PLOS Medicine

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.

Background The historic decline in childhood pneumonia mortality was driven substantially by single-pathogen vaccines against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae. Yet the pathogen spectrum underlying child pneumonia deaths is diversifying: the effective number of pathogens rose from 5.57 in 1990 to 9.94 in 2023, and the residual burden is shifting toward opportunistic and hospital-associated pathogens for which no licensed childhood vaccines exist. This paper asks how resources should be sequenced between single-pathogen interventions and platform investments as this transition proceeds. Methods We analyzed Global Burden of Disease Study 2023 deaths from 29 pathogens in ages 0-19 years by super-region, combined with WHO/UNICEF Estimates of National Immunization Coverage (WUENIC) for PCV3 and Hib3. We quantified the spectrum transition under two denominators (26- and 29-pathogen calibers), constructed a share-by-intervenability matrix assigning each pathogen to a dominant intervention channel (vaccine-reachable, mixed, platform-sensitive) under explicit classification rules, compared platform-sensitive deaths with a transparently computed scenario of residual vaccine-preventable deaths, and cross-classified pathogens by age tropism and poverty lock. We anchored platform interventions to verified published evidence. Results The vaccine-preventable group share fell from 54.0% to 40.2% while the opportunistic/hospital group rose from 18.1% to 23.1% (29-pathogen caliber, 1990-2023). Super-region vaccine coverage showed no significant association with pathogen-share change (PCV3 Spearman rho = 0.108, p = 0.818; Hib3 rho = -0.036, p = 0.939), a null result we report as evidence that simple coverage-burden correlations do not hold at the regional level, not as evidence against vaccine value. In 2023, vaccine-reachable pathogens accounted for 441,410 deaths (45.7%, channel including COVID-19), mixed for 126,926 (13.1%), and platform-sensitive pathogens for 396,995 (41.1%). Platform-sensitive deaths were 2.9-5.1 times the scenario estimate of residual vaccine-preventable deaths (52,435-77,512). Nine of 14 classifiable pathogens fell into the poverty-locked, infant-tropic cell (480,922 deaths; Fisher OR = 9.0, p = 0.1758). Conclusions The marginal value of single-pathogen strategies declines as the spectrum diversifies and residual deaths concentrate in platform-sensitive, poverty-locked, infant-tropic pathogens. Vaccine scale-up remains a certain and sizeable opportunity; the next increment of marginal resources should increasingly fund platform capabilities (oxygen systems, antimicrobial access and stewardship, infection prevention and control, referral, and nutrition) delivered as a package to the populations where the residual burden is locked.

Background Alcohol-associated injury is a leading cause of emergency department (ED) utilization in the United States and a clinically important driver of preventable morbidity across the adult lifespan. Prior surveillance research has characterized how the rate and severity of alcohol-associated injury vary by patient age, but whether the seasonal timing of injury risk is equally predictable across age groups (a question directly relevant to the timing of clinical screening intensification and public health intervention) has not been formally tested. Methods We conducted a retrospective surveillance analysis of 45,876 alcohol-associated ED visits among adults aged 18 years and older, identified from the National Electronic Injury Surveillance System (NEISS), 2019-2025 (weighted national estimate: 2,092,319 visits), using the structured Alcohol_Involved indicator introduced into NEISS case abstraction in 2019. Patients were stratified by sex and five age groups (18-24, 25-34, 35-49, 50-64, and [&ge;]65 years). Single-harmonic cosinor (Poisson) regression was used to estimate the seasonal peak day of injury risk (acrophase) for each stratum. To assess reliability, we performed leave-one-year-out jackknife resampling (seven iterations per group), case-resampling bootstrap confidence intervals (1,000 iterations), and likelihood-ratio tests of seasonal-phase interactions. Results Peak injury timing differed significantly across age groups (X^2 [8] = 2356.2, p < .0001). Adults aged 25-64 years showed a highly reproducible early-to-mid-July peak, with jackknife estimates shifting [&le;]14 days when any single study year was excluded. Adults aged [&ge;]65 years showed significant seasonal variation annually (all p < .0001, amplitude comparable to younger groups) but a pooled peak estimate that shifted by up to 100 days across jackknife iterations. Sex-stratified analyses revealed that this instability was driven entirely by females aged [&ge;]65 years (jackknife range: 332 days, peak consistently in late October through early January) rather than males aged [&ge;]65 (jackknife range: 31 days, peak consistently in early August). Hospital admission rates increased monotonically with age from 9.0% (18-24 years) to 31.8% ([&ge;]65 years). Conclusions Alcohol-associated injury follows a reproducible, calendar-stable summer seasonal pattern in adults aged 25-64 years. Among adults [&ge;]65 years, the previously reported temporal instability is concentrated in the female subgroup, whose seasonal injury risk does not converge on a fixed calendar window. These findings suggest that fixed-calendar prevention and screening strategies are well suited to working-age adults and older men, but older women may require a year-round, individually tailored approach. Keywords: Alcohol-related injury; Emergency department; Seasonality; Age factors; Sex differences; Injury surveillance; Cosinor analysis; Older adults

Background Lower respiratory infections (LRI) remain the leading infectious cause of death in children, and survival once ill is a direct tracer of health-system quality. Whether countries are converging toward the best survival performance achieved within their own region has never been tested at national level. We measured each country's distance to an empirical episode-fatality-ratio (EFR) frontier in 204 countries from 1990 to 2023. Methods For each country and year we computed EFR = LRI deaths/incident episodes using Global Burden of Disease (GBD) 2023 estimates for ages 0-19 years. Deaths span the full 1990-2023 series; episodes are observed for 1990, 2019 and 2023, with intermediate years linearly interpolated. The frontier was the 10th-percentile country EFR within each GBD super-region and year (sensitivity: 5th and 25th percentiles); the gap = EFR_country/EFR_frontier. We classified 33-year gap trajectories into catch-up phenotypes, ranked COVID-window (2019-2023) movers, cross-tabulated gap against avoidable deaths to build a priority list, and benchmarked upper respiratory infections (URI) at three time points as a near-zero-fatality contrast. Findings The median country's gap was 1.86 in 1990, 1.80 in 2019 and 1.86 in 2023; the share of countries more than twice their regional frontier was 44.6% in 1990 and 46.6% in 2023. Of 137 eligible countries, 67 narrowed and 69 widened their gap, with one unchanged. Nineteen countries achieved sustained catch-up, concentrated in North Africa and the Middle East (7) and Latin America (5), with China closing from 2.43 to 0.50, below its regional frontier; 28 countries regressed, led by Central Asia (Uzbekistan x3.5) and including the United States (x2.0). Over the COVID-19 window the median gap peaked at 2.00 in 2021 (+10.8% versus 2019, from unrounded medians) before returning to 1.86. Combining gap with avoidable deaths identifies two distinct policy problems: high-burden, moderate-gap giants (Nigeria 67,490 avoidable deaths, gap 2.4; India 54,109, gap 1.6) and extreme-gap outliers (Uzbekistan, gap 28.6). The Sub-Saharan Africa frontier fell further behind the High-income frontier (ratio 4.2 in 1990, 9.5 in 2023); the median Sub-Saharan African country sits 11.0 times the global 10th-percentile frontier but only 1.78 times its own regional frontier, so within-region benchmarking understates the region's true distance. URI gaps likewise did not converge (median 4.15 to 4.60). Interpretation Convergence toward the survival frontier is not the default national trajectory: over three decades the typical country made no net progress toward the best decile of its own region, and pandemic-era divergence was only partly reversed. National gap trajectories separate system-wide quality shortfalls from extreme outliers warranting audit, and expose a measurement trap in which regions whose frontiers stagnate appear closer to best practice than they are.

Background Respiratory infections remain the leading infectious cause of death among children and adolescents, yet the share of these deaths that could be averted with currently feasible care is not routinely quantified. Existing amenable-mortality frameworks rely on cause lists and population-level mortality benchmarks and do not exploit information on how many episodes occur. We propose an episode-fatality-ratio (EFR) frontier approach and apply it to lower respiratory infections (LRI), whooping cough (pertussis) and upper respiratory infections (URI) in 204 countries, 1990-2023. Methods For each cause, country and year we computed EFR = deaths/incident episodes using Global Burden of Disease (GBD) 2023 estimates for ages 0-19 years. The frontier was defined as the 10th-percentile country EFR within each GBD super-region, cause and year; avoidable deaths = max(0, deaths - episodes x frontier EFR). Primary estimates are deterministic; 95% uncertainty intervals (UIs) come from 2,000 Monte Carlo draws. Sensitivity analyses varied the frontier percentile, applied an aspirational global frontier, constructed pertussis counterfactuals, and recomputed all estimates within the single under-5 age band. Results In 2023, 333,803 childhood deaths from lower respiratory infections (95% UI 289,123-417,460; 46.9% of LRI deaths) were avoidable. Summing the three causes deterministically gives 391,034 avoidable deaths (46.5% of 840,444); the combined figure is a deterministic sum, and a UI is available for the LRI component only. The pertussis (43,958; 39.0%) and URI (13,273; 81.0%) estimates are secondary: their deterministic point values fall below their own Monte Carlo intervals and the underlying death estimates carry very wide uncertainty (global pertussis UI 12,545-321,874). Avoidable deaths fell from 1,050,468 (44.9%) in 1990, but between 2019 and 2023 the avoidable share for LRI+URI barely moved (48.7% to 47.7%) while absolute avoidable deaths fell 14.5%, a pattern consistent with stalled convergence to the frontier. Sub-Saharan Africa plus South Asia held 73.1% of avoidable deaths in 2023 versus 41.8% in 1990; ten countries accounted for 59.1%. Conclusion Nearly half of childhood respiratory-infection deaths remain avoidable relative to within-region best practice, and the residual burden is increasingly concentrated in low-income settings. In the pertussis counterfactual, most countries kept pace with their regional frontier, so further gains require advancing the frontier itself through quality-of-care improvements.

Introduction. By the end of 2023, many low-income countries had not reached 50% COVID-19 vaccine coverage, while most high-income countries had exceeded 80%. It remains unclear whether receiving vaccine deliveries translated into faster population coverage. We examined cross-national inequalities in the timing of the vaccine rollout and whether deliveries through the COVID-19 Vaccines Global Access (COVAX) facility were associated with subsequent national uptake. Methods. We conducted an observational study of 218 countries and territories using country-level data up to December 2023. We used generalized additive mixed models to identify country-level correlates of coverage at an early and a later stage of the pandemic, survival analysis to compare the time to 50% coverage between COVAX Advance Market Commitment (AMC) and non-AMC countries, and an event study to estimate the association between the timing of the first COVAX delivery and subsequent monthly coverage in AMC countries. Results. AMC-supported countries reached 50% coverage substantially more slowly than non-AMC countries. The hazard of reaching the threshold was 0.17 times that of non-AMC countries at month 1 (95% CI 0.07 to 0.41) and 0.53 times at month 18 (95% CI 0.33 to 0.85). One year after rollout began, 65.9% of AMC countries (95% CI 56.7 to 76.6) had not reached 50% coverage, compared with 21.1% of non-AMC countries (95% CI 15.1 to 29.5). The timing of COVAX deliveries was not significantly associated with subsequent national uptake in any post-delivery month. In the early stage of rollout, higher maternal mortality was associated with lower coverage, while a larger urban population was associated with higher coverage. By the end of the observation period, larger household size was associated with lower coverage, while higher health expenditure and a larger urban population were associated with higher coverage. Conclusion. Receiving COVAX deliveries was not, on its own, associated with faster coverage. Coverage differences were more consistently associated with country-level structural and health-system characteristics, while we found no significant association with the timing of the first COVAX delivery. Achieving vaccine equality likely requires strengthening the capacity of health systems to convert deliveries into administered doses, and preparedness efforts should invest in last-mile delivery capacity ahead of future emergencies.

To evaluate the cost-utility and 5-year budget impact of first-line olaparib plus abiraterone versus abiraterone alone for metastatic castration-resistant prostate cancer (mCRPC) in China after the eleventh round of volume-based procurement (VBP). The intention-to-treat (ITT) population was assigned primary decision-analytic weight; the prespecified BRCA1/2-mutated (BRCAm) subgroup was a supporting analysis.

Objectives Emergency department (ED) crowding is recognised as an important public health concern internationally, and is driven principally by exit block, the shortage of inpatient beds for patients requiring admission. This study aimed to evaluate whether a complex intervention targeting hospital occupancy improved ED patient flow, and quantified the change in attendances. Methods A controlled interrupted time series using weekly, publicly reported Public Health Scotland data from 1 January 2022 to 1 February 2026. The multi-component intervention focused on reducing hospital occupancy and included additional adult social care funding; engagement with regional social care providers; accelerated implementation of the Discharge without Delay programme; re-evaluation of whole-hospital escalation thresholds and response; resource and data supporting inpatient department reductions in length of stay; and additional investment in remote clinical assessment. The intervention commenced at a large tertiary ED on 01 February 2025. Primary outcomes were the proportions of attendances spending [&ge;]4, [&ge;]8 and [&ge;]12 hours in the ED. The secondary outcome was attendance volume. Segmented regression was fitted with a contemporaneous control series, seasonal terms and autoregressive moving average errors. Long waits were additionally illustrated as potentially avoided deaths. Results The analysis covered 161 pre-intervention and 52 post-intervention weeks. Relative to pre-intervention levels, the proportion of attendances waiting over 4 hours fell by 10.4% (95% CI 1.6 to 19.2%), by 16.4% (95%CI 1.3 to 31.5%) over 8 hours and by 24.3% (95%CI 2.6 to 46.1%) over 12 hours. Using established associations between long ED waits and excess mortality, by one-year the intervention was potentially associated with 54 fewer excess deaths (95%CI 19 to 93). Attendances rose by 3.8% (95%CI 1.3 to 6.4%) against the counterfactual. Conclusions A complex intervention targeting hospital occupancy was associated with a reduction in long ED waits despite rising attendances. Interventions addressing hospital occupancy can meaningfully improve ED crowding.

Background Preventing sexually transmitted re-infections brings health benefits and can be significantly less costly than treating their sequelae. Safetxt is a potential novel digital intervention developed to promote safer sexual behaviours. However, a recent randomised controlled trial of safetxt found no effect on reinfection at 1 year (OR 1.13, 95%CI: 0.98-1.31). We investigated if safetxt's effect was mediated through sexually risky behaviours. Methods We used data from 6248 young people with STIs from 92 UK sexual health clinics. The direct and indirect effects of safetxt on reinfection were estimated using the counterfactual approach. Condom use at last sexual encounter, number of sexual partners and STI testing were assessed as mediators. These were analysed singly and together, using regression models and a formal weighting approach. The assumptions of each approach were considered and tested. Analyses were repeated in the subgroup showing the most promising effect of safetxt: men who have sex with men or with men and women (MSM/MSMW). Results No evidence was found for the total, indirect or direct effects differing from the null. Despite not being significant, for MSM/MSMW, some of safetxt's effect on reducing reinfection was identified as being offset through its effect on number of sexual partners. Conclusions There was no evidence that safetxt's effect on reinfection was mediated through changes in sexually risky behaviours. Adaptations to specifically target these behaviours are unlikely to improve safetxt's overall effect. However, improving safetxt's effect on the number of sexual partners a participant has may improve its effect for MSM/MSMW.

Abstract Preventable neonatal deaths remain a major public health problem in Zimbabwe, where near-universal antenatal and facility-delivery coverage coexist with a rising neonatal mortality rate. This study evaluated whether institutionalising three core "vital signs" of the community health system (a trained village health worker (VHW) workforce, functional community governance structures, and modified women's and men's participatory learning and action groups) reduces preventable neonatal deaths in Mashonaland West Province. An embedded QUAN (qual) mixed-methods design was used, with a two-arm, parallel-group cluster-randomised controlled trial as the dominant strand. Fifty-two ward-level clusters were randomised 1:1 to the institutionalised community health system package or to standard Ministry of Health and Child Care community services, and 984 pregnant women were enrolled between 1 September 2020 and 31 October 2021, with each mother-infant pair followed to 28 days after delivery, yielding 973 mother-infant pairs for intention-to-treat analysis. The primary outcome was neonatal death within 28 days of life, expressed per 1,000 live births. The primary analysis used a three-level mixed-effects log-binomial regression model with cluster and community-health-worker random intercepts, adjusted for pre-specified covariates. Supervised machine-learning classifiers with leave-one-cluster-out cross-validation, Cox proportional-hazards regression, and multilevel logistic models were fitted as supplementary analyses. An embedded longitudinal process evaluation used key informant interviews and focus group discussions, which were analysed thematically and integrated with the quantitative findings. The neonatal mortality rate was 44.8 per 1,000 live births in the intervention arm versus 110.1 per 1,000 in the control arm. The adjusted risk ratio for neonatal death was 0.43 (95% CI 0.26-0.70; p < 0.001), a 57% relative reduction, with a number needed to treat of 16 mother-infant pairs (95% CI 11-29). Low birthweight (<2,500 g), birth interval under two years, and low community women's literacy were the strongest risk factors, while trained VHWs, functional community governance, early antenatal care, and sustained participatory group attendance were independently protective. The women's and men's groups were protective in a dose-dependent manner, becoming significant at four or more cycles (about 14 meetings) (adjusted odds ratio 0.71; 95% CI 0.60-0.85; p = 0.001). A random forest classifier discriminated against neonatal deaths with a cross-validated area under the curve of 0.842 and a sensitivity of 0.912. Qualitative findings converged with the trial results, identifying male engagement, earlier care-seeking, danger-sign literacy, social-network activation, and community death audits as the behavioural and structural mechanisms of change. Institutionalising the community health system package (trained VHWs, functional governance, early antenatal engagement, and sustained participatory groups) was associated with a substantial reduction in preventable neonatal deaths. The findings suggest that in high-coverage, high-mortality settings, the binding constraint is structural rather than clinical, and that scaling functional community governance and workforce infrastructure in the most disadvantaged communities may accelerate progress toward neonatal survival targets. The principal limitations are a one-year follow-up period, the rarity of neonatal death, and concurrent national programming that only partially reached the control clusters. Trial registration: Pan African Clinical Trials Registry, PACTR202607591142118 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=PACTR202607591142118); registered retrospectively on 7 July 2026.

Inappropriate antibiotic use presents a major global health challenge, particularly in low-resource settings where access to quality care is limited but antibiotics remain relatively unrestricted. This study estimates the causal effect of frontline primary care quality on inappropriate community antibiotic use, combining detailed community-based data from approximately 100 rural villages in rural China with an instrumental variable (IV) approach embedded within a double/debiased machine learning (DML) framework. We linked objective measures of village doctor clinical practice quality, measured through unannounced standardized patient visits, to household-level antibiotic use data collected from the same villages. To identify the causal effect, we constructed multiple candidate instruments from extensive provider characteristics and used an ensemble of machine learning algorithms within a flexible DML-IV framework to approximate an optimal instrument, addressing a many-weak-instruments problem. We found that improving village provider clinical practice quality reduced both antibiotic receipt during healthcare encounters for common diseases and household antibiotic storage for future self-medication. Our findings suggest that strengthening frontline primary care quality can meaningfully reduce inappropriate community antibiotic use without restricting access to essential treatment. More broadly, this study illustrates how causal machine learning can strengthen conventional causal estimation in complex observational settings in global health economics research.

Purpose Despite the high documented prevalence of hunger and poor mental health in adolescent girls and young women (AGYW) in South Africa, this relationship remains understudied, with existing studies limited by their cross-sectional designs. This longitudinal study aimed to identify the association of hunger trajectories with anxiety and depressive symptoms, and hope in AGYW. Methods We used secondary data from the HIV Prevention Trials Network (HPTN) -068 conducted in rural Agincourt, South Africa. Complete data from 1779 AGYW collected at baseline (2011/12) and three annual follow-up visits were used. Hunger trajectories, measured using the Household Hunger Scale, were estimated via Group-Based Trajectory Modelling. Self-reported incident anxiety and depressive symptoms and hope were assessed based on AGYWs last two follow-up visits. Covariate adjusted modified Poisson regression models estimated the association between hunger trajectories and incident anxiety symptoms, incident depressive symptoms, and hope. Results Moderate-severe hunger was prevalent in 11.0%, 10.8%, and 6.0% of the households at baseline, follow-up 1, and 2, respectively. Incident anxiety symptoms were reported by 4.5%, incident depressive symptoms by 20.0% and hopelessness by 52.8% of the AGYW. Two hunger trajectories were identified- no hunger (82%) and marginal hunger (18%). Hunger trajectories were not associated with incident anxiety symptoms [RR:1.09, 95% CI: 0.55, 2.18], incident depressive symptoms [RR: 0.97; 95% CI: 0.72, 1.33] nor hope [RR: 1.00; 95% CI: 0.81, 1.23] in AGYW. Conclusion Better understanding of the factors that promote resiliency and mental health of AGYW in this setting is warranted to inform the design of interventions.

Background: In 2019, WHO recommended three consecutive reactive serological test results for HIV diagnosis to reduce false-positive diagnoses. Malawi changed from a two-test to a three-test strategy in 2022 as HIV test positivity declined. We assessed diagnostic performance, implementation fidelity, and costs. Methods: We analysed national HIV testing data from Nov 1, 2022, to Oct 31, 2025. Using observed three-test classifications as the reference standard, we reconstructed classifications under the two-test strategy. We estimated positive predictive value (PPV), implementation fidelity, potential false-positive diagnoses prevented, incremental costs, and time to offset testing costs through avoided antiretroviral therapy expenditure. Results: Among 9,885,599 encounters eligible for implementation-fidelity analysis, 99.98% followed a valid three-test pathway. The diagnostic-performance analysis included 9,862,908 encounters, of which 171,351 (1.7%) were classified HIV-positive and 9,138 (0.09%) were inconclusive. Under the two-test strategy, 1,209 inconclusive encounters with a T1+/T2+/T3- sequence would have been classified as HIV-positive. Retesting and reference-laboratory data indicated that 82.5% of these would subsequently be classified as HIV-negative, corresponding to 997 false-positive diagnoses prevented (10.3 per 100 000 three-test non-positive encounters; 95% CI 9.7-10.9). Retesting within 1-2 weeks was associated with the highest odds of potential false-positive classification (adjusted OR 39.37, 95% CrI 30.63-50.61). The incremental cost was US$471 per false-positive diagnosis averted and was offset within 7.30 years. Conclusions: Malawi's transition to a three-test HIV testing strategy prevented false-positive diagnoses and unnecessary antiretroviral therapy at modest cost, supporting broader adoption of WHO guidance in similar settings. Funding: Gates Foundation.

South Asian communities in the UK experience disproportionate maternal and child health inequalities linked to non-recommended infant feeding practices, limited health literacy, and socioeconomic constraints. Participatory learning and action (PLA) is effective in low- and middle-income countries, but high-income evidence is scarce. This pilot assessed the feasibility of a community facilitator-led PLA intervention to improve infant feeding among South Asian families in East London. A three-arm pilot feasibility cluster randomised controlled trial (ISRCTN10234623) was conducted in Tower Hamlets and Newham, East London (May-September 2022), with 12 wards randomised 1:1:1 to face-to-face PLA, online PLA, or usual care. Multilingual community facilitators delivered eight biweekly sessions over 14 weeks. Feasibility outcomes were assessed against prespecified Go/Stop criteria; exploratory outcomes included child feeding behaviours (Children's Eating Behaviour Questionnaire, CEBQ), parental feeding style (Parental Feeding Style Questionnaire, PFSQ), and child BMI Z-scores. Of 263 enrolled participants, 261 had a recorded trial arm allocation; consent to the pilot feasibility study was 70.7% (186/263; 95% CI 65.0-75.9%) meeting the [&ge;]50% Go criterion. Attendance was 37% (Tower Hamlets 59%, Newham 29%), below the [&ge;]80% Go threshold. Six-month retention was 54.8% (Tower Hamlets 78%, Newham 48.5%; 95% CI 41.8-55.3%), triggering the Definite Stop criterion. Significant baseline imbalances included BMI Z-score (p = 0.005), ethnicity, borough, and education; no between-arm BMI differences were observed at follow-up (p = 0.249). CEBQ and PFSQ baseline completion was 24.5% and 23.0%, with no usable follow-up data. PLA Phases 3 and 4 were not completed by any group; all participants providing feedback reported it acceptable. Recruitment was feasible and the intervention acceptable, but a Definite Stop criterion was triggered in Newham, no group completed the full PLA cycle, and outcome data were insufficient for evaluation. A definitive trial requires stratified randomisation, digitised multilingual data collection, participant reimbursement, and explicit PLA phase-completion criteria.

Human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection is associated with accelerated liver disease, but whether coinfection is associated with newly documented social determinants of health (SDoH) is unclear. We conducted a retrospective cohort study using TriNetX across 110 U.S. healthcare organizations (2010-2026). We propensity score matched adults with HIV/HBV to adults with HIV or HBV monoinfection. We organized newly documented SDoH indicators using a dynamic individual-level framework with four clinically recognized domains of social disadvantage: material vulnerability, healthcare access and engagement, interpersonal adversity, and psychosocial vulnerability. Matched cohorts included 10,071 HIV/HBV-HIV pairs and 9,659 HIV/HBV-HBV pairs (mean age, 47 years; 79% male; 66% non-White; median follow-up, 3.3 years). Over 178,900 person-years, HIV/HBV was associated with higher risk of the primary SDoH composite compared with HIV (11.5% vs 9.7%; incidence rate, 2.50 vs 1.97 per 100 person-years; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.15-1.37) and HBV (11.0% vs 6.4%; incidence rate, 2.39 vs 1.67; HR, 1.50; 95% CI, 1.35-1.67). HIV/HBV was also associated with higher material vulnerability and healthcare access and engagement composites in both comparisons, including housing instability, food insecurity, financial insecurity, insurance instability, and care disengagement/nonadherence (HR range, 1.22-3.33 vs HIV; 1.31-1.94 vs HBV). In the HBV comparison, HIV/HBV was additionally associated with interpersonal adversity, primary support stressors, and violence or victimization (HR range, 1.36-2.16). Findings were robust across sensitivity analyses. HIV/HBV was associated with more newly documented SDoH than monoinfection, supporting dynamic SDoH assessment.

Background Childhood respiratory infectious deaths are partitioned across four Global Burden of Disease cause modules-26 etiological attributions within lower respiratory infections, tuberculosis, COVID-19, and whooping cough-never jointly reported. Whether the structure of this combined mortality spectrum has changed over time, and with what implications for intervention design, has not been quantified. We assembled and analyzed the integrated spectrum for children and adolescents aged 0-19 years, 1990-2023. Methods We integrated Global Burden of Disease Study 2023 (release v8352) estimates into a 29-node spectrum-26 lower respiratory infection etiologies plus tuberculosis, COVID-19, and pertussis-globally and across seven super-regions, with uncertainty propagated by summing bounds. We computed Shannon diversity, Herfindahl concentration, and effective cause counts; phenotyped pandemic-window collapse and rebound per cause; linked pathogen shares to WHO/UNICEF vaccine coverage; and mapped geographic concentration in sub-Saharan Africa and South Asia. Reporting follows GATHER. Results In 2023 the 29 causes jointly accounted for 965,330 deaths (95% uncertainty interval [UI] 680,096-1,342,437). Shannon diversity rose from 2.336 to 2.711 (+16.1%) between 1990 and 2023; the effective number of causes nearly doubled (5.57 to 9.94), inversely coupled to total deaths (Spearman rho = -0.997). Whooping cough ranked second (112,954 deaths; 95% UI 64,576-185,708; 11.7%) and showed the spectrum's only rebound above 100% (-57.4% collapse, +111.0% rebound). Tuberculosis ranked third (87,764; 57,779-124,912; 9.1%) with the highest concentration in sub-Saharan Africa and South Asia (87.1%). COVID-19 entered at rank five (52,899; 47,275-59,183; 5.5%). Nineteen of 29 causes exceeded the poverty-lock threshold (>80.59% of deaths in sub-Saharan Africa plus South Asia). Conclusions Childhood respiratory infectious mortality has become more diverse and more concentrated in poverty as it has declined. Single-pathogen interventions now address a shrinking share; the spectrum's structure argues for platform interventions-oxygen, antimicrobial access, referral-tailored jointly by age and geography, implying that pathogen-specific strategies alone cannot finish the remaining mortality agenda.

Background: HIV/HBV coinfection is associated with substantial liver-related morbidity and mortality, yet the impact of social vulnerability (SV) on clinical outcomes has not been systematically assessed. We evaluated associations of multidimensional SV with mortality, hepatic, virologic, and extrahepatic organ outcomes among adults with HIV/HBV. Methods: We conducted a retrospective cohort study using TriNetX data from 110 U.S. healthcare organizations (2010-2026). We propensity score matched adults with HIV/HBV with and without documented SV 1:1 (2,024 per group). SV was defined using a four-domain framework encompassing material, healthcare access and engagement, interpersonal, and psychosocial vulnerability. Results: Over 15,900 person-years, SV was associated with higher mortality (hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.72-2.47), liver composite events (HR, 1.37; 95% CI, 1.07-1.76), hepatic decompensation (HR, 1.94; 95% CI, 1.39-2.70), hepatic failure (HR, 2.39; 95% CI, 1.53-3.73), HBV viremia (HR, 1.69; 95% CI, 1.32-2.16), and HIV viremia (HR, 2.05; 95% CI, 1.71-2.46). SV was also associated with major adverse cardiovascular events (HR, 1.47), chronic kidney disease (HR, 1.49), and diabetes (HR, 1.25). Multidomain SV generally showed stronger associations than single-domain SV for most hepatic and virologic outcomes, with HR ranges of 1.76-2.62 versus 1.35-1.76 for single-domain SV. Healthcare access and engagement vulnerability was most consistently associated with mortality and hepatic outcomes. Conclusions: SV was associated with mortality, hepatic disease, impaired HIV/HBV control, extrahepatic organ morbidity, and acute care utilization in adults with HIV/HBV. SV assessment may improve risk stratification and identify actionable intervention targets during HIV/HBV care.

BACKGROUND People with type 2 diabetes mellitus (T2DM) are at higher risk of cerebral small vessel disease and left ventricular hypertrophy (LVH), potentially contributing to cognitive decline and dementia. We aimed to describe brain volume and cognitive trajectories over 2 years in a cohort of people with T2DM and to determine whether LVH causes increased brain atrophy and cognitive decline. METHODS Diabetes and Dementia (D2) study is a multicentre observational cohort study in Melbourne, Australia. Participants aged >50 years were recruited via 2 hospital outpatient clinics, 3 private clinics, and study advertisements. Participants with pre-existing cognitive impairment, life-limiting medical illness, and severe chronic renal impairment were excluded. Participants attended study visits for brain MRI, transthoracic echocardiography (TTE), and cognitive testing at baseline and 2 years. The exposure was LVH determined on baseline TTE. Pre-specified outcomes were total brain volume (TBV) change and cognitive decline (z-score change?-1 in any cognitive domain) over 2 years. Regression analyses examined associations between baseline variables and outcomes. A causal inference approach was utilized using inverse probability of treatment weighting to standardize for confounding covariates, excluding participants for non-positivity on age and baseline TBV. RESULTS Participants were recruited 20May2016 to 20March2020: 2378 screened, 702 eligible, 196 consented, 150 baseline and 123 2-year assessments with complete MRI, TTE, and cognitive data (17.4% attrition). At baseline, LVH was associated with female sex, older age, lower educational attainment, lower mood, hypertension, obesity, beta-blocker use, and smaller TBV. Participants with baseline cognitive impairment exhibited greater brain atrophy. Lower educational attainment, hypertension, and lower baseline cognitive scores were associated with cognitive decline. Causal inference analysis included 62 participants with no LVH (20(32%) women; mean [SD]=66.9[5.9] years), and 31 with LVH (17(55%) women, 67.4[5.4] years). LVH caused lower TBV change: standardized mean difference (95% CI) 6.3 (0.1, 12.5) cm3, P=.048. LVH had no effect on cognitive decline. CONCLUSIONS Brain atrophy and cognitive decline were associated with baseline cognitive impairment. LVH caused less brain atrophy and cognitive decline in people with T2DM. We conclude that guideline-directed LVH therapies such as beta-blockers have both cardioprotective (remodelling) and neuroprotective effects. TRIAL REGISTRATION ACTRN12616000546459 UTN: U1111-1181-6659

BACKGROUND The optimal antiplatelet regimen in patients with acute coronary syndrome (ACS) and multivessel disease undergoing drug-coated balloon (DCB) angioplasty remains unclear. METHODS This was a prespecified subgroup analysis of the REC-CAGEFREE II trial, which was conducted at 41 sites in China and randomized 1948 exclusively DCB-treated participants with ACS to stepwise dual antiplatelet therapy (DAPT) de-escalation or standard DAPT. The primary endpoint was net adverse clinical events (NACE; including all-cause death, stroke, myocardial infarction, revascularization, and BARC type 3 or 5 bleeding) at 12 months. Participants were stratified into multivessel and single-vessel subgroups according to angiographic characteristics. RESULTS Overall, 720/1948 (37.0%) patients had multivessel disease. The multivessel subgroup was associated with a significantly higher risk of NACE compared with the single-vessel subgroup (12.5% versus 6.7%, HR IPTW:1.84, 95%CI:1.35-2.51, P<0.001). No significant interaction was observed between vessel status (multivessel or single-vessel) and treatment allocation with respect to NACE (Pinteraction=0.542). In the multivessel subgroup, NACE occurred in 44/368 (12.1%) and 45/352 (12.9%) in the stepwise de-escalation and standard DAPT groups (HR IPTW:0.95, 95%CI:0.62-1.75, P=0.818), respectively. In the single-vessel subgroup, NACE occurred in 43/607 (7.1%) and 39/621 (6.3%) in the stepwise de-escalation and standard groups (HR IPTW:1.12, 95%CI:0.72-1.70, P=0.611), respectively. For the prespecified hierarchical secondary endpoint, win ratio analyses yielded more wins for stepwise de-escalation in both subgroups. CONCLUSIONS Among patients with ACS undergoing DCB-only angioplasty, those with multivessel disease were associated with a higher risk of NACE than those with single-vessel disease. Stepwise DAPT de-escalation and standard DAPT exhibited similar risk-benefit profiles in both subgroups.

Background Excess sodium intake is a major contributor to the global burden of disease, but its role in infection susceptibility remains largely unexplored. Although sodium has been considered antimicrobial, high sodium intake may impair immune responses and host defense. We therefore examined whether habitual addition of salt to foods was associated with the long-term risk of incident infections. Methods We included 360,314 UK Biobank participants without prior hospital-treated infections. Frequency of adding salt to foods was self-reported at baseline. Incident infections were identified using ICD-10 codes from hospital and death records. Associations were assessed using multivariable Cox regression. Results Over a median follow-up of 14.3 years, 84?146 participants developed hospital-treated infections. Compared with those who never or rarely added salt, participants who sometimes, usually, and always added salt had progressively higher risks of incident infections (adjusted hazard ratios 1.04 [95% CI 1.03?1.06], 1.08 [1.06?1.11], and 1.29 [1.26?1.33], respectively; p for trend <0.001). The association remained robust across models and broadly consistent across pathogen types and infection sites. The association appeared stronger among participants with normal weight (P for interaction <0.001). Conclusions Habitual addition of salt to foods was associated with a dose-dependent higher risk of hospital-treated infections in this large prospective cohort. These findings extend the potential health relevance of excess sodium intake beyond cardiometabolic disease and suggest that lower habitual salt intake may have implications for infection risk. Further studies are needed to replicate these findings and clarify the underlying immunological mechanisms.