PLOS Medicine

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.

Summary Background We used sequential target trial emulation (TTE) to examine associations between opioid analgesic initiation and adverse maternal and neonatal outcomes while accounting for gestational timing, time at risk, and potential confounding. Methods Using the Early Life Course platform, comprising linked population-based data for births in New South Wales, Australia (2013-2019), we emulated a new trial at each gestational week, comparing women who initiated a prescribed opioid analgesic with eligible non-initiators. Baseline covariates were balanced using inverse probability weighting. Weighted logistic regression estimated odds ratios (ORs) for neonatal outcomes, postpartum haemorrhage, and severe maternal morbidity. Pooled logistic regression estimated hazard ratios (HRs) for other maternal outcomes, combined across gestational weeks using fixed-effects meta-analysis. Sensitivity analyses assessed unmeasured confounding, exposure misclassification, and potential reverse causation. Findings Among 511,357 pregnancies, over 80% of opioid initiators received only one dispensing. Opioid initiation was not associated with increased risks of placental abruption (HR 0.94, 95% CI 0.75-1.16), severe maternal morbidity (OR 1.05, 0.97-1.11), postpartum haemorrhage (OR 0.98, 0.95-1.02), low Apgar score (OR 0.99, 0.87-1.08), small for gestational age (OR 0.90, 0.85-0.95), or neonatal abstinence syndrome (OR 0.98, 0.72-1.30). Risks were elevated for PPROM (HR 1.10, 0.98-1.23), preterm birth (HR 1.26, 1.19-1.33), severe neonatal morbidity (OR 1.08, 1.02-1.17), and perinatal death (OR 1.29, 1.10-1.52). Perinatal death estimates attenuated in analyses addressing potential reverse causation. Interpretation Using a TTE approach that accounted for gestational timing and time at risk, we found no appreciable increase in most maternal or neonatal outcomes following predominantly short-term opioid initiation. Elevated risks of preterm birth, perinatal death, and third-trimester PPROM may reflect causal effects or confounding by pregnancy-related indications. Studies using time-appropriate designs and detailed information on prescribing indications and their timing are needed to clarify these associations.

BACKGROUND: Regional stroke-prevention priorities usually rest on what a bloc's members share. Where members span multiple Global Burden of Disease (GBD) super-regions and genetic ancestry groups, population, individual, and genetic evidence face different transportability limits, and earlier combined studies did not prespecify what counts as disagreement. METHODS: We studied the Shanghai Cooperation Organisation, which spans four super-regions and five ancestry groups and is land-contiguous. For five metabolic risk factors we triangulated GBD 2023 attributable fractions of stroke DALYs in ten states, incident stroke among 7896 adults in the China Health and Retirement Longitudinal Study (2011-18; SHRs per 1 SD), and subtype-specific Mendelian randomisation in three ancestries. An explicit rule set, with one pre-submission amendment, classified convergence and divergence by whether a listed mechanism accounted for it. FINDINGS: High systolic blood pressure converged: 53-71% of attributable DALYs, the strongest cohort exposure (SHR 1.37, 95% CI 1.26-1.48), and genetically supported in both ancestries. LDL cholesterol (GBD attribution restricted to ischaemic stroke; European genetic evidence for that subtype; no cohort association) and body-mass index (last in attribution but second in the cohort, with a 1.80-fold [1.48-2.18] gradient inside the 20-25 kg/m2 minimum-risk window) showed structural discordance. The cohort lacked subtype data to establish LDL dilution. Fasting glucose and kidney dysfunction diverged without such a mechanism. INTERPRETATION: Systolic blood pressure had the strongest cross-stream support. LDL cholesterol and body-mass index require qualified interpretation; fasting glucose and kidney dysfunction could not be ranked reliably. The framework identifies where priorities require scrutiny. FUNDING: None.

Objectives: To compare high-sensitivity C-reactive protein (hsCRP) profiles in Korean and US adults with low-density lipoprotein cholesterol (LDL-C) below 100 mg/dL and examine differences after adiposity adjustment. Study design: Cross-sectional analysis of national health examination surveys. Methods: We analysed the Korea National Health and Nutrition Examination Survey 2022-2024 (n=5,785) and US National Health and Nutrition Examination Survey August 2021-August 2023 (n=1,056). Eligible adults had Sampson-calculated LDL-C below 100 mg/dL and hsCRP of 10 mg/L or less; elevated hsCRP was defined as 2-10 mg/L. We estimated survey-weighted prevalence differences and adjusted prevalence ratios (PRs). Results: LDL-C distributions closely overlapped (weighted medians, 79.7 vs 80.1 mg/dL), whereas median hsCRP was 0.50 vs 1.34 mg/L. Elevated-hsCRP prevalence was 12.2% in Korea and 35.7% in the United States (difference, 23.5 percentage points; 95% CI, 19.4-27.7); the age-sex-standardised difference was 23.4 percentage points. Among 6,235 common complete cases, the age-sex-adjusted US-versus-Korea PR was 2.86 (95% CI, 2.48-3.30), decreasing to 1.66 (1.40-1.98) after waist circumference adjustment and 1.92 (1.62-2.26) after body mass index adjustment. Conclusions: Similar LDL-C distributions coexisted with markedly different hsCRP profiles. Waist adjustment attenuated the between-country contrast more than BMI adjustment, supporting joint consideration of inflammatory, lipid and anthropometric measures in population surveillance.

Importance: In the US, Human papillomavirus (HPV) related cancers cause significant morbidity and mortality, yet HPV vaccine is underutilized. Vaccination is recommended routinely at age 11-12 years but can be given at 9 years. There is controversy about whether earlier introduction would increase completion of the HPV series before by age 13 years or whether it might decrease rates of delivery of other routinely recommended vaccines at 11-12-years [quadrivalent meningococcal conjugate (MenACWY) vaccine, and tetanus-diptheria-acellular pertussis (Tdap) vaccine]. Objective: To determine whether introduction of the HPV vaccine at ages 9-10 versus 11-12 years, results in earlier median age of series completion (primary outcome) and higher rates of initiation and completion by age 13 years. We also examined the effect of earlier introduction of HPV on rates of Tdap and MenACWY initiation and completion by age 13 years. Design: Two-arm cluster-randomized trial involving 31 pediatric practices in Colorado and California between 10/2021-4/2026. Practices were randomized using covariate constrained randomization within each state to Intervention (introduction of HPV vaccination at ages 9-10) or Control (introduction at ages 11-12). Both study groups received similar annual training about best practices for HPV vaccination with recommended initiation age as the only difference. Results: Age at HPV series completion was substantially earlier in the Intervention group (median 12.2 v. 13.3 years; adjusted hazard ratio [aHR] 2.37; 95% CI 1.94-2.89). Key secondary outcomes were also improved in the intervention group: age at series initiation (median 11.0 v. 11.8 years; aHR 2.19; 95% CI 1.84-2.62), series completion by 13 years (61.6% v. 45.1%; RR 1.37; 95% CI 1.04-1.74), and vaccine initiation by age 13 years (77.1% v. 67.0%; RR 1.15; 95% CI 1.00-1.33). The intervention group was more likely to receive Tdap (aHR 1.47;95%CI 1.13, 1.92) during the trial; receipt of both vaccines by age 13 years did not differ. Conclusions: Earlier introduction of HPV vaccination resulted in earlier age of series completion, and more adolescents initiating and completing the series by age 13 without decreasing rates of other routinely recommended vaccines. Our findings support a preferential recommendation at 9-10 years. Trial registration number: NCT04722822 ClinicalTrial.gov

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 Long-acting HIV pre-exposure prophylaxis (LAP) could transform HIV prevention in sub-Saharan Africa, but its public-health impact and value-for-money will depend on whether programmes can reach people at greatest risk. We quantified the potential impact and efficiency of targeted LAP deployment across sub-Saharan Africa. Methods We developed a deterministic, age-structured compartmental model of HIV among adults aged 15 years or older in African countries accounting for 98% of adults living with HIV in sub-Saharan Africa. Antiretroviral therapy (ART) was assumed to reach 95% coverage by 2030 in all countries. LAP was assumed to reduce HIV acquisition by 96%. In model analyses, LAP was allocated according to rules that specify the degree to which programmes can effectively allocate it to those at greatest risk of acquiring HIV, including using a person's district, sex and age-group, and other signals of risk. Findings Across 34 countries, allocating a fixed quantity of LAP by district, sex and age averted 2 - 21 times as many infections as uniform allocation; perfect identification of within-group risk, an upper bound, raised this to 5 - 32 times. Multipliers were largest in low-prevalence countries, where absolute impact was smallest; in higher burden settings, they were 2 - 6 and 5 - 11, respectively. If 3 million people used LAP from 2028 in the 11 countries currently receiving Global Fund-supported lenacapavir, uniform allocation would avert about 41,000 infections by 2050, targeting by district, sex and age about 601,000 (range 360,000 - 1,660,000), and perfect risk targeting about 972,000 (490,000 - 3,570,000). Discounted averted ART costs fully offset LAP costs by 2050 at a total cost of up to ~US$50 per person-year with perfect risk targeting, $30 with targeting by district, sex and age, and $2 with uniform allocation. Expansion to 15 million users by 2035 brought modelled adult incidence across sub-Saharan Africa below 0.1 per 1000 person-years in 2049, about a decade earlier than projected without LAP, under the assumption that ART coverage reaches 95% in every country by 2030. Interpretation Targeting determines both the impact and the net cost of LAP. Allocation by district, sex and age is feasible now and multiplies the infections averted by each person-year of LAP. LAP offsets its cost through averted treatment only when it is targeted and its fully loaded cost is near the low end of current estimates. Better identification of people at highest risk within demographic groups, and sustained use among them, could add substantially to impact. The same approach could guide the allocation of LAP in other settings where HIV risk is concentrated.

Background: In England, a national school-based human papillomavirus (HPV) vaccination programme was introduced in September 2008. Routine vaccination against HPV16/18 is offered to girls aged 12-13 and a 'catch-up' offer ran for girls aged 14-18 during the programme's first two years. Methods: Data from 19,407 women aged 25-29yrs attending cervical screening across England 2016-2025 were collected and residual samples from 4,837 high-risk (HR) HPV-screening-positive women were genotyped to monitor type-specific HR-HPV prevalence and evaluate vaccination impact. Results: Type-specific HR-HPV results were available for 3,683 HR-HPV-screen-positive samples. Estimated age-adjusted prevalence of HPV16 and HPV18 was 91% (95% confidence interval [CI]: 87-94%) and 84% (95%CI: 65-93%) lower respectively among routine-eligible women than vaccination-ineligible women. Large declines were also observed for HPV31 (85% [95%CI: 72-92%]) and HPV45 (84% [95%CI: 73-90%]) but not for other HR-HPV types. Among 618 women with cytological abnormalities, HPV16/18 was present in samples from 53.9% (95%CI: 34.8-73.1%) of vaccination-ineligible, 18.1% (95%CI: 13.5-22.7%) of catch-up-eligible, and 6.5% (95%CI: 3.6-9.3%) of routine-eligible women. Conclusions: The early years of the HPV vaccination programme in England conferred strong protection against HPV16, 18, 31 and 45, and dramatically changed the target remaining for screening strategies to detect and reduce cervical disease.

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

Abstract Background: Randomized trials show substantial weight loss with semaglutide and tirzepatide under structured care, but little is known about whether patients in routine practice continue therapy, reach a maintenance dose, and have their weight measured. Objectives: To describe the first year after initiation of semaglutide or tirzepatide for obesity, including care patterns, maintenance-dose attainment, weight documentation, and total body weight loss (TBWL). Methods: This retrospective cohort study used Epic Cosmos, an electronic health record network of >350 US health systems, to identify adults with obesity and without diabetes who initiated injectable semaglutide or tirzepatide in 2024. Outcomes over 12 months included prescribing persistence, discontinuation, switching, add-on therapy, and reinitiation; attainment of Food and Drug Administration (FDA)-labeled maintenance doses; availability of follow-up weight; and TBWL across progressively restricted populations. Results: Among 743,153 adults (60.1% semaglutide; mean age, 48.5 years; 72.5% female), 12-month prescribing persistence was 29.9% for semaglutide and 35.9% for tirzepatide. FDA-labeled maintenance-dose attainment was 28.3% and 55.0%, respectively, and only 8.8% and 16.4% remained prescribing persistent at a maintenance dose with a recorded weight at 12 months. About half of initiators lacked a 12-month weight. Among all initiators, [&ge;]5% TBWL was documented in 25.6% (semaglutide) and 30.4% (tirzepatide), rising to 51.9% and 61.9% among those with recorded weight, 66.1% and 79.5% among those also prescribing persistent, and 82.9% and 87.3% among those further at a maintenance dose. Conclusions: In routine practice, most patients initiating semaglutide or tirzepatide did not remain on therapy, reach a maintenance dose, and have weight documented through the first year. Documented weight loss was greatest among those completing each step of care, suggesting continuation, dose escalation, and monitoring as targets for improvement.

Introduction: Japan achieves high retention and viral suppression among people on antiretroviral therapy, yet treatment starts late. Most people obtain subsidised treatment through a physical disability certificate for HIV-related immune dysfunction, which requires two blood tests at least four weeks apart. We quantified the diagnosis-to-treatment cascade, identified who waits and tested whether the second test changes certification. Methods: Retrospective cohort of people newly diagnosed with HIV at 11 designated AIDS core hospitals in 2015 to 2024. We measured intervals from screening to hospital visit and to antiretroviral therapy, and emulated certification from the first test alone and from the two-test rule under every possible number of non-laboratory criteria (k = 0 to 8). Results: Of 1302 people (96% men; 68% with CD4 <350 cells/L or AIDS), 1036 (80%) followed the two-test pathway and 261 started treatment after one test, mostly because of AIDS or acute infection. People reached the hospital a median of 11 days after screening. Treatment then began a median of 70 days after the first visit in the two-test pathway and 11 days in the single-test pathway; 0.2% and 60.9% started within 14 days. Delay rose with CD4 count: 46 days when the mean count was [&le;]200 cells/L, 117 days when it was >500 with a laboratory criterion (16% of the two-test pathway) and 334 days when it was >500 without one (3%; adjusted hazard ratio 0.14, 95% confidence interval 0.09 to 0.23). Medians ranged from 35 to 96 days across facilities. The second test changed little: the first CD4 count agreed with the mean of two (intraclass correlation coefficient 0.959), HIV-RNA [&ge;]5000 copies/mL persisted in 97.6%, and certification status agreed in 99.0% for k [&ge;]1 (92.5% for k = 0), with discordance concentrated near 500 cells/L; the first test gave a milder grade in at most 2.9%. Conclusions: The statutory second test adds at least four weeks before antiretroviral therapy in Japan without changing who is certified, and delays most the people with the highest CD4 counts. Certification on a single test, with treatment separated from the subsidy procedure, would remove a delay that has no clinical or administrative justification.

Importance: Gun violence and youth mental illness are urgent public health concerns. Although prior studies have linked community violence with pediatric mental health outcomes, little is known about the connection between exposure to hyperlocal gun violence and the short-term risk of a psychiatric emergency at the individual level. Objective: To estimate the impact of recent, nearby gun violence exposure on pediatric recurrent psychiatric exacerbation risk following an index psychiatric hospital admission or emergency department (ED) visit. Design: Retrospective longitudinal cohort study using survival analyses with Cox proportional hazards models adjusted for season and census tract-level community deprivation and chronic crime. Participants: Children and adolescents <18 years of age with a psychiatric hospital admission or ED visit at Cincinnati Children's between January 1, 2016, and December 31, 2024, and a geocoded residential address within Cincinnati, Ohio. Exposure(s): Recent, nearby gun violence, defined as at least one incident occurring within 400 meters of a patient's geocoded residential addresses during the preceding 14 days. Main Outcome(s) and Measure(s): Recurrent psychiatric exacerbation, defined as a subsequent psychiatric hospital admission or ED visit after an index exacerbation encounter. Results: Among 4,730 children and adolescents (median age 13.7 years; [IQR, 10.6- 15.7]; 54.1% female; 68.0% Black), participants contributed 2.1 million person-days of follow-up (median, 225 days [IQR, 38-654]). A total of 1,622 (34.3%) participants experienced a recurrent psychiatric exacerbation. Nearly half (41.5%) of participants were exposed to at least one nearby gun violence incident during follow-up. Exposure to gun violence within 400 meters of their home during the prior 14 days was associated with a higher hazard of recurrent psychiatric exacerbation in unadjusted (hazard ratio [HR], 2.26; 95% CI, 1.76-2.89) and adjusted (HR, 2.45; 95% CI, 1.91-3.14) models. Findings were robust across alternative spatial and temporal exposure definitions. Conclusions and Relevance: Among youth with prior psychiatric emergency utilization, exposure to recent nearby gun violence was associated with a substantially increased risk of recurrent psychiatric exacerbation. Gun violence may represent an acute environmental trigger of psychiatric crises and a potentially actionable target for interventions to support vulnerable youth.

Background: Age is an important determinant of tuberculosis (TB) risk, but population-level age patterns in TB prevalence have not been systematically quantified across settings. We conducted a systematic review of surveys conducted in low- and middle-income countries to quantify trends in TB prevalence across age groups. Methods: We collated age-stratified TB prevalence data for individuals aged 15+ years, from population-based surveys reported between 1993 and 2025. We analyzed data using Bayesian meta-regression models, estimating trends in bacteriologically confirmed pulmonary TB prevalence across age groups. We extended models to understand how age trends varied with alternative outcome definitions and data subsets, and examined correlations between TB age trends and sociodemographic determinants. We also estimated age-stratified notification-to-prevalence ratios as a measure of diagnostic delays for untreated TB. Findings: We included 82 unique surveys reporting age-stratified TB prevalence, spanning 30 countries and 4.6 million participants. These data demonstrated a pattern of increasing bacteriologically confirmed TB prevalence with older age, with each 10-year increase associated with a 30% (95% credible interval: 22, 38) increase in prevalence. TB prevalence for the oldest age group (75+: 796 per 100,000 [522, 1178]) was 6.4 (4.0, 10.4) times higher than the youngest (15-19: 127 per 100,000 [79, 186]), and positive age gradients were estimated for all countries (interquartile range: 23-40% increase per 10-year increase in age). Age gradients were lower in Africa compared to other regions, and for smear-positive compared to bacteriologically confirmed TB. Countries with HIV prevalence [&ge;]5% had flatter age gradients above 40 years of age. Age gradients declined slowly over the study period. Notification-to-prevalence ratios demonstrated a negative age gradient, declining by 10% (7, 14) per 10-year increase in age. Interpretation: The prevalence of untreated TB disease increases substantially throughout adulthood, and lower notification-to-prevalence ratios suggest poorer case detection among older individuals.

Background Women living with HIV (WLHIV) have an increased risk of persistent human papillomavirus (HPV) infection and cervical cancer. We evaluated the lifetime health impact and cost-effectiveness of HPV vaccination strategies targeting WLHIV across 13 African countries. Methods We developed an age-structured Markov model of HPV infection and cervical cancer in a closed cohort of 100,000 females, stratified by HIV status, and calibrated it separately for each country to age-specific cervical cancer incidence, cervical cancer mortality, and female HIV prevalence. Six HIV-targeted strategies were compared with routine two-dose vaccination at age 14 years. The strategies either provided a booster dose to previously vaccinated WLHIV or combined a booster for previously vaccinated WLHIV with a three-dose primary catch-up course for previously unvaccinated WLHIV. Interventions were delivered at ages 18 or 24 years under standard- and high-coverage assumptions. Outcomes included cervical cancer cases averted, cervical cancer deaths averted among WLHIV, discounted disability-adjusted life-years (DALYs) averted, additional physical vaccine doses, and incremental costs from the health-system and vaccination-programme perspectives. Results All six strategies generated additional health gains relative to routine vaccination alone. Mean DALYs averted across countries ranged from 8.21 for booster vaccination at age 24 years to 81.36 for high-coverage combined booster and catch-up vaccination at age 24 years. Booster-only strategies produced the greatest health gains per additional physical vaccine dose, whereas the high-coverage combined strategy at age 24 years produced the largest average absolute health gain. However, the relative performance of vaccination at ages 18 and 24 years varied by strategy and country. From the health-system perspective, 68 of 78 country-strategy comparisons were more effective and less costly than routine vaccination after accounting for avoided cervical cancer treatment costs. From the vaccination-programme perspective, all strategies required additional expenditure. Conclusions HPV vaccination strategies targeting WLHIV generated additional health benefits beyond routine adolescent vaccination and were cost-saving in many country-strategy comparisons when avoided cervical cancer treatment costs were included. Booster-only strategies were the most dose-efficient, whereas combined booster and primary catch-up strategies produced larger absolute health gains. The relative performance of strategies delivered at ages 18 and 24 years was context dependent and should not be interpreted as evidence of a universal advantage of later vaccination. Given the limited direct evidence on the clinical effectiveness and duration of protection following HPV booster vaccination among WLHIV, the booster scenarios should be interpreted as exploratory.

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.

Abstract Background Estimates of the healthcare costs associated with influenza treatment are essential for cost-effectiveness analyses that inform preventative and treatment strategies such as vaccination and non-pharmaceutical interventions. Existing evidence varies across treatment settings, age groups, and countries and there is little data from low- and middle-income settings. Methods We conducted an umbrella review of systematic reviews and meta-analyses reporting direct admitted and non-admitted hospitalisation costs of seasonal influenza treatment in children, adults, and older people. We supplemented an evidence gap with a systematised review of studies reporting adult non-admitted treatment costs. Costs were extracted and adjusted to 2023 USD. We fitted a Bayesian mixed-effects model to estimate influenza treatment costs using national economic indicators, age group, and treatment setting as a priori predictors. We predicted admitted and non-admitted treatment costs for children, adults, and older people in 195 countries and territories. Results Seven reviews were included in the umbrella review, supplemented by 17 primary studies for adult non-admitted care. Extracted data points most frequently described admitted treatment costs and came from high-income countries. The best-fitting model used healthcare expenditure per capita to predict treatment costs, with country-level random effects. Estimated costs increased with healthcare expenditure per capita, were higher for admitted than non-admitted care, and were highest for adults and lowest for children. Conclusions This study provides novel estimates of influenza-associated healthcare costs across age groups and treatment settings by synthesising the available global evidence. By extrapolating to settings without data, our estimates can inform future economic evaluation studies of influenza interventions worldwide.

Elevated systolic blood pressure (SBP) is a major modifiable driver of cardiovascular morbidity. Digital food-as-medicine and home-blood-pressure-monitoring programs increasingly support its management outside the clinic, but most published evaluations are single-arm, pre/post designs; because enrolment is conditioned on an elevated baseline reading, regression to the mean (RTM) is expected to inflate any observed improvement, and this is rarely checked against an internal comparator. We conducted a retrospective, single-arm cohort study of home blood-pressure monitoring within a commercial digital food-as-medicine program serving a US employer-sponsored population with obesity. Of 329 members included, 136 were at-goal (<130/80 mmHg), 74 at Stage 1 (130-134/80-84 mmHg) and 119 at Stage 2 ([&ge;]135/85 mmHg) at baseline; follow-up SBP was evaluable for 128, 68 and 112 members in these strata at 3 months and for 62, 34 and 53 at 6 months, respectively. The primary estimand was the unadjusted within-member change in home SBP at 6 months among members with Stage-1 and Stage-2 blood pressure at baseline; a secondary estimand corrected for RTM using an ANCOVA linear mixed model with the at-goal stratum as an internal negative-control population. Among Stage-1 members (n = 34), unadjusted SBP change was -4.36 mmHg (95% CI -7.43 to -1.28; p = 0.0069), paired with an RTM-corrected secondary change of -3.33 mmHg (-6.40 to -0.26; p = 0.033). Among Stage-2 members (n = 53), unadjusted change was -10.17 mmHg (-12.94 to -7.40; p < 0.001), paired with an RTM-corrected secondary change of -5.50 mmHg (95% CI -8.50 to -2.50; p = 0.00037); RTM accounted for ~24% and ~46% of the unadjusted decline in Stage-1 and Stage-2, respectively. RTM-corrected estimates were robust to sensitivity analyses on measurement modality, seasonality, covariates and model specification, with no evidence of attrition bias. Program participation was associated with a decline in home SBP among Stage-1 and Stage-2 members that remained significant, though smaller, after RTM correction, supporting RTM-adjusted SBP change as the appropriate metric for evaluating food-as-medicine interventions.

Background: Alcohol use disorder (AUD) is associated with increased dementia risk, but its long-term relationship with dementia, variation by age and subtype, and how this risk compares with that associated with alcohol consumption remain poorly characterised. We investigated these questions in a large prospective cohort of UK women. Methods: We analysed Million Women Study participants recruited aged 50-64 years and followed for more than 20 years through linked health records. Women with hospital-recorded AUD were matched to up to five controls. Cox models estimated associations between time-varying AUD and incident dementia overall, by subtype and attained age, with exposure lags of up to 15 years and competing-risk analyses. Self-reported alcohol consumption was analysed separately. Findings: Among 1,288,359 women, 20,070 with AUD were matched to 100,339 controls. Dementia occurred in 3,774 women with AUD and 8,239 matched controls. AUD was associated with all-cause dementia (HR=3.73 [95% CI 3.52-3.95]), with strongest associations for mixed (5.03 [3.88-6.51]), unspecified (4.29 [3.92-4.70]), and vascular dementia (3.96 [3.44-4.56]). Associations were substantially stronger before age 70 years (10.68 [9.02-12.63]) than at ages 70-79 years (3.75 [3.47-4.04]) or 80 years or older (2.34 [2.11-2.60]). Risk remained elevated with a 15-year lag (2.16 [1.81-2.58]) and after accounting for competing mortality. Associations with self-reported alcohol consumption were substantially weaker. Interpretation: Clinically recognised AUD identifies women at markedly increased and prolonged dementia risk, particularly at younger ages and for vascular and mixed dementia, not captured by drinking quantity alone. People with AUD should be considered a priority population for earlier dementia prevention and risk reduction. Funding: Wellcome Trust Career Development Award to AT (306069/Z/23/Z); NIH grants P50AA012870 and R01DA054869 (JG). The Million Women Study is supported by the UK Medical Research Council (grant number UKRI1464).