BMC Medicine

This study aims to elucidate the association of circadian rhythm disruption with male testosterone levels and reproductive health using integrated epidemiological and experimental evidence. In the UK Biobank (n = 38,562), rest-activity rhythm amplitude was associated with lower serum testosterone levels (-0.21 nmol/L comparing the lowest vs. highest quartiles) and increased risks of orchitis and hydrocele (hazard ratios: 1.23 and 1.14, respectively). These findings were replicated in an occupational study of shift workers in China (n = 118), where shift work was independently associated with decreased testosterone levels ({beta} = -0.301, P = 0.015). In mouse models, circadian disruption induced testicular and epididymal atrophy, spermatogenic disorders, and suppressed circulating testosterone levels, accompanied by downregulation of key steroidogenic proteins. Together, these findings provide converging evidence that circadian rhythm disruption impairs testosterone synthesis, potentially through dysregulation of steroidogenesis, highlighting circadian rhythm as a modifiable environmental determinant of male reproductive health.

Background: Colon capsule endoscopy (CCE) has been proposed as a non-invasive alternative to colonoscopy for colorectal cancer (CRC) screening, offering greater patient comfort and potentially reducing healthcare burden. However, its cost-effectiveness in population-based screening remains uncertain. Methods: This study used a state-transition (Markov) model to simulate lifetime outcomes of CRC screening in Denmark, Scotland, and Spain, comparing the standard pathway based on fecal immunochemical testing (FIT) followed by colonoscopy with an alternative pathway replacing colonoscopy with CCE after a positive FIT result. The model incorporated costs (2024 euros), quality-adjusted life-years (QALYs), and CRC cases avoided, applying a yearly discount rate of 3%. Deterministic sensitivity analyses explored uncertainty in capsule cost, adherence, and reinvestigation rates for non-advanced polyps. Results: Across all settings, CCE resulted in higher costs but slightly increased effectiveness and utility (mean QALYs 28.7 vs. 28.8; CRC detected 0.032-0.034 vs. 0.035-0.037 per person). Incremental cost-effectiveness ratios (ICER) ranged from 43,538EUR in Spain to 136,930EUR in Denmark per additional CRC detected. Capsule cost was the main driver of ICER variation, whereas adherence rates had minimal effect on cost-effectiveness. Changes in the prevalence of non-advanced polyps had a modest impact, except when capsule prices were high. Conclusions: Overall, replacing colonoscopy with CCE slightly increases detection and health gains at the expense of higher costs. Cost-effectiveness largely depends on capsule price and adherence. Artificial intelligence-assisted CCE interpretation may further improve diagnostic and economic performance, potentially supporting adoption in large-scale CRC screening programs.

Background and Aims: MASLD has become the most prevalent chronic liver disease globally. Although MVPA and plasma fatty acids have been individually studied in relation to metabolic health, their independent and combined associations with MASLD incidence remain unclear. We aimed to investigate these associations. Methods: This study included 51,717 UK Biobank participants free of liver disease at baseline, with MVPA measured using wrist-worn accelerometers and plasma fatty acids quantified via NMR. Multivariable-adjusted Cox models and restricted cubic splines were used. Results: Over a median follow-up of 7.8 years, 472 incident cases were identified. In fully adjusted models, meeting recommended MVPA levels together with higher n-6 PUFA concentrations was associated with a 71% lower risk (HR 0.29, 95% CI 0.18-0.45). The MVPA-MASLD association was nonlinear, with risk reduction plateauing at approximately 189 minutes per week. Higher n-6 PUFA was associated with reduced risk, whereas n-3 PUFA showed no significant association. Conclusions: These findings suggest that behavioral and metabolic factors may jointly influence MASLD risk. Further studies in diverse populations are needed to confirm these associations.

Background Robust quantitative evidence on the impact of rotavirus vaccines, their potential benefits in countries without vaccination, and strategies to improve performance in low- and middle-income countries (LMICs) is essential for informing policy decisions aimed at sustaining and expanding vaccination programs. Methods and Findings We used an age-structured compartmental model of rotavirus gastroenteritis (RVGE) transmission that accounts for the natural history of infection to estimate vaccine impact across 112 LMICs. The model incorporates country-specific data on demographics, transmission dynamics, vaccination schedules, coverage levels, and vaccine performance. We simulated multiple scenarios, including the continuation of current vaccination programs, vaccine introduction in countries without programs, the addition of a third dose, scale-up of coverage to 95% in low-coverage settings, and suspension of vaccination. We quantified health impacts by estimating cases, deaths, and disability-adjusted life years (DALYs) averted from 2006 to 2024 and projected over 2025 to 2034 using either no vaccination or the current program as counterfactual. We estimated that rotavirus vaccination averted a median of 268 million RVGE cases (95% uncertainty interval [UI]: 228-306 million), 35 million moderate-to-severe cases (95% UI: 30-38 million), 817 thousand deaths (95% UI: 684-928 thousand), and 53 million DALYs (95% UI: 45-61 million) between 2006 and 2024, resulting from 81 countries with vaccination programs out of 112 LMICs. Using the current vaccination as a baseline, we estimated substantial additional benefits for all strategies, except for suspension, which would increase the RVGE burden over the next 10 years. Scaling up coverage to at least 95% across all 112 LMICs, with countries without the vaccine using the 6/10/14-week schedule, could avert a median of 296 million RVGE cases (95% UI: 243-358 million), 832 thousand deaths (95% UI: 694-932 thousand), and 55 million DALYs (95% UI: 45-61 million), respectively. Furthermore, adding a third dose in the 51 countries currently using a two-dose schedule could enhance vaccine impact, averting a median of 123 million RVGE cases (95% UI: 102-145 million), 377 thousand deaths (95% UI: 310-440 thousand), and 24 million DALYs (95% UI: 20-28 million), respectively, compared to the two-dose schedule. Conclusions Our model demonstrates that rotavirus vaccination provides substantial health benefits, with an even greater impact achievable through broader adoption and increased coverage. Adding a third dose to the standard two-dose Rotarix schedule could be an additional strategy to improve vaccine impact in LMICs. These findings support continued efforts to sustain and expand vaccination programs across LMICs. The country-specific, model-estimated rotavirus burden can also inform economic evaluations to guide more effective vaccination strategies.

Title and abstract screening limit the timeliness of systematic reviews used for clinical guidelines. We evaluated audited large language model (LLM) triage at Sweden's National Board of Health and Welfare. Ten LLMs from five model families were tested on 419 Cochrane reviews comprising 26,892 records, and the selected ensemble was externally validated on 133 reviews including 8,501 records matched to planned guideline topics. The same locked model pair was then used prospectively across 24 systematic reviews in two national guideline programmes. On the 419-review selection benchmark, the selected Gemini-3-flash plus GPT-5.1 ensemble achieved 98.0% (95% CI, 97.3-98.7) mean review-level sensitivity, while topic-matched validation yielded 96.7% sensitivity (95% CI, 93.7-98.9). Prospective deployment screened 74,679 records, placed 63,858 (85.5%) in the AI-excluded pool and reduced estimated first-pass screening effort from 415 to 34 person-days. Across 600 randomly sampled AI-excluded records from the migraine and dementia programmes, none was confirmed as a final false negative after post-unblinding adjudication; across the completed 680-record audit, all 38 final retained records had been AI flagged, whereas locked blinded human consensus missed seven. These findings support locked, audited LLM triage, with human oversight and programme-specific monitoring, for systematic reviews used in national guidelines.

Background. The 2026 FIFA World Cup will bring an estimated 1--5~million international visitors to 11~US host cities between June~11 and July~19, 2026---the largest tournament in history. Large-scale international gatherings accelerate importation of infectious diseases from diverse source populations. Advance estimation of importation risk is essential for public health preparedness and surveillance prioritization. Methods. We developed a Poisson importation framework applied to five diseases (dengue fever, influenza, malaria, measles, and pertussis) across the 11~US venue cities. Three nested travel models of increasing resolution were constructed: a baseline model using routine June~2024 arrival data; a World Cup--adjusted model incorporating projected visitor growth factors; and a schedule-driven model routing WC fans to specific cities based on match assignments. WHO incidence and BTS T-100 routing fractions were combined with Monte Carlo uncertainty propagation (5,000 Uniform draws on under-reporting and travel-while-infectious parameters) to yield median importation estimates with 95\% uncertainty intervals. Results. Dengue posed the highest importation risk at most venue cities under the schedule-driven model (median $\Lambda > 10$ expected importations from Brazil alone; 95\% uncertainty interval 5.9--33.1), robust across the full literature-supported parameter range; Atlanta was the exception, where malaria probability exceeded dengue, driven by direct travel from West and Central African nations. Influenza ranked second at most cities, coinciding with the Southern Hemisphere winter peak. Pertussis showed broad geographic spread but carries the widest relative uncertainty, as the assumed detection rate sits at the upper bound of the literature range. Background tourism accounted for the dominant share of total importation risk; the World Cup fan increment contributed approximately 8.3\% of projected arrivals for WC-qualified nations. Conclusions. This Poisson importation framework, built entirely from publicly available data, provides reproducible importation risk estimates for mass gathering events. The framework extends to additional diseases, cities, and gatherings, offering a transparent baseline complementary to proprietary modeling systems.

Background. Despite the decline of the 2022 global outbreak, mpox remains an ongoing public health concern, with persistent transmission and emerging viral clades sustaining resurgence risk. Improving preparedness and response is a priority, yet it remains unclear how best pre-exposure vaccination and community response can effectively limit transmission under realistic conditions and whether behavioral adaptation is critical. Methods. We used a data-driven network model of mpox transmission among men who have sex with men in the Paris region, parameterized with sexual behavioral data and calibrated to surveillance data from the 2022 outbreak. We evaluated counterfactual scenarios by varying vaccination timing, rollout speed, prioritization, and behavioral responses. Results. Here we show that, with respect to the 2022 epidemic in the Paris region, vaccination alone delivered at the observed rollout speed would not have reproduced the observed epidemic decline, even if initiated the day of the first European alert, corresponding to 12 days before the first case was reported in France. Achieving comparable control through vaccination alone would have required more than a fourfold increase in rollout speed. Large-scale and long-term reductions in sexual contacts remain instrumental to limit the epidemic size, although earlier vaccination reduces the proportion of MSM needing to change behavior. In contrast, short-term behavioral measures adopted by the vaccinees, such as sexual abstinence during the 14-day immunity-building period, combined with moderately faster vaccine rollout, (+68% for 50% compliance; +34% for 75% compliance) could achieve comparable epidemic control. Targeting individuals with higher sexual activity further improved intervention efficiency. Conclusions. Under realistic reactive vaccination scenarios, mpox control still requires strong behavioral responses. Combining timely vaccination with short-term behavioral change guidance at vaccine administration offers a feasible path to limit transmission and strengthen outbreak preparedness and response.

Background: In 2024, the BMJ updated its data-sharing policy for clinical trials, requiring deidentified individual patient data (IPD) to be openly deposited prior to publication. Our objective was to discover if data-sharing increased after introduction of the new policy. Method: All data-sharing statements were downloaded from BMJ trials published in 2023 (submitted pre-updated policy) and 2025 (submitted post-updated policy). Data for 2025 were gathered for trials in five comparison medical journals. Data-sharing statements were coded to specify whether IPD were immediately available, and if not, the reason why. Where a statement gave a link to a repository, we checked whether data were available. Results: Openly available IPD for BMJ trials increased from 0/32 prior to the new policy to 19/33 (58%) after the updated policy; seven articles gave repository links that did not yield any data. In the five comparison journals, rates of open IPD varied from 0% to 5.6%. Conclusions: There was a substantial increase in open sharing of IPD after introduction of the new policy compared to a prior period. Open sharing of IPD is possible, but it is unpopular with authors and is unlikely to be achieved without firm editorial enforcement

Background Lifestyle interventions can increase the probability of remission of prediabetes to normal glucose tolerance, but their economic value remains unclear. We assessed the within-trial and lifetime-horizon modeled cost-effectiveness of intensive and conventional lifestyle interventions in risk-stratified participants with prediabetes. Methods A health economic evaluation was conducted alongside the 12-month multicenter PLIS trial (n=1,105). High-risk participants were randomized to intensive (HR-INT) or conventional (HR-CONV); low-risk participants to conventional lifestyle intervention (LR-CONV) or control (only short single consultation; LR-CTRL) with risk stratification based on insulin secretion, insulin sensitivity, and liver fat content. Within-trial analyses estimated incremental costs per additional remission to normoglycemia and per quality-adjusted life year (QALY). Lifetime cost-effectiveness was modelled using a four-state Markov Model. Findings At 12 months, HR-INT and LR-CONV increased remission compared with their respective comparators. The incremental cost per additional remission was {euro}7,081 (95% CI: dominated-47,277) for HR-INT and {euro}4,278 (1,312-11,793) for LR-CONV from a health insurance perspective. A willingness-to-pay of {euro}22,000 (HR-INT) and {euro}7,500 (LR-CONV) per additional remission corresponded to 90% probability of cost-effectiveness. Neither intervention was cost-effective in terms of QALYs gained within the 12-months period. Lifetime modelling suggested that both HR-INT and LR-CONV are not only cost-effective, but also cost-saving, relative to HR-CONV and LR-CTRL, respectively. Also in the probabilistic sensitivity analysis, most simulations indicated dominance (71.7% for HR and 88% for LR). Interpretation Based on short-term economic evaluation, the interventions assessed were cost-effective regarding additional participants with remission, not for incremental QALYs gained. Lifetime modelling suggests cost savings for both risk groups. Targeting populations with lifestyle interventions to achieve prediabetes remission seems to generate good value for money in the long term.

Background: The Universal Periodic Review (UPR) is a peer-review mechanism established to hold UN Member States accountable for human rights including the right to health, yet evidence on its impact on health outcomes is limited. We evaluated whether UPR engagement is associated with accelerated improvements in maternal health trajectories. Methods and Findings: We conducted a longitudinal ecological analysis of 89 countries with a baseline maternal mortality ratio (MMR) of 70 or greater per 100,000 live births in 2005. Outcomes were trajectories of annual MMR, skilled birth attendance (SBA), and contraceptive prevalence rate (CPR), from 2005 to 2023. The exposure was the volume of health-related UPR recommendations received across three cycles, thematically classified using a validated rule-based algorithm. Mixed-effects models adjusted for time-varying GDP per capita and historical fragility. The 89 countries received 41,733 UPR recommendations across three cycles, of which 405 (1%) were related to maternal health. Maternal health recommendations were preferentially directed at countries with higher baseline MMR and lower SBA. After adjustment, each additional maternal health recommendation was associated with a 0.24% [95% confidence interval (CI): 0.08, 0.40] faster annual reduction in MMR, a 0.52% [0.12, 0.91] faster annual gain in the odds of SBA, and a 0.21% [0.09, 0.34] faster annual gain in the odds of CPR. Broader recommendations on women's health and health systems and services were also associated with faster annual improvements in trajectories across all three outcomes; recommendations on abortion, family planning, sexual health and wellbeing, and sexual education tended to be directed towards lower-burden countries and were not associated with differences in any trajectories. It is important to note that the ecological design precludes causal inference. Conclusions: Receiving UPR recommendations on the themes of maternal health, womens health, and health systems and services are associated with accelerated improvements in maternal health trajectories among high-burden countries. These findings suggest that international human rights accountability mechanisms may have a role in supporting national progress on maternal health.

ProblemThe anti-microbial protein granulysin is present in vaginal secretions during the follicular phase of the menstrual cycle but nearly disappears during the luteal phase. The reason for this change is unknown. Method of studyParticipants (n = 23) with regular menstrual cycles collected daily vaginal swabs for granulysin ELISAs. Endocervical cytobrushes, ectocervical biopsies, vaginal biopsies, and PBMC were collected across the cycle to enumerate granulysin-expressing cells by flow cytometry. Cycle phase was determined by daily urinary luteinizing hormone testing and confirmed by serum progesterone levels. ResultsGranulysin levels in secretions were up to 10,000 times higher during menstruation than during the luteal phase (menstruation, median 3,924 pg/mL [IQR 400-17,280]; luteal, median and IQR undetectable [<7.81 pg/mL]). In the endocervical canal, granulysin-expressing cells were much more abundant during menstruation than during the mid-follicular or mid-luteal phases. In contrast, the number of granulysin-expressing cells in the ectocervix and vagina remained stable during the cycle. The most abundant granulysin-expressing cell types in the mucosa were CD8 T cells and NK cells. In a minority of participants, granulysin was consistently detected in luteal-phase swabs; this phenomenon was associated with parity. ConclusionsGranulysin in vaginal secretions is associated with menstruation, which also drives a spike in granulysin-expressing cells in the endocervical canal. This result explains the much higher granulysin levels in secretions during the follicular than the luteal phase. In contrast, immune cells from ectocervical and vaginal biopsies express granulysin independently of the menstrual cycle, indicating their continuous ability to respond to microbial infection.

Summary Background Persistent transmission from relapsing Plasmodium vivax infections threatens malaria elimination programs in the Asia-Pacific and Americas. Tools to identify people at risk of relapse are urgently required. We aimed to validate a panel of eight P. vivax serological biomarkers for predicting future relapses. Methods In this observational study, soldiers returning from malaria-endemic Papua to non-endemic East Java, Indonesia, were screened at enrolment using antibody measurement (Luminex) and trained random forest classification algorithms, then followed for 6 months. Active case detection was performed fortnightly by microscopy. Algorithms classified soldiers as recently infected (last nine months) and thus at risk of relapse, based on anti-vivax antibody measurements at enrolment. Findings Between December 2018 and July 2022, 592 soldiers were enrolled, with 553 completing follow-up; 119 experienced a P. vivax relapse. Of these, 102 were correctly classified as at risk of relapse at enrolment, corresponding to 86% sensitivity and 86% specificity, with an AUC of 0.92. Interpretation P. vivax serological biomarkers can identify people at risk of relapse with high sensitivity and specificity and could be used as a novel public health intervention, P. vivax serological testing and treatment (PvSeroTAT), to reduce relapse-driven transmission.

Introduction Care home (CH) influenza vaccination of staff improves resident health, yet uptake remains low at just over 11% (England, 2025/2026). We report an economic evaluation (EE) of "FluCare", an intervention to increase staff influenza vaccination through: vaccination clinics at CHs; promotional materials; and CH financial incentives. Method Seventy-five CHs were randomised to FluCare or control. A cost-consequence analysis took the influenza vaccination programme funder perspective, but also extended to the National Health Service (NHS) and CH perspective. Costs included: influenza vaccination; administration fee; FluCare components; CH resident NHS utilisation. Outcomes were: staff influenza vaccination rates; staff sickness; and resident mortality. Sensitivity analyses excluded intervention CHs that did not host vaccination clinics. Results Compared to control CHs, adjusted analysis found intervention homes with a mean absolute increase in vaccination rates of 1.8% (95% CI: -6.0%, 10.8%; p=0.572) at an increased cost of {pound}451 (95% CI: {pound}239, {pound}675; p<0.001) to the vaccination programme funders: {pound}249 per additional percentage point (PAPP) per CH. Vaccination clinics were delivered late in the influenza season, with 80% taking place from February 2023. Including only intervention CHs that hosted staff flu vaccination clinics (23/35), increases the mean difference to 10.1% (95% CI: 0.9%, 21.9%; p=0.018) and costs to {pound}805 (95% CI: {pound}603, {pound}1,079; p<0.001): {pound}79 PAPP per CH. Differences between trial arms in other costs and outcomes were marginal and generally non-significant. Conclusions FluCare delivered little improvement when staff flu vaccination clinics did not occur and had little impact on other costs/outcomes. Cost-effectiveness depends on willingness-to-pay for increased staff vaccination, but cost PAPP per CH improved from {pound}249 to {pound}79 when only CHs hosting clinics were considered. Late implementation, likely reduced impact by limiting clinic delivery, as reflected in sensitivity analysis. Future evaluations should implement FluCare earlier in the season.

Background Large-for-gestational-age (LGA) and macrosomic newborns are at increased risk of adverse perinatal outcomes, including death, yet the burden of neonatal mortality associated with these conditions in low- and middle-income countries (LMICs), where ongoing nutritional and epidemiological transitions suggest their prevalence will rise, remains poorly quantified. In this study, we quantify the neonatal mortality risk associated with LGA and macrosomia from 16 subnational birth cohorts in low- and middle-income countries between 2000 and 2017. Methods and findings This is an individual-participant meta-analysis to estimate neonatal mortality rates (NMRs) and relative risks among LGA infants (>90th and >97th percentile birth weight-for-gestational-age using INTERGROWTH-21st) versus appropriate-for-gestational-age (AGA, 10th-90th percentile) infants. Macrosomic ([&ge;]4000 g and [&ge;]4500 g) neonates were compared with those weighing 2500 g-3999g. Missing birth weights were imputed using recalibration and multiple imputation methods. We used random effects meta-analysis to pool relative risks. Median prevalences of LGA >90th and >97th percentile were 5.3% (interquartile range 3.6-8.2) and 2.6% (IQR 1.3-4.5), respectively; macrosomia ([&ge;]4000 g and [&ge;]4500 g) prevalences were 1.0% (IQR 0.3-3.1) and 0.06% (IQR 0.0, 0.30), respectively. Mortality was highest among preterm plus LGA infants (61.3 per 1000). LGA infants in the >90th percentile had over twofold increased mortality compared with appropriate-for-gestational-age infants (RR: 2.46; 95% CI: 1.86-3.25), while >97th percentile infants had a higher risk (RR: 3.77; 95% CI: 2.50-5.69). Term LGA >97th percentile infants also showed elevated mortality (RR: 3.14; 95% CI: 1.58-6.22). For LGA >97th percentile, the risk was higher in the early neonatal period (RR: 2.71; 95% CI: 1.92-3.82) than late (RR: 1.69; 95% CI: 1.22-2.34). There was no overall association between macrosomia ([&ge;]4000 g) and neonatal mortality. Population attributable fractions were 7.2% for LGA >90th percentile and 0.4% for macrosomia ([&ge;]4000 g). Conclusions Neonatal mortality risks were elevated among LGA infants in low- and middle-income countries, particularly at extreme values (>97th percentile) and during the early neonatal period. Macrosomia showed weaker, less robust associations. Although LGA prevalence is currently low ([~]5%) and contributes less to neonatal mortality than small newborns, ongoing nutritional and epidemiological transitions suggest increasing prevalence. This highlights the need for strengthened surveillance, monitoring, and improved delivery planning to ensure that no population is left behind.

Background and AimsSteatotic liver disease (SLD) is characterized by excessive lipid accumulation in hepatocytes, and alcohol consumption may modify the disease course, but the evidence is inclusive. This systematic review and meta-analysis aimed to holistically evaluate the impact of mild, moderate, and high levels of alcohol consumption on hepatic and extrahepatic outcomes in SLD. MethodsWe systematically searched EMBASE, MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials for relevant studies. The study outcomes included liver related events, malignancy, mortality and cardiovascular disease among adults with SLD who consumed alcohol. ResultsOf 2228 records identified, twenty-six studies comprising 466611 adults with SLD were included. High alcohol consumption was associated with an increased risk of liver-related events compared with abstinence (2.97, 95% CI 1.61-5.50; p<0.001), and a similar association was observed among alcohol drinkers overall (HR 1.93, 95% CI 1.60-2.33; p<0.001). Moderate alcohol consumption was associated with a higher incidence of malignancy (HR 1.41, 95% CI 1.13-1.78; p=0.677). In contrast, mild alcohol consumption was associated with lower all-cause mortality compared with abstinence (HR 0.88, 95% CI 0.78-0.98; p=0.001). No association was observed between alcohol consumption and cardiovascular disease incidence or hepatocellular carcinoma ConclusionsAlcohol intake may increase the risk of liver-related complications and cancer risk in individuals with SLD. Mild alcohol consumption was associated with lower all-cause mortality, and alcohol intake showed no association with cardiovascular disease incidence. Further studies are needed to clarify the dose-dependent effects of alcohol on hepatic and extrahepatic outcomes in SLD.

Background During infectious disease outbreaks, characteristics of reported cases are routinely collected. These give information on becoming infected but not on infecting others. We assess whether linking infectees to infectors, together with their characteristics, can help understand transmission. Methods From the start of the COVID-19 pandemic in the Netherlands, reported cases were asked to identify their most probable infector in routine surveillance, enabling the linking of cases. We assess for the period 27 February 2020 - 11 April 2022 whether the infectees of these transmission pairs are representative of all reported cases, whether the transmission pairs yield verifiable estimates of epidemiological characteristics (here the serial interval), and whether they provide information on transmission that cannot be obtained otherwise. Results Of 8,003,008 reported cases, 678,482 (8.5%) could be linked to their most probable infector. These infectees were largely representative of the reported cases regarding age group, sex, and geographical location. The mean serial interval of 3.6 days (sd 3.4 days) from transmission pairs aligns with literature. Transmissions between age groups largely follow known contact patterns. Most transmissions in September 2021 occurred between persons who were not (fully) vaccinated, indicating the effectiveness of the vaccine, and relatively few between persons with different vaccination status, indicating assortative mixing in vaccination status. Conclusion Transmission pairs can be efficiently collected in routine surveillance, providing insight into disease transmission. The current post-pandemic period provides an excellent opportunity to adjust reporting systems for linking infectees to their most probable infector as preparation for future outbreaks.

OBJECTIVES To quantify socioeconomic inequalities in antibiotic prescribing for common infections in primary care, and assess whether these inequalities arise from differences in consultation frequency, prescribing behaviour, or variation in vaccination uptake, smoking, and body mass index. DESIGN Population based cohort study. SETTING Primary care data from Clinical Practice Research Datalink, England. PARTICIPANTS 17,195,399 children and adults estimated to have been registered with a general practice in 2019. MAIN OUTCOME MEASURES Antibiotic prescribing rates (prescriptions per person-year), consultation rates (consultations per person-year), and probability of receiving an antibiotic prescription following consultation. RESULTS Higher deprivation was associated with higher antibiotic prescribing rates for most respiratory tract indications. In children, prescribing rates were 44.8% (95% confidence interval [CI] 41.9% to 47.7%) higher for upper respiratory tract infections and 47.6% (95% CI 44.2% to 51.3%) higher for lower respiratory tract infections in the most versus least deprived twentile. In adults, prescribing rates for lower respiratory tract infections were 22.7% (95% CI 21.4% to 24.1%) higher in the most deprived twentile. Prescribing rates for other indications showed weak, U-shaped, or negative associations with deprivation. Prescribing inequalities were primarily driven by inequalities in consultation rates rather than probability of receiving antibiotics once consulted. Lower influenza vaccination uptake partly accounted for higher consultation rates for respiratory infections among more deprived children, while smoking prevalence contributed to inequalities among adults. CONCLUSIONS Socioeconomic inequalities in antibiotic prescribing vary by indication type and are largely explained by consultation frequency. Reducing inequalities may require interventions that decrease the need to consult, e.g. improving influenza vaccination coverage in children and reducing smoking among adults, rather than focussing solely on prescribing behaviour.

Introduction: Respiratory infections are a leading cause of morbidity. Newly available vaccines to prevent respiratory syncytial virus (RSV) disease and encouraging clinical progress on vaccines for human metapneumovirus (hMPV) and parainfluenza (PIV) could reduce the disease burden beyond existing influenza and SARS-CoV-2 immunisation programs. However, evidence on the contribution of these viruses to respiratory disease burden across the lifespan remains limited. Methods: We reviewed studies from 01/2002-11/2025 reporting age-stratified, medically attended cases of influenza, and at least one of RSV, hMPV, or PIV, in high-income countries, excluding periods substantially overlapping with the COVID-19 pandemic. Using only studies that tested for all four viruses, we estimated the age-specific proportion of cases that were non-influenza (total across RSV, hMPV and PIV) compared to influenza using a mixed-effects logistic regression model. Results: Following exclusions and screening, 61 studies were included in the primary analysis comprising >500,000 detections of the four viruses. We found that a substantial proportion of medically attended respiratory illness in infants and young children was due to PIV, hMPV and RSV, rather than influenza, with a non-influenza virus proportion of 90.2% (95% CI 85.9-93.2%) in young infants aged 0-6 months. The converse was true for school-aged children, with a non-influenza virus proportion of 34.8% (95% CI 26.5-44.2%) in children aged 5-18 years. In adults aged 65+ years, non-influenza causes of medically attended disease were common at 60.2% (95% CI 50.0-69.5%). Restricting to studies reporting hospitalised cases (n=19) produced broadly similar age-specific trends in relative virus burden contributions. Discussion: We highlight the significant burden of medically attended illness due to PIV, hMPV and RSV across ages, particularly in infant and preschool-aged children and older adults, supporting the need for effective vaccines targeting this burden.

Background Despite the significant impact of longstanding paediatric pneumococcal conjugate vaccine (PCV) use in the United Kingdom (UK), pneumococcal disease burden remains substantial and is primarily driven by nonPCV13 serotypes. Higher valent vaccines such as the 20 valent PCV (PCV20) may provide additional public health and economic benefits, yet their value in the contemporary UK setting has not been fully assessed using recent data. Methods We updated an age structured dynamic transmission model using post COVID 19 UK epidemiology (2001 to 2023) to compare pediatric PCV20 with PCV13 and PCV15. Over a 10 year horizon, we assessed cost effectiveness and number needed to vaccinate (NNV), capturing invasive and non invasive disease cases, deaths, costs, quality adjusted life years, and incremental cost effectiveness ratios. PCV20 was evaluated under 1+1 and 2+1 schedules; PCV13 and PCV15 were assessed under 1+1. Scenario analyses examined key uncertainties. Results PCV20 was estimated to avert more cases and deaths than PCV13 or PCV15, driven by broader serotype coverage and indirect effects. Both PCV20 schedules were dominant or cost saving versus lower valent comparators, with lower NNVs. PCV20s higher vaccination costs were offset by reductions in downstream healthcare expenditures. Conclusion Paediatric PCV20 implementation in the UK could deliver substantial health gains while improving economic efficiency, supporting timely adoption.

Background Coeliac disease (CD) diagnosis on duodenal biopsies is limited by interobserver variability. We have previously demonstrated pathologist-level performance with our artificial intelligence (AI) model for the histopathological diagnosis of adult CD, but not in paediatric practice. As paediatric CD screening programmes expand internationally, accurate and scalable diagnostic tools are needed. We investigated whether an AI model trained exclusively on adult whole-slide images (WSIs) can generalise to paediatric CD diagnosis across independent centres. Methods A training and validation dataset of 9,958 WSIs from 8,421 adult patients (961 CD) from five centres was used to develop an ensemble of multiple-instance learning models using features from a foundation model. Testing was performed on 708 consecutive paediatric patients (86 CD) from two centres (Edinburgh and Southampton) not included in training. Model calibration was assessed, and probability outputs were grouped into clinically interpretable categories. Findings In adult cross-validation, the AI model achieved an area under the receiver operating characteristic curve (AUC) of 98.7%, sensitivity of 84.9%, specificity of 99.0%, and negative predictive value (NPV) of 98.1%. On testing (paediatric) datasets, performance remained high (AUC 98.8%, sensitivity 80.2%, specificity 98.4%, NPV 97.3%). Restricting analysis to predictions outside the intermediate-probability range (predicted CD probability <10% or [&ge;]65%; 85.3% of cases) improved sensitivity to 100% and specificity to 98.7%. No misclassifications were observed among high-confidence predictions (<2% or [&ge;]85%; 66.0% of cases). The expected calibration error was 0.03. Performance improved significantly when biopsies from both duodenal sites (bulb [D1] and descending [D2/3]) were considered. Interpretation Our AI model, trained on adult biopsies, generalises to paediatric CD diagnosis across centres and scanner platforms. Well-calibrated probability outputs provide clinically interpretable measures of diagnostic confidence and could support safe identification of CD-negative biopsies within defined thresholds. These findings demonstrate the feasibility of applying adult-derived AI models in paediatric populations and reinforce the importance of multi-site (D1 & D2) biopsy sampling.