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%.

IMPORTANCENicotinamide metabolites have recently been implicated in increased risk of major cardiovascular events (MACE). Supportive data about clinical risk of MACE for nicotinamide users is lacking. OBJECTIVETo determine whether nicotinamide use results in an increase of MACE. DESIGN, SETTING, PARTICIPANTSRetrospective cohort study of two patient cohorts, Vanderbilt University Medical Center (VUMC) and Military Veteran Program (MVP). The risk of MACE in patients exposed to nicotinamide was compared to the risk of MACE in unexposed patients. In the VUMC cohort, 1228 patients were exposed to nicotinamide based on keyword entry for "nicotinamide" or "niacinamide" and hand-review of charts, while 253 were unexposed but had documented recommendation for use. In the MVP cohort, there were 1594 with exposure to nicotinamide propensity score matched to 2694 without exposure. EXPOSURESThe primary exposure for the VUMC cohort was a confirmed exposure to nicotinamide in chart review. The primary exposure for the MVP cohort was medication entry for "nicotinamide" or "niacinamide". MAIN OUTCOME(S) AND MEASURE(S)The primary outcome was development of MACE based on a validated phenotype. RESULTSBetween both cohorts, 6039 patients were included, of whom 5125 were male with a mean age of 63.2 years. Neither cohort had significant differences in mean age, sex, race and ethnicity between the nicotinamide exposed and unexposed groups. In the VUMC cohort, there was no significant association between nicotinamide exposure and the primary outcome of MACE (HR 0.76, 95% CI 0.46 - 1.25, p = 0.28). MACE prior to nicotinamide exposure was strongly associated with subsequent MACE (HR 9.01, 95% CI 5.90 - 13.70, p < 0.001). In the MVP cohort, we adjusted for MACE risk factors as potential confounding variables and saw no significant association between nicotinamide exposure and MACE (HR 1.00 95% CI 0.75 - 1.32), while history of prior MACE remained strongly associated with subsequent MACE (HR 9.50, 95% CI 6.38 - 14.1). CONCLUSIONS AND RELEVANCEIn this retrospective cohort study of 6039 adults from two different patient populations, we found no increased risk of MACE in patients with nicotinamide exposure.

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.

IntroductionWhile voluntary medical male circumcision (VMMC) reduces the individual- level risk of HIV acquisition by approximately 60% in randomised-controlled trials, little is known about the real-world long-term effect of medical and traditional male circumcision on the cumulative risk of HIV infection. We estimate the association between these for the first time using a quasi-experimental study design--a household fixed-effects analysis--for sub- Saharan Africa, the global region with the largest HIV burden. MethodsWe pooled individual-level cross-sectional data from the nationally-representative Demographic and Health Surveys and AIDS Indicator Surveys across all sub-Saharan African countries in which the surveys included data on both male circumcision and HIV status. We estimated the association between male circumcision and HIV status using modified Poisson regression models with household fixed-effects--which control for unobserved and observed confounding shared by men living in the same household--and included additional individual- level controls for demographic characteristics, socio-economic factors, and sexual behaviour. ResultsWe included individual data from 279,351 male participants in 48 nationally- representative surveys conducted in 29 countries between 2003-2018. The mean survey-level prevalence of male circumcision was 65.9% (median 84.5%, IQR 28.8%-68.1%) and HIV was 5.6% (median 2.5%, IQR 1.2%-10.2%). We estimated that male circumcision was significantly associated with a nearly one-fifth reduction in the cumulative risk of HIV infection (adjusted risk ratio 0.81, 95% CI 0.73-0.89). ConclusionsMale circumcision was associated with a significant reduction in the risk of HIV infection in sub-Saharan Africa over the past two decades. Increased political and financial commitment to VMMC could likely lead to further reductions in HIV prevalence, especially when rolled out as a HIV prevention option in combination with other interventions.

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.

IntroductionWomen living with HIV (WLHIV) face an increased risk of cervical cancer (CC). With inequitable HPV vaccine access and a programmatic focus on girls-only school-based delivery, many WLHIV in high HIV prevalence countries remain vulnerable to HPV infection and CC. We assessed the incremental impact of adding catch-up vaccination for WLHIV in South Africa. MethodsWe used two independently developed HPV/CC and HIV transmission models to predict the incremental impact of catch-up HPV vaccination for WLHIV compared to routine-only vaccination of girls aged 9-14 (90% cohort coverage) from 2020 onward using a nonavalent vaccine (lifelong 100% protection). We assessed two catch-up scenarios vaccinating WLHIV aged 15-24 or 15+ (attaining 90% cohort coverage for at least three years), maintaining baseline CC screening. We report the predicted median annual prevalence of vaccine-type high-risk HPV (VT HR-HPV), CC incidence, and cumulative fraction of CC averted compared to routine-only vaccination among WLHIV overall (age-standardized) and by age. ResultsWith routine-only vaccination, overall coverage among WLHIV remained substantially (>50%) lower than in all women for 35-40 years, with gaps persisting even after 80 years. Adding catch-up vaccination for WLHIV aged 15-24 increased coverage and benefits mainly among young WLHIV, with the largest annual reductions (relative to routine-only vaccination) in VT HR-HPV prevalence and CC incidence for WLHIV <30 years, reaching up to 36-52% across models within 15 years and 38-100% after 15-25 years, respectively. If catch-up included WLHIV aged 15+, overall vaccination coverage among WLHIV would immediately increase to 90%, extending benefits to older WLHIV -reducing peak annual relative reductions in CC incidence among WLHIV 50+ by an extra 19%-points compared to catch-up vaccination of WLHIV aged 15-24, and shifting the peak 25 years earlier. Over 55-60 years, catch-up vaccination of WLHIV aged 15-24 and 15+ could avert up to 3-8% and 14% of CC cases among WLHIV, respectively. ConclusionsCatch-up vaccination of WLHIV can reduce their CC burden in the short to medium term, even in the presence of girls-only routine vaccination programs with high cohort coverage. To maximize impact, vaccines should be offered to WLHIV of all ages, not only younger women.

ImportanceAssessment of the burden of mortality due to excess body weight in a population and its subgroups is important for designing health policies for interventions. Mendelian randomization (MR) studies can provide an opportunity to correct for unmeasured confounding bias present in observational studies, but such evidence has not been used to assess population burden of mortality due to excess BMI. ObjectiveCombine results from a recent Mendelian randomization (MR) study and data from the National Health Surveys to estimate preventable fraction (PF) of 10-year all-cause and cause-specific mortality by different degrees of BMI reduction in the US adult population and underlying risk strata. DesignsWe use cross-sectional data on the distribution of BMI and other risk factors of mortality from the National Health and Nutritional Examination Surveys (NHANES) across two-time spans (1999-2006 and 2017-2018). We use linked data from National Death Index to characterize the observed risk of 10-year mortality associated with BMI and other risk factors based on the NHANES 1999-2006 cohort. We further import results from an external MR study on linear and non-linear effects of BMI and use novel methods to estimate preventable fraction (PF) for deaths under different counterfactual scenarios of BMI reduction in the NHANES population. SettingsPrimary analysis is restricted to the NHANES non-Hispanic white population (age range 40-69 years) due to the unavailability of MR studies in other groups, but projections are provided for the African American population under the assumption of homogeneity of causal effects. OutcomePreventable fraction for 10-year all-cause mortality and cause-specific mortality due to 50% and 100% reduction of excess BMI (BMI>25.6 kg/m2) for the US adult population in the age range of 40-69 years. ResultsNearly 33% and 43% of the NHANES 2017-2018 target population are overweight (25.6 kg/m2 [&le;]BMI<30.7 kg/m2) and obese (BMI>30.7 kg/m2), respectively, according to WHO definitions. Estimates of relative risks for different BMI categories (relative to normal BMI) from the external MR study range from 1.05 (25.6 kg/m2 [&le;] BMI < 27.8 kg/m2) to 5.95 (BMI> 42.4 kg/m2). We estimate PF for 10-year all-cause mortality due to 50% and 100% reduction of excess BMI for the population to be 24% (95% CI: 14 - 34) and 35% (95% CI: 22-48), respectively. The estimate of PF of death due to heart disease and cancer for this population reaches up to 48% (95% CI: 25[&le;]71) and 18% (95% CI: -2-38), respectively. Partitioning of PF shows that 60% of all BMI-attributable deaths arise from only 12% of the population who are at the highest risk due to obesity and a combination of other risk factors. ConclusionsNearly one in three deaths in a contemporary US adult population can be attributed to overweight and obesity. A substantial fraction of these deaths are likely to be preventable through pragmatic and targeted BMI interventions.

AbstractsO_ST_ABSBackgroundC_ST_ABSMaternal mortality remains far above the Sustainable Development Goal (SDG) target in many settings, and global strategies lack an empirically derived coverage threshold for "safe" delivery. MethodsWe assembled a longitudinal panel of 2 184 country-year observations from 182 countries (2000-22), linking UN Maternal Mortality Estimation Inter-agency Group estimates with WHO and World Bank indicators. The primary exposure was institutional-birth coverage (% of livebirths in health facilities); the outcome was maternal mortality ratio (MMR; deaths per 100 000 livebirths). Using two-way fixed-effects models with restricted cubic splines, adjusted for anaemia prevalence and adolescent birth rate, we estimated the within-country association between institutional births and log(MMR). We then applied Hansen-type panel threshold regression to identify coverage levels at which the slope of this association changed, and repeated analyses by WHO region. FindingsMedian institutional-birth coverage was 72{middle dot}4% (IQR 54{middle dot}2-90{middle dot}7) and median MMR 173 deaths per 100 000 livebirths (81-328). Globally, each 10-percentage-point increase in institutional births was associated with a 7{middle dot}8% (95% CI 6{middle dot}1-9{middle dot}5) reduction in log(MMR). Threshold analysis identified a single global inflection at 70{middle dot}2% coverage (95% CI [~]68-72). Below this threshold, each 10-point increase in institutional births was associated with a 12{middle dot}6% (10{middle dot}2-14{middle dot}8) reduction in log(MMR), compared with 4{middle dot}1% (2{middle dot}5-5{middle dot}7) above the threshold--an almost three-fold difference in marginal effect. Region-specific thresholds ranged from 65% in the African Region to over 90% in the Western Pacific. InterpretationSeventy per cent institutional-birth coverage represents a "safe-delivery" threshold: below this level, expanding facility births yields large reductions in maternal mortality; above it, further gains require investments in quality of care, emergency obstetric capacity, and equity. Embedding this empirically derived threshold into SDG 3{middle dot}1 and universal health coverage monitoring could sharpen accountability, guide resource allocation, and accelerate progress towards ending preventable maternal deaths. FundingNone.

ObjectiveWe aimed to compare health outcomes and costs in obstetric-led continuity versus multi-professional non-continuity models of care. DesignObservational study with linked administrative data SettingAustralian public and private maternity care Population867,334 births, coverall all births in three states of Australia between 2016 and 2019 MethodsWe analysed outcomes from pregnancy onset to four weeks post-birth in a whole-of-population linked perinatal data asset. Tightly matched cohorts were generated, with bootstrapping of 50 re-matched datasets and sensitivity analyses. Main outcome measuresStillbirths or neonatal deaths; neonatal intensive care admissions; APGAR score <7 at 5 minutes; 3rd or 4th degree perineal tears; maternal haemorrhages; mean cost per pregnancy episode. ResultsHigher adverse outcomes in the multi-professional non-continuity model compared to the obstetric-led continuity model of care, including 786 more stillbirths or neonatal deaths (OR 2.0, 95% CI: 1.8 - 2.1), 2,780 more APGAR score <7 at 5 minutes (OR 2.0, 95% CI: 2.0 - 2.1), 3,327 more 3rd or 4th degree perineal tears (OR 2.9, 95% CI: 2.7 - 3.1) and 10,530 additional maternal haemorrhages (OR 2.7, 95% CI: 2.6 - 2.8). Obesity and mode of birth correlated with neonatal death. Mean cost in AUD per pregnancy episode was $5,888 higher in multi-professional non-continuity model versus obstetric-led continuity, equating to $1.77 billion in extra annual cost to government. Findings persisted across bootstrapping, sensitivity analyses and socioeconomic quintiles. ConclusionWe have shown significant disparity and inequality in outcomes and costs, challenging universal value-based care, with lower adverse health outcomes and costs in the obstetric-led continuity model. FundingNational Health and Medical Research Council (NHMRC).

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.

BackgroundThe importance of adolescent cardiorespiratory fitness for long-term risk of type 2 diabetes (T2D) remains poorly investigated, and whether the association is influenced by unobserved familial confounding is unknown. MethodsWe conducted a sibling-controlled cohort study based on all Swedish men who participated in mandatory military conscription examinations from 1972 to 1995 around the age of 18, and who completed standardized cardiorespiratory fitness testing. The outcome was T2D, defined as a composite endpoint of diagnosis in inpatient or specialist outpatient care, or dispensation of antidiabetic medication, until 31 December 2023. Findings1 124 049 men, of which 477 453 were full siblings, with a mean age of 18.3 years at baseline were included. During follow-up, 115 958 men (48 089 full siblings) experienced a first T2D event at a median age of 53.4 years. Compared to the first decile of fitness, higher fitness levels were associated with a progressively lower risk of T2D. In cohort analysis, the hazard ratio (HR) in the second decile was 0.83 (95% CI, 0.81 to 0.85), with a difference in the standardized cumulative incidence at age 65 of 4.3 (3.8 to 4.8) percentage points, dropping to a HR of 0.38 (0.36 to 0.39; incidence difference 17.8 [17.3 to 18.3] percentage points) in the tenth decile. When comparing full siblings, and thus controlling for all unobserved behavioral, environmental, and genetic confounders that they share, the association replicated, although with attenuation in magnitude. The HR in the second decile was 0.89 (0.85 to 0.94; incidence difference 2.3 [1.3 to 3.3] percentage points), and in the tenth decile it was 0.53 (0.50 to 0.57; incidence difference 10.9 [9.7 to 12.1] percentage points). Hypothetically shifting everyone in the first decile of fitness to the second decile was estimated to prevent 7.2% (6.4 to 8.0) of cases at age 65 in cohort vs. 4.6% (2.6 to 6.5) in full-sibling analysis. The association was similar in those with overweight as in those without. InterpretationHigher levels of adolescent cardiorespiratory fitness are associated with lower risk of T2D in late adulthood, with clinically relevant associations starting already from very low levels of fitness, and similarly in those with overweight compared to those without. The association replicates, but becomes weaker, after adjusting for unobserved familial confounders shared between full siblings. This suggests that adolescent cardiorespiratory fitness is a robust marker of long-term T2D risk, but that conventional observational analysis may yield biased estimates. FundingNone. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSType 2 diabetes is a growing public health issue, affecting at least half a billion people globally. Modifiable factors such as physical activity and the closely related trait cardiorespiratory fitness, which are inversely associated with type 2 diabetes, are declining, particularly among youth. Since these traits track from youth into adulthood, early-life interventions might have important implications for prevention. However, previous studies have typically focused on middle-aged individuals, leaving gaps in understanding whether fitness in youth is associated with type 2 diabetes in the long-term. Moreover, they have not been designed to adequately account for unobserved confounders. Triangulating the evidence across different methods, such as using sibling comparison analysis, would be important to obtain more accurate and reliable estimates of the causal relationship. Added value of this studyIn this nationwide sibling-controlled cohort study encompassing more than 1 million young men, of which half a million were full siblings, higher levels of adolescent cardiorespiratory fitness were associated with a substantially lower risk of developing type 2 diabetes up to five decades later. The association was clinically relevant already from low levels of fitness, and it appeared similar in those with overweight as in those without overweight. While the association replicated after adjusting for unobserved familial confounders shared between full siblings, the magnitude of association attenuated by an amount that appeared clinically relevant. For example, the incidence differences between deciles of fitness were about 40% smaller in sibling-comparison analyses as compared to cohort analysis, and the preventable share of type 2 diabetes associated with hypothetical interventions shifting the population-level of fitness was reduced by about one-third. Implications of all the available evidenceAdolescent cardiorespiratory fitness is a strong marker of long-term risk of type 2 diabetes, both in those with and without overweight. These findings render support to large-scale surveillance of fitness from a prevention perspective, and if the findings are confirmed using other lines of causal analysis, they may render support to interventions targeting fitness already from a young age. Yet, these findings also highlight the importance of triangulation for obtaining more reliable evidence of the magnitude of association, and shed light on the pitfalls of conventional observational analysis which may yield biased estimates.

BackgroundThe prevalence of type 2 diabetes mellitus (T2DM) is increasing in China, and T2DM is linked to higher risk of several cancers, particularly obesity-related cancers (ORCs). Whether these associations are causal remains unclear due to potential biases. MethodsWe conducted a matched cohort study within the China Kadoorie Biobank (512,724 participants recruited 2004-08) to examine causal associations between new-onset T2DM and cancer incidence. To minimise bias, we: (i) included only incident T2DM cases, (ii) applied sex-specific sequential longitudinal matching, (iii) restricted analysis to pre-diagnosis body mass index (BMI), and (iv) accounted for detection time bias. Cox models stratified on the matched set estimated sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs). Results were triangulated with two-sample Mendelian randomisation (MR). FindingsAfter 1:3 matching, 8,657 men and 13,680 women with new-onset T2DM were retained, matched to 25,852 and 40,938 unexposed individuals, respectively. During follow-up to 31 Dec 2018, the incidence rate (IR) of total cancer was 1,365.1 per 100,000 person-years (95% CI 1,250.1-1,480.0) in men with T2DM versus 800.2 (749.7-850.7) in unexposed matches, and 864.7 (794.5-935.0) in women with T2DM versus 629.4 (594.7-664.1) in unexposed matches. T2DM was associated with increased risk of total cancer in men (HR 1.57, 95% CI 1.38-1.79) and women (HR 1.30, 95% CI 1.15-1.47). There was evidence of associations with liver (men HR 2.12, 95% CI 1.42-3.15; women HR 2.39, 95% CI 1.42-4.04) and pancreatic cancer (men HR 2.57, 95% CI 1.35-4.92; women HR 3.95, 95% CI 1.92-8.13). In MR, liability to T2DM was causally related with pancreatic cancer (pooled OR 1.08, 95% CI 1.02-1.15, P = 0.01), but not other cancers. Triangulation supported a causal link between T2DM and pancreatic cancer in East Asians. InterpretationThese findings provide strong evidence for a causal relationship only between T2DM and pancreatic cancer risk in Chinese, while evidence for other cancer sites was weak or discordant. FundingChina Scholarship Council; NIHR Manchester Biomedical Research Centre Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe systematically searched PubMed and Google Scholar for observational studies and/or Mendelian randomisation (MR) studies describing the associations between type 2 diabetes mellitus (T2DM) and incident cancer in Chinese. Existing Chinese cohort studies consistently suggested a modest excess risk in overall cancer incidence--driven mainly by liver, pancreas, colorectum, and in women, breast--but the strength of evidence was limited by recurring methodological shortcomings (e.g., inadequate covariate adjustment, immortal time and survivor biases, competing-risk bias). In MR studies among East Asians, except for pancreatic cancer, "counterintuitive" inverse associations were reported for several digestive cancers (e.g., stomach, liver, colorectum, oesophagus), raising concerns about potential flaws in the design of the source genome-wide association studies (GWAS). Overall, current evidence is constrained by substantial heterogeneity across studies, the likelihood of residual confounding (particularly from adiposity and lifestyle factors), other sources of bias, and possible publication bias. Robust, population-specific studies are needed to clarify the causal relationships between T2DM and site-specific cancer risks in China. Added value of this studyTo our knowledge, this is the first national-level prospective cohort study in China to employ a sex-specific, longitudinal matching strategy explicitly designed to minimise multiple sources of bias when evaluating the potential causal link between T2DM and cancer. Using rigorous methodology and triangulation with MR evidence, our findings provide causal support for an effect of T2DM on pancreatic cancer risk only. By contrast, many previously reported associations with other cancers, such as colorectum or female breast, are likely due to a range of biases. Implications of all the available evidenceOur findings, together with prior research, indicate that the excess risks of most cancers observed in people living with T2DM are unlikely to be causal. The exception is pancreatic cancer, for which convergent evidence from both observational and genetic analyses supports a causal role of T2DM. In China--where diabetes prevalence is rising sharply-- these results suggest that cancer prevention strategies should not treat T2DM as a broad carcinogenic exposure but rather focus on modifiable upstream determinants such as adiposity and lifestyle factors.

BackgroundIntegrase inhibitors, including dolutegravir, may increase risk of major adverse cardiovascular events (MACEs). However, limited data exists from low- and middle-income countries, where tenofovir disoproxil fumarate, lamivudine and dolutegravir (TLD) has largely replaced tenofovir disoproxil fumarate, emtricitabine and efavirenz (TEE). MethodsWe used de-identified data from a South African managed-healthcare organisation from people living with HIV (PLHIV) without cardiovascular disease, who either initiated TEE or TLD between April 2020-Dec 2023 (initiation cohort) or were receiving TEE in April 2020 and eligible for TLD (transition cohort). In the initiation cohort, we emulated a target trial using pooled logistic regression models with inverse probability of treatment weights and bootstrapped confidence intervals to compare standardised 3-year MACE risk between TLD versus TEE. In the transition cohort, we used similar methods in 44 emulated monthly sequential trials, comparing MACE risk in people transitioned to TLD with those remaining on TEE. FindingsIn the initiation cohort, 7310 PLHIV initiated TLD (n=3711) or TEE (n=3599). Median follow-up was 21 months (IQR 10-33), with 18 MACEs with TLD (3-year risk 0.78%, 95%CI 0.37-1.32) and 28 with TEE (3-year risk 0.96%, 0.60-1.40; RR 0.81, 0.35-1.59; RD -0.18, -0.82-0.50). In the transition cohort, 22338 people contributed to 2837 person-trials with TLD and 706615 with TEE. Median follow-up was 25 months (14-36), with 19 MACEs with TLD (3-year risk 1.09%, 0.48-1.99) and 5420 with TEE (3-year risk 1.21%, 1.05-1.41; RR 0.90, 0.41-1.64; RD -0.12, -0.75-0.75). InterpretationAmong PLHIV in South Africa we found no increased MACE with TLD. FundingGates Foundation; National Institute of Health and Social Care Research RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed with no language restrictions on March 6th, 2025, with the terms "(dolutegravir) AND (cardiovascular disease OR coronary heart disease OR cerebrovascular disease OR stroke)" and identified additional studies using hand searches of reference lists and citing papers. We found no randomised trials which were adequately powered to directly assess the risk of major adverse cardiovascular events (MACEs) between dolutegravir (or integrase strand transferase inhibitors [INSTIs]) and efavirenz (or non-nucleoside reverse transcriptase inhibitors). We identified one systematic review from 2018 of eight trials, predominantly from high-income settings, which found 15/2202 (0.7%) serious adverse cardiovascular events with dolutegravir versus 8/2215 (0.4%) with other antiretrovirals (relative risk 1.69, 95% CI 0.71 to 4.03). We identified five observational studies which assessed risk of cardiovascular events with INSTIs versus non-INSTI antiretroviral therapy (ART). A study using medical insurance claims data from the United States between 2008 and 2015 found initiating an INSTI was associated with fewer cardiovascular events compared to non-INSTI initiation, while a later study using the same dataset from 2013 to 2021 found no difference in MACE between INSTI versus non-INSTI initiation, although INSTI use was associated with increased myocardial infarction. An observational study using 17 European and Australian cohorts found an association between cumulative INSTI exposure up to 24 months and increased risk of cardiovascular events, although the study design has been questioned. Two studies used observational data to emulate target trials comparing risk of cardiovascular events among people using INSTI versus non-INSTI ART. In a Swiss cohort, people initiating INSTIs were not found to be at increased risk of cardiovascular events, while in a larger study using data from European and North American cohorts, 4-year cardiovascular risk was similar between INSTI and non-INSTI users in both ART naive and ART experienced individuals. Added value of this studyOur study is the first to evaluate risks of MACEs with tenofovir disoproxil fumarate, lamivudine and dolutegravir (TLD), the most widely used INSTI-based regimen in low- and middle-income countries (LMICs), where the majority of people living with HIV (PLHIV) live. This is important as this regimen has been recommended by the World Health Organisation (WHO) for first-line ART since 2018, replacing the previously recommended regimen of tenofovir disoproxil fumarate, emtricitabine and efavirenz (TEE). Using robust emulated target trial methods, we found no evidence of increased risk of MACEs with TLD versus TEE in both people initiating ART, or people already ART-experienced, in a large South African cohort. These findings are relevant for the over 20 million people estimated to be taking TLD in LMICs, where risk factors for cardiovascular disease may differ from high-income settings. Implications of all the available evidenceWe found no large increased risk of MACEs in the short-to medium term with TLD, which is supported by the majority of evidence investigating risks with INSTIs from high-income settings. These findings support the ongoing use of dolutegravir-based ART as part of the WHO public health approach in LMICs, although studies with greater follow-up time are required.

BackgroundGuidelines recommend three-site (urine, anal, pharynx) three-monthly (3X3 screening) screening for Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) in men who have sex with men (MSM) taking HIV pre-exposure prophylaxis (PrEP). We present the first randomized controlled trial to compare the effect of screening versus non-screening for NG/CT on the incidence of these infections in MSM taking PrEP. MethodsA multicenter, randomized, controlled trial of 3X3 screening for NG/CT versus non-screening was conducted among MSM taking PrEP in five HIV reference centers in Belgium. Participants attended the PrEP clinics quarterly for 12 months. NG/CT was tested at each visit in both arms, but results were not provided to the non-screening arm. The primary outcome was the incidence rate (IR) of NG/CT infections in each arm, assessed in the per-protocol population. Non-inferiority of the non-screening arm was proven if the upper limit of the 95% confidence interval of the IR ratio (IRR) was lower than 1.25. The trial protocol was registered at clinicaltrials.gov (NCT04269434). FindingsBetween September 2020 and June 2021, 508 subjects were randomized to the 3X3 screening arm and 506 to the non-screening arm. The overall IR of NG/CT was 0.155 cases/100 person-days (95%CI 0.128-0.186) in the 3x3 screening arm and 0.205 (95%CI 0.171-0.246) in the non-screening arm. The IR was significantly higher in the non-screening arm (IRR 1.318, 95%CI 1.068-1.627). Participants in the non-screening arm had a higher incidence of CT infections and symptomatic CT infections. There were no significant differences in NG infections. Participants in the non-screening arm consumed significantly less antimicrobials. No serious adverse events were reported. InterpretationWe failed to show that non-screening for NG/CT is non-inferior to 3-site 3-monthly screening in MSM taking PrEP in Belgium. However, screening was associated with higher antibiotic consumption and had no effect on the incidence of NG. Therefore, our findings do not provide strong support for screening for NG/CT in this population. FundingBelgian Healthcare Knowledge Center (KCE - INV18-1133)

BackgroundLong Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194). The design simultaneously assessed three oral medications (metformin, ivermectin, fluvoxamine) using two by three parallel treatment factorial assignment to efficiently share placebo controls and assessed Long Covid outcomes for 10 months to understand whether early outpatient treatment of SARS-CoV-2 with metformin, ivermectin, or fluvoxamine prevents Long Covid. MethodsThis was a decentralized, remotely delivered trial in the US of 1,125 adults age 30 to 85 with overweight or obesity, fewer than 7 days of symptoms, and enrolled within three days of a documented SARS-CoV-2 infection. Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total; ivermectin 430mcg/kg/day for 3 days; fluvoxamine, 50mg on day one then 50mg twice daily through 14 days. Medical-provider diagnosis of Long Covid, reported by participant by day 300 after randomization was a pre-specified secondary outcome; the primary outcome of the trial was severe Covid by day 14. ResultThe median age was 45 years (IQR 37 to 54), 56% female of whom 7% were pregnant. Two percent identified as Native American; 3.7% as Asian; 7.4% as Black/African American; 82.8% as white; and 12.7% as Hispanic/Latino. The median BMI was 29.8 kg/m2 (IQR 27 to 34); 51% had a BMI >30kg/m2. Overall, 8.4% reported having received a diagnosis of Long Covid from a medical provider: 6.3% in the metformin group and 10.6% in the metformin control; 8.0% in the ivermectin group and 8.1% in the ivermectin control; and 10.1% in the fluvoxamine group and 7.5% in the fluvoxamine control. The Hazard Ratio (HR) for Long Covid in the metformin group versus control was 0.58 (95% CI 0.38 to 0.88); 0.99 (95% CI 0.592 to 1.643) in the ivermectin group; and 1.36 in the fluvoxamine group (95% CI 0.785 to 2.385). ConclusionsThere was a 42% relative decrease in the incidence of Long Covid in the metformin group compared to its blinded control in a secondary outcome of this randomized phase 3 trial. Trial registrationNCT04510194. IND152439

Introduction The COVID-19 pandemic has been associated with substantial rates of all-cause excess mortality. The contribution of external causes of death to excess mortality including drug overdose, homicide, suicide, and unintentional injuries during the initial outbreak in the United States is less well documented. MethodsUsing public data published by the National Center for Health Statistics on February 10, 2021, we measured monthly excess mortality (the gap between observed and expected deaths) from five external causes using national-level data published by National Center for Health Statistics; assault (homicide); intentional self-harm (suicide); accidents (unintentional injuries); and motor vehicle accidents. We used seasonal autoregressive integrated moving average (sARIMA) models developed with cause-specific monthly mortality counts and US population data from 2015-2019 and estimated the contribution of individual cause-specific mortality to all-cause excess mortality from March-July 2020. ResultsFrom March-July, 2020, 212,825 (95% CI 136,236-290,776) all-cause excess deaths occurred in the US). There were 8,540 excess drug overdoses (all intents) (95% CI 5,106 to 11,975), accounting for 4% of all excess mortality; 1,455 excess homicide deaths (95% CI 708 to 2202, accounting for 0.7% of excess mortality; 5,492 excess deaths due to unintentional accidents occurred (95% CI 85 to 10,899, accounting for 2.6% of excess mortality. Though a non-significantly 135 (95% CI -1361 to 1,630) more MVA deaths were recorded during the study period, a significant decrease in April (525; 95% CI -817 to -233) and significant increases in June-July (965; 95% CI 348 to 1,587) were observed. Suicide deaths were statistically lower than projected by 2,067 (95% CI 941-3,193 fewer deaths). MeaningExcess deaths from drug overdoses, homicide, and addicents occurred during the pandemic but represented a small fraction of all-cause excess mortality. The excess external causes of death, however, still represent thousands of lives lost. Notably, deaths from suicide were lower than expected and therefore did not contribute to excess mortality.

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).

ImportanceSevere cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS-TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed drug eruption (GBFDE), are rare but life-threatening drug hypersensitivity syndromes. Due to their low incidence and diagnostic complexity, large-scale characterization of SCAR is challenging. ObjectiveTo characterize the demographics, causative agents, trends, latency, and phenotypic overlap of SCAR using a large-scale, sanitized pharmacovigilance dataset from FAERS (FDA Adverse Event Reporting System). DesignCross-sectional study of spontaneous adverse event reports. Cases were drawn from the U.S. Food and Drug Administration Adverse Event Reporting System (FDA FAERS) from January 2004 to December 2023 and subjected to sanitization and deduplication. Disproportionality analysis was used to characterize causative agents. Machine learning (random forest classifiers) was used to analyze predictors of drug latency and mortality. SettingGlobal pharmacovigilance reports submitted to FAERS. ParticipantsA total of 56,683 deduplicated SCAR reports were identified, representing 0.33% of reports during the study period. ExposuresSuspected causative drugs, including both small molecules and biologics. Main Outcomes and MeasuresMain outcomes included the frequency and distribution of SCAR syndromes, reporting trends over time, latency from drug start to reaction onset, drug-specific disproportionality (PRR, ROR, IC), and co-reporting between SCAR types and related conditions. ResultsA total of 56,683 unique SCAR reports were identified, including SJS-TEN (28,871), DRESS (22,444), AGEP (6,183), and GBFDE (150). We identified 237 drugs with significant disproportionality for SCAR overall. Co-reporting between SCARs was significantly enriched (p < 10-200), suggesting overlapping phenotypes. Latency varied by drug and syndrome (median: GBFDE 3 days, AGEP 4 days, SJS-TEN 15 days, DRESS 24 days). Conclusions and RelevanceSCAR syndromes display distinct but overlapping phenotypes, with variable latency and diverse causative agents. These findings, based on the largest SCAR dataset to date, highlight the need for improved classification frameworks and molecular validation. Large-scale pharmacovigilance, integrated with genomic and histopathologic data, will be critical to improving diagnosis, mechanistic understanding, and clinical management of SCAR.

BackgroundThe role of distinct type- and energy-based extracorporeal shockwave therapy (ESWT) in clinical practice is unclear. ObjectivesTo appraise meta-analytically determined effectiveness and safety of type- and energy-based ESWT for diseases or conditions, and visualize evidence maps of findings. MethodsNine online databases and reference lists were systematically searched for systematic reviews (SRs) of randomized controlled trials (RCTs) evaluating the effectiveness or safety of ESWT from inception to September 2023. SRs were then updated if up-to-date RCTs were eligible. Overall effects were re-estimated using random-effects model and reported as relative risk or standardized mean difference with 95% confidence intervals. Methodological quality, certainty of evidence, and safety were assessed with AMSTAR 2, GRADE tool, and MedDRA, respectively. ResultsOur research identified 210 relevant SRs encompassing 636 RCTs and 41649 participants across 7 therapeutic areas and 37 diseases and conditions. Methodological quality of most published SRs was low or critically low. Four treatment statuses of type- and energy-based ESWT were identified, including potential dominant efficacy (plantar fasciitis, erectile dysfunction, lateral epicondylitis, knee osteoarthritis, frozen shoulder, cerebral palsy spasticity, post-stroke lower limb spasticity; GRADE moderate), potential positive efficacy (chronic prostatitis/chronic pelvic pain syndrome, myofascial pain syndrome, patellar tendinopathy, achilles tendinopathy, stenosing tenosynovitis, frozen shoulder, rotator cuff tear, cerebral palsy spasticity, post-stroke upper limb spasticity, cervical spondylotic radiculopathy; GRADE low or very low), potential similar efficacy (osteonecrosis of the femoral head, plantar heel pain, patellar tendinopathy; GRADE low or very low), and potential adverse efficacy (patellar tendinopathy; GRADE very low). Along with courses of ESWT treatment, pain, flushing, and swelling were the most prevalent side effects and serious adverse reactions were limited. ConclusionVariable type- and energy-based ESWT is probably effective and safe in clinical practice. Due to lack of available data and high certainty in current evidence, future research should prioritize large-scale and well-designed studies. RegistrationPROSPERO number CRD42023477234

BackgroundChildren living with HIV have few second-line antiretroviral therapy(ART) options, especially fixed-dose-combinations(FDC). MethodsChildren from Uganda, Zambia, Zimbabwe were randomised to second-line tenofovir alafenamide(TAF)/emtricitabine(FTC) or standard-of-care(SOC) backbone (abacavir(ABC) or zidovudine(ZDV) with lamivudine(3TC)) in the factorial CHAPAS-4 trial. The second randomisation (reported elsewhere) was to dolutegravir(DTG), ritonavir-boosted darunavir(DRV/r), atazanavir(ATV/r) or lopinavir(LPV/r) as anchor drug. All drugs were dosed using WHO weight-bands and children <25kg received a new paediatric TAF/FTC(15/120mg) FDC tablet. The primary endpoint was viral load(VL)<400copies/ml at week-96, analysed using logistic regression, hypothesising that TAF/FTC would be non-inferior to SOC (10% margin). Secondary endpoints included safety and immunological outcomes. Analyses were intention-to-treat. Results919 children 3-15years, 497(54%) male, median[IQR] baseline viral load(VL) 17,573copies/ml [5549-55,700] and CD4 count 669cells/mm3[413-971], spent 99% of time on allocated NRTI backbone. At week-96, 406/454(89.4%) receiving TAF/FTC vs. 378/454(83.3%) receiving SOC had VL<400copies/mL (adjusted difference[95%CI]: 6.3%[2.0%,10.6%], p=0.004), with no evidence that this varied by ABC/3TC or ZDV/3TC SOC. CD4 count improved similarly in both arms. Growth was better with TAF/FTC vs. SOC, without evidence of excess weight-gain with any backbone/anchor drug combination (including DTG{+/-}TAF/FTC, interaction p=0.51). Bone health parameters were similar between arms, irrespective of anchor drug. One child died (treatment-unrelated); 29(3%) had serious adverse events without differences between arms. ConclusionsTAF/FTC was virologically superior to SOC ZDV/3TC or ABC/3TC with a favourable safety profile, irrespective of anchor drug. Development of child-friendly TAF/FTC FDCs ({+/-}anchor drug) would increase cost-effective ART options for children and reduce drug access gaps between children and adults.(ISRCTN22964075)