BMC Medicine

BackgroundAuditing geographical representation in medical publishing could help to mitigate possible national and regional disparities. MethodsUsing the Web of Science indexing database, we collected bibliometric data of original research articles published between 2010-2019 in The New England Journal of Medicine, Nature Medicine, Journal of the American Medical Association, The BMJ, and The Lancet. We studied the corresponding authors geolocation in regard to publication and citation count, their temporal evolution, and the journals and citing organizations nationality. ResultsWe identified 10,558 articles. Based on the nationality of the corresponding authors institutes, only 32 countries published more than 10 publications in 10 years equaling to 98.9% of all publications. English-speaking countries USA (48.2%), UK (15.9%), Canada (5.3%), and Australia (3.2%) were most represented, but with a declining trend in recent years. Normalized to their accumulated citations, 9/32 countries were associated with [≥]10% publication excess, of which USA (n=1,174 publications) and UK (n=410) accounted for 85.7%. Similar findings were replicated at the municipal level where all top 10 most productive cities were located in USA (n=7), UK (n=2), or Canada (n=1), and 21 out of 25 most productive cities published more articles than predicted based on their accumulated citations. Finally, we discovered that both journals published, and researchers cited more commonly research conducted in the same country. DiscussionThe audit revealed Anglocentric dominance, domestic preference occurring in both journals and citation selection, and increased geographical representation in recent years in medical publishing.

ABSTRACTO_ST_ABSBackgroundC_ST_ABSWe urgently need innovative strategies to combat a growing epidemic of chronic liver disease (CLD). ID-LIVER was a collaborative project aiming to improve detection of reversible-stage CLD in a region with high prevalence of critical risk factors. ObjectiveTo determine the cost-effectiveness of ways to identify people with significant CLD, including proactive case-finding in the community (supplementing reactive referrals from primary care) and/or risk-stratification (using FIB-4 or ID-LIVER-ML -- a novel machine-learning risk-stratification tool). DesignState-transition decision-analytic model estimating lifetime healthcare costs (2023/24 GBP) and quality-adjusted life-years (QALYs) associated with six alternative strategies for case-finding and risk-stratification. We simulated cohorts of people with alcohol-related liver disease (ARLD) and metabolic dysfunction-associated steatotic liver disease (MASLD). We populated the model with data collected in ID-LIVER, supplemented by parameters from literature and routine data-sources. We estimated incremental cost-effectiveness and performed deterministic and probabilistic sensitivity analyses. ResultsAny case-identification strategy costing [≤]3,300 GBP per person with significant CLD identified would meet English cost-effectiveness thresholds (20,000 GBP/QALY). In our decision-set, the cheapest strategy is to use FIB-4 in the reactive-only population. ID-LIVER-ML generates more population health at reasonable cost (10,490 GBP/QALY gained). Introducing proactive case-finding generates further health benefits, costing 12,952 GBP/QALY gained. Using ID-LIVER-ML in the proactive-and-reactive population has the highest probability of maximising cost-effectiveness, when valuing QALYs at 20,000 GBP. ConclusionSmart methods of case-finding and risk-stratification identify people with significant CLD in the community, and are likely to represent good value for money in England.

IntroductionDespite the high COVID-19 vaccination coverage among adults, there is concern over a peak in SARS-CoV-2 infections in the coming months. To help ensure that healthcare systems are not overwhelmed in the event of a new wave of SARS-CoV-2 infections, many countries have extended vaccination to adolescents (those aged 12-17 years) and may consider further extending to children aged 5-11 years. However, there is considerable debate about whether or not to vaccinate healthy adolescents and children against SARS-CoV-2 because, while vaccination of children and adolescents may limit transmission from these groups to other, more vulnerable groups, adolescents and children themselves have limited risk of severe disease if infected and may experience adverse events from vaccination. To quantify the benefits of extending COVID-19 vaccination beyond adults we compare daily cases, hospital admissions, and intensive care (IC) admissions for vaccination in adults only, those 12 years and above, and those 5 years and above. Methods and FindingsWe developed a deterministic, age-structured susceptible-exposed-infectious-recovered (SEIR) model to simulate disease outcomes (e.g., cases, hospital admissions, IC admissions) under different vaccination scenarios. The model is partitioned into 10-year age bands (0-9, 10-19, ..., 70-79, 80+) and accounts for differences in susceptibility and infectiousness by age group, seasonality in transmission rate, modes of vaccine protection (e.g., infection, transmission), and vaccine characteristics (e.g., vaccine effectiveness). Model parameters are estimated by fitting the model piecewise to daily cases from the Dutch notification database Osiris from 01 January 2020 to 22 June 2021. Forward simulations are performed from 22 June 2021 to 31 March 2022. We performed sensitivity analyses in which vaccine-induced immunity waned. We found that upon relaxation of all non-pharmaceutical control measures a large wave occurred regardless of vaccination strategy. We found overall reductions of 5.7% (4.4%, 6.9%) of cases, 2.0% (0.7%, 3.2%) of hospital admissions, and 1.7% (0.6%, 2.8%) of IC admissions when those 12 years and above were vaccinated compared to vaccinating only adults. When those 5 years and above were vaccinated we observed reductions of 8.7% (7.5%, 9.9%) of cases, 3.2% (2.0%, 4.5%) of hospital admissions, and 2.4% (1.2%, 3.5%) of IC admissions compared to vaccination in adults only. Benefits of extending vaccination were larger within the age groups included in the vaccination program extension than in other age groups. The benefits of vaccinating adolescents and children were smaller if vaccine protection against infection, hospitalization, and transmission (once infected) wanes. DiscussionOur results highlight the benefits of extending COVID-19 vaccination programs beyond adults to reduce infections and severe outcomes in adolescents and children and in the wider population. A reduction of infections in school-aged children/adolescents may have the added benefit of reducing the need for school closures during a new wave. Additional control measures may be required in future to prevent a large wave despite vaccination program extensions. While the results presented here are based on population characteristics and the COVID-19 vaccination program in The Netherlands, they may provide valuable insights for other countries who are considering COVID-19 vaccination program extensions.

SummaryThis 12-month study in 286 early postmenopausal women evaluated the efficacy and safety of SBD111, a synbiotic medical food, in reducing bone loss. SBD111 did not significantly reduce bone loss for the full cohort, but did produce evidence of reduced bone loss in women with osteopenia and BMI [≥] 30. PurposeTo determine the efficacy of SBD111, a synbiotic medical food comprising probiotics and prebiotics, in reducing bone loss in women post-menopause, including prespecified subpopulations of women with osteopenia or elevated BMI. MethodsIn this prospective, multicenter, double-blind, randomized, placebo-controlled clinical food trial (NCT05009875), 286 healthy, non-osteoporotic women between 1-6 years post-menopause were enrolled and consumed SBD111 (4.75x1010 colony forming units) or placebo (maltodextrin) capsules twice daily for 12-months. The primary endpoint was change in areal BMD at the lumbar spine (LS). Secondary endpoints included change in areal BMD at the femoral neck (FN) and total hip (TH), trabecular volumetric BMD at the LS, markers of bone turnover and inflammation, and safety. Changes in gut microbiome composition were exploratory. The hypotheses being tested were formulated before data collection. Results286 Women [age 55 {+/-} 3 years (mean {+/-} standard deviation)] were enrolled, with 221 (77%) completing the study. For the primary outcome, SBD111 administration was not associated with significantly less bone loss in the LS after 12-months [0.15% (-0.52%, 0.82%), mean effect size (95% CI) by linear mixed effects regression]. However, SBD111 was associated with reduced BMD loss in the TH for women with BMI [≥] 30 [0.97% (0.015%, 1.925%)] and modestly reduced BMD loss in the FN for women with osteopenia [0.89% (-0.277%, 2.051%)]. ConclusionsThese findings indicate SBD111 did not significantly reduce BMD loss for the full cohort. However, the trial produced evidence that SBD111 reduced bone loss in women with osteopenia and BMI [≥] 30.

BackgroundMulti-pathogen molecular diagnostics enable assignment of diarrhoea aetiology, but defining thresholds of pathogen quantity to accurately attribute aetiology is challenging in high-burden settings where coinfections are common. The Antibiotics for Children with severe Diarrhoea (ABCD) trial provides an opportunity to leverage the azithromycin treatment response to inform which diarrhoea episodes are bacterial. MethodsWe analysed data from ABCD, which randomized children with watery diarrhoea to azithromycin or placebo. We quantified heterogeneity in the azithromycin treatment response by the quantity of enteric pathogens detected by qPCR as a tool for understanding aetiology. ResultsThe heterogeneity in azithromycin treatment response was most prominent for Shigella. The risk ratio for diarrhoea on day 3 post enrolment for azithromycin compared to placebo was 13% (95% CI:3, 23) lower per log10 increase in Shigella quantity. The protective effect of azithromycin on diarrhoea at day 3 also became stronger as pathogen quantities increased for Vibrio cholerae, ST-ETEC, and tEPEC. No association between pathogen quantity and azithromycin response was observed for Campylobacter, LT-ETEC or EAEC. The associations were consistent for the outcome of 90-day hospitalisation or death. ConclusionsThe relationships between response to azithromycin treatment and bacterial pathogen quantities observed for Shigella, Vibrio cholerae, ST-ETEC and tEPEC confirm prior evidence that these pathogens are the likely cause of diarrhoea when detected at high quantities. The lack of a similar response pattern for Campylobacter, LT-ETEC or EAEC is consistent with the limited association between pathogen quantity and diarrhoea symptoms previously observed in large studies of diarrhoea aetiology. Key message (3 succinct bullet points, each a single sentence)O_LIWe investigated whether heterogeneity in treatment response observed in the ABCD trial, where children with diarrhoea were randomised to receive azithromycin or placebo, could be used to inform aetiological attribution of diarrhoea to bacterial enteric pathogens. C_LIO_LIThe protective effect of azithromycin on diarrhoea at day 3 and hospitalisation or death at day 90 became stronger as pathogen quantities increased for Shigella, Vibrio cholerae, ST-ETEC and tEPEC but not for Campylobacter, LT-ETEC or EAEC. C_LIO_LIThe relationships between Shigella, Vibrio cholerae, ST-ETEC and tEPEC quantity and response to antibiotic treatment confirm prior evidence that these pathogens are the likely cause of diarrhoea when detected at high quantities and could be used to inform which diarrhoea cases should be treated with antibiotics. C_LI

BackgroundThe Measles-Mumps-Rubella vaccine is given as a two-dose course in childhood, but the schedule of the second dose varies between countries. England recommended bringing forward the second dose from three years and four months to 18 months by 2025. We aim to quantify how changing the vaccine schedule could impact measles transmission dynamics. MethodsWe used a mathematical model stratified by age group and region to generate stochastic outbreaks with different vaccine schedules. We used detailed information on vaccine uptake for different age groups by region and year from electronic health records and modelled alternative scenarios changing the timing of the second MMR dose or changing uptake of either dose. We simulated measles incidence between 2010 and 2019 and compared the number of cases in each scenario. Results and discussionDelivering the second MMR vaccine at younger age resulted in a lower number of cases than in the reference set of simulations with 16% (IQR: 1.93- 28.48%) cases averted when the second dose was given at 18 months. The number of cases decreased even if the coverage of the second dose decreased by up to 3% (median reduction 15.94%; IQR: 0.41 -28.21%). The impact on case numbers was equivalent to increasing first dose coverage by 0.5% every year between 2010 and 2019 (16.38 % reduction, IQR:1.90 - 28.45), more cases could be avoided (28.60%, IQR: 17.08 - 38.05) if the first dose coverage was increased by 1% every year. Our data highlighted how patterns of vaccination uptake translate into outbreak risk. Although increasing coverage of the first MMR dose led to the best results, this may be challenging to achieve requiring substantial resources with already high coverage of the first dose. Hence, an earlier second MMR dose presents a good alternative for mitigating the risk of measles outbreaks.

Introduction: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) has become less effective at preventing malaria due to rising parasite resistance. IPTp with dihydroartemisinin-piperaquine (DP) alone or in combination with SP (DP+SP) dramatically lowers the risk of malaria in pregnancy compared to SP but is associated with lower birthweight and early life wasting. We estimated the effect of IPTp-DP, DP+SP, and SP on infant growth outcomes and assessed possible treatment mechanisms through a causal mediation analysis. Methods: We used infant follow-up data (N=761) from a trial (NCT04336189) that randomized pregnant women to receive monthly IPTp-DP, SP, or DP+SP. We compared weight-for-length (WLZ) and length-for-age (LAZ) z-scores between treatment arms. We assessed possible mediation through pregnancy, birth, and infancy factors using interventional indirect effect models. Results: Compared to IPTp-SP, IPTp-DP+SP decreased mean WLZ by 0.18 [95% confidence interval (CI) -0.03, 0.39] between 1-3 months and 0.28 (95% CI 0.07, 0.49) between 4-6 months, with the largest differences among primigravidae. Lower risk of active placental malaria in IPTp-DP+SP helped reduce differences in mean WLZ vs IPTp-SP (+0.06, 95% CI 0.02, 0.10). The IPTp-DP+SP arm had up to 0.28 lower mean LAZ between 7-13 months compared to IPTp-DP, particularly among children who were wasted between 0-6 months; low birthweight had a persistent, mediating effect on linear growth. Conclusion: Adverse birth outcomes contributed to early growth faltering among children born to mothers receiving IPTp-DP+SP vs IPTp-SP, but the prevention of placental malaria partially counteracted the negative effects of IPTp-DP+SP on ponderal growth.

BackgroundPregnant women are at increased risk of adverse outcomes following SARS-CoV-2 infection, including venous thromboembolism, admission to critical care and death. Their infants may also suffer from pre-term birth, stillbirth and severe disease. Vaccination may protect both mothers and their infants against severe COVID-19 disease. MethodsWe used a test-negative, case-control study design to estimate vaccine effectiveness against symptomatic disease and hospitalisation with the Delta and Omicron variants in pregnant women who gave birth in 2021 in England. We also estimated the protection conferred by prior infection and maternal vaccination against symptomatic disease and hospitalisation with the Delta and Omicron variants in their infants. FindingsVaccine effectiveness against symptomatic disease (Delta and Omicron) and against hospitalisation (Delta only) was high and similar to that observed in the general population. Maternal vaccination during and post-pregnancy as well as previous infection also provided sustained protection from symptomatic disease and hospitalisation following Delta and Omicron infection in infants up to 8 months of age, with the highest protection being observed when maternal vaccination occurred during later pregnancy. Unlike non-pregnant women, a booster dose provided sustained protection with no evidence of waning up to 15 weeks after vaccination. InterpretationMaternal vaccination prevents mild and severe disease in pregnant women and their infants up to 6-8 months after birth. Our findings support the promotion of both primary and booster vaccination for pregnant women, irrespective of prior infection status, to protect themselves and their infants. FundingNone. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSPregnant women were included in the UKs priority risk groups for COVID-19 vaccination from 2 December 2021 when they were encouraged to complete vaccination with an mRNA booster vaccine of either Pfizer BioNTech or Moderna. We searched PubMed using the terms pregnancy, COVID-19, vaccine and vaccine effectiveness, with no date restrictions on 1 March 2023, and used the snowball process to identify additional relevant publications. We also scoped preprint databases for relevant COVID-19 vaccine effectiveness studies undertaken after the emergence of the more immune-evasive Omicron variant from December 2021. Studies have shown moderate COVID-19 vaccine effectiveness after a second dose in pregnant women against symptomatic Omicron disease with evidence that booster doses of mRNA vaccines confer higher protection against serious Omicron disease, comparable with population-based immunity. In addition to evidence of transplacental transfer of maternal antibody, real-life evidence from test-negative case-control studies have demonstrated protection in infants following maternal vaccination which is highest after vaccination in the third trimester and wanes with increasing infant age. Added value of this studyOurs is the largest study of the effectiveness of maternal COVID-19 vaccines against both maternal and infant disease, in addition to the protection conferred by past infection in the mother to the infant. In pregnant women, vaccine effectiveness against symptomatic Delta and Omicron infection, and against hospitalisation with Delta, remained high after vaccination with limited waning observed at the longest time points investigated post vaccination. Both prior infection and maternal vaccination protected infants after birth against symptomatic disease and hospitalisation with Delta and Omicron. Vaccine effectiveness was highest when maternal vaccination occurred in the later stages of pregnancy. Implications of all the available evidenceThese findings support the benefits of maternal vaccination in preventing disease in the mother and in her infant in the first months of life, regardless of prior infection status in the mother. Policy decisions need to balance the suggestion of higher protection after vaccination later in pregnancy with the need to ensure adequate opportunities for vaccination before women reach the pregnancy stage when they are at greatest risk from COVID-19 disease and to optimise the infant benefit even in pre-term births.

BackgroundPublication track record can impact careers of researchers. Therefore, monitoring gender representation in medical research is required to achieve equity in academia. MethodsWe gathered bibliometric data on original research articles published between 2010 and 2019 in The New England Journal of Medicine, Nature Medicine, Journal of the American Medical Association, The BMJ, and The Lancet using the Web of Science indexing database. We associated publication and citation frequency with author gender, count, and institute affiliation, and research keywords. FindingsWe analyzed 10,558 articles and found that women published and were cited less than men. There were fewer women as senior (24.8%) than leading authors (34.5%, p<0.001). The proportion of female authors varied by country with 9.1% last authors from Austria, 0.9% from Japan, and 0.0% from South Korea. The gender gap decreased longitudinally and faster for last (-24.0 articles/year, p<0.001) than first authors (-14.5 articles/year, p=0.024). The trend varied by country and even increased in China and Israel. Author count was associated with higher citation count (R 0.46, p<0.001) as well as with male first (n=11 vs. n=10, p<0.001) and last authors (n=11 vs. n=10, p<0.001). We also discovered that usage of research keywords varied by gender, and it partly accounted for the difference in citation counts by gender. InterpretationGender representation has increased both at the leading and senior author levels although with country-specific variability. The study frame can be easily applied to any journal and time period to monitor changes in gender representation in science.

BackgroundCOVID-19 non-pharmaceutical interventions (NPIs) disrupted transmission of many infectious diseases worldwide. While disruption patterns are well-documented, systematic analysis of post-pandemic recovery trajectories across diverse pathogens remains limited. We examined disruption and recovery of 47 nationally notifiable diseases in Australia from 2015 to 2025. MethodsWe analysed NNDSS surveillance data for 47 diseases across six transmission modes, quantifying disruption using observed-to-expected (O/E) ratios against 2015-2019 baselines. We applied difference-in-differences (DiD) to estimate causal NPI effects, Kaplan-Meier survival analysis for time-to-recovery, and bootstrap 95% confidence intervals for cumulative immunity debt. ResultsDuring 2020-2021, 28 diseases decreased (median O/E 0.51), with border-sensitive and vaccine-preventable diseases most affected. DiD analysis estimated that border closures were associated with significantly greater suppression among import-dependent diseases (coefficient -0.50, 95% CI -0.90 to -0.10, p=0.016). By 2025, recovery was heterogeneous: 17 diseases exceeded baseline levels, 12 returned to expected levels, 15 remained below baseline (9 partially recovered, 6 in sustained suppression), and 3 had insufficient data for trajectory classification. Five diseases showed suppression-then-overshoot trajectories suggestive of immunity debt, though bootstrap 95% confidence intervals confirmed statistically significant cumulative excess for only one (rotavirus); for influenza, high baseline variability precluded statistical confirmation despite a large absolute overshoot. ConclusionsPost-pandemic disease recovery in Australia is heterogeneous and incomplete. Fifteen of 47 diseases have not returned to baseline levels by 2025, while 17 exhibit overshoot. These findings argue for differentiated surveillance of still-suppressed diseases and targeted catch-up vaccination in pandemic birth cohorts. Article summaryWe analysed disruption and recovery of 47 nationally notifiable diseases in Australia from 2015 to 2025, finding that 15 diseases remain below pre-pandemic levels three years after NPI relaxation. Border closures caused disproportionate suppression of import-dependent diseases, and recovery trajectories varied by disease characteristics, with immunity debt statistically confirmed for only one of five candidate diseases.

BackgroundInfant rotavirus vaccination was introduced in the UK in July 2013, and was followed by a rapid reduction in rotavirus disease. We compare immunity to rotavirus in sera of age-stratified cohorts to assess the effect of vaccination on natural exposure to rotavirus. MethodsResidual serum samples were selected from a reference laboratory biobank based on age, and year of collection. Anti-rotavirus Immunoglobulin G (IgG) and IgA antibodies were measured using ELISA. We used censored linear spline regression models and anti-rotavirus IgA correlate of protection (CoP) thresholds to estimate immunity by age and vaccine eligibility (defined by date of birth). ResultsWe analysed serum from 1,200 individuals obtained between 2000 and 2019, of which 807 were vaccine-ineligible and 393 were vaccine-eligible. Among infants aged 3-11 months, a seven-fold increase in IgG levels was observed in the vaccine-eligible cohort (Geometric Mean Concentration [GMC], 1388.67 U/mL; 95% confidence interval [CI], 675.03-2856.78) compared to the vaccine-ineligible cohort (GMC, 198.54 U/ml; 95% CI, 71.31-552.78). Models showed increasing IgG and IgA antibody concentrations in the vaccine-ineligible cohort through childhood and into adulthood, but not in the vaccine-eligible cohort. The proportion of children <7 years with IgA[&ge;]160 U/ml, a proxy CoP against rotavirus disease, was lower among the vaccine-eligible population (adjusted odds ratio, 0.66; 95% CI, 0.48-0.91). ConclusionsThe introduction of rotavirus vaccination has reduced rotavirus disease burden but has disrupted the subsequent acquisition of naturally-acquired immunity. The impact of this on susceptibility to rotavirus disease in later life remains to be determined.

BackgroundIn England, individuals with chronic liver disease (CLD) are among those with the lowest seasonal influenza vaccine uptake despite being at elevated risk of severe influenza. We examined the relationship between CLD severity and aetiology, and influenza vaccine uptake in England. MethodsA retrospective cohort study of adults (18-115 years) using Clinical Practice Research Datalink Aurum primary care data was conducted for five seasons (2019/20-2023/24). Poisson regression was used to estimate rates of uptake by CLD severity (clinical diagnoses categorised as low, moderate, or severe) and aetiology (alcohol-related, viral-related, and diagnoses in the Green Book guidelines). FindingsThere were 182,174-277,470 with CLD per cohort. Among those who were additionally age-eligible for vaccination, uptake was 71{middle dot}1-79{middle dot}7% compared to 30{middle dot}9-40{middle dot}5% in those not additionally age-eligible. Among individuals below age eligibility without other comorbidities, severity was associated with higher uptake (incidence rate ratio [IRR] moderate 1{middle dot}80, 95% CI 1{middle dot}69-1{middle dot}90; severe 1{middle dot}95, 95% CI 1{middle dot}84-2{middle dot}08 in 2023/24); there was no effect in those with at least one additional comorbidity (moderate 1{middle dot}05, 95% CI 0{middle dot}99-1{middle dot}10; severe 1{middle dot}05, 95% CI 1{middle dot}01-1{middle dot}09). Alcohol- and viral-related aetiology were also associated with increased uptake in those not additionally age-eligible. Among individuals meeting age eligibility without additional comorbidities, severity was associated with a reduced uptake (moderate 0{middle dot}81, 95% CI 0{middle dot}73-0{middle dot}90; severe 0{middle dot}79, 95% CI 0{middle dot}74-0{middle dot}85), with attenuation in those with additional comorbidities (moderate 0{middle dot}99, 95% CI 0{middle dot}94-1{middle dot}04; severe 0{middle dot}91, 95% CI 0{middle dot}89-0{middle dot}94). InterpretationCLD severity and aetiology were important determinants of uptake in the absence of additional indications for influenza vaccination. Future research should prioritise understanding facilitators and barriers to vaccine uptake in individuals with CLD, particularly for those at highest risk of severe infection. FundingNIHR Health Protection Research Unit in Vaccines and Immunisation (NIHR200929/NIHR207408). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed up to June 2025 using the terms "chronic liver disease", "cirrhosis", "hepatitis", "influenza vaccination", "seasonal influenza", and "vaccine uptake". Previous research, including national data from England, has shown that people with chronic liver disease tend to have lower seasonal influenza vaccine uptake than individuals with other medical comorbidities which qualify for vaccination such as diabetes, chronic kidney disease or immunosuppression. The reasons for low influenza vaccine uptake in people with chronic liver disease are not well understood, and it is therefore difficult for vaccination providers, principally primary care services in England, to tailor interventions aimed to increase uptake. Qualitative research involving individuals aged less than 65 years living in England with clinical risk comorbidities, most commonly diabetes, found that chronic disease management pathways inconsistently provided information about the importance of influenza vaccination as part of chronic disease management. Individuals with long-term conditions reported low perceived risk of influenza infection and limited awareness of vaccine benefits as important reasons for non-uptake. We hypothesised that the severity and aetiology of chronic liver disease may be important determinants of uptake. Added value of this studyWe conducted a population-based study to examine how chronic liver disease severity and aetiology influence seasonal influenza vaccine uptake in adults in England. Using primary care electronic health record data from five consecutive influenza seasons (2019/20-2023/24), we found that more severe chronic liver disease was associated with a substantial increase in vaccine uptake in those without additional indications for seasonal influenza vaccination (age-based eligibility or other qualifying clinical risk comorbidities). Alcohol- and viral-related aetiology were also associated with increased uptake in those who were not additionally age-eligible for vaccination. In contrast, severity, alcohol- and viral-related underlying aetiology were associated with a modest reduction in uptake for individuals with chronic liver disease who also qualified for vaccination due to age. Implications of all the available evidenceDespite clear clinical vulnerability to infection and a substantially elevated risk of morbidity and mortality following infection, a large proportion of adults with chronic liver disease, particularly those aged under 65 years, remain unvaccinated against seasonal influenza each year. This study suggests that chronic liver disease severity and underlying aetiology are important determinants of uptake in individuals not meeting age-based vaccine eligibility, particularly in those without additional clinical risk comorbidities. This could be because of differing perceptions of influenza risk, or due to varying degrees of interaction with healthcare specialists as part of chronic disease management. In individuals who met age-based vaccination eligibility, the negative effect of severity on influenza vaccine uptake may reflect greater barriers to accessing vaccination services by those with more complex health needs, or competing medical priorities for long-term condition management during consultations. To inform targeted vaccination strategies, future research should aim to understand the specific facilitators and barriers to influenza vaccination experienced by individuals with chronic liver disease. This should include perspectives of individuals with different disease severity, across different age groups, in those with and without additional co-morbidities.

BackgroundCalcium supplementation during pregnancy can reduce the risk of preeclampsia and preterm birth. Few countries have implemented WHO-recommended high-dose calcium supplementation (1500-2000mg/day), due to adherence and cost concerns. However, low-dose calcium supplementation (one 500mg tablet daily) has recently been shown to be similarly efficacious as high-dose supplementation. We assessed the cost-effectiveness of low-dose calcium supplementation during pregnancy, in low- and middle-income countries (LMICs) with low dietary calcium intake. MethodsUsing a mathematical model, we estimated the lifetime health outcomes (cases, deaths and DALYs averted) and costs of low-dose calcium supplementation provided through routine antenatal care to women giving birth in 2024, as compared to no supplementation. We assessed costs (2022 USD) from a health system perspective, including cost-savings from averted care for preeclampsia and preterm birth. FindingsLow-dose calcium supplementation was estimated to prevent 1.3 (95% uncertainty interval: 0.2, 2.6) million preterm births (a 10% (2, 18) reduction), 1.8 (1.0, 2.8) million preeclampsia cases (a 23% (14, 32) reduction), as well as 5.9 (1.3, 12.9) million disability-adjusted life years (DALYs). Intervention costs would be $267 (220, 318) million and produce cost-savings of $56 (26, 86) million, with incremental costs per DALY averted of $90 (38, 389) across all countries, and a return on investment of 19.1 (3.8, 39.5). The intervention was cost-effective in 119 of 129 countries modeled when compared to setting-specific cost-effectiveness thresholds. While there was substantial uncertainty in several inputs, cost-effeciveness conclusions were robust to parameter uncertainty and alternative analytic assumptions. InterpretationLow-dose calcium supplementation provided during pregnancy is cost-effective for prevention of preeclampsia and preterm birth in most LMICs.

BackgroundIn an era of endemic SARS-CoV-2 transmission, countries are continuing to evaluate how best to schedule ongoing COVID-19 booster vaccinations. Mathematical modelling provides a useful tool to predict the benefit of future vaccination strategies, incorporating the loss of protection due to waning immunity and strain mutation. MethodsWe adapted a combined immunological-population transmission model for SARS-CoV-2, to better capture contemporary understanding of exposure- and vaccine-derived immunity, to simulate ongoing endemic transmission of SARS-CoV-2 in a highly exposed high-income setting. We used this model to estimate the impact of targeted booster dose strategies in the older population, both in the context of continued circulation of the current dominant viral strain, and in the presence of a new antigenically distinct variant. ResultsWe found that at the population level, an annual COVID-19 vaccine booster dose to the 65+ years population at 60% coverage could avert 10-17% of hospitalisations over a single wave, depending on how well-matched the vaccine is to the circulating SARS-CoV-2 strain. With lower coverage of 40%, estimated impact was between 9-12%. A second booster dose to the 75+ population after 6 months was particularly beneficial if a new distinct variant strain increases the magnitude of the wave. ConclusionsThis adapted model captures endemic viral transmission and could readily be used to explore vaccine impact across other settings.

BackgroundOsteomyelitis (OM) poses a significant clinical challenge, especially among individuals with diabetes mellitus (DM). While both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) have been linked to an elevated risk of OM, the precise causal relationships remain uncertain. MethodsWe conducted Mendelian randomization (MR) analyses using summary statistics from genome-wide association studies (GWAS) to explore the causal effects of T1DM, T2DM, their complications, and glycemic traits on OM risk. The study utilized the inverse variance weighted (IVW) method, along with weighted median and MR-Egger for causal estimation, and performed various sensitivity analyses to ensure robustness. Multivariable MR (MVMR) analysis assessed direct effects, while two-step mediation MR analyses investigated the mediating role of DM between rheumatoid arthritis (RA) and OM. ResultsThe MR analysis unveiled distinct causal effects of T1DM and T2DM on OM risk. Genetically determined T2DM, rather than its complications, significantly increased OM risk (primary dataset: IVW: OR = 1.13, 95% CI 1.056-1.209, p = 4E-04; validation dataset: IVW: OR = 1.317, 95% CI 1.14-1.522, p =2E-04; Meta-analysis: OR=1.206; 95% CI 1.037-1.402; p=0.014), with no observable heterogeneity or horizontal pleiotropy. MVMR analysis confirmed the robustness of the causal association between T2DM and OM, even after adjusting for potential confounders such as body mass index. Conversely, T1DM and its complications showed no significant causal link with OM in either the primary dataset (IVW: p = 0.071), the validation dataset (IVW: p = 0.276), or the meta-analysis (IVW: p = 0.242). Additionally, there was no robust evidence supporting the causal risk of glycemic traits on OM. Mediation MR analysis underscored T2DM as a pivotal contributor to the differential effects of RA on OM. ConclusionsMendelian randomization analysis provides compelling evidence of a significant causal relationship between genetically determined T2DM and increased OM risk, while T1DM exhibits distinct causal effects. Additionally, our findings highlight the role of T2DM in mediating the association between RA and OM. Further research is warranted to elucidate the underlying mechanisms and guide targeted interventions for OM prevention and management in diabetic populations.

BackgroundTwo RSV immunisations products: a maternal vaccine, Abrysvo, and a long-acting monoclonal antibody, nirsevimab, both designed to prevent RSV illness in infants, have recently become available. Modelling evidence is required to inform how to optimally use these products in immunisation programs to reduce the burden of RSV in young children. MethodsWe extend a dynamic transmission model calibrated to RSV-hospitalisation data of children aged < 5 years in temperate Western Australia (WA) to simulate a range of potential RSV immunisation programs. Using our model, we estimate the impact of both single-product and hybrid RSV immunisation programs. The analysis considers timing of administration, coverage levels and targeting of high-risk groups. Impact on RSV burden is analysed in the context of the WA setting and the possible significant cost differences between the two products. ResultsAll programs analysed were effective in reducing RSV burden. Programs using nirsevimab for newborn infants at similar coverage levels to the Abrysvo programs, averted more RSV-hospitalisations annually. Seasonal programs that focused on protection during high RSV activity and programs targeting high-risk infants were the most efficient in reducing RSV burden. When dose cost is considered alongside program impact on RSV burden, we find evidence to support further economic analysis of hybrid programs as they could mitigate the cost differential between the two products while remaining highly effective in reducing RSV burden. ConclusionsOur study is the first to comprehensively analyse hybrid RSV immunisation programs that use Abrysvo and nirsevimab. RSV immunisation programs can substantially reduce the burden of RSV in young children. Our modelling analysis provides evidence on immunisation type, timing, coverage, high-risk groups and dosage cost that will support decision makers and can be used in economic evaluations.

Background & AimsNon-alcoholic fatty liver disease (NAFLD) is globally prevalent and confers a high risk of morbidity via progression to non-alcoholic steatohepatitis (NASH). Circadian disruption in mouse models contributes to the development of hepatic steatosis and inflammation, however evidence in humans is lacking. We investigated how shift working and chronotype were associated with NAFLD/NASH in UK Biobank participants. MethodsWe stratified 282,303 UK Biobank participants into day, irregular-shift, and permanent night-shift workers. We compared the likelihood of NAFLD/NASH in these groups using: a) Dallas Steatosis Index (DSI), b) NAFLD/NASH ICD10 codes, and c) liver proton density fat fraction (PDFF) after serially adjusting for age, sex, ethnicity, sleep, alcohol, smoking, and body mass index. We further assessed the relationship of baseline chronotype with likelihood of NAFLD/NASH using the same outcomes and covariates. ResultsCompared to day workers, irregular-shift workers were more likely to have NAFLD/NASH defined by high DSI (odds ratio (OR) 1.29 (95% CI 1.18-1.4)) after adjusting for all covariates excluding BMI, with some attenuation after additional adjustment for BMI (OR 1.12 (1.03-1.22)). Likelihood of DSI-defined NAFLD/NASH was also higher in permanent night-shift workers (OR 1.08 (0.9-1.29)) in the fully-adjusted model. Compared to participants with intermediate chronotype, those with extreme late chronotype had a higher likelihood of DSI-defined NAFLD/NASH (OR 1.45 (1.34-1.56)) and a higher likelihood of NAFLD/NASH by ICD10 code (OR 1.23 (1.09-1.39)). Liver PDFF was elevated in irregular shift workers, but not permanent night shift workers. ConclusionsIrregular-shift work and chronotype are associated with NAFLD/NASH, suggesting circadian misalignment as an underlying mechanism. These findings have implications for health interventions to mitigate the detrimental effect of shift work.

BackgroundA threshold of [&ge;] 500 ml blood loss within 24 hours of childbirth has conventionally been used to initiate postpartum haemorrhage (PPH) treatment. We assessed the cost-effectiveness of initiating PPH treatment at lower blood loss thresholds, alone and in combination with any other abnormal haemodynamic marker (pulse, systolic and diastolic blood pressure, shock index), compared with the conventional [&ge;] 500 ml threshold. MethodsA decision tree model was developed to assess the cost per disability-adjusted life years (DALYs) averted from a healthcare provider perspective when the World Health Organization (WHO) first-response treatment bundle was initiated using alternative criteria. Sensitivity and specificity of scenarios for identifying women at high risk of a composite outcome of maternal mortality or severe morbidity was estimated using a WHO individual participant data meta-analysis. Direct medical costs (2022 US$) were derived from randomised trial data in Kenya, Nigeria, South Africa, and Tanzania. FindingsTreatment initiation based on lower blood loss thresholds could avert additional composite outcomes. Use of lower blood loss thresholds in combination with any other abnormal haemodynamic marker was more cost-effective than blood loss alone. Combining blood loss thresholds (stepwise from 450 to 300 ml) with any other abnormal haemodynamic marker could avert 15-27% of composite outcomes, increase costs by 9-30% per woman, and have a cost of US$260-479 per DALY averted, compared to using 500 ml blood loss alone. Scenarios were more cost-effective for vaginal births, and cost-saving for populations with a composite outcome incidence [&ge;] 9%. InterpretationExpanding the conventional criteria for initiating PPH treatment to include lower blood loss thresholds in combination with any other abnormal haemodynamic marker is cost-effective in improving maternal health outcomes, particularly for obstetric populations with high incidence of PPH mortality and severe morbidity. Further research is warranted in women undergoing caesarean birth. FundingThis study was funded by The Gates Foundation (INV-063940) and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a co-sponsored programme executed by the World Health Organization. Panel: Research in contextO_ST_ABSEvidence before this studyC_ST_ABSA threshold of 500 ml or more blood loss after childbirth has conventionally been used to initiate treatment for postpartum haemorrhage (PPH). Lower blood loss thresholds in combination with any other abnormal haemodynamic marker have been proposed as newer alternative diagnostic criteria to prompt earlier treatment and potentially improve maternal outcomes. However, such approaches risk overtreatment and higher costs which are critical considerations in low-resource settings where the burden of PPH morbidity and mortality is greatest. Until recently, limited evidence on the prognostic accuracy of clinical markers of postpartum bleeding in predicting maternal mortality and morbidity prevented robust cost-effectiveness analyses of diagnostic criteria for PPH treatment initiation. In 2025, the World Health Organization (WHO) concluded a prognostic accuracy study based on individual participant data (IPD) meta-analysis including 312 151 women from 12 datasets. The prognostic accuracy study estimated the sensitivity and specificity of clinical markers of postpartum bleeding (blood loss, pulse, systolic and diastolic blood pressure, and shock index) in predicting a composite outcome of maternal mortality or severe morbidity (blood transfusion, surgical intervention to stop bleeding, or intensive care admission), providing the first opportunity to evaluate the economic implications of alternative criteria for initiating PPH treatment compared to the conventional 500 ml or more blood loss threshold. Added value of this studyBuilding on the WHO IPD meta-analysis, we assessed the cost-effectiveness of initiating PPH treatment at lower blood loss thresholds (stepwise from 450 ml, 400 ml, 350 ml, 300 ml), alone and in combination with any other abnormal haemodynamic marker (defined as abnormal pulse rate, systolic or diastolic blood pressure, or shock index), compared with the conventional [&ge;] 500 ml blood loss threshold. Where treatment initiation was based on lower blood loss thresholds and any abnormal haemodynamic marker, the 500 ml blood loss threshold was retained as an additional criterion, to ensure that women who continue to bleed in the absence of any other abnormal haemodynamic marker still receive treatment as per current convention. We found that lower blood loss thresholds could avert additional composite outcomes, but diagnostic criteria combining lower blood loss thresholds with any other abnormal haemodynamic marker were more cost-effective than those based on blood loss alone, owing to higher specificity and reduced overtreatment. Compared with 500 ml blood loss alone, the cost per disability-adjusted life year (DALY) averted for treatment initiation at 300 ml plus any other abnormal haemodynamic marker (US$479) represents less than 100%, 50%, and 25% of gross domestic product (GDP) per capita for 97%, 85%, and 70% of low- and middle-income countries. For vaginal births, the cost per DALY averted (US$77) was less than 25% of GDP per capita for 99% of low- and middle-income countries. In high-risk obstetric populations with [&ge;] 9% incidence of the composite outcome, all scenarios combining blood loss with any other abnormal haemodynamic marker were cost-saving (compared to 2.5% incidence in the IPD meta-analysis). Implications of all the available evidenceFrom a health economics perspective, our findings support expanding diagnostic criteria for initiating PPH treatment to include blood loss thresholds lower than 500 ml in combination with any other abnormal haemodynamic marker. This strategy improves maternal outcomes at acceptable or favourable cost-effectiveness ratios, particularly in low-resource settings with high burden of life-threatening PPH complications. As most women in the WHO IPD meta-analysis had vaginal births, further research is warranted to evaluate the cost-effectiveness of expanded treatment initiation criteria for caesarean births.

BackgroundThere is continuing uncertainty regarding the longevity of immunological responses to both SARS-CoV-2 natural infection and COVID-19 vaccines. MethodsWe analysed data from two serological cohorts in Singapore among residents of a COVID-19 affected migrant worker dormitory between May-July 2020, and among mRNA COVID-19 vaccine recipients between May 2021 and January 2022. We compared SARS-CoV-2 neutralising antibody levels by age group, sex, presence of pre-existing medical conditions, type of mRNA vaccine received and number of doses received. We investigated the effect of time since infection or vaccination on antibody levels in naturally infected individuals and two- and three-dose vaccinees. ResultsAfter two vaccine doses, neutralising antibody responses were higher in Spikevax (Moderna) recipients, females, younger individuals and those with no underlying medical conditions. However, antibody levels waned to similar levels in all groups over time. A third dose boosted these to similarly high levels in all groups. Waning was apparent among two-dose but not three-dose recipients over a period of six months. Both two and three-dose vaccine recipients showed consistently higher neutralising antibody levels compared with naturally infected individuals over the 12-week period following infection or vaccination. ConclusionsOur findings support the broad use of booster doses to improve population protection from COVID-19. However, recent increases in transmission of new SARS-CoV-2 variants, even in the presence of high levels of neutralising antibody in a highly vaccinated population, point to vaccine breakthrough as an important mechanism for maintaining SARS-CoV-2 circulation and indicate the need for variant-specific or universal COVID-19 vaccines. SummaryYounger individuals, females and those with no pre-existing conditions have higher neutralising antibody levels after two doses of COVID-19 mRNA vaccine. Subsequently these wane to levels seen in other groups. A booster dose promotes similarly high levels in all groups.

BackgroundTwo immunising products are emerging to prevent the burden of respiratory syncytial virus (RSV) in infants: long-lasting monoclonal antibodies (mAbs) and maternal vaccines given during pregnancy (MV). This study assesses the potential cost-effectiveness of programs involving each product, to help inform policy decisions related to their implementation in the Australian context. MethodsWe developed an individual-based dynamic transmission model of RSV infection, linked to a clinical pathways model and cost-effectiveness model. We modelled key scenarios exploring varying eligibility and coverage of immunisation products for at-risk and not-at-risk populations, in addition to sensitivity analyses of immunisation characteristics, program costs, and the impact of potential under-ascertainment of RSV burden. We estimated the cost-effectiveness of each program from a health system perspective, with results presented as incremental cost-effectiveness ratios in terms of cost per quality-adjusted life year gained (QALY). FindingsWe found a combined program in which administration of MV during pregnancy is supplemented with a birth-dose of mAbs for newborns born without protection from MV is likely to be cost-saving, compared to the status quo of no MV or mAbs delivered. This program averted on average 41% of infant hospitalisations per year and reduced QALY losses by 33%. InterpretationPrograms combining infant immunisation products are likely to significantly reduce the burden of RSV disease in Australia, and be cost-saving. However, their estimated impact and cost-effectiveness is strongly dependent on key assumptions i) the consistency and completeness of ascertainment of disease burden over time; ii) the cost of a hospitalisation and immunising dose; iii) the efficacy and durability of protection of the modelled products, and; iv) the timing and coverage of the immunisation delivery. FundingThis modelling was commissioned by the National Immunisation Division of the Australian Government Department of Health, Disability and Ageing.