BMC Medicine

Background: Early pandemic responses must balance transmission control against socioeconomic costs but the strategy that minimises total costs and whether it varies by country remain unknown. We analysed country-specific cost-optimal intervention strategies and examined whether national indices could inform response targets. Methods: We fitted mechanistic models to the first year of reported COVID-19 cases in 110 countries and assessed structural identifiability and parameter uncertainty. Multi-objective optimisation identified efficient trade-offs between transmission reduction and infections across 26-, 40-, and 52-week horizons without vaccination. We selected cost-minimising strategies using GDP-scaled intervention costs and infection costs incorporating quarantine and mortality. Excess-cost ratios, defined as the relative cost increase over the optimum, quantified deviations from the cost-minimising strategy. We also examined associations with national socioeconomic and health-system indices. Results: Cost-optimal average transmission reduction ranged from 31.2% to 57.3% across countries. Across the time horizons, the mean excess-cost ratio for 110 countries was 55.2% (median 30.8%). Excess costs increased asymmetrically around the country-specific optimal transmission reduction: a five-percentage-point transmission reduction below the optimum was associated with excess-cost ratios exceeding 400%, compared with 10-80% for an equivalent increase above the optimum. The range of transmission reduction associated with excess-cost ratios below 40% widened 1.47-fold as the horizon increased from 26 to 52 weeks. Among national indices, the Socio-Demographic Index (SDI) and GDP per capita had the largest redundancy indices (0.40 and 0.37, respectively). Conclusions: Under the modelled assumptions, transmission reduction below the country-specific optimum resulted in greater excess costs than reduction above the optimum, highlighting the potential value of precautionary early-response strategies when intervention effectiveness is uncertain. National socioeconomic and health-system indices may provide a broad indication of cost-optimal intervention intensity, although country-specific conditions remain important. These findings provide a quantitative framework for balancing intervention intensity, infection burden, and economic costs across diverse national settings.

Background: Invasive non-typhoidal Salmonella (iNTS) disease causes high childhood mortality in sub-Saharan Africa. Malaria infection is postulated to increase iNTS risk through impairment of bactericidal immunity. We quantify malaria's causal contribution to iNTS and explore burden mitigation via integrated antimalarial and iNTS prevention strategies. Methods: We analyzed 443 weeks of surveillance data (September 2017-March 2026) from Kisantu health zone, Democratic Republic of Congo. Analyses included interrupted time series of perennial malaria chemoprophylaxis (PMC; November 2023) and R21/Matrix-M vaccine (October 2024) rollouts, causal mediation analysis, calibration of an age-structured co-infection Susceptible-Infected-Recovered-Susceptible (SIRS) model via the neural ordinary differential equation (ODE) adjoint method, and a 15,435-scenario grid search for NTS infection elimination coverage thresholds. Findings: Malaria burden was 80% lower at PMC full coverage (incidence rate ratio [IRR] 0{middle dot}197, 95% CI: 0{middle dot}096-0{middle dot}401 ; p<0{middle dot}001). A declining iNTS trend emerged post-ramp (IRR 0{middle dot}990/day, 95% CI: 0{middle dot}981-0{middle dot}998 ; p=0{middle dot}018). The calibrated SIRS model estimated ~12-fold iNTS susceptibility during malaria infection ({psi}M[-&gt;]N = 12{middle dot}0, 95% CI: 3{middle dot}6-28{middle dot}3). Combined malaria prevention strategies provided immediate iNTS burden reduction ([&le;] 37%), but full iNTS elimination requires a [&ge;]70% efficacious iNTS vaccine. Interpretation: Malaria control interventions deliver meaningful iNTS co-benefits. This analysis support their prioritization along with further evaluation of integrated malaria-iNTS prevention strategies in high-burden settings. Our results show that full NTS elimination additionally requires a high-efficacy iNTS-specific vaccine. Funding: The Gates Foundation (INV-047715, INV-007844, INV-082265, INV-077454), The European and Developing Countries Clinical Trials Partnership (RIA2017S-2027), and the Swedish Styrelsen for internationellt utvecklingssamarbete (17106)

Neighbourhood deprivation is one of the few potential policy-modifiable risk factors for psychiatric and neurological disorders, but the neurobiological pathways underlying these associations remain unclear. We investigated these relationships across three cohorts spanning the life span: the Healthy Brain and Child Development (HBCD) Study (n = 84, aged 0 to 4 weeks postnatal), the Adolescent Brain Cognitive Development (ABCD) Study (n = 4,792, aged 9 to 10 years), and the UK Biobank (UKB; approximately 500,000 adults, aged 44 to 87 years). Neighbourhood deprivation was associated with elevated disease risk, and individual lifestyle factors accounted for only a small fraction of this burden, indicating that the much larger residual effect reflects broader contextual characteristics of deprived environments rather than individual behaviours alone. Across all cohorts, greater deprivation consistently predicted lower cortical and subcortical brain volume, with effects detectable in early development and substantially stronger in adulthood. Across disorders, regional brain volume emerged as a consistent neuroanatomical mediator linking neighbourhood deprivation to neuropsychiatric disease. We further showed that deprivation preferentially affects brain regions intrinsically vulnerable to neuropsychiatric disorders. Spatial decoding analyses implicated dopaminergic and serotonergic neurotransmitter systems together with specific excitatory and inhibitory neuronal classes. Importantly, both the deprivation effects and their neuroanatomical mediation patterns were replicated across independent populations. Our study delivers a translational framework linking neighbourhood deprivation to brain health, which could inform public health policies and preventive interventions.

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/Objectives We evaluated the impact of the COVID-19 adolescent vaccination in England at two different epidemic points: the autumn (August-November) 2021, in the presence of a large Omicron epidemic wave, and the autumn (August-November) 2022, when the subsequent Omicron epidemic was at an endemic stage. Methods Using the Covasim SARS-CoV-2 model for England, under varying vaccine uptake and onset time, we evaluated the impact of a)vaccinating 18+ only versus additional 12+ vaccination from the autumn 2021; and b)the current immunisation strategy at the time versus additional 12+ vaccination from September 2022, projecting the number of new daily SARS-CoV-2 infections, hospitalisations and deaths. Results In presence of the BA.1 Omicron wave in late 2021, the expanded adolescent vaccination averted ~3,000,000 cases across all-ages, ~1,010,000 SARS-CoV-2 infections in the period 2-6 months from vaccine onset in the vaccinated cohort. During the Omicron waves in 2022, additional adolescents vaccination did not significantly reduce the COVID-19 burden in the entire population, nor within the vaccinated cohort. Conclusions Our findings highlight that adolescent vaccination impact depends on the timing/speed of implementation, other present intervention strategies, and the status of the epidemic at the time and it should not be considered as a stand-alone immunisation strategy.

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.

Background: Endometriosis affects approximately 10% of reproductive-age women and is associated with substantial diagnostic delay and heterogeneous symptom presentation. Prior machine-learning prediction models have relied on comorbidity data alone or on small candidate-variant genetic scores, with inconsistent or incompletely reported performance. No study has combined a well-powered, multi-ancestry polygenic risk score (PRS) with environmental, reproductive, and symptom data in a single hybrid model. We developed and evaluated hybrid risk-prediction models integrating a genome-wide, multi-ancestry PRS with clinical and symptom data for endometriosis in the US-based All of Us Research Program. Methods: Among 69,376 participants (15,382 endometriosis cases, 53,994 controls) across six genetically inferred ancestry groups, we computed individual-level PRS values using PRS-CS weights derived from an independent, multi-ancestry GWAS. Five nested logistic regression, random forest, and XGBoost models progressively added age, ancestry, and within-ancestry genetic principal components (Model 1), environmental and reproductive factors (Model 2), symptom and comorbidity indicators (Model 3), all covariates combined (Model 4), and PRS x environment interactions (Model 5). Performance was assessed by AUROC in a held-out test set and 5-fold cross-validation, with class-weighted, Youden-optimized thresholds used for sensitivity, specificity, and predictive values; permutation importance identified top contributors. Pairwise AUROC differences were tested with a Holm-corrected DeLong-type test. Results: Discrimination improved from AUROC 0.63 (PRS, age, ancestry, principal components) to 0.72 for the full model, driven mainly by symptom and comorbidity data. XGBoost consistently outperformed logistic regression and random forest. The PRS ranked among the top individual predictors by permutation importance in nearly every model, alongside age, while genetic and demographic information alone gave only modest discrimination, and PRS x environment interactions did not improve on environmental factors alone. Threshold optimization yielded balanced sensitivity and specificity (~0.67/0.65) versus near-zero sensitivity at a default threshold. Conclusions: Combining the PRS with symptom and comorbidity data gave the best discrimination compared to solely a well-powered, multi-ancestry PRS as a predictor of endometriosis. This study clarifies both the promise and current limits of hybrid genetic-clinical prediction for endometriosis and points to symptom-based phenotyping, molecular subtyping, and external validation as priorities.

Background: Inequalities exist for many health outcomes, but there is limited evidence regarding menstrual symptoms despite their importance for health and wellbeing. We aimed to investigate inequalities in menstrual symptoms according to socioeconomic position and childhood adversity. Methods: In two generations (G0 mothers and G1 offspring) from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective cohort study, we examined associations of multiple indicators of socioeconomic position (SEP) and adverse childhood experiences (ACEs) with menstrual symptoms (pain, abnormal uterine bleeding, and premenstrual syndrome (PMS) measured 3-8-years post-birth in G0 and 17-21-years-old in G1), using multivariable logistic regression. Samples ranged from 4,828 to 9,335 G0 participants and 1,288 to 2,757 G1 participants depending on the exposure-outcome association. Missing data were addressed using multiple imputation and inverse probability weighting. Results: Financial difficulties were associated with greater odds of menstrual pain (G1 OR 1.41; 95% CI 1.07, 1.86: G0 OR 1.55; 95% CI 1.36, 1.76) and irregular cycles (G1 OR 1.60; 95% CI 1.12, 2.29: G0 OR 1.48; 95% CI 1.27, 1.72) in both generations, as well as with short/long cycle lengths in G0 only. Lower education and manual social class were also associated with these three menstrual symptoms in at least one generation. Conversely, higher SEP was associated with PMS in both generations. Higher cumulative ACEs were consistently associated with menstrual pain (4+ compared to none: G1 OR 2.15; 95% CI 1.48, 3.11: G0 OR 1.52; 95% CI 1.29, 1.80) and irregular cycles (G1 OR 1.92; 95% CI 1.20, 3.09: G0 OR 1.54; 95% CI 1.26, 1.87) but not cycle length. Lower parental education, financial difficulties, and cumulative ACEs were associated with heavy bleeding in G1 offspring only, whereas financial difficulties, own manual social class, and cumulative ACEs were associated with prolonged bleeding in G0 mothers only. Higher cumulative ACEs were also associated with PMS in G1 offspring only. Conclusions: We found evidence of inequalities according to socioeconomic disadvantage and childhood adversity for multiple menstrual symptoms, although some associations were only observed in one generation. Findings suggest that menstrual symptoms are disproportionately experienced by socially and socioeconomically disadvantaged women.

Background Interruptions are common in hospital outpatient departments (OPDs) and are linked to error. Many are clinically necessary, so the aim is to regulate them. Most interventions target the individual clinician. Little is known about how doctors manage interruptions in practice or what makes their strategies work. Methods Qualitative study using focus groups and interviews with 42 doctors working in UK National Health Service OPDs (19 sessions, September to November 2025). Participants were purposively sampled by clinical experience and self-reported patient complexity. Data were analysed using Framework Analysis, informed by Cognitive Load Theory and Social Identity Theory. Results We developed four themes. (1) Pre-emptive protection of attention. Doctors withdrew, signalled unavailability and set thresholds for interrupting. These depended on colleagues learning and sharing the norm, which staff rotation eroded. (2) Sharing the burden through team coordination. Designated roles and time-limited rotas moved interruptions to colleagues with capacity set aside for them and made interrupting legitimate. (3) Real-time cognitive repair. Doctors asked interrupters to wait while they secured the task, and rebuilt the consultation on return, sometimes with the patient's help. Asking a colleague to wait depended on seniority or team membership; some trainees described difficulty doing this with senior colleagues. (4) Organisational recognition as the precondition for sustainable regulation. Where supervision was built into job plans, the interruptions it generated were expected and doctors held capacity in reserve for them. Advice, vetting and telephone queries were rarely counted as work. Conclusions Each strategy served a cognitive purpose, and social and organisational conditions decided whether it was perceived to work. Interventions could make norms shared and roles explicit, count interruption work in job plans and keep routes open for junior staff to raise concerns. Evaluations should ask who is able to use them.

Objectives. The primary objective is to determine the extent to which fetal growth profiles in opioid and opioid agonist (OAT) exposed pregnancies are influenced by cannabis exposure. Secondary objectives are to examine differences in fetal and neonatal morbidity and mortality. Design. Population-based cohort study. Setting. Ontario, Canada, in a public healthcare system. Participants. All live/stillborn births between April 1st, 2013, and March 31st, 2021. Exposures. Substance exposure in pregnancy, including opioids, opioid agonist therapy, cannabis, and nicotine. Main Outcome Measures. Primary outcome measures included incidence of small for gestational age (<3rd and <10th percentile for sex) and intrauterine growth restriction. Secondary outcome measures included incidence of stillbirth, severe neonatal morbidity (SNM), neonatal mortality, and neonatal abstinence syndrome (NAS). Results. 959,731 births are included with exposures classified as 864,508 (88.0%) no substance, 73,815 (7.7%) nicotine, 23,003 (2.4%) cannabis, 7,694 (0.8%) opioid, and 5,353 (0.6%) OAT. Cannabis co-exposure was reported in 1 out of every 6 opioid and/or OAT exposed births. The observed proportions of SGA and IUGR were approximately doubled across substance-exposed groups compared with the no substance exposure group. In adjusted analyses, cannabis exposure alone was associated with an 84% increased risk of IUGR, compared with 14% for opioid exposure alone and 60% for OAT exposure alone. SNM was observed in 7.2% of no substance exposure neonates, compared to 13.9% and 14.2% of opioid and OAT exposed neonates, respectively. NAS was diagnosed in 70.6% of all OAT exposed neonates, compared to 34.3% of all opioid exposed neonates. Risks for all outcomes across all cannabis co-exposure groups were significantly elevated relative to the no substance exposure group, with estimates ranging from 43% to 107% increased risk. Conclusions. Prenatal co-exposure to opioid and/or OAT along with cannabis appears to place infants at the highest risk. Isolated cannabis use has similar, if not more significant, impacts on fetal growth as opioid and/or OAT use. This information may serve as an important starting point in the design of effective harm reduction strategies in this patient population.

Importance: Maternal vaccination and long-acting monoclonal antibodies are now available in the U.S. to prevent RSV. Long-acting monoclonal antibody administration in the U.S. commonly occurs after hospital discharge in outpatient settings, leaving some infants unprotected early in life when severe RSV risk is highest. Comparative effectiveness between the two interventions and whether delays affect effectiveness estimates have not been quantified. Objective: To evaluate the effectiveness of infant long-acting monoclonal antibody strategies and a maternal vaccination strategy, each compared to no intervention, and the comparative effectiveness of intervention strategies when accounting for real-world delays in monoclonal antibody receipt. Design: Cohort study using target trial emulation to compare four strategies for prevention of RSV-related outcomes. Setting: The U.S. between 2023 and 2025 using a nationwide database of employer-sponsored commercial insurance claims. Participants: 120,586 commercially insured mother-infants, whose infants were born in the U.S. during the 2023-2024 or 2024-2025 RSV season. Infants who could not be paired with their mother's record, did not enroll in commercial insurance within 75 days from birth, received palivizumab, and had an implausible birth date were excluded. Interventions: Comparison of four RSV prevention strategies: (i) maternal RSVpreF; (ii) long-acting monoclonal antibody given within the first week of life (mAb as intended); (iii) long-acting monoclonal antibody given within a six-month grace period from birth (mAb within grace period); and (iv) a control. Main outcomes and measures: Effectiveness against first RSV-associated hospitalization and medically-attended RSV illness was summarized using adjusted hazard ratios (aHR) and estimated using an inverse propensity weighting approach, with weights accounting for maternal age, maternal comorbidities affecting pregnancy, obstetric and newborn complications, season, region, and birth timing relative to October 1. A weighted Kaplan Meier estimator was used to estimate strategy-specific cumulative incidence of RSV outcomes over time. Results: In the first five weeks of life, the mAb within grace period strategy doubled the hazard of RSV hospitalization (aHR: 2.0 [95% CI: 1.0-4.9]) and increased the hazard of medically-attended RSV (aHR: 1.6 [95% CI: 1.0-2.7]) compared to the maternal RSVpreF strategy. The hazard for RSV hospitalization was similar for the mAb as intended strategy compared to the maternal RSVpreF strategy (aHR = 0.9 [95% CI: 0.3-1.9]). Conclusions and relevance: RSVpreF and monoclonal antibodies were similarly effective when monoclonal antibodies were administered close to birth, but when accounting for real-world delays in monoclonal antibody receipt, the maternal RSVpreF strategy was more effective than the mAb within grace period strategy.

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.

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 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: Heavy menstrual bleeding (HMB) and menstrual pain (MP) are among the most common menstrual cycle related symptoms with substantial impacts on quality of life. Despite this, population-level evidence on their prevalence across the life course is scarce. Methods: We conducted descriptive analyses of six longitudinal population-based cohorts from the United Kingdom, United States, Norway, and Australia. We estimated cumulative prevalence (across all available timepoints) and age-specific point prevalence of HMB and MP. Cumulative prevalence estimates were stratified by sociodemographic factors, where data permitted. We also examined HMB and MP incidence in adolescent cohorts with repeated measurements. Findings: HMB and MP are commonly reported, with cumulative prevalence across all the cohorts and timepoints (i.e., ever reported) ranging from 36% to 89% for HMB and 46% to 72% for MP. In adolescence, MP (point-prevalence: 33% to 47%) is more commonly reported than HMB (16% to 24%), whereas in later ages (45 years and above), HMB (47% to 70%) is more prevalent than MP (24% to 40%). We found no consistent evidence that symptoms were more likely to co-occur than occur independently; patterns varied across life stages and cohorts. Symptoms were more common in those from lower socioeconomic backgrounds and minoritised ethnic groups. Incidence of both HMP and MP peaked in the years immediately following menarche. Interpretation: Most women experience heavy and/or painful periods at some point. MP is more common in adolescence and HMB in later reproductive life. Generating robust life-course evidence on menstrual symptom patterns is essential to inform clinical guidelines, reduce diagnostic delays, and address inequalities in menstrual health.

Objective To examine whether prospectively recorded maternal BMI in early pregnancy is associated with offspring multiple sclerosis (MS) risk, including childhood-onset and adult-onset MS. Design Nationwide population-based cohort study. Setting Swedish national health and demographic registers. Participants 1,524,863 singleton children born in Sweden from 1992 to 2007 and followed through 2025. Exposures Maternal BMI recorded at the first antenatal visit, categorised as underweight (<18.5), normal weight (18.5-24.9), overweight (25.0-29.9), and obesity ([&ge;]30.0), and also modelled continuously. Main outcome measures MS in offspring, identified as at least three ICD-10 G35 codes recorded on separate dates. Cox models estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) adjusting for confounders. Results During follow-up, 1539 offspring (0.1%) were diagnosed with MS at a median age of 24 years (interquartile range, 20-27 years). MS incidence rates by maternal BMI category were 0.37 per 10,000 person-years for both underweight, and normal weight, 0.42 for overweight, and 0.45 for obesity. Compared with normal weight women, maternal overweight and obesity were associated with higher hazards of offspring MS, with adjusted HRs of 1.20 (95% CI, 1.05 to 1.37) and 1.35 (95% CI, 1.11 to 1.64), respectively. Onset-specific analyses showed similar findings for adult-onset MS and less precise but directionally consistent estimates for paediatric-onset MS. Each 1-unit increase in maternal BMI was associated with a 3%, 4%, and 3% higher hazard of overall, paediatric-onset, and adult-onset offspring MS, respectively. Conclusions In this population-based cohort study, higher maternal BMI were associated with an increased rate of MS in offspring. The findings provide large-scale prospective evidence that maternal adiposity may be related to offspring MS risk and support further investigation of the prenatal metabolic environment in the early-life origins of MS.

Background: Endometriosis is a chronic gynecologic condition which has been linked with higher cardiovascular disease (CVD) risk. Although systemic inflammation is central to endometriosis and CVD pathophysiology, it remains unclear whether endometriosis is associated specifically with early-onset CVD and whether systemic inflammation modifies this association. Methods: This was a cross-sectional study of 5,345 women aged 20-54 years from the National Health and Nutrition Examination Survey (1999-2006). Endometriosis and early-onset CVD were self-reported. Early-onset CVD was defined as a composite measure of coronary heart disease, angina/angina pectoris, heart attack, congestive heart failure, or stroke. Systemic inflammation was measured using C-reactive protein [CRP; low/moderate ([&le;] 3 mg/L) and high (>3mg/L)] and the systemic immune-inflammation index (SII; tertiles). Survey-weighted logistic regression was used to assess associations and heterogeneity by systemic inflammation, with stabilized inverse probability weighting (IPW) to adjust for confounding. Results: Of the 5,435 women, 370 (6.9%) reported an endometriosis diagnosis and 162 (3.0%) early-onset CVD. After IPW adjustment for age, body mass index, smoking status, education, age at menarche, physical activity and race/ethnicity, endometriosis was associated with higher odds of early-onset CVD (prevalence odds ratio [POR] = 1.91, 95% CI: 1.23-2.97). This association was strongest among women with high CRP (POR= 2.33, 95% CI: 1.49-3.66), but not among those with low/moderate CRP levels (p-interaction= 0.086). Across SII strata, the strongest association was observed among women in the medium SII tertile (POR = 2.92, 95% CI: 1.47-5.78), with no associations in the low or high tertiles (p-interaction = 0.288). Conclusion: Endometriosis was associated with higher odds of early-onset CVD in this nationally representative sample of U.S. women. Although the strength of the association varied across CRP and SII strata, formal tests for interaction were not statistically significant. These findings should be understood as exploratory and require further investigation in prospective studies

Background: Circulating proteins are promising biomarkers of colorectal cancer risk. Most studies combine colon and rectal cancer despite their biological differences. Objective: To identify proteins associated with colorectal, colon, and rectal cancer risk and triangulate findings using cross-cohort confirmation and Mendelian randomisation (MR). Design: We profiled 6,402 proteins, using the SomaScan 7K assay in a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC; 658 colon and 319 rectal cancers). Cox models identified proteins associated with cancer risk at a false discovery rate <5%. Findings were confirmed in the Atherosclerosis Risk in Communities study (ARIC; SomaScan; 235 colon, 36 rectal) and UK Biobank (Olink Explore; 321 colon, 164 rectal). MR and genetic colocalisation evaluated potential causality. Results: We identified 36 proteins associated with colorectal cancer, 50 with colon cancer, and 2 with rectal cancer; 20 of the 36 were also associated with colon cancer and none with rectal cancer, and no protein was associated with both sites. Seven of the 40 colon cancer proteins available in ARIC were confirmed, including COMP, MIC-1/GDF15, TFF3, and THIK. Of these, MIC-1/GDF15 and TFF3 were also confirmed in UK Biobank. COMP was inversely associated with colon cancer risk observationally and in MR analyses. Conclusion: Colon and rectal cancers have different pre-diagnostic proteomic profiles, underlining the need for site-specific analyses. COMP, MIC-1/GDF15, and TFF3 were the most robustly supported biomarkers of colon cancer risk. Future work should prioritise experimental validation of these associations and use of repeated measures to define timing.

Background In 2025, COVID-19 vaccination programmes in England targeted adults aged [&ge;]75 years and immunosuppressed individuals, with JN.1-based vaccines offered in spring and KP.2-based vaccines offered in autumn. This study evaluated vaccine effectiveness (VE) against COVID-19 hospitalisation following these campaigns and assessed VE in immunosuppressed populations. Methods VE against COVID-19 hospitalisation in adults aged [&ge;]75 years following the 2025 spring JN.1 and autumn KP.2 vaccination campaigns was estimated using a test-negative case-control design. Logistic regression was used to calculate VE among eligible hospitalised individuals, adjusting for covariates. Manufacturer-specific analyses were performed for the spring 2025 campaign. VE in immunosuppressed and non-immunosuppressed adults aged [&ge;]75 years was assessed by pooling estimates from the autumn 2024 and spring and autumn 2025 campaigns using fixed-effects meta-analysis. Results Spring 2025 JN.1 vaccines conferred moderate protection, peaking at 55% (95%CI: 45-62%) within 5-9 weeks and declining to 17% (95%CI: -18-42%) from 35 weeks onwards. Autumn 2025 KP.2 VE peaked at 48% (95%CI: 34-59%) at 5-9 weeks, with follow-up needed to assess long-term protection. No significant differences were observed between manufacturers in the spring campaign. VE following autumn KP.2 vaccination was lower among individuals who received a spring JN.1 vaccine. When assessed across three campaigns, there was some evidence that VE was lower in individuals with immunosuppression than those without. Conclusion The 2025 COVID-19 vaccination programmes in England provided moderate protection against COVID-19 hospitalisation in adults aged [&ge;]75 years, with protection waning over time. The findings support the continued benefit of seasonal vaccination in high-risk groups, including immunosuppressed individuals.

Background England's population is ageing rapidly, with those aged 80 years and older projected to increase 85% by 2047. Aging populations may change the dynamics of future pandemics, since older individuals face higher risks of severe outcomes and require a disproportionate share of early vaccine supply, for certain respiratory infections, despite having fewer social contacts. The net pandemic-risk implications of these competing effects cannot be resolved without dynamic transmission modelling. Methods We used an age-structured stochastic SARS-CoV-2 transmission model, previously calibrated to the real-time COVID-19 epidemic across seven NHS regions of England. Running the fitted model under the ONS principal population projection for 2047 as a counterfactual, we held all non-pharmaceutical interventions fixed and scaled vaccine supply to overall population growth. Nine counterfactual scenarios spanned three vaccine deployment strategies and three ONS migration assumptions. Findings The basic reproduction number remained largely unchanged by the projected age distribution. However, under the central counterfactual scenario, cumulative hospital admissions in the first two years of the pandemic were 674,004 - a 40.3% increase over the historic baseline - and hospital deaths increased by 49.4%, disproportionate to the 13.9% total population increase. Trajectories were similar before the Delta variant emerged but diverged thereafter, as a larger elderly cohort delayed vaccine protection in younger, higher-contact groups. Projected burden was robust to migration assumptions (664,451--689,833 admissions). Vaccine deployment strategy had substantially greater influence, with admissions ranging from 625,859 (optimistic age-scaled deployment) to 1,193,883 (non-scaled). Interpretations Population ageing will disproportionately amplify England's pandemic burden, driven primarily by the interaction between a growing elderly cohort and fixed age-ordered vaccine allocation, rather than by population growth alone. This vulnerability is largely independent of future migration uncertainty but is strongly modifiable through demographically-adaptive vaccine deployment planning developed before, not during, the next pandemic.