PLOS Medicine

Background Infections have been associated with adverse mental health outcomes, including suicide, but evidence beyond severe or central nervous system infections is limited. We investigated associations between a range of acute infections and subsequent suicide/self-harm outcomes. Methods We conducted six infection-specific matched cohort studies using English primary care records from the Clinical Practice Research Datalink Aurum (2007-2024), linked to hospital admissions and mortality data. Adults ([≥]18 years) with a primary care record of infection (gastroenteritis, lower respiratory tract [LRTI], skin/soft-tissue [SSTI], urinary tract [UTI], sepsis, meningitis/encephalitis [positive control]) were matched (age, sex, practice, calendar period) to up to five comparators without infection. We estimated hazard ratios (HRs) for suicide/self-harm outcomes using Cox regression, stratified by matched set and implicitly adjusting for matching factors, with additional adjustment for deprivation, lifestyle factors, and comorbidities. We examined whether associations varied over time, by infection severity, antimicrobial treatment, sex, and prior mental health conditions. Findings Cohorts ranged from 18,192 individuals with meningitis/encephalitis (matched to 90,915 without) to 398,099 with SSTI (matched to 1,743,747). After adjustment, individuals with infection had a higher hazard of suicide/self-harm outcomes than comparators across all cohorts: sepsis (HR 1.79, 95% CI 1.65-1.93), gastroenteritis (1.62, 1.55-1.70), meningitis/encephalitis (1.56, 1.32-1.84), UTI (1.41, 1.33-1.50), SSTI (1.37, 1.31-1.43), and LRTI (1.37, 1.31-1.44). Risk was highest in the year post-infection, attenuating over time, and was higher among severe infections and those without prior mental health conditions. Interpretation Common acute infections recorded in primary care are associated with increased risk of suicide and self-harm, particularly following severe infections and in the year post-infection. Findings support suicide risk monitoring following acute infection, particularly among individuals without prior mental health conditions, and highlight infection prevention as a potentially modifiable strategy in vulnerable populations. Funding Wellcome and La Caixa. Copyright This work is licensed under a Creative Commons Attribution (CC BY) licence.

Abstract Background Tuberculosis (TB) kills 1.3 million people annually. Global efforts focus on ending pulmonary TB (PTB); however, extrapulmonary TB (EPTB) is rising and poses significant health and economic burden. The PreVenTB Phase III trial evaluated VPM1002 in household contacts aged [≥]6 years across India, and did not meet its primary composite endpoint for all TB. Disaggregated prespecified secondary endpoints revealed a substantially stronger EPTB signal (vaccine efficacy 42.3%, 95% CI (-9.1 to 69.4, p=0.09) in the modified intention-to-treat (mITT) population. No existing TB model translates these disaggregated hazard ratios into population-level effectiveness across heterogeneous demographics, or against a dynamic baseline accounting for ongoing National Tuberculosis Elimination Programme (NTEP)-driven incidence decline. Methods We developed a 1,296-compartment deterministic dynamic compartmental model (4 age x 2 HIV x 3 BMI x 3 socioeconomic strata x 18 states). Separate PTB and EPTB vaccine-efficacy posteriors were derived by Bayesian evidence synthesis of the PreVenTB trial's per-protocol and mITT analyses (power-prior-adjusted conjugate normal-normal update; =0.082) and propagated through Monte Carlo simulation (n=1,000 iterations per scenario). A dynamic no-vaccine baseline was constructed by fitting time-varying case-detection-rate CDR(t) and treatment-success-rate TSR(t) logistic curves to WHO/NTEP data (2015 to 2024; incidence validation R2=0.896, RMSE 4.90 per 100,000), projecting PTB and EPTB incidence to 2050. Economic analysis used societal (value-of-statistical-life-inclusive BCR) and health-system (cost-effectiveness acceptability curves) perspectives, discounted at 3% annually. Findings Posterior vaccine effectiveness was substantially higher against EPTB than PTB (EPTB 40.0% [95% CI -5.6 to 69.1%] vs PTB 12.8% [-19.0 to 37.9%]; all-TB 16.2% [-11.7 to 38.6%]). EPTB accounted for 74% of deaths averted (381 of 513) and 73% of DALYs averted (5,347 of 7,308) in the 10-year/dynamic scenario. EPTB cases averted exceeded PTB and concurrent disease combined in every scenario. Mean cases averted ranged from 2,047 (3-year protection, dynamic baseline) to 3,394 (10-year, static) per 1,000,000 vaccinated; mean disability-adjusted life years (DALYs) averted ranged from 4,792 to 8,125. The benefit-cost ratio (BCR; societal perspective) ranged from 3.4 (3-year protection, dynamic baseline) to 8.2 (10-year protection, static baseline), exceeding break-even in every scenario. Median gross incremental cost-effectiveness ratio (ICER) ranged from US$647 (10-year static) to US$1,568 (3-year dynamic) per DALY averted, below India's 3x gross domestic product (GDP)-per-capita threshold (approximately US$8,084) in every scenario. Interpretation This 1,296-compartment model provides the first dynamically-baselined, dual-perspective health-economic evaluation of VPM1002 to separately track pulmonary and extrapulmonary outcomes. EPTB protection is VPM1002's proportionally larger and more statistically reliable efficacy signal and drives a majority of averted cases, mortality, and DALYs. Policy assessments anchored to composite pulmonary endpoints systematically underestimate this vaccine's population value. Funding In part funded by Serum Life Science Europe GmbH.

Objective To estimate the potential health and equity impacts of a tobacco free generation (TFG) and T21 policy (increasing the legal age of sale to 21) in Australia, in the context of a complex market including widespread illicit tobacco and e-cigarette product availability. Design A Markov macrosimulation model, parameterised with yearly net movements between legal smoking, illicit smoking, vaping, and dual use states, combined with a proportional multi-state lifetable. Setting The Australian population, modelled as an open cohort for 40-years. Intervention A 'business-as-usual' (BAU) scenario was compared to TFG and T21 policies, with both starting in 2026. Variations to policy impacts were tested under increasing background illicit market enforcement. Main outcome measures The model estimates the health-adjusted life years (HALYs) and deaths over 40 years, under each scenario, with differences across age and socioeconomic status (SES) presented. Results The TFG policy reduced daily smoking prevalence among 15-24-year-olds to 4.6% (95% uncertainty interval [UI] 3.8-5.7%) in 20 years' time, compared to 7.2% under the T21 policy and 7.9% under BAU trends. Vaping was minimally impacted by either policy. The TFG policy resulted in 178,000 (95% UI 87,800-314,000) HALYs being gained over 40 years. The policy impact was largest when accompanied by increased illicit market enforcement, reducing daily smoking among 15-24-year-olds to 1.4% within 20 years. Both policies had greater prevalence and health impacts on more disadvantaged compared to advantaged SES groups. Conclusion A TFG policy is expected to produce long-term benefits for the Australian population but would be most effective in combination with increased enforcement of illicit tobacco and e-cigarette markets. Novel strategies to increase quitting in addition to reducing uptake are needed to improve tobacco-related outcomes in the short to medium term.

Background: Suicide is the second leading cause of death in US adolescents aged 10-24. Method use strongly influences lethality and design of prevention strategies, but recent trends remain unclear. We therefore aimed to investigate trends in suicide mortality rates by method, age group, and sex. Methods: This cross-sectional study used suicide mortality data from the National Center for Health Statistics for a quarter-century period, between 1999 and 2024. All individuals aged 10-24 years at the time of death, with suicide as the underlying cause, were included. We estimated suicide mortality rates (i.e., the number of suicide deaths per 100,000 people) and annual percent change by method (firearm, asphyxiation, poisoning, other), age group (10-14, 15-19, 20-24), and sex. Changing trend time points were determined using Joinpoint regression models Results: From 1999 to 2024, 159,241 suicide deaths occurred among individuals aged 10-24. While suicide rates declined across all age groups between 2017 and 2024, the male-to-female gap narrowed by 18.9%. Among 10-14-year-olds, declining rates among males masked a consistent increase in female suicide rates since 2011. Although asphyxiation-related suicides decreased across all groups since 2018, firearm suicide rates increased for females in the 10-14 and 20-24 age groups. Albeit not as common as firearms or asphyxiation, poisoning suicide rates increased in the 15-19 and 20-24 age groups. Since 1999, suicide rates by other less common methods (e.g., jumping) showed significant increases, for both sexes, especially among individuals aged 20-24. Suicide rates were consistently highest in the 20-24 age group across all study years. Conclusion: The decrease in suicide mortality rates among individuals aged 10-24 was largely driven by declines in males and reductions in asphyxiation-related suicides. However, increasing female suicide rates in the 10-14 age group, as well as increasing rates of death by less common means, warrant close attention. While suicide prevention efforts like structural interventions and means restriction have shown effectiveness among male adolescents, priority should now be given to adapting these approaches for female adolescents, particularly those aged 10-14.

Importance Childhood sexual abuse (CSA) is linked to adverse psychiatric outcomes in adulthood, but evidence on its association with cardiovascular disease and mortality from large, diagnostically ascertained cohorts remains limited. Objective To assess the 10-year risk of all-cause mortality, suicide or self-harm, drug overdose or poisoning, and cardiovascular disease among patients with a diagnosed history of CSA compared with a matched unexposed cohort. Methods In this retrospective cohort study, we used deidentified electronic health record data from 68 health care organizations in the TriNetX US Collaborative Network. Patients diagnosed with confirmed or suspected childhood sexual abuse (CSA) before age 18 between January 1, 2003, and December 31, 2015, who had a subsequent adult encounter, were propensity score matched 1:1 with unexposed patients on age, sex, race and ethnicity, and baseline psychiatric and medical comorbidities (n = 9,083 per cohort). Outcomes--all-cause mortality, suicide or self-harm, drug overdose or poisoning, and cardiovascular disease--were assessed over 10 years from the index adult encounter using risk and time-to-event analyses to estimate risks, risk ratios, and hazard ratios. Results Among 18,166 matched patients (mean [SD] age, 19.0 [2.0] years; 14,813 [81.6%] female), CSA was associated with significantly elevated risk of suicide or self-harm (5.1% vs 2.8%; risk ratio [RR], 1.84; 95% CI, 1.57-2.16), drug overdose or poisoning (5.5% vs 3.7%; RR, 1.47; 95% CI, 1.28-1.69), and cardiovascular disease (12.3% vs 9.3%; RR, 1.31; 95% CI, 1.20-1.44), with concordant hazard ratios (all P < .001). All-cause mortality was numerically higher but not statistically significant (0.5% vs 0.4%; RR, 1.16; 95% CI, 0.75-1.79; P = .51). Conclusions and Relevance A diagnostically confirmed history of CSA was associated with substantially elevated 10-year risk of self-harm, overdose, and cardiovascular disease, independent of baseline demographic and psychiatric comorbidity. These findings support integrated psychiatric and cardiovascular screening for adult survivors of CSA and trauma-informed care extending beyond mental health services alone.

Background Loss to follow-up (LTFU) during tuberculosis treatment is a major programmatic gap, but its causal effect on mortality has been difficult to quantify. We estimated this effect using a sequential landmark cohort analysis. Methods and Findings We constructed a retrospective cohort of individuals aged [&ge;]15 years initiating their first tuberculosis treatment in Sao Paulo State, Brazil (2013-2023), using the State registry (TBweb) linked to the national mortality system (SIM). To account for immortal-time bias, we compared mortality between LTFU and continued-treatment patients in time-aligned monthly cohorts, applying a symmetric 30-day grace period to align eligibility. Cause-specific Cox models estimated adjusted hazard ratios for late (6-24 month) mortality, with non-TB mortality as a within-cohort negative control. We also computed standardized (g-formula) absolute mortality risk differences over the same window. Effect modification was assessed across pre-specified subgroups (age, sex, HIV, homelessness, drug-resistance status, calendar period). Of 171,048 individuals initiating tuberculosis therapy, 20,830 (12.2%) experienced LTFU. LTFU at any month substantially increased late mortality (adjusted hazard ratios [aHR] 1.83 [95% CI 1.27-2.64] to 2.85 [2.34-3.48] by month of LTFU), corresponding to standardized late-window mortality risk differences of up to 1.6 percentage points. The excess was concentrated in TB-attributable deaths (aHR 1.60-4.36) and was essentially null for non-TB mortality (0.96-1.48). Relative effects were largest in younger, stably housed individuals with low baseline mortality, whereas the largest absolute excess fell on people living with HIV (risk difference 3.0 percentage points). Conclusions LTFU at any point in tuberculosis therapy substantially increased late TB-attributable mortality, consistent with a causal pathway through interrupted treatment. Preventing LTFU should be a programmatic priority.

Importance: Doxycycline post-exposure prophylaxis (doxyPEP) is recommended to prevent bacterial sexually-transmitted infections (bSTIs) among certain men who have sex with men and transgender women. Impacts on bSTI transmission are unknown. Objective: To quantify the impact of doxyPEP implementation on bSTI risk, distinguishing indirect and direct protection. Design: Longitudinal cohort study, January 2022 to June 2025, with a nested test-negative design study among individuals potentially eligible to receive doxyPEP. Setting: Kaiser Permanente Southern California healthcare system. Participants: Individuals aged 16-59 years, including: 'at-risk males' assigned male sex at birth, who were living with HIV or who recently received HIV pre- or post-exposure prophylaxis; other males; and females. The nested test-negative design study included at-risk males who received bSTI testing after doxyPEP implementation. Exposures: Oral doxyPEP prescription dispense, defined as a 30+ dose supply of 200mg doxycycline absent accompanying bSTI diagnoses. Main outcomes and measures: Incident laboratory-confirmed gonorrhea, chlamydia, and syphilis. We quantified indirect effects as incidence rate ratios comparing observed to expected incidence of each bSTI, absent doxyPEP implementation, among doxyPEP non-recipients. We quantified direct effects among recipients via the adjusted odds ratio of recent doxyPEP dispenses among individuals testing positive or negative for each bSTI. Results: Analyses included 30,185 at-risk males, among whom 2,713 (9.0%) received 1+ doxyPEP fill; 1,212,854 other males; and 1,321,363 females. Among all at-risk males, overall doxycycline consumption increased 2.31-fold (95% confidence interval: 1.99-2.64; absolute increase by 18,953 [16,052-21,048] defined daily doses per 1,000 person-years) after doxyPEP implementation, without accompanying changes in consumption among other males or females. Resulting indirect protection was associated with 41.4% (95% confidence interval: 33.0-48.8%) and 29.0% (13.4-41.8%) lower-than-expected incidence of chlamydia and syphilis, respectively, among at-risk males who did not receive doxyPEP. We observed no indirect effect against gonorrhea among at-risk males, and no indirect effect against any bSTI among other males or females. Among 22,937 at-risk males in the nested test-negative design study, direct protection from doxyPEP was associated with 66.8% (47.6-78.7%) and 50.1% (2.1-74.2%) further reductions in chlamydia and syphilis risk, respectively, and no reduction in gonorrhea risk. Among doxyPEP recipients, one case of chlamydia and one case of syphilis was prevented for every 2,785 (1,553-5,491) and 20,001 (5,725-182,569) doses dispensed, respectively. Conclusions and relevance: DoxyPEP implementation conferred indirect as well as direct protection against chlamydia and syphilis among at-risk males. However, substantial volumes of antibiotic use were needed to realize this benefit. Tailoring doxyPEP guidance to circumstances associated with the greatest bSTI risk may be warranted to minimize unnecessary antibiotic use.

Background Having achieved the UNAIDS 95-95-95 targets, Eswatini faces a growing burden of non-communicable diseases which are major contributors to morbidity and mortality. Hypertension-associated cardiovascular disease (CVD) is rising among people living with HIV (PLHIV) as survival improves and metabolic risks - including those linked to dolutegravir (DTG) - increase. We projected CVD burden among PLHIV and HIV-negative adults (PLWHIV) through 2045 to inform integrated HIV-CVD planning. Methods EMOD-HIV, an agent-based model calibrated to Eswatini's epidemic, generated HIV prevalence trajectories. These were combined with age-standardized Global Burden of Disease CVD estimates and published relative risks (RRs) to produce HIV-stratified CVD projections. CVD burden trajectories were then projected through 2045 using a logistic generalized additive model with Monte Carlo uncertainty quantification. Five scenarios were evaluated to assess how different assumptions about RR of CVD among PLHIV versus PLWHIV affect projected burden: (1) CVD prevalence under a constant RR; (2) CVD mortality under a constant RR; (3) HTN-attributable CVD mortality under a constant RR; (4) HTN-attributable CVD mortality under a post-DTG RR increase following Eswatinis 2021 dolutegravir rollout; and (5) HTN-attributable CVD mortality under a gradual RR increase from 2010-2045 reflecting cumulative metabolic and demographic shifts. Results PLHIV consistently exhibited higher CVD burden than HIV-negative adults. Scenario 1: CVD prevalence was 11.0% (95% UI: 9.0-13.5%) among PLHIV versus 6.8% (6.0-7.8%) in 2025, stable through 2045. Scenario 2: CVD mortality rate was 0.60% (0.47-0.76%) versus 0.37% (0.31-0.45%) in 2025, declining modestly through 2045 with consistent excess. Scenario 3: HTN-attributable mortality was 73% (70-76%) versus 64% (61-66%) in women and 61% (58-64%) versus 58% (55-60%) in men, stable through 2045. Scenario 4: Following DTG rollout, mortality rose from 73% to 85% in women and 61% to 70% in men by 2022, remaining stable thereafter. Scenario 5: By 2045, mortality reached 85% (82-88%) in women and 67% (64-70%) in men with HIV, versus 60% (57 - 63%) and 55% (53 - 57%) in HIV-negative adults. Conclusions While excess CVD burden among PLHIV is projected to persist even under stable risk conditions, ART-related metabolic trajectories - particularly those linked to DTG - may drive substantial widening of this gap through 2045. HTN-attributable CVD mortality is particularly elevated among women with HIV. Strengthening integrated HIV-NCD services, including blood pressure screening, risk-based therapy, and sex-specific DTG counseling, will be essential to sustain long-term health gains.

Study objective. Some acetaminophen-overdose patients develop hepatotoxicity despite acetylcysteine treatment. Established tools struggle to prospectively identify this cohort. We developed a model using only routine admission biomarkers to identify acetylcysteine-treated patients at highest risk, and compared it with the current benchmark, the alanine aminotransferase x acetaminophen product (ALTxAPAP). Methods. Retrospective cohort of all acetaminophen overdose admissions (ICD-10 T39.1) to three UK hospitals (2008-2024) with alanine aminotransferase (ALT) >1000U/L at admission. We fitted elastic-net logistic models stratified by presentation ALT. The outcome was peak ALT >1,000U/L. Performance was assessed on a 25% held-out test set and benchmarked against ALTxAPAP. Results. Of 4,705 admissions, 119 (2.5%) developed hepatotoxicity. The model used seven routine blood tests, four per stratum: acetaminophen, sodium, potassium and lymphocyte count where presentation ALT was <50U/L; ALT, bilirubin, alkaline phosphatase and lymphocyte count where it was 51-1,000U/L. In the test set (n=1,175) it achieved an area under the curve of 0.93 (95% CI 0.89-0.97) versus 0.82 (0.72-0.91) for ALTxAPAP (paired difference 0.11; 95% CI 0.01-0.22; p=0.03), with higher specificity and a higher positive likelihood ratio at every matched sensitivity. Matched to current ALTxAPAP >1,500 practice (sensitivity 89.7%), specificity was 82.5% versus 62.6% and the positive likelihood ratio 5.1 versus 2.4, more than halving false-positive escalations (171 versus 365 per 1,000 patients). Conclusion. A stratified model using only routine admission biomarkers identifies acetylcysteine-treated patients at highest residual hepatotoxicity risk, outperforming the ALTxAPAP rule across decision thresholds, supporting selection for intensified therapy.

Objectives: To examine changes in seasonal influenza vaccine uptake among clinical risk groups over periods of differing age-based eligibility. Design: Retrospective cohort study. Setting: Individuals in England registered in the Clinical Practice Research Datalink Aurum. Participants: Between 1,239,802 (2019/20) and 1,289,330 (2023/24) individuals aged 40-69 years in clinical risk groups. Interventions: Natural experiment involving temporary expansion of age-based eligibility for influenza vaccination to include 50-64-year-olds from 2020/21 to 2022/23. Main outcome measures: Influenza vaccine uptake from 1st September to 28th February, incidence rate ratio (IRR) of vaccine uptake across consecutive seasons within age groups, and the ratio of IRRs between age groups. Results: Influenza vaccine uptake increased in all age groups in 2020/21 relative to 2019/20. The increase was larger in individuals aged 50-64 years (13.3%; IRR 1.50, 95% CI 1.50-1.51) compared with those aged 40-49 years (8.3%; IRR 1.35, 95% CI 1.34-1.35) and 65-69 years (6.8%; IRR 1.34, 95% CI 1.33-1.35). From 2020/21 to 2022/23, vaccine uptake decreased, with a more pronounced decline among those aged 40-49 years (-5.4%) compared with age-eligible groups (50-64 years: -3.0%; 65-69 years: -3.1%). The reversion of age eligibility in 2023/24 was associated with a larger decrease in uptake among those aged 50-64 years (-9.6% vs 2022/23; IRR 0.79, 95% CI: 0.79-0.79) compared with those aged 40-49 years (-4.9%; IRR 0.87, 95% CI: 0.87-0.88) and 65-69 years (-3.3%; IRR 0.97, 95% CI: 0.96-0.97). Patterns were broadly consistent across clinical risk groups. Conclusions: The COVID-19 pandemic saw a general increase in seasonal influenza vaccine uptake in clinical risk groups. This increase was larger and more sustained in 50-64 year-olds who had also become eligible based on age. Our findings highlight the potential gains in vaccine coverage among clinical risk groups based on expanded age-based eligibility.

Background: Alcohol use disorder (AUD) is an underrecognized cardiovascular risk factor linked to accelerated atherosclerosis, arrhythmias, and ischemic heart disease (IHD). National trends in IHD mortality among adults with AUD, particularly during the COVID-19 pandemic, remain poorly characterized. We assessed temporal trends and demographic and geographic disparities in IHD-AUD mortality in the United States from 1999 to 2024. Methods: Mortality data for US adults aged [&ge;]25 years were obtained from the CDC WONDER Multiple Cause-of-Death database (1999-2024). Deaths listing both IHD (ICD-10 I20-I25) and AUD (F10) were included. Age-adjusted mortality rates (AAMRs) per 100,000 population were calculated, and Joinpoint regression was used to estimate annual percent changes (APCs) with 95% confidence intervals (CIs). Results: Between 1999 and 2024, 150,273 deaths involved both IHD and AUD. The AAMR declined slightly from 2.0 to 1.9 per 100,000 between 1999 and 2011, increased to 2.7 by 2018, and rose sharply to 3.7 during 2018-2021 (APC, +12.52% [95% CI, 4.97-20.61]; P=0.003), before stabilizing at 3.6 through 2024. Overall mortality increased by approximately 80% from baseline. Mortality increased persistently among adults aged 35-44 years after 2014 (APC, +8.33%) while adults aged 55-64 had the highest mortality rate. Rates were higher in men than women (peak 6.6 vs 1.2 per 100,000). American Indian or Alaska Native individuals had the highest mortality (peak 7.4), whereas Asian or Pacific Islander individuals had the lowest. Black or African American individuals experienced the steepest increase during 2018-2021 (APC, +16.54%). Rates were highest in the West, increased longest in the South, and remained higher in nonmetropolitan than metropolitan areas. Conclusion: IHD mortality among adults with AUD increased substantially over the study period, accelerating during the COVID-19 pandemic. Marked disparities among men, American Indian or Alaska Native and Black or African American individuals, younger adults, and rural populations highlight the need for integrated cardiovascular and addiction care.

Background: Observational research reports positive associations between type 2 diabetes mellitus (T2DM) and obesity-related cancers (ORCs), but causality remains unclear due to confounding (namely the shared risk factor of obesity, commonly approximated as body mass index, BMI), immortal time bias, and detection-time bias. Here, we aimed to use causal inference methods to minimise the above problems and estimate causal associations between new-onset T2DM and incident cancer. Methods: We performed a cohort study within UK Biobank, comparing new-onset T2DM with unexposed individuals matched 1 to 3 on BMI, age, and sex using a sequential longitudinal approach. The primary outcomes were total incident cancer, divided into ORCs and non-obesity-related cancers (NORCs). The secondary outcomes were site-specific cancers. We developed Cox models to estimate time-split hazard ratios (tsHRs) and 95% confidence intervals (CIs) stratified by sex. Findings: 23,771 participants with new-onset T2DM were matched with 71,170 unexposed participants. During a median follow-up of 5 years, there were 7694 (T2DM: 2432; unexposed: 5262) incident cancers. In men, there was evidence for an effect of T2DM on obesity-related cancer (tsHR 1.39, 95% CI 1.21-1.59), particularly on hepatocellular carcinoma (tsHR 3.97, 95% CI 2.38-6.65), pancreatic (tsHR 1.77, 95% CI 1.15-2.72) and kidney (tsHR 1.62, 95% CI 1.13-2.32) cancers. In women, there was evidence for an effect on obesity-related cancers (tsHR 1.33, 95% CI 1.16-1.52). Importantly, there were no associations with post-menopausal breast and endometrial cancers, two cancer types consistently associated with elevated BMI. There was no effect of new-onset T2DM on incidence of NORCs. There was evidence of detection-time bias, particularly in men. Interpretation: This is the first large-scale study to demonstrate evidence of a BMI-independent associations between new-onset T2DM and incident cancer. In men, this was primarily driven by hepatocellular carcinoma, pancreatic cancer, and kidney cancer. In women, the underlying cancers driving this relationship were less clearly defined. Funding: This study was funded by Cancer Research UK and administered through the Manchester Cancer Research Centre MB-PhD scheme (SEBCATP-2023/100010).

Background Childhood adversity can affect propensity to risk-taking behaviors. We aim to investigate the relation between childhood adversity and risk-taking behaviors in youth using emergency room (ER) admissions and survey data. Method Using the DANLIFE study, we included 1.2 million Danes. Individuals were assigned into five groups based on childhood adversity exposure from ages 0 to 15 years. We applied survival analyses on repeated outcomes to model ER-admissions due to substances, violence and unintentional injury in the full cohort between ages 16 and 24. We applied logistic regression models to weighted survey data on frequent binge drinking, cannabis use, drug use, and unsafe sex in a nested subsample of 34,064 18 year olds from the Danish National Birth Cohort. Results The high adversity group was at highest risk of ER-admissions due to substances (HR=3.27, 95% CI [3.10, 3.46]), violence (HR=2.67, 95% CI [2.58, 2.76]) and unintentional injuries (HR=1.30, 95% CI [1.28, 1.33]). In the nested subsample, the high adversity was at highest risk of cannabis use (OR=1.59, 95% CI [1.21, 2.09]), drug use (OR=2.44, 95% CI [1.71, 3.49]) and unsafe sex (OR=1.72, 95% CI [1.34, 2.22]), but at lower risk of frequent binge drinking (OR=0.57, 95% CI [0.37, 0.87]). Conclusion These findings highlight how childhood adversity is associated with increased engagement in and harm from risk-taking behaviors. To prevent inequalities in health in youth, there is a need for interventions and policies that promote child welfare, as well as targeted support for youth with harmful behavioral patterns.

Background: Continuous glucose monitoring (CGM) improves glycaemic control in people with type 1 diabetes (T1D), but high costs limit uptake in low- and middle-income (LMIC) countries. Evidence on the cost-effectiveness of CGM is limited in LMIC settings. Objective: To evaluate the short- and long-term cost-effectiveness of intermittently-scanned continuous CGM (cCGM) and intermittently-scanned periodic CGM (pCGM) (one sensor every three months), versus standard self-monitoring of blood glucose (SMBG) in the South African public-sector. Methods: A three-arm randomised controlled trial (ACCEDE) was conducted among T1D individuals with HbA1c [&ge;]10% in South Africa. A within-trial cost-effectiveness analysis was conducted from a partial societal perspective over 9-months, using resource use data and QALYs derived from EQ-5D. A cost-utility analysis using a Markov microsimulation model was conducted for two populations: total T1D, and youth (<20 years). Results: Within-trial analysis showed no statistically significant differences in QALYs or HbA1c between arms. Costs were highest for cCGM (USD 1,504), followed by pCGM (USD 742) and SMBG (USD 467). CGM strategies were dominated in the within-trial analysis. In contrast, long-term modelling showed that CGM was more effective than SMBG and was cost-effective for youth when used periodically. cCGM delivered additional QALYs at a higher cost (ICERs USD 15,259-30,852/QALY) and was only potentially cost-effective in youth when sensor prices were reduced by >45%. Conclusions: While CGM was not cost-effective in the short term, modelling suggests pCGM use may offer value-for-money under specific assumptions and in select populations, highlighting the need for further evidence on long-term effectiveness, engagement, and pricing.

Background: Global HIV programmes are transitioning virally suppressed children and adolescents with HIV (CAWH) from prior regimens to dolutegravir-based antiretroviral therapy (ART). However, the supporting evidence largely stems from randomised trials in viraemic CAWH. The effect of transition for virally suppressed CAWH is unknown. Methods: We used observational, de-identified data from 724 clinics in KwaZulu-Natal, South Africa. We sequentially emulated three distinct target trials to estimate the effect of transitioning to dolutegravir-based ART in three paediatric populations: i) ages 8-17 years taking efavirenz-based ART, ii) 8-17 years taking ritonavir-boosted lopinavir (LPV/r)-based ART, and iii) 0-7 years taking LPV/r-based ART, all with a last viral load <1,000 copies/mL. The risk difference (RD) of death or viraemia >1,000 copies/mL through 12 and 24 months was estimated using an inverse probability weighting approach. Findings: From January 2020 to August 2024, 37,145 CAWH contributed 454,081 person-trials. In CAWH initially taking efavirenz, the standardised 12-month risk of death or viraemia was 11.9% with continued efavirenz and 6.7% with transition to dolutegravir (RD -5.2 [95% CI -5.8 to -4.6]). In older CAWH initially taking LPV/r, these risks were 17.8% and 9.5%, respectively (RD -8.3 [-10.0 to -6.8]). In younger children, the respective risks were 15.8% and 6.7% (RD -9.0% [-12.7 to -5.4]). Where available, 24-month endpoints showed slightly greater RDs. Interpretation: This large-scale, causal analysis highlights improvements in viral suppression and strongly supports ongoing transition to dolutegravir-based ART for virally suppressed CAWH. Funding: Gates Foundation, National Institute for Health and Care Research, Swiss National Science Foundation

Private pharmacies are ubiquitous yet underutilized for HIV pre- and post-exposure prophylaxis (PrEP and PEP) delivery. In a cluster-randomized trial in Kenya (NCT05842122), we randomized 60 pharmacies 1:1:1:1 to: client-sustained delivery (~$2/visit user fee); implementor-sustained delivery (~$2/visit reimbursement); counselor-supported delivery (task shifting; ~$1/visit reimbursement); or clinic referral (control; ~$1/referral reimbursement). Commodities were supplied free to pharmacies from government stock. Primary outcomes were PrEP initiation and one-month continuation (any dispensing or refilling, respectively), self-reported by clients 60 days post-enrollment (multiple-comparisons threshold: p=0.017). From June 2023-April 2025, 5,808 clients enrolled; 64% were PEP candidates. Compared to referral, the counselor-supported arm had significantly higher PrEP initiation (RR=6.5, 95% CI [2.6, 16], p<0.001) and continuation rates (RR=5.1, 95% CI [1.4, 19], p=0.016); all intervention arms had significantly higher PEP initiation rates. One seroconversion, one social harm, and two provider needlestick injuries occurred. Pharmacy PrEP/PEP delivery outperformed clinic referral, particularly when fully subsidized and counselor-supported.

Objectives: To examine the association between small-area socioeconomic deprivation and risk of early-onset pre-eclampsia (diagnosed <34 weeks gestation) in England, and to assess the relative contributions of individual-level risk factors and variation between maternity care sites to observed inequalities. Design: Retrospective population-based cohort study. Setting: National Health Service (NHS)-funded maternity services in England between 1 January 2021 and 31 March 2025. Participants: 1,027,707 nulliparous pregnant women aged 13-60 years receiving NHS-funded maternity care in England with singleton pregnancies and non-missing deprivation data. Secondary analyses were conducted for 940,505 multiparous pregnant women. Main outcome measures: Early-onset pre-eclampsia, defined as diagnosis before 34 completed weeks of gestation. Results: Increasing socioeconomic deprivation was associated with higher odds of early-onset pre-eclampsia among nulliparous women across all regression models. In the confounder-adjusted model, each one-point increase in the continuous deprivation score (scaled 0-10) was associated with a 3.4% increase in odds of early-onset pre-eclampsia (adjusted odds ratio (aOR) 1.034, 95% confidence interval (CI) 1.027 to 1.041). Adjustment for theorized mediators attenuated the association modestly (aOR 1.023, 95% CI 1.017 to 1.030), while additional adjustment for hospital site further attenuated the association (aOR 1.016, 95% CI 1.009 to 1.023). Elevated BMI, circulatory disease, maternal age over 40 years, Black ethnicity, and endocrine/metabolic disease were among the strongest predictors of early-onset pre-eclampsia. Similar but stronger deprivation associations were observed among multiparous women. Associations between deprivation and late-onset pre-eclampsia were comparatively weak or absent after adjustment. Conclusions: Socioeconomic deprivation was associated with increased risk of early-onset pre-eclampsia in England, particularly among multiparous women. Both individual-level risk factors and variation between maternity care sites appeared to contribute to observed inequalities. These findings support the importance of combining targeted clinical risk reduction with efforts to reduce unwarranted variation in NHS maternity care delivery. Keywords: Maternity care, Pregnancy, Pre-eclampsia, Socioeconomic deprivation, Health equity, National Health Service

Background: Curable sexually transmitted infections (STIs) are associated with adverse birth outcomes, yet little cost-effectiveness evidence guides antenatal STI screening policy in high-burden settings. We conducted a cost-effectiveness and cost-utility analysis of the Philani Ndiphile trial in South Africa, comparing One-Time and Two-Time antenatal screening for C. trachomatis, N. gonorrhoeae, and T. vaginalis with standard syndromic management. Methods: A decision-analytic model from the provider perspective simulated costs and outcomes for pregnant women and infants. Costs included diagnostics, treatment, and neonatal hospitalisation for a primary composite outcome of preterm birth and/or low birthweight and its components (secondary trial outcomes). Modelled outcomes included incremental cost (US$) per composite (preterm birth and/or low birthweight) case, per component case and per disability-adjusted life year (DALY) averted. The analysis captured infant outcomes in the first year. Univariate and probabilistic sensitivity analyses were conducted to assess parameter uncertainty and robustness of results. Results: Screening for C. trachomatis, N. gonorrhoeae, and T. vaginalis twice during pregnancy was not cost-effective for preventing the primary composite outcome, nor for preventing low birthweight alone. However, two-time screening was cost-saving for preventing preterm birth alone, averting more DALYs and thereby yielding better health outcomes while reducing healthcare costs compared with syndromic management. One-time screening was not cost-effective for preventing any outcome. Conclusions: Repeat antenatal screening for C. trachomatis, N. gonorrhoeae, and T. vaginalis has the potential to prevent preterm births while reducing healthcare costs in high-burden settings. These findings support further research to confirm the clinical effectiveness of repeat screening and to evaluate longer-term health and economic impacts.

Antimicrobial resistance is a growing threat to health systems, but stewardship programs must compete for funding with many urgent health priorities in low- and middle-income countries. Evidence that quantifies not only effectiveness but also economic value is therefore essential for policy and budget decisions. We evaluated targeted antimicrobial stewardship programs in four tertiary hospitals in Nepal and Laos using interrupted time-series analyses of antibiotic use, combined with micro-costing to estimate benefit-cost ratios. Stewardship was associated with immediate reductions in antibiotic use across the three Nepal hospitals, whereas effects in Laos were more heterogeneous. Economic returns were positive across sites, with the largest returns observed in the private hospital in Nepal. Here, we show that pragmatic, ward-focused stewardship can reduce antibiotic use and generate measurable economic value in resource-constrained hospital settings, supporting its prioritization as a scalable investment for antimicrobial resistance control.

The analysis uses a global 2010-2023 panel comprising 3,038 economy-years across 217 economies. It explicitly separates between-economy and within-economy estimands and tests the longitudinal interpretation using an identical-sample temporal analysis with cluster-aware coefficient contrasts, a formal isometric log-ratio sensitivity analysis, independent fixed-effects replication, and wild-cluster-bootstrap inference. The central finding is deliberately calibrated: cross-economy agreement cannot validate national sugar availability for longitudinal obesity surveillance. The study identifies temporal and construct instability without claiming that sugar is protective or that the mechanisms producing the instability have been identified. The manuscript aligns well with PLOS ONEs emphasis on technically sound, transparent and reproducible research of broad relevance. All data required to reproduce the findings, complete metadata, executable code, full-precision results, diagnostic outputs and a completed STROBE checklist are provided as S1-S5. Figures are provided separately as compliant 350-dpi TIFF files. The study used only publicly available, aggregated economy-year statistics and involved no individual participants, identifiable information or biological specimens; institutional ethics review and consent were therefore not required. This is original work; it is not under consideration elsewhere, and the sole author has approved the submission and accepts responsibility for its content. Funding and competing-interest declarations will be entered accurately in the submission portal. An Academic Editor with expertise in nutritional epidemiology, global health metrics, longitudinal panel methods, or food-system surveillance would be well placed to assess the work.