BMC Medicine

IntroductionIntermittent 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. MethodsWe 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. ResultsCompared 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. ConclusionAdverse 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. Key MessagesO_LIIntermittent preventive treatment of malaria in pregnancy (IPTp) with a combination of dihydroartemisinin-piperaquine (DP) and sulfadoxine-pyrimethamine (SP) leads to lower birth weight compared to SP alone, but it is unclear whether effects persist through infancy and what mechanisms drive these differences. C_LIO_LIDP+SP provided some improvements to ponderal growth over SP by preventing active placental malaria, but these benefits were not large enough to offset negative effects associated with other prenatal factors. C_LIO_LIInfants born to mothers who received IPTp with DP+SP were at higher risk of growth faltering in the first year of life compared to DP or SP alone; while differences in weight-for-length subsided over time, some children developed chronic forms of malnutrition that may be difficult to recover from. C_LI

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.

Pre-eclampsia (PE) is a major contributor to maternal and neonatal morbidity and mortality. Research in high-income countries has shown that biomarker-based PE screening can improve timely detection and management of women at high risk of PE. We conducted a pre-trail cost-effectiveness analysis of introducing biomarker screening in Tanzania to identify key parameters informing a full, trial-based economic evaluation. We developed a decision tree comparing current practice with two biomarker-based screening strategies: Strategy 1 introducing placental growth factor (PlGF), and Strategy 2 adding soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio. Under both strategies we assumed early aspirin prophylaxis and/or close monitoring for high-risk women. For each of the three options, we modelled PE diagnosis, as well as maternal and neonatal outcomes over a one-year time horizon, assuming a healthcare sector perspective. We quantified health outcomes in terms of disability-adjusted life years (DALYs) and costs in 2023 US$. When compared to current practice, the incremental cost per DALY averted was $410.45 for Strategy 1 and $1,011.78 for Strategy 2. Limiting the novel strategies to nulliparous women, decreased incremental cost-effectiveness ratios to $184.15 (Strategy 1) and $413.33 (Strategy 2). Key parameters impacting cost-effectiveness were PE prevalence, biomarker screening accuracy, adherence to and effectiveness of preventive treatment and monitoring, and related costs. Based on our findings, biomarker screening has the potential to be cost-effective in Tanzania, particularly if introduced early in pregnancy and targeted at nulliparous women. Further research in low-resource settings is needed to overcome the current data and evidence gaps.

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.

ObjectiveInvestigate a strategy of mass asymptomatic testing and isolation ("pulse testing") aimed at early containment of outbreaks in prisons in comparison to or combination with a symptom-based isolation strategy. MethodsSimulations using an individual-based time-since-infection model were run under different pathogen and intervention strategy scenarios. Measured outcomes were the proportion of outbreaks contained and number of individuals isolated. ResultsFor R0 = 2, 25% probability of being asymptomatic (pa = 0.25), a COVID-19-like infection dynamics and perfect adherence, one pulse test contained approximately 20% of outbreaks, and three tests up to 50%. With no asymptomatic cases, three tests performed similarly to isolating cases one day after symptoms ({approx} 55% outbreaks contained), but symptom-based isolation degraded significantly faster than pulse testing with increasing pa. With perfect adherence, combining both interventions contained between {approx} 25% (R0 = 3, pa = 0.5) and > 90% (R0 = 1.5, pa = 0) of outbreaks. Across all scenarios, pulse testing isolated substantially fewer individuals than symptom-based isolation, e.g. {approx} 5% versus {approx} 30% for R0 = 2 and pa = 0.25. ConclusionIf implemented promptly upon outbreak declaration and with high adherence, pulse testing may stop outbreaks early, substantially reducing the number of isolations and mitigating the impact on prison regime and resident/staff wellbeing. However, for large R0 or delayed implementation, effectiveness drops rapidly.

BackgroundPractical alcohol risk-reduction strategies are widely recommended in public-facing alcohol guidance, but randomized evidence from socially interactive drinking episodes remains limited. We conducted a pilot cluster randomized trial to evaluate the feasibility and preliminary effects of a package intervention comprising practical drinking-strategy information, participant self-selection of same-day strategies, and a brief commitment declaration in a social drinking laboratory. MethodsThis single-center, parallel-group pilot trial was conducted in Japan. Pre-existing social groups participated. One or two groups scheduled in the same session slot were combined into a time-slot allocation unit, which was randomized 1:1 either to the package intervention or to alcohol-related knowledge only. The primary outcome was total pure alcohol intake during the first 120 min. Session satisfaction on a Visual Analog Scale (VAS) was a prespecified secondary participant-experience outcome. ResultsOf 83 interested individuals, 63 were randomized and 59 participants in 17 social groups and 12 allocation units were included in the modified intention-to-treat analysis. The mean paired intervention-control difference for 120-min alcohol intake was-8.84 g (95% confidence interval [CI]-27.92 to 10.23; exact sign-flip p = 0.281). The corresponding exploratory 0-30 min difference was-4.90 g (95% CI-10.48 to 0.68; exact sign-flip p = 0.094). In a genotype-adjusted participant-level sensitivity analysis, the intervention coefficient for 120-min intake was-16.0 g (95% CI-30.9 to-1.1; p = 0.036). Session satisfaction was high in both arms with no clear between-arm difference. Next-day follow-up was 100%, and no adverse-event-related discontinuations occurred. ConclusionsThe intervention was feasible to deliver in a socially interactive drinking setting, and session satisfaction was high in both arms. Primary allocation-unit estimates favored lower alcohol intake but were imprecise. Larger trials are needed to estimate effects more precisely, while considering the potential influence of genotype imbalance on effect estimation in East Asian samples. Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) UMIN000060685. Registered 17 February 2026.

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.

Objectives: This meta-review compares methodological and reporting approaches between systematic reviews examining alcohol dose and cardiovascular disease (CVD) and assesses whether alcohol industry involvement is associated with divergent conclusions. Methods: KSR Evidence was searched 6 May 2025 to update a cohort of 60 systematic reviews from previous review. Reviews were included if they examined any dose-response relationship between alcohol consumption and CVD. Two reviewers independently screened records and extracted data on review characteristics, and citations. Methodological quality was appraised using AMSTAR 2. For a matched sample of reviews with and without known alcohol industry funding, the overlap of included primary studies was compared using Corrected Covered Area (CCA) analysis. Results: Thirty additional systematic reviews met the inclusion criteria, yielding 90 systematic reviews (1996-2025). Most (60.0%, 54/90) concluded that alcohol had a cardioprotective effect, whereas 31.1% (28/90) concluded no evidence of protection, and 8.9% (8/90) were inconclusive. Twenty reviews (22.0%) had declared or inferred alcohol industry funding or author connection; all but one reported a protective effect at lower doses, the other was inconclusive. Industry-connected reviews were cited more often (mean 575.9 vs 193.0, p=0.0002) and more commonly examined overall CVD rather than specific conditions (such as hypertension or stroke). Study overlap was low (CCA 2.59%) and 99% of reviews were rated as critically low quality. Conclusions: The fragmented evidence base is of poor methodological quality with selective inclusion of studies. Alcohol industry connections are strongly associated, with conclusions favouring alcohol consumption, highlighting the need for independent high-quality systematic reviews.

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.

BackgroundReliable estimates of immunization delivery costs are essential for planning, budgeting, and economic evaluation of vaccination programs. Although a number of empirical costing studies have been conducted in recent years, many low- and middle-income countries (LMICs) continue to lack up-to-date, accurate delivery unit cost estimates--particularly for adolescent and campaign vaccination strategies. Building on prior work, this study aimed to produce updated, standardized country-level estimates of immunization delivery unit costs for different vaccination modalities across all LMICs. MethodsUsing data on study-level unit cost estimates reported by empirical costing studies in the 2024 update of the Immunization Delivery Cost Catalogue, we fitted Bayesian meta-regression models predicting per-dose delivery costs for routine childhood vaccination, routine adolescent vaccination (using human papillomavirus vaccination as a proxy), and vaccination delivered via mass campaigns. Regression models incorporated country-level covariates (per-capita gross domestic product, population size, third-dose diphtheria-tetanus-pertussis vaccination coverage, urbanization, population density, and under-five mortality) and study-level characteristics (cost category, financial versus economic costing perspective, and full versus incremental costing methodology). Fitted models were used to generate country-specific and population-weighted average economic and financial cost per dose estimates for 2024, in 2024 US dollars. ResultsThe analysis included 142 observations for routine childhood vaccination, 63 observations for routine adolescent vaccination, and 113 observations for campaign vaccination. For 2024, the population-weighted mean economic cost per dose across all LMICs was estimated at $5.86 (95% uncertainty interval: $2.74-13.43) for routine childhood vaccination, $17.65 ($7.76-44.30) for routine adolescent vaccination, and $3.13 ($2.03-4.78) for campaign vaccination. Corresponding financial costs per dose were $3.02 ($1.52-6.29), $10.08 ($4.15-25.01), and $1.79 ($1.11-2.91), respectively. Substantial heterogeneity in delivery costs was observed across countries, delivery modalities, and cost perspectives. The estimated associations between predictors and unit costs may be influenced by unobserved study characteristics, and therefore should be interpreted as correlational rather than causal. ConclusionsBy leveraging an expanded empirical evidence base and a Bayesian meta-regression framework, this study provides updated per-dose delivery costs for routine childhood vaccination and estimates new per-dose delivery costs for routine adolescent vaccination and campaign vaccination. As policy decisions often must be made despite incomplete information, these estimates provide a practical source of evidence to support analyses when direct cost data are unavailable.

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.

Abstract Background: While total physical activity is a recognized modifier of cancer risk, accelerometer-derived digital phenotyping enables high-resolution mapping of circadian behavior. Whether these multidimensional patterns comprising step counts, sleep, physical activity, circadian rhythmicity, and light exposure independently influence the risk of incident colorectal cancer (CRC) has not been comprehensively evaluated Methods: We performed an exposure-wide association study (ExWAS) of 224 accelerometer-derived metrics among 95,050 UK Biobank participants who were free of CRC at accelerometry. To comprehensively define circadian rhythm patterns, we systematically categorized these metrics into five core behavioral domains: step counts, sleep architecture, physical activity bouts, circadian rhythmicity, and light exposure. Hazard ratios (HRs) and 95% confidence intervals were estimated using Cox proportional hazards models with age as the underlying timescale. Results: During a median follow-up of 8.5 years, 775 participants developed CRC (503 colon; 269 rectal). In minimally adjusted models, 121 metrics showed nominal significance (31 for overall CRC, 89 for colon, and 1 for rectal cancer). Protective associations were predominantly observed for metrics characterizing activity intensity and bout structure; notably, higher mean acceleration during 5-10 minute bouts of moderate-to vigorous physical activity was associated with reduced CRC risk (HR 0.88 per SD). In contrast, no metrics within the defined sleep or light exposure domains reached nominal significance. These associations attenuated substantially following progressive adjustment for lifestyle and metabolic covariates, suggesting potential confounding or shared biological pathways. Conclusions: Our findings identified specific behavioral phenotypes within a multidimensional framework of circadian rhythm, including step counts, physical activity intensity, and bout structure, as being associated with CRC risk. However, the marked attenuation of signals after multivariable adjustment suggests these markers may not serve as independent predictors. These results underscore the complexity of multidimensional circadian digital biomarkers and necessitate independent replication to clarify their utility in cancer risk stratification.

BackgroundThe first 1000 days from conception to age 2 years represent a critical window for kidney development, during which nutritional exposures may have lifelong programming effects. Whether early-life sugar restriction reduces long-term kidney disease risk remains unknown. MethodsUsing the UK sugar rationing policy (1942-1953) as a natural experiment, we compared risks of chronic kidney disease (CKD) and acute kidney injury (AKI) among 64,942 UK Biobank participants born around the rationing period. Duration of early-life exposure was categorised. Cox proportional hazards models estimated hazard ratios (HRs). Negative control analyses included non-UK-born UK Biobank participants and the Chinese CHARLS cohort. Mediation analyses integrated clinical phenotypes and metabolomic profiles. FindingsCompared with never-exposed individuals, those exposed to sugar rationing throughout the first 1000 days (in utero to age 2 years) had lower risks of CKD (adjusted HR 0.78, 95% CI 0.66-0.93) and AKI (0.79, 0.69-0.90). Negative control analyses showed null associations. Mediation analyses indicated that metabolic efficiency (basal metabolic rate), body composition (fat-free mass), and lipid metabolism mediated 4-9% of the protective association. A distinct metabolomic signature characterised by higher polyunsaturated fatty acids and lower VLDL subfractions was identified. InterpretationSugar restriction during the first 1000 days is associated with lower risks of CKD and AKI in adulthood, partially mediated by favorable metabolic efficiency, body composition, and lipid profiles. These findings identify early-life sugar exposure as a modifiable developmental programming factor for lifelong kidney health and support public health strategies to reduce added sugar intake during pregnancy and early childhood. FundingNational Natural Science Foundation of China, and others

BackgroundLung cancer remains a major public health burden, with poor survival largely driven by late-stage diagnosis. With declining and very low smoking prevalence in Singapore at 4.7% in 2024 among 18-29-year-olds, questions arise about future screening efficiency, eligibility criteria, and the impact of smoking cessation, including tobacco elimination. MethodsWe developed a large-scale microsimulation model calibrated to real-world data, generating individual life histories, smoking trajectories, and disease progression for Singapores 4.18 million residents to project smoking prevalence and lung cancer burden. We evaluated 271 low-dose computed tomography (LDCT) screening strategies (by age, gender, uptake, and frequency) under five tobacco control scenarios, from status quo to a complete smoking ban, between 2025 and 2050. FindingsUnder the status quo, all screening strategies were cost-effective relative to the 2024 GDP per capita threshold ([~]SGD 120,000). Among strategies with [≤]10% overdiagnosis, annual screening of eligible ever-smokers aged 50- 80 years was most life-saving, yielding 51,312 (95% uncertainty interval: 36,821-72,830) QALYs at a total cost of SGD 12.2 (9.7-16.1) billion. Adding an immediate smoking ban increased QALY gains by 2.8 (2.2-3.5) times while reducing the total cost by 23.3% (17.0%-30.0%). Extending eligibility to individuals with lower smoking exposure or a first-degree family history remained cost-effective. InterpretationsTobacco elimination yields substantial health and economic benefits, while well-designed risk-based LDCT screening of residual high-risk populations remains cost-effective, supporting a continued role for screening even in settings with declining smoking prevalence.

Background Malaria rapid diagnostic tests (RDTs) are widely used to detect and treat malaria infections, yet a diagnostic gap remains. With turnaround times of ~15 minutes, RDTs may be too slow to enable broad-scale implementation in certain contexts. Novel non-invasive diagnostics (NIDs) have potential to provide faster (<5 minutes), sensitive (90% for symptomatic, 65% for asymptomatic carriage), and cost-effective alternatives, which may increase testing throughput, enhance case detection, guide appropriate antimicrobial use, and reduce waste by using fewer consumables. Their potential impact has yet to be investigated. Methods We modeled a country-agnostic population of 10 million individuals to assess the impact of population-level scale-up of four malaria testing strategies for active case-finding: 1) current practice (50% syndromic diagnosis and 50% RDTs), 2) full RDT scale-up, 3) full NID implementation, and 4) NID screening plus confirmatory RDT, using a decision-tree model of the malaria diagnostic and care cascade. We varied prevalence (0.02-0.25) and proportion of cases with symptoms (0.05-0.60) to evaluate strategy performance across epidemiological contexts. We investigated case detection rates, antimicrobial use, incremental cost-effectiveness ratios (ICERs) per disability adjusted life year (DALY) averted, net positive treatment outcomes, and threshold performance levels at which an NID would outperform RDTs. Results Full NID implementation (strategy 3) yielded the highest case detection rates (up to 85%), followed by strategies 2, 4, and 1 (45%, 38%, 36% respectively). NID-based methods (strategies 3 and 4) saved costs and RDT scale-up was cost-effective at averting DALYs compared to current practice (ICERs: $60-1,270). Despite high case detection, universal NID testing spiked unnecessary antimicrobial use. Overall, our results suggest that an NID with 55% asymptomatic sensitivity and 84% specificity, followed by RDT confirmation (strategy 4), could simultaneously improve case detection, reduce antimicrobial overuse, and limit costs. Conclusions This modeling analysis suggests that NIDs can sustainably optimize malaria case detection in symptomatic and asymptomatic cases and reduce costs, potentially making them a valuable addition to the diagnostic toolbox. When paired with confirmatory RDTs, they could help reduce inappropriate antimicrobial use, supporting drug efficacy amid rising resistance. Further research should assess their real-world utility, feasibility, and scalability for malaria surveillance and elimination efforts.

BackgroundWomen are twice as likely to experience depression compared with men. Midlife is a period of increased vulnerability to depression in women and is a stage that coincides with the menopausal transition. Although prospective studies suggest that depressive symptoms increase during this period, findings are inconsistent and it remains difficult to disentangle the effects of reproductive aging from chronological aging. We examined trajectories of depressive symptoms across midlife in relation to reproductive and chronological aging and assessed the association between menopause stages and depression. MethodsWe analysed data from 2,036 women from a UK community-based pregnancy cohort followed over three decades from the early 1990s to early 2020s. Depressive symptoms were assessed at up to 11 timepoints using the Edinburgh Postnatal Depression Scale (EPDS), with depression defined as a score [&ge;] 13. Linear mixed effects models were used to characterise trajectories of depressive symptoms across reproductive and chronological age, and to estimate associations between menopause stages and depression, adjusting for ethnicity, social class, age at menarche, educational attainment, material hardship, social support, smoking status, body mass index (BMI), and alcohol intake. ResultsDepressive symptoms increased gradually with both reproductive and chronological age; however, there was little evidence of a marked increase in levels of depressive symptoms during the peri- or postmenopause stages. Compared with the reproductive period, perimenopause was associated with higher odds of depression (OR 1.19; 95% CI 1.03 to 1.39), whereas there was no evidence of increased odds during postmenopause (OR 0.99; 95% CI 0.83 to 1.19). ConclusionsOverall, reproductive ageing appears to contribute relatively little to long-term changes in depressive symptoms beyond the broader effects of chronological ageing. The odds of depression were highest in the perimenopause and did not persist into postmenopause, indicating that this stage may represent a window of vulnerability for a subgroup of women. Identifying such subgroups could help inform targeted prevention and support strategies.

ObjectivesCD4+ T cells play key roles in regulating immune responses during pregnancy, therefore we aimed to understand the CD4+ T cell surface proteome and transcriptome during pregnancy. MethodsCD4+ T cells were analysed in blood and decidua from term-pregnancies (>37 weeks), and non-pregnant blood. >350 surface proteins were screened via flow cytometry, and transcriptomes were analysed using single-cell RNA sequencing with >130 CITE-seq barcoded antibodies. ResultsSurface protein screening identified changes to ILT4/CD85d, CD9, IFN-{gamma} receptor {beta}-chain, CX3CR1 and CCR5 in the pregnant blood and decidual CD4+ T cells. CX3CR1 and CCR5 had the highest expression on the effector-memory T cell (TEM) subset in the blood, with expression consistent across subsets in decidua. CD126/IL-6R was lower in pregnant blood and decidual CD4+ T cells, while scRNAseq identified enrichment in the IL-6R signalling pathway in naive CD4+ T cells in pregnant blood. Both sIL-6R and IL-6 concentrations were increased in plasma during pregnancy, suggesting perturbations to the IL-6/IL-6R signalling axis. Meanwhile, decidual CD4+ T cells had increased expression of transcription factor RUNX3 in the CD69+ tissue-resident-like subset. ConclusionsOur findings demonstrate altered molecular expression in CD4+ T cells during pregnancy. This provides important mechanistic insight of their adaptation and regulation during placental development, which may drive placental dysfunction or pregnancy complications including preeclampsia, fetal growth restriction and stillbirth. These new data may inform future studies that focus on determining the significance of differentially- expressed immune features in pregnancy to identify potential targets for immune modulation to treat pregnancy complications and infections.

Background Lumbar fusion and decompression procedures are widely used for degenerative spine conditions but are associated with substantial health care costs and variable outcomes. Orthobiologic treatments, including platelet rich plasma (PRP) and bone marrow aspirate concentrate (BMAC), have emerged as less invasive options for select patients who meet surgical criteria. However, concerns remain that orthobiologic care may delay rather than avert surgery, potentially increasing downstream utilization and costs. Comparative evidence on real world utilization and costs is limited. Methods We conducted a retrospective, observational study using linked commercial insurance claims and a national orthobiologic treatment registry. Adults with lumbar degenerative disc disease (DDD) who met criteria for lumbar fusion or laminectomy, foraminotomy, discectomy, and facetectomy (LFDF) procedures, and who received PRP injection (with or without BMAC) or surgery between 2016 and 2023 were included. Two comparisons were evaluated: PRP versus lumbar fusion and PRP versus lumbar decompression procedures. Propensity score matching was used to balance cohorts on demographic characteristics, comorbidities, spine related diagnoses, prior health care use, and severity proxies. Outcomes included spine-related health care resource use and aggregate costs at 12 and 24 months, with exploratory analyses at 36 and 48 months. Costs were estimated using multiple approaches, including Medicare based estimates and commercial payer methods. Results After matching, 133 patients receiving PRP were compared with 2,560 patients undergoing fusion, and 198 patients receiving PRP were compared with 3,960 patients undergoing LFDF. Rates of subsequent spine surgery following PRP were low and below cell suppression thresholds through 24 months, with similar findings in exploratory longer-term analyses. Compared with surgical cohorts, patients receiving PRP had lower rates of postoperative imaging, home health services, and outpatient visits, with no consistent differences in opioid use, magnetic resonance imaging, or physical therapy. At 12 and 24 months, mean aggregate costs were significantly higher for fusion and LFDF cohorts across most costing methods. Cost differences were largest for fusion comparisons and were driven primarily by index procedure costs and higher reoperation and imaging rates in surgical cohorts. Findings were generally consistent across sensitivity and exploratory analyses. Conclusions Among select patients with degenerative spine conditions who meet surgical criteria, PRP was associated with lower health care utilization and substantially lower costs compared with lumbar fusion or LFDF, without evidence of increased progression to surgery. These findings support consideration of orthobiologic options for appropriately selected patients when surgery is not the only viable treatment option. Limitations include selection bias, absence of patient reported outcomes, and claims-based severity measures.

BackgroundUnderstanding the underlying mechanisms for differences in vaccine uptake between migrants and non-migrants is crucial in order to design targeted interventions encouraging vaccination and to ensure vaccine-related equity. Therefore, this study examined to what extent migration-related disparities in COVID-19 vaccination were associated with psychological factors, based on the established 5C model of vaccine behaviour (Confidence, Complacency, Constraints, Calculation, Collective Responsibility). MethodsData were obtained from the German study "Corona Monitoring Nationwide - Wave 2" (RKI-SOEP-2 study), which was carried out between November 2021 and March 2022. The association between COVID-19 vaccination and migration status, while considering the psychological factors, was investigated using multivariable binary logistic regressions. A decomposition analysis (Karlson-Holm-Breen method) was conducted to examine the extent to which migration-related disparities in vaccine uptake were associated with the psychological factors of the 5C framework. ResultsMigrants were less likely to be vaccinated against COVID-19 compared to non-migrants, especially participants from the Middle East and North Africa (MENA) region. Our decomposition showed that almost two-thirds of the disparities in COVID-19 vaccine uptake between migrants and non-migrants were associated with the psychological factors (first-generation: 61.2%, second-generation: 64.2%). Confidence in safety of the vaccine was the most relevant factor in the 5C framework. Furthermore, the results highlighted the importance of a differentiated analysis regarding country of origin: While the 5C model accounted for only 19.4% of the difference between participants from the MENA region and non-migrants, the proportion for participants from Eastern Europe was 73.5%, suggesting that the underlying mechanisms for the lower uptake in the MENA group need further investigation. ConclusionsOverall, migration-related disparities in COVID-19 vaccination were significantly associated with differences in psychological factors of vaccine behaviour. To increase vaccine acceptance within the heterogeneous group of migrants in general, tailored and proactive health communication interventions are needed.

BackgroundPolycystic ovary syndrome (PCOS) is a prevalent endocrine disorder with complex pathophysiology and limited therapeutic options. Identifying key molecular drivers and potential drug candidates is critical for improving clinical outcomes. MethodsWe integrated multi-cohort transcriptomics (GSE155489, GSE138518, GSE226146) with weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network analysis, and drug repurposing. Differential expression analysis identified 1,039 DEGs, and WGCNA identified 10 PCOS-associated modules. Intersection of DEGs with module genes yielded 498 core candidate genes, which were subjected to functional enrichment, PPI network analysis, and connectivity map-based drug repurposing (CLUE/LINCS). Candidate drugs were further evaluated by molecular docking and ADMET prediction using a triple intersection strategy (hub genes, high differential expression, drug-target evidence). ResultsFunctional enrichment revealed significant enrichment in cell adhesion and TGF-beta signaling. PPI network analysis identified CD44 as the top hub gene (degree=42). Drug repurposing identified 106 candidate drugs, including troglitazone and enzalutamide. Using the triple intersection strategy, five genes (ID2, NR4A1, GJA5, ID1, MYH11) were prioritized for molecular docking. GJA5 showed strong predicted binding affinity with flufenamic acid (-7.88 kcal/mol), and cytosporone B exhibited favorable druglikeness (0 Lipinski violations). ConclusionThis study systematically characterizes PCOS-associated gene networks and provides a prioritized set of candidate targets and drugs through a purely computational framework. CD44 emerges as a key network node with potential relevance in PCOS pathophysiology. These findings offer testable hypotheses for future mechanistic studies and drug discovery efforts in PCOS.