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.

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 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.

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 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.

Leisure time physical activity (LTPA) in mid-life may have beneficial effects on risk factors for hip fracture in later life. Conversely, physical activity may increase fracture risk through risk of injury, and the optimal amount of physical activity for reducing hip fracture risk remains unclear. We explored the associations between volume and intensity of LTPA in mid-life, and subsequent risk of hip fracture ascertained from linked health data. This prospective observational study used middle aged adults aged 40- 65 years from UK Biobank. LTPA volume (LTPAv) was derived from self-reported walking, moderate and vigorous activity at baseline (2006- 2010). Cox proportional hazard and Fine-Gray sub-distribution models were used to estimate the association between activity and hip fracture, which was sex-stratified. From 324,284 participants with complete data 53% were female and mean age at baseline was 54.5 (SD 7.3). Across 16 years of follow-up there were 2,674 hip fractures. In terms of LTPA volume, the lowest risk of hip fracture occurred in quintile 3 for women (HR 0.78, 95% CI 0.67-0.91), and men (HR 0.74, 95% CI 0.60- 0.90), relating to approximately one hour/day of leisure time physical activity. When activity intensities were examined separately, the lowest estimated hazards were observed for vigorous activity, at quintile 4 in women (HR 0.65, 95% CI 0.55 - 0.76) and quintile 3 in men (HR 0.64, 95% CI 0.52- 0.79), corresponding to approximately 60- 90 minutes of vigorous activity per week. In conclusion, moderately high volumes of mid-life physical activity, particularly vigorous activity, were related to lower risk of subsequent hip fracture, but these relationships appear to attenuate at higher volumes.

Routine infant vaccination has helped reduce cases and deaths from diphtheria, tetanus, and pertussis globally. However, these diseases continue to pose serious health risks as protective immunity wanes over time. Three booster doses of diphtheria-tetanus-pertussis-containing vaccine (DTPCV) administered from 12-months to 15-years of age increase duration of protection beyond childhood. Growing demands on government health spending underscore the importance of understanding the health and economic impact of vaccines prior to introduction. Using an integrated multi-disease epidemiological-economic model, we estimated the health impact (cases averted, deaths averted, and changes to population immunity) and budget impact of introducing DTPCV booster doses in Uganda. Compared to no DTPCV boosters, introducing all three booster doses is projected to result in 2.2 times the proportion of the population protected against symptomatic diphtheria and 2.8 times against tetanus infection among Ugandans under 15 years of age by 2039. Compared to introduction of the early childhood booster (EC) at 18 months of age, introducing all three DTPCV boosters simultaneously is projected to avert 3.2 times the number of tetanus cases over fifteen years at 2.4 times the incremental cost. The projected government vaccination cost per planned dose was USD 0.58 for simultaneous introduction of all three boosters compared with USD 0.68 for the EC booster alone. The average annual incremental cost of all three DTPCV booster doses is USD 2.79 million. Under modelled assumptions, simultaneous introduction of all three DTPCV booster doses in Uganda provides the greatest health gains, with a lower government vaccination cost per planned dose than introduction of the EC booster alone, but may still pose affordability challenges for Ugandas government.

Background: Short birth intervals are a well-documented, modifiable risk factor for child death in low- and middle-income countries, yet nationally representative evidence from Ghana's most recent Demographic and Health Survey has not been fully examined. This study assessed the association between the preceding birth interval and under-five mortality using the 2022 Ghana Demographic and Health Survey. Methods: The analysis used the complete birth history reported by women aged 15-49 years. The cohort comprised births occurring 60-119 completed months (5-10 years) before the survey, which allowed a complete five-year observation window for under-five survival (n = 8,418; 397 deaths). Spacing models were restricted to second-or-higher-order births with a defined preceding interval (n = 6,340; 282 deaths), categorised as under 18, 18-23, 24-35 (reference), 36-47, and 48 or more months. Crude and adjusted odds ratios were estimated using survey-weighted, Taylor-linearised logistic regression, adjusting for birth order, child sex, plurality, maternal age, residence, region, maternal education, wealth quintile, and marital status. Results: Weighted under-five mortality in the cohort was 45.4 per 1,000 live births (4.54%). Among second-or-higher-order births, weighted mortality fell from 9.3% after intervals of under 18 months and 8.0% after 18-23 months to 4.2%, 3.2%, and 3.5% after 24-35, 36-47, and 48 or more months, respectively. Relative to 24-35 months, the adjusted odds of death were higher after intervals of under 18 months (adjusted odds ratio [AOR] 2.58, 95% confidence interval [CI] 1.48-4.49, p < 0.001) and 18-23 months (AOR 2.09, 95% CI 1.33-3.29, p = 0.001); longer intervals did not differ from the reference. Multiple birth (AOR 2.48, 95% CI 1.33-4.63) and having a mother who was never in union (AOR 3.25, 95% CI 1.29-8.17) were also associated with higher odds of death, and marked regional variation persisted after adjustment. Conclusion: A short preceding birth interval, particularly one of under 18 months, was independently associated with an approximately two- to two-and-a-half-fold increase in the odds of under-five death in this nationally representative sample. The findings support continued investment in postpartum family planning to help women space births at least 24 months apart, alongside closer attention to multiple births, unmarried mothers, and the regions carrying the greatest burden.

Background: Both fetal and maternal genomes contribute to birthweight, but the timing and relative magnitude of their effects during gestation remain unclear. Polygenic risk scores (PRSs), constructed from genome-wide association studies (GWAS), capture the cumulative influence of common birthweight-associated variants to quantify genetic predisposition to fetal growth. We constructed fetal and maternal PRSs for birthweight in two UK birth cohorts, the Pregnancy Outcome Prediction Study (POPS) and Born in Bradford (BiB), to evaluate their associations with estimated fetal weight (EFW) throughout pregnancy and with birthweight at delivery. We also investigated whether PRSs could improve risk stratification of infants born below the 10th centile by distinguishing those with pathological intrauterine growth restriction (IUGR) from those who are constitutionally small-for-gestational-age (SGA). Methods: In POPS and BiB, we used LDpred2-auto to estimate PRSs based on the largest available maternal and fetal GWAS for birthweight. We longitudinally assessed EFW associations with PRSs using linear mixed effects models in POPS and BiB. We evaluated birthweight associations with PRSs using linear models, where birthweight was adjusted for gestational age and fetal sex. We estimated R2 and conducted variance decomposition analyses for all models. Genetically-predicted birthweights were estimated from joint models of fetal and maternal PRSs plus ten genetic principal components (PCs). BiB analyses were conducted separately for genetically-inferred European (EUR) and South Asian (SAS) ancestry. Results: While PRSfetus was significantly associated with EFW at baseline ([~]22 weeks gestation) across cohorts, PRSmother was not. Both the interaction of PRSfetus and PRSmother with gestational age (GA) were significantly associated with EFW. The effect of PRSmother on EFW increased more quickly across gestation than the effect of PRSfetus in POPS, but this finding was not replicated in BiB. Jointly, fetal and maternal polygenic risk explained 4% of variance in EFW in POPS and 1% in BiB-EUR. In POPS, fetal and maternal PRSs showed independent contributions to EFW variance of 3% and 0.5%, respectively. Joint and univariable linear models showed significant positive associations of PRSfetus and PRSmother with observed birthweight. In POPS, PRSfetus and PRSmother accounted for [~]10% and [~]4% of variance in birthweight over covariates alone, respectively, which was replicated in BiB-EUR. Maternal and fetal genetic effects jointly explained 11% of birthweight variance in POPS, similar to BiB-EUR, at 12%; however, the variance explained was reduced by half in BiB-SAS, at 6%. Among POPS babies born <10th birthweight centile, the magnitude of the difference between observed and genetically-predicted birthweight was greater in the group judged clinically to be IUGR vs. SGA (p=0.008; point estimate=0.29, 95%CI: 0.12, 0.47). Conclusions: Maternal and fetal PRSs jointly account for [~]11-12% of birthweight variance in European ancestry groups, but much less in a South Asian cohort. In POPS, the effect of birthweight-associated SNPs on estimated fetal weight increases more rapidly across pregnancy for maternal than for fetal genetic effects. Deviation from genetically-predicted birthweight may be a useful metric to help distinguish growth-restricted from constitutionally small babies.

Background: Maternal cigarette smoking is associated with adverse birth outcomes, but low birthweight may reflect preterm delivery, restricted fetal growth, or both. Contemporary evidence distinguishing smoking trajectories is limited. Objectives: To examine associations between maternal cigarette-smoking trajectories and low birthweight among U.S.-resident singleton live births in 2023 to 2024. Methods: We analyzed 5,861,166 U.S.-resident singleton live births in the 2023 to 2024 National Vital Statistics System natality files. Low birthweight was defined as birthweight <2,500 g. Trajectories were never smoking, quitting before pregnancy, quitting during pregnancy, persistent smoking, or other/intermittent smoking. Modified Poisson regression estimated adjusted risk ratios (aRRs) and 95% confidence intervals controlling for birth year and maternal, pregnancy, and infant characteristics. Results: Low-birthweight prevalence was 6.4% among never smokers, 7.7% among mothers who quit before pregnancy, 11.2% among those who quit during pregnancy, 14.6% among persistent smokers, and 10.2% among those with other/intermittent smoking. Compared with never smoking, adjusted risks were higher for quitting before pregnancy (aRR 1.06, 95% CI 1.03, 1.09), quitting during pregnancy (aRR 1.46, 95% CI 1.42, 1.51), persistent smoking (aRR 1.95, 95% CI 1.93, 1.98), and other/intermittent smoking (aRR 1.36, 95% CI 1.25, 1.49). Associations varied little by year (joint interaction P = 0.102). Conclusions: Persistent smoking showed the strongest association with low birthweight. Because the outcome combines preterm delivery and impaired fetal growth, the estimates should not be interpreted as associations with fetal growth restriction alone. Keywords Cigarette Smoking; Smoking Cessation; Pregnancy; Low Birthweight; Birthweight; United States

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).

Background Oral glucose tolerance test (OGTT), the gold standard for diagnosing gestational diabetes mellitus (GDM), faces significant implementation challenges, prompting interest in alternative biomarkers, such as glycated hemoglobin (HbA1c), for early detection. This study aimed to assess the association between early pregnancy HbA1c and subsequent GDM and adverse perinatal outcomes in low- and middle-income countries. Methods We analyzed data from the Pregnancy Risk, Infant Surveillance, and Measurement Alliance - Maternal and Newborn Health (PRISMA-MNH) cohort, which followed pregnant women enrolled before 20 weeks of gestation across five study sites in Kenya, India, Pakistan, and Zambia. We excluded participants with overt diabetes, severe anemia (Hb <7.0 g/dl), multiple gestations, or pregnancies that ended before 24 weeks of gestation. HbA1c was measured at enrollment. The primary outcome was GDM, diagnosed according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria based on OGTT performed after 24 weeks of gestation. Secondary outcomes included hypertensive disorder of pregnancy, emergent Cesarean section, preterm birth, large for gestational age, and stillbirth after 28 weeks. We used AUC and ROC analyses to evaluate predictive performance and single- and two-threshold approaches to identify optimal cutoffs for predicting GDM. We used modified Poisson regression with robust standard errors to assess associations between early HbA1c and outcomes, and meta-analysis to pool site-specific estimates. Results Among 10,918 pregnancies, GDM prevalence was 6.4%. Women with GDM were older (28.0 +/- 5.4 versus 26.0 +/- 5.3 years) and had higher BMI at enrollment (25.0 +/- 5.8 versus 22.9 +/- 5.0 kg/m2) than women without GDM. The AUC for HbA1c alone in predicting GDM was 0.65 (95% confidence interval 0.63-0.67). A single early HbA1c threshold of 5.4%, based on the largest Youden's index, showed limited predictive performance (sensitivity 46.7%, specificity 75.8%). A two-threshold approach identified rule-out and rule-in cutoffs of 5.0% (sensitivity 80.3%, specificity 35.6%) and 5.5% (sensitivity 34.5%, specificity 83.1%), respectively. In adjusted models, each 0.1% increase in HbA1c was associated with a 12% higher risk (RR 1.12, 95% CI 1.10-1.15) of GDM, while no significant associations were observed for any secondary outcomes. Conclusion Early pregnancy HbA1c is independently associated with an increased risk of subsequent GDM. However, it demonstrated limited discriminatory ability as a standalone alternative to OGTT for identifying women who would later develop GDM. The identified rule-out threshold may help identify women at low risk of GDM, although the majority would still require OGTT for definitive diagnosis.

Objectives To examine the prevalence of interruptions during UK secondary care outpatient consultations, their association with clinician mental workload, and the strategies clinicians use to manage them. Design Nationwide cross-sectional online survey. Setting Secondary care outpatient clinics, United Kingdom. Participants A sample of 465 UK secondary care doctors across a range of grades and specialties, recruited through a medical defence organisation's network. Primary and secondary outcome measures Mental workload (NASA Task Load Index, Raw-TLX); interruption frequency; perceived cognitive impact of interruptions; task resumption difficulty; perceived social effects on colleague interactions and team cohesion; and interruption-management strategy use. Results 61.1% of clinicians reported being interrupted often or very often, and mean overall workload was high (Raw-TLX 66.2, SD 11.5). Interruption frequency, patient complexity and perceived cognitive impact were each associated with higher workload across multiple NASA-TLX subscales. In fully adjusted models, interruption frequency retained independent associations with overall workload (beta = 1.79, p = 0.004) and temporal demand (beta = 0.94, p < 0.001). Task resumption difficulty was associated with worse perceived performance (beta = -0.59, p = 0.014), while perceiving interruptions as socially positive was associated with better performance (beta = 0.75, p = 0.003) and lower frustration (beta = -1.16, p < 0.001). Years of experience showed only small effects, and self-reported strategy use (38.7%) was not consistently associated with lower workload. Exploratory natural language processing of open-text descriptions identified three strategy clusters; cognitive offloading, anticipating and preparing, and blunt responses, with distinct emotional profiles. Conclusions Interruptions were commonly reported during UK secondary care outpatient consultations and were associated with measurable cognitive and temporal burden. The perceived social framing of interruptions was independently associated with frustration and self-rated performance. Binary strategy use showed no consistent workload association, indicating a need for system-level approaches addressing interruption frequency, task resumption support and the social context of interruptions rather than reliance on individual coping.

Background While overall application volume by ethnic minority doctors into UK postgraduate medical training has expanded significantly, workforce diversity varies substantially across specialties. Previous reports have suggested that doctors from certain ethnic backgrounds and international medical graduates (IMGs) experience lower likelihoods of securing training posts, but granular longitudinal evaluations across all specialty training levels and recruitment stages remained limited. Therefore, this study evaluates longitudinal trends in self-reported ethnicity and country of qualification across postgraduate medical training in England between 2021 and 2025, maps specialty representation, and tests the hypothesis that recruitment success rates differ significantly between ethnic minority and White baseline applicants. Methods We conducted a retrospective national longitudinal analysis of mandatory NHS specialty recruitment data across England from 2021 to 2025, encompassing over 300,000 applications across ST1/CT1 (entry-level) and ST3+ (higher specialty) pathways. Applicants were categorised into census-aligned broad and granular ethnic groups, alongside IMG classifications. Unadjusted odds ratios (ORs) with 95% confidence intervals were calculated using White graduates and internal sub-ethnic baselines as comparators. Specialty-level ecological correlations (Spearman's rho) were performed to evaluate whether international workforce reliance moderated ethnic recruitment disparities. Results Between 2021 and 2025, applicant volume expanded rapidly, with ethnic minority applicants and IMGs comprising numerical majorities. However, Asian and Black applicants experienced substantially lower odds of receiving training offers compared to White baseline applicants across multiple high-volume specialties (e.g., emergency medicine and anaesthetics at ST1, where Black applicants faced multi-fold reductions in success odds: OR 0.03 to 0.05, p<0.001). Granular analyses revealed notable intra-ethnic heterogeneity, including lower success among Pakistani and Bangladeshi applicants compared to Indian applicants. Furthermore, UK graduates maintained higher offer success than IMGs across most specialties. Ecological correlations demonstrated that higher international applicant reliance was moderately and significantly associated with wider recruitment disparities at higher training levels for Black applicants {rho}=-0.43, p=0.019). Conclusions Centralised medical recruitment in England exhibits some persistent ethnic and international qualification disparities despite rising application diversity. The findings highlight the necessity of disaggregating ethnic groups and addressing subjective evaluation vulnerabilities within multi-stage recruitment processes to foster equity. Trial registration: Not applicable

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.

We analyse the effect of waiting time for elective musculoskeletal treatment on labour market outcomes in England using hospital records for working-age adults who received treatment between April 2015 and March 2023 to Census, tax and benefit records. To address clinical prioritisation and unobserved severity, we leveraged provider-level waiting time as an instrument for individual waiting time and estimated two-stage least squares models adjusted for baseline labour market outcomes, demographic and socioeconomic characteristics, and provider, referral-time and procedure fixed effects. We find that longer waits reduce annual employee earnings, with effects persisting for up to five years. For an additional four weeks of waiting, the largest estimated annual losses range from {pound}301 for osteoarthritis to {pound}487 for other joint disorders. There was no evidence of effects on employment status or benefit receipt, suggesting that delays primarily operate through reduced productivity or hours worked among those who remain employed. Reducing waiting times may not only improve health outcomes but help patients maintain earnings and support economic