2.66, 95% CI 1.25-5.70) and direct participants (AOR 2.10, 95% CI 0.99-4.44) showed increased use versus control, demonstrating behavioral diffusion. No intervention-related adverse events were observed in any arm. An SN approach targeting AWs, husbands, mothers-in-law, and adopted friends achieved greater effects than standard implementation despite 50% lower coverage, with evidence of diffusion to non-participants. Leveraging social networks may improve impact of family planning programs in high-fertility settings.

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).

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.

Potassium-containing low-sodium salt substitutes (LSSS) may lower sodium intake, increase potassium intake, and reduce cardiovascular risk in mixed adult populations, but the review literature is overlapping and methodologically heterogeneous. This umbrella review assessed the efficacy, safety, and evidence quality of potassium-containing LSSS for blood pressure, cardiovascular outcomes, and adverse events. Following a registered PROSPERO protocol (CRD420261294404), we searched PubMed, Embase, Web of Science, Global Health (EBSCO) and the Cochrane Database of Systematic Reviews from inception to 6 March 2026 for systematic reviews, meta-analyses and umbrella reviews of potassium-containing LSSS. Eleven reviews met eligibility criteria. Methodological confidence was high in one review, moderate in three, low in five and critically low in two. Primary-study overlap was very high (corrected covered area 28.5%). Review-level pooled estimates consistently favoured potassium-containing LSSS for systolic blood pressure (mean differences -4.61 to -8.87 mmHg) and diastolic blood pressure (-1.42 to -4.04 mmHg). Later reviews also reported lower all-cause mortality (RR 0.88-0.89), cardiovascular mortality (RR 0.72-0.87), composite cardiovascular events and selected stroke outcomes; however, clinical-outcome estimates were heavily influenced by the Salt Substitute and Stroke Study. Serum potassium changed minimally (-0.02 to 0.18 mmol/l), and pooled estimates for hyperkalaemia and serious adverse events showed no clear excess risk in trial populations that largely excluded participants at higher risk of impaired potassium handling. Potassium-containing LSSS consistently lower blood pressure and may improve cardiovascular outcomes, but further trials are needed outside Eastern Asia, with clearer formulation reporting, prespecified baseline CVD-history strata, and stronger safety data in higher-risk populations.

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.

IntroductionObstetric litigation is the largest single category of NHS clinical negligence by cost. The last systematic analysis of NHS obstetric litigation data was published in 2012 [1]. Despite major national safety programmes, annual costs have continued to escalate. This study aims to update the analysis and consider ethical and resource implications. MethodsFOI claims data were obtained from NHS Resolution for 2015/16-2024/25, supplemented by cerebral palsy and brain damage (CP/BD) data for the most recent six years. Activity-weighted HRG unit costs for 2024/25 and 2023/24 were used to compare planned vaginal birth (PVB) and planned caesarean section (PCS) pathway costs, incorporating indemnity attribution by cause-code proportion. The consent architecture was reviewed against Montgomery v Lanarkshire Health Board [2015] UKSC 11. ResultsOver the period, 11,881 claims were notified (approximately one per 500 England NHS births); 7,216 were settled, with total damages of {pound}5,974 million, rising approximately 85% in real terms. Four intrapartum monitoring failure codes and seven labour-exclusive delivery complication codes together accounted for {pound}2,776 million paid (55.9% of all obstetric damages). CP/BD claims represented 16.6% of volume but 77.7% of obstetric damages over 2019/20-2024/25, at an average of {pound}3.58 million per claim. Activity-weighted HRG analysis at 2024/25 tariff showed PCS at {pound}6,202 versus PVB at {pound}6,339 per birth. ConclusionsObstetric litigation costs continue to escalate, driven overwhelmingly by labour-attributable harm. NHS England data show, for the first time, PCS tariff costs below PVB. Including indemnity under the primary eleven-code attribution, total system cost excess of PVB reaches approximately {pound}1,032-{pound}3,082 per birth (2024/25 cash to actuarial basis). Consent architecture for planned mode of delivery raises a potential inconsistency with Montgomery. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSObstetric litigation is the largest single category of NHS clinical negligence by cost, driven overwhelmingly by intrapartum harm, yet no systematic analysis of cause-code data has been published since 2012. What this study addsTen years of NHS Resolution FOI data show that eleven labour-exclusive cause codes account for 55.9% of obstetric damages; NHS England tariff data show, for the first time, that planned caesarean section ({pound}6,202) is less costly than the planned vaginal birth pathway ({pound}6,339), and when indemnity is included the total system cost excess of planned vaginal birth reaches {pound}1,032-{pound}3,082 per birth. How this study might affect research, practice or policyA formal comparative-risk consent process at booking, equivalent to that currently required for planned caesarean section under RCOG Consent Advice No. 14, should be considered standard for all women; NICE should update its economic analysis of mode of delivery to incorporate litigation costs; and NHS tariff methodology should be reviewed to ensure indemnity is allocated in proportion to the pathway-level mechanisms that generate it.

ImportanceCesarean delivery is the most common surgery in the US with more than 1 million performed each year; it is also the most significant risk factor for postpartum infection. The Cesarean Section Optimal Antibiotic Prophylaxis trial demonstrated that the addition of azithromycin at the time of cesarean birth performed in labor reduces postpartum infection. ObjectiveTo determine the real-world adoption and effect of this trial on clinical practice and postpartum infections among U.S. pregnant persons undergoing cesarean delivery in labor. DesignDifference-in-differences analysis from 2013-2024. SettingPopulation-based, patient-level analysis using Epic Cosmos, a large longitudinal national electronic health record database of patients seen in health systems using Epic. ParticipantsPregnant individuals who received outpatient prenatal care in the system, who labored and gave birth to a liveborn singleton infant at 24-43 weeks of gestation were included. Exclusion criteria included unknown mode of delivery and intraamniotic infection. ExposuresThe treatment group included those delivered by cesarean and the control group included those who delivered vaginally. The pre-period was defined as 2013-2016, excluding a washout period from trial publication until December 31, 2016, and the post-period was defined from 2017-2024. Main Outcomes and MeasuresThe primary outcomes were perioperative azithromycin administration and postpartum infection within 6 weeks of delivery. Results1,663,341 participants were included in the final analysis. In the pre- and post-periods, azithromycin was administered in 0.01% and 0.04% of vaginal births and in 2.2% and 39.6% of cesarean births, respectively. In the pre- and post-periods, postpartum infection occurred in 2.0% and 2.7% of vaginal births and 9.2% and 8.0% of cesarean births. In the adjusted difference-in-difference analysis, the trial resulted in an absolute increase in azithromycin use by 37.6 percentage points (pp) (95% CI: 33.1 to 42.2 pp); postpartum infection decreased by 2.0 pp (95% CI: -2.5 to -1.4 pp), a relative decrease of 20%. Conclusions and RelevanceOutside the clinical trial setting, this study provides evidence that azithromycin significantly reduces postpartum infection among pregnant persons undergoing a cesarean delivery in labor. Key PointsO_ST_ABSQuestionC_ST_ABSDid evidence from the Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial change real-world clinical practice and decrease postpartum infections among U.S. pregnant persons who underwent a cesarean delivery in labor? FindingsIn this difference-in-differences analysis of 1.6 million births, azithromycin use increased 37.6 percentage points and postpartum infections decreased by 2.0 percentage points following the C/SOAP trial. MeaningOutside the clinical trial setting, this study provides evidence that azithromycin significantly reduces postpartum infection among individuals having a cesarean delivery in labor.

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.

BackgroundNovel HIV prevention interventions such as long-acting pre-exposure prophylaxis (PrEP) could substantially reduce HIV transmission in Africa. However, efficient implementation in high-prevalence settings where incidence has declined requires an understanding of the contemporary dynamics driving new infections. MethodsWe identified incident HIV cases from a longitudinal, population-based cohort in Uganda. We individually matched cases to HIV-negative controls; traced and enrolled reported sexual partners; and enrolled female sex workers (FSWs) from reported venues. Conditional logistic regression, transmission modeling, and phylogenetics were used to characterize transmission networks. FindingsFrom 2021-2024, 38,899 HIV tests among 22,255 people identified 187 people with incident infections (47.6% male); 164 (88%) were enrolled and matched to 164 HIV-negative controls. Overall, 593 non-sex-worker partners (371 enrolled,62.6%), 146 FSW partners (21 enrolled,14.4%), and 28 venues (208 FSWs enrolled) were reported. Incident infection was most strongly predicted by partnership with a FSW (odds ratio:15.5; 95%CI:3.7-64.8), identified in 43.0% of male cases versus 6.3% of controls. Men with FSW partners had larger sexual networks than men without (median:6 vs 2 partners), and 91.2% of men with FSW partners also had non-sex-worker partners. Transmission modeling attributed 34.4% (95%CI:31.5-36.8%) of all male infections and 80.0% (95%CI:73.2-84.4%) of infections among male clients to sex with FSWs. Oral PrEP use among HIV-negative partners of incident cases was low (8.9% in women; 2.1% in men). InterpretationMen with FSW partners accounted for a substantial share of incident HIV infections and had markedly higher odds of infection than men without such partnerships. Together with the high potential for onward transmission within male client networks, these findings suggest that inclusion of male clients in long-acting HIV prevention strategies could be highly efficient and impactful. FundingNational Institutes of Health, United States; Gates Foundation; National Health and Medical Research Council, Australia

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

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.

BackgroundThe 2025-2026 COVID-19 vaccine season introduced updated formulations targeting the LP.8.1 lineage. This study assessed the absolute vaccine effectiveness (aVE) of mRNA-1283 and BNT162b2 on COVID-19 outcomes in adults aged [&ge;]65 years. MethodsThis retrospective study used linked electronic health record and administrative claims data through Jan 31, 2026. Adults [&ge;]65 years who received the mRNA-1283 or BNT162b2 2025-2026 COVID-19 vaccine were matched to unvaccinated individuals. Inverse probability of treatment weighting was applied to each vaccines matched cohorts to balance covariates. Each vaccine was evaluated independently against its own unvaccinated comparator group. aVE against COVID-19 related hospitalization and medically-attended COVID-19 was estimated using Cox proportional hazards models; aVE = 100 x (1 - hazard ratio [HR]). ResultsWe identified 233,072 mRNA-1283 recipients and 422,610 BNT162b2 recipients [&ge;]65 years. The aVE (95% confidence interval) of mRNA-1283 against COVID-19 related hospitalization and medically-attended COVID-19 was 59.3% (39.0%, 72.9%) and 42.0% (35.0%, 48.3%) among adults [&ge;]65 years and 66.9% (45.9 %, 79.8%) and 50.2% (42.1%, 57.2%) in [&ge;]75 years, respectively. The aVE of BNT162b2 against COVID-19 related hospitalization and medically-attended COVID-19 was 48.3% (32.4%, 60.5%) and 41.2% (36.2%, 45.8%) in [&ge;]65 years and 45.9% (26.0%, 60.4%) and 44.0% (37.8%, 49.6%) in [&ge;]75 years, respectively. ConclusionsThis is the first real-world evidence showing that mRNA-1283 prevents COVID-19-related hospitalizations and medically attended events in vulnerable older adults at highest risk of severe disease. These findings support mRNA-1283 as an important public health tool for reducing the ongoing burden of COVID-19.

We estimated the number needed to vaccinate (NNV) with an M72/AS01E-like vaccine to prevent one tuberculosis case in U.S. high-risk groups. Targeted vaccination of Mycobacterium tuberculosis-infected persons yielded NNVs of 217 (persons with HIV) to 2,486 (U.S.-born), within the range of established adult vaccines.

Background: Child acute malnutrition remains persistently above emergency thresholds in Chad's Sahelian drylands, with a predictable, but rarely recognized, dry season peak linked to declining pasture and livestock productivity, reduced milk availability and heightened exposure to zoonotic infections. Humanitarian responses remain largely reactive and treatment-focused, with limited evidence on preventive strategies that address drivers embedded in local livelihood systems. We evaluated the effectiveness and return on investment (ROI) of an integrated livestock management intervention designed to prevent the dry-season peak of child acute malnutrition in pastoral and agro-pastoral communities in Chad. Methods: We conducted a cluster-randomised controlled trial in Kanem and Barh-El-Gazel provinces, Chad. Seventy-six villages were randomised (1:1) to intervention or control. Eligible households had at least one child aged 6-59 months and access to milking livestock during the dry season. The intervention (December 2024-June 2025) combined livestock feed supplementation to sustain milk production near households during the dry season, household-level zoonotic risk mitigation, and nutrition counselling. Primary outcomes were the prevalence of global acute malnutrition (GAM) and severe acute malnutrition (SAM) at the dry-season peak (May 2025), assessed in a prespecified random subsample of 52 clusters. All 76 clusters were assessed post-peak (July 2025). Analyses followed an intention-to-treat approach using mixed-effects models. A societal ROI analysis was conducted over six months with projections to 24 months. Findings: At the dry-season peak, 821 children 6-59 months from 521 households were assessed across 52 villages. GAM prevalence was 22.2% in intervention villages versus 47.4% in controls (adjusted OR 0.29 [95% CI 0.18-0.49]; p<0.001), and SAM prevalence was 4.4% versus 19.4% (adjusted OR 0.17 [0.08-0.37]; p<0.001). Intervention households had higher daily milk availability (+588 mL per household; p<0.001), and children consumed more milk (+102 mL per day; p=0.008). Odds of self-reported diarrhoeal disease and acute respiratory infection were substantially lower among children in intervention villages (aOR 0.21 [0.10-0.44] and 0.22 [0.11-0.46], respectively). Post-peak, women's dietary diversity increased (aOR 3.68 [1.90-7.13]), alongside reduced workload, lower household food insecurity and distress livestock sales, improved livestock condition, and a benefit-cost ratio of 5.40 at six months, rising to 16.40 at 24 months. Interpretation: Protecting livestock productivity and sustaining children's access to milk while reducing zoonotic exposure during the pastoral lean season effectively prevents seasonal peaks of child acute malnutrition. This integrated anticipatory action and One Health livelihood-based approach offers a scalable, dignifying, high-return lifesaving preventive model for pastoral and agro-pastoral humanitarian settings.

Gabapentin and pregabalin are renally cleared gabapentinoids with markedly different pharmacokinetic profiles in chronic kidney disease: gabapentin half-life extends from 5-7 hours to 52-132 hours in advanced chronic kidney disease, while pregabalin accumulation is more predictable. In an active comparator new-user cohort of 33,791 adults aged [&ge;]40 years with hypertension initiating gabapentinoids (2018-2024) from the Rutgers Clinical Research Data Warehouse, chronic kidney disease substantially amplified gabapentin-associated dementia risk (hazard ratio 7.39, 95% confidence interval 3.43 to 15.92, P<0.001), whereas patients without chronic kidney disease showed near-null effect (hazard ratio 1.09, 95% confidence interval 0.89 to 1.34; P=0.41; interaction P<0.001). This effect was independent of prescribed dose: within the low-dose stratum, chronic kidney disease patients showed hazard ratio 5.06 versus 1.27 in patients without chronic kidney disease. Pre-existing chronic kidney disease conferred significantly elevated risk (hazard ratio 1.78; P=0.001), while incident chronic kidney disease showed a nonsignificant trend (hazard ratio 1.32; P=0.16), consistent with cumulative pharmacokinetic burden. Independent replication in the NIH All of Us Research Program Controlled Tier (N=47,079; hazard ratio 1.593, 95% confidence interval 1.349 to 1.882; P<0.001) confirmed the overall gabapentin-pregabalin signal; eGFR-staged analysis showed the expected pharmacokinetic pattern (mild CKD [eGFR [&ge;]45]: hazard ratio 1.15, not significant; severe CKD [eGFR <45]: hazard ratio 1.77, directionally elevated but underpowered with 51 events). Food and Drug Administration Adverse Event Reporting System data corroborated the renal mechanism (odds ratio 1.642 for renal events in elderly co-exposed patients). These converging findings suggest that chronic kidney disease is a clinically important modifier of gabapentin-associated cognitive risk, and that gabapentinoid selection in chronic kidney disease patients should integrate renal function status into prescribing decisions. Significance StatementGabapentin is the most prescribed gabapentinoid in the United States, with approximately 59 million annual prescriptions, and is entirely dependent on renal clearance. In this active comparator cohort study of 33,791 gabapentinoid initiators, chronic kidney disease amplified gabapentin-associated dementia risk nearly 7-fold compared with pregabalin, an effect that was independent of prescribed dose and persisted even among patients receiving low-dose gabapentin. External replication in the NIH All of Us Research Program and FDA pharmacovigilance data corroborated the signal. These findings suggest that current dose-adjustment guidelines for gabapentin in CKD may be insufficient to prevent cognitive harm, and that renal function status should be incorporated into gabapentinoid selection decisions.