The Lancet Healthy Longevity

Background Emerging evidence has linked frailty to individual chronic diseases, but whether it predicts a broad disease spectrum and accelerates multimorbidity accumulation over time remains unknown. This study aimed to systematically evaluate the associations of physical frailty with the burden of incident disease across a wide range of chronic conditions, and with the long-term rates of multimorbidity accumulation. Methods In this prospective cohort study of 466,864 UK Biobank participants , frailty status was assessed using the Fried frailty phenotype and categorized as robust, pre-frailty, or frailty. Chronic diseases were defined based on International Classification of Diseases (ICD)-10 codes, and disease patterns were identified using network analysis. Cox proportional hazards models were used to examine the associations of frailty status with incident chronic diseases, and linear mixed models were used to assess the annual rate of chronic disease accumulation. Results During a median follow-up of 13.8 years (IQR: 13.1-14.5), 536 incident chronic diseases across multiple systems were recorded. Physical frailty was associated with a significantly increased risk of 458 incident diseases (Bonferroni-corrected P < 0.05/536). In the overall cohort, compared with robust participants, those with pre-frailty ({beta} = 0.266, 95% confidence interval [CI]: 0.264-0.267) and frailty ({beta} = 0.941, 95% CI: 0.936-0.946) exhibited significantly faster rates of multimorbidity accumulation. This accelerated multimorbidity accumulation was consistently observed across strata of baseline disease burden, including participant with 0 ({beta} = 0.644, 95% CI: 0.635-0.653), 1 ({beta} =0.748, 95% CI: 0.727-0.768), [&ge;] 2 ({beta} =0.940, 95% CI: 0.933-0.947) chronic conditions at baseline. Similar associations were also found across distinct disease patterns, including neurodegenerative, metabolic, and psychiatric patterns. Conclusions Physical frailty predicts a broad range of incident diseases and is associated with accelerated multimorbidity accumulation. Incorporating frailty assessment into prevention strategies may help mitigate the growing burden of multimorbidity.

Background Ageing clocks are promising non-invasive tools to assess biological ageing, but they generally cannot guide intervention. We aimed to develop a urinary peptidomic ageing clock, expected to react to intervention, and to test whether the resulting age acceleration predicts all-cause mortality and adverse health outcomes. Methods In this retrospective multi-cohort study, urinary peptides were measured by capillary electrophoresis-mass spectrometry (CE-MS). An unconditioned clock (UPBioAge) was developed in a kidney function-preserved derivation cohort (n = 1,811), then conditioned on estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) by Filtrate-Aware Calibration (FAC) fitted in an independent kidney-diverse cohort (n = 7,798), resulting in k-UPBioAge. Age prediction accuracy was evaluated in three cohorts independent of model development. Kidney-conditioned age acceleration (k-UPBioAgeAcc) was related to all-cause mortality and incident disease in a clinically enriched follow-up cohort (n = 7,469; 625 deaths; median follow-up 3.95 years) using Cox models adjusted for age, sex, comorbidities, body-mass index, mean arterial pressure and eGFR. Findings After standard age-bias correction, k-UPBioAge estimated chronological age with a calibrated holdout mean absolute error of 4.91 years (r = 0.945), and 5.43-5.47 years in two validation cohorts (one population cohort and the other samples analysed in an external site). Each SD increment in k-UPBioAgeAcc was associated with all-cause mortality (HR 1.48, 95% CI 1.35-1.63), incident coronary artery disease (1.44, 1.27-1.63), heart failure (1.27, 1.14-1.42) and chronic kidney disease progression (1.35, 1.05-1.73). The association did not differ by sex (P for interaction = 0.33), and none of four comorbidity interactions survived correction for multiple testing (adjusted P = 0.65-0.72), but no association was evident in participants with an eGFR of 15-29 mL/min/1.73 m2 (n = 433, 84 deaths) or macroalbuminuria (n = 92, 34 deaths). Interpretation Multiple urinary peptides are significantly associated with ageing, enabling the establishment of a robust biological ageing clock. As urine is generated in the kidney, a urinary ageing clock is affected by kidney function, mandating correction. The corrected urinary peptide-based biological ageing clock is affected by disease, and may warrant evaluation for monitoring or guiding personalised interventions.

Background Severe COVID-19 is associated with immune dysregulation, microbiome disruption, and increased vulnerability to secondary infections. However, the longer-term risk of acute gastroenteritis (AGE) following COVID-19 remains poorly studied. We compared AGE incidence among community-managed and hospitalised COVID-19 patients with test-negative controls and hospitalised sepsis patients. Methods We conducted a retrospective cohort study using electronic healthcare data. Patients with a recorded SARS-CoV-2 PCR test between 01 March 2020 and 01 March 2022 were allocated to test-negative, community COVID-19, or hospitalised COVID-19 cohorts. A hospitalised sepsis cohort was assembled for an age-, sex- and time-matched analysis. AGE incidence rates were calculated for the two years before enrolment and during follow-up. Negative binomial regression and conditional Poisson models estimated incidence rate ratios (IRRs) adjusting for demographic and clinical covariates. Results Among 788 103 patients, AGE incidence in the pre-pandemic period was higher among individuals later hospitalised with COVID-19 or sepsis compared with community cases. During follow-up, AGE incidence was slightly lower in community COVID-19 cases than test-negative controls (adjusted IRR 0.88 [95% CI 0.85-0.92]), but substantially higher among hospitalised COVID-19 patients (IRR 5.80 [95% CI: 5.38-6.25]). Matched analyses confirmed increased AGE rates compared with community controls (IRR 4.63 [95% CI: 4.15-5.17]) and hospitalised sepsis controls (IRR 1.41 [95% CI 1.21-1.64]). Conclusions COVID-19 hospitalisation is associated with a marked increase in AGE risk after discharge, exceeding that associated with sepsis hospitalisation. By contrast, lower AGE rates in community COVID-19 cases likely reflect baseline differences rather than protective effects of infection. Overall, these findings demonstrate heightened post discharge vulnerability to gastrointestinal illness after COVID 19 hospitalisation and support the need for improved follow up and surveillance strategies.

Abstract Background Persistent pain in later life is associated with functional decline. Identifying resources associated with preserved daily function may broaden pain research beyond symptom burden alone. Objective To examine six prespecified resource indicators-physical activity, depressive symptoms, recall performance, current partner status, education and wealth-in relation to subsequent maintenance of independence in activities of daily living (ADL). Methods This longitudinal observational study analysed adults aged 50 years or older with pain at both the initial and baseline assessments in the Health and Retirement Study (HRS), the English Longitudinal Study of Ageing (ELSA) and the Survey of Health, Ageing and Retirement in Europe (SHARE). ADL maintenance was defined as no difficulty in all five prespecified ADL activities at baseline and no difficulty in all five at follow-up. Indicator-specific risk ratios were estimated using modified Poisson regression with robust variance and pooled using random-effects meta-analysis. The six meta-analysis P values were adjusted using the Holm procedure. Each indicator used a separate complete-case sample; no common six- indicators sample was constructed. Results The descriptive samples comprised 8,279 HRS person-windows contributed by 4,688 unique participants, 1,200 ELSA participants and 6,995 SHARE participants; indicator-specific denominators varied. Physical activity was associated with a higher probability of ADL maintenance across all three cohorts (pooled risk ratio, 1.145; 95% CI, 1.097-1.195; P = .005; Holm-adjusted P = .032) and was the only prespecified hypothesis to meet the Holm-adjusted criterion. The other five hypotheses did not meet this criterion; failure to do so should not be interpreted as evidence that the corresponding associations were absent. Several of these pooled estimates showed substantial heterogeneity. Conclusions Among older adults with persistent pain, physical activity was associated with a higher probability of ADL maintenance, and the physical activity hypothesis was the only one of the six prespecified hypotheses to meet the Holm-adjusted criterion in the three-cohort meta-analysis. These observational findings support further study of physical activity and functional maintenance but do not establish causal benefit.

Biological aging, the decline in physiological resilience that increases our vulnerability to disease and death as we grow older, can be measured from standard clinical-laboratory panels. Measurement of biological aging from laboratory data embedded in electronic health records (EHRs) could enhance precision healthcare. However, suitability of EHR-embedded laboratory records for this purpose is uncertain. We evaluated feasibility of EHR biological age measurement in a cohort of n=4,313 cardiothoracic-surgery patients at a large US Hospital and tested whether measured biological aging was associated with patient outcomes. Patients who were biologically older prior to surgery more often died or experienced adverse outcomes as compared to those measured to be biologically younger. Postoperative biological-aging trajectories were associated with length of intensive-care-unit (ICU) stays and in-hospital death. EHR laboratory data provide an opportunity for scalable implementation of biological aging measurement within healthcare systems, with potential to enhance patient monitoring and risk stratification.

Importance: Preclinical and human observational studies suggest that metformin may decrease age-related pathology, including frailty. Objective: Determine whether metformin reduces frailty progression and biological age in older adults with glucose intolerance, a population at increased risk of becoming frail. Design, Setting and Participants: Randomized, double-blind, placebo-controlled trial of metformin in 145 non-frail or pre-frail older adults. Participants (72 +/-5 years, 48% female, 94% White, 35% Hispanic) were randomized to metformin vs. placebo for two years. Main Outcomes and Measures: Effect on frailty was primarily determined using generalized estimating equations by change in the Fried frailty phenotype score (based on weight loss, exhaustion, physical activity, gait speed, and grip strength). Because metformin can cause significant weight loss, effects on the Fried score were assessed with and without the weight loss criterion. Frailty also was assessed by change in the frailty index (composite of 95 deficits). Biological age was estimated by DNA methylation-based epigenetic clocks in blood. Results: Metformin led to a non-linear response in the Fried score rate of change, with an upward trajectory in year 1 (0.72 +/-0.22 per year vs. placebo, p=0.0011) and stabilization in year 2 (-0.33 +/-0.17 per year vs. placebo, p=0.056). Metformin led to more weight loss than placebo (-5.7 +/-5.2 vs. -2.3 +/-5.4 kg, p=0.0002); thus, when assessing effect on Fried score without the weight loss criterion, no difference was observed, indicating that weight loss in year 1 accounted for the change in Fried score. Notably, metformin caused a steady improvement in the frailty index (-0.006 +/-0.0026 per year vs. placebo, p=0.0222) that persisted with covariates adjustment including body mass index. Metformin reduced biological age estimated by PC-Horvath2 (-0.40 +/-0.16 per year, p=0.014) and PC-Hannum (-0.33 +/-0.16 per year, p=0.047) clocks. Metformin was well tolerated. Conclusions and Relevance: Metformin halts the progression of the deficit accumulation frailty index and reduces biological age, suggesting potential benefit for extending healthspan. Trial Registration: ClinicalTrials.gov: NCT02570672.

Background Population aging is rapidly increasing the burden of multimorbidity and frailty, yet there is limited evidence on how healthy aging policies are implemented across different demographic and health system contexts. Methods We conducted a mixed-methods comparative case study in Spain, Italy, Chile, and Colombia, integrating a Targeted review of policy documents and relevant literature, quantitative indicators, and expert interviews. Results Chile and Colombia showed faster aging dynamics (compound annual growth rates of 4.18% and 4.21%) than Italy (1.96%) and Spain (1.39%), with estimated doubling times of 17 versus 36-50 years. All four countries have established policy frameworks; implementation remains uneven. Key barriers included fragmented services, limited community care, workforce constraints, and misaligned financing. Conclusions The central challenge lies not in the absence of policy frameworks but in their effective implementation. Strengthening primary care, embedding frailty assessment, and improving health-social care integration are key priorities for systems facing rapid demographic transition.

BackgroundMultimorbidity is common among U.S. skilled nursing facilities (SNFs) residents and complicates pharmacologic management, yet real-world evidence on treatment patterns in this population remains limited. This study evaluated medication order rates and identified resident- and facility-level factors among SNF residents with multimorbidity. MethodsRetrospective, observational study using electronic health record (EHR) data from PointClickCares Life Sciences database. Participants were 728,222 residents active in a U.S. SNF on April 30, 2025 with at least one documented diagnosis of hypertension, hyperlipidaemia, type 2 diabetes (T2D), depression, or Alzheimers disease and related dementias (ADRD). The outcome was presence of guideline-recommended medication order for each condition, modelled with modified Poisson regression to estimate adjusted prevalence risk ratios (RRs) and 95% confidence intervals. ResultsMedication order rates were 79% for ADRD, 79.1% for T2D, 87.7% for hypertension, 83.3% for hyperlipidaemia, and 90.8% for depression. Rates varied across comorbidity combinations: ADRD was associated with lower medication order prevalence, while cardiometabolic multimorbidity profiles associated with higher prevalence. Black/African American identity had the lowest likelihoods of a medication order for 3 of 5 conditions (RRs of 0.93 to 0.92), while having hypertension or hyperlipidaemia medication order was associated with higher likelihood of having orders for 3 of remaining 4 conditions (RRs of 1.02 to 1.19). ConclusionsMost SNF residents with multimorbidity had a medication order for common chronic conditions, although important variability and disparities remain. Differences by comorbidity profile and social context underscore the need for targeted strategies supporting equitable, integrated prescribing and person-centred care in SNFs.

Importance: The ASPREE randomized trial found no overall benefit of low-dose aspirin for disability-free survival among older adults. However, individual estimates in pre-specified subgroups indicated potential benefit among racial and ethnic minoritized participants in the United States (US). Objective: To evaluate whether the effect of low-dose aspirin vs placebo on disability-free survival differed across US Black and Hispanic ASPREE participants using individualized treatment-effect estimation. Design, Setting, and Participants: Post hoc clinical trial analysis of ASPREE, a randomized, double-blind, placebo-controlled clinical trial of daily low-dose aspirin vs placebo. This analysis included US ASPREE participants who self-identified as non-Hispanic Black or Hispanic, were aged 65 years or older, and had complete baseline predictor and outcome data. Interventions: Randomization to daily 100-mg aspirin or placebo. Main Outcomes and Measures: The primary outcome was loss of disability-free survival, defined as death, persistent physical disability, or dementia. Individualized treatment effects were estimated post hoc using a Random Survival Forest X-learner. Heterogeneity was evaluated on the relative scale with Cox proportional hazards models and on the absolute scale with 5-year risk differences. Results: Among 2411 US ASPREE participants, 1270 were included in the Black and Hispanic analytic cohort (897 non-Hispanic Black and 373 Hispanic participants; mean age, 71.8 years). Aspirin was associated with lower risk of disability-free survival loss compared with placebo (hazard ratio [HR], 0.65; 95% CI, 0.45-0.93). In model-derived tertiles, aspirin was associated with lower risk in the greatest predicted-benefit group (HR, 0.36; 95% CI, 0.19-0.71; 5-year absolute risk difference [ARD], -11.1 percentage points; 95% CI, -22.0 to -0.1) but not in the lowest predicted-benefit group (HR, 1.26; 95% CI, 0.70-2.27; ARD, +3.9 percentage points; 95% CI, -5.9 to 13.6). Conclusions and Relevance: In these analyses of US Black and Hispanic ASPREE participants, aspirin effects on disability-free survival appear to be heterogeneous, with benefit concentrated in a subset of participants. Because these findings are from post-hoc models, they should be externally validated before being incorporated into clinical decision-making. Trial Registration: ClinicalTrials.gov Identifier: NCT01038583; https://clinicaltrials.gov/study/NCT01038583

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

Diabetic neuropathy is associated with substantial systemic disease burden, but short-term mortality risk among affected intensive care unit (ICU) patients remains difficult to characterize. We evaluated whether temporal information from the first 24 hours of ICU care improves post-landmark mortality prediction beyond severity scores and static clinical summaries. Patients aged > 18 years with diabetic neuropathy were identified in MIMIC-IV v3.1. A 24-hour landmark was used: only patients alive and still hospitalized at 24 hours were included, and the outcome was subsequent in-hospital death. The final cohort included 1,347 patients, including 83 deaths (6.16%). Data were divided into an 80% development set and a locked 20% test set. Feature selection, hyperparameter tuning, calibration, and threshold selection were restricted to development data. Logistic regression, random forest, and XGBoost were evaluated. Random forest had the highest development cross-validated PR-AUC and was selected for interpretation. On the locked test set, random forest achieved an AUROC of 0.851 (95% CI 0.765-0.924), PR-AUC of 0.339, and Brier score of 0.051; XGBoost and logistic regression achieved AUROCs of 0.847 and 0.806. In a post hoc strictly nested analysis, adding temporal predictors increased discrimination across all three algorithms; random-forest AUROC increased from 0.815 with severity and static predictors to 0.870 with the full temporal representation. First-day temporal information therefore showed additional prognostic value, but external validation is required before clinical use.

Background: Care home research often fails to address issues that matter most to residents, families, and staff. Priority-setting exercises can help reduce this lack of inclusivity, but few have received significant resident responses. Objectives: To identify research priorities of UK care home stakeholders (including residents; relatives; care staff, managers and owners; healthcare professionals; policymakers and researchers), and to assess whether these priorities can be addressed using existing research datasets. Methods: PREACH was an 18-month research priority-setting study involving 1063 stakeholders, across 50 care homes, including 381 residents. Participants submitted ideas of what care home research should focus on through 1) care home activity sessions or 2) an online survey. Responses underwent content analysis to identify themes, and these themes were mapped against a national repository of care home trial data. Results: Fifty-one themes were identified. The most frequent priority across all stakeholder groups was access to meaningful activities for residents (22%). Relatives and residents emphasised social connection and day-to-day experience, whereas staff more often highlighted system pressures. No stakeholder-prioritised topics were directly addressable using existing secondary datasets. Conclusions: Collaboration with care home teams to reach large numbers of residents offers a practical route to producing more relevant and timely care home research. Care home stakeholders consistently prioritise quality of life, meaningful activity and staffing over disease-specific or health-focused research. Existing research datasets measure relatively few of the priorities identified by residents, highlighting the need for resident-centred outcome measures and data collection.

Urban nature is increasingly recognized as a determinant of healthy aging. However, research has largely focused on the quantity of greenness rather than biodiversity. Evidence supports an association between biodiversity and mental health, but physical aging evidence is very limited. We examined the longitudinal association between residential bird biodiversity and frailty severity using electronic health records. We conducted a retrospective cohort study of 20,388 adults aged 65 years and older receiving primary care in the Mount Sinai Health System in New York City, contributing 123,103 patient-years of follow-up (2011-2023). Residential bird biodiversity was derived from eBird citizen-science data as a modeled, bias-corrected latent Shannon diversity surface at the census-tract level yearly. Frailty severity was measured annually as the deficit count on the 31-item Veterans Affairs Frailty Index (VA-FI). We estimated associations using a negative binomial generalized additive model adjusted for age, sex, race and ethnicity, insurance, tract-level poverty, and non-Hispanic Black proportion, reporting results as the percent change in expected deficit count. We tested effect modification by age group (65-74, 75-84, over 85 years). Each interquartile range increase in residential bird Shannon diversity was associated with a 1.4% lower expected VA-FI deficit count (95% CI -2.1% to -0.8%). The association was strongest among adults aged 65-74 years (-3.0%, 95% CI -3.9% to -2.1%), attenuated among those aged 75-84 years (-0.8%, 95% CI -1.9% to 0.3%), and no longer evident among those aged 85 and older (+1.6%, 95% CI -0.0% to 3.3%). Greater residential bird biodiversity (reflecting both species richness and evenness) was associated with lower frailty severity, with the largest association in early old age. As a bioindicator of underlying environmental quality shaped by modifiable urban design, bird diversity may point to a avenue for supporting healthy aging in dense cities.

Background Clostridioides difficile infections (CDI) continue to cause substantial morbidity and mortality, with increasing incidence in some countries post-COVID-19. Recurrence affects 10-20% of CDI patients: whether risk factors have changed over time is unclear, particularly post-COVID-19. Methods Using electronic health records from hospitals in Oxfordshire, UK, including results from community samples, we estimated the incidence of CDI recurrence across different calendar periods between 2000-2025. To investigate whether risk factors had changed over time, we used interaction tests within multivariable Fine-Gray regression models (modelling death as a competing risk), using backwards elimination, starting from 39 risk factors identified from the literature. Results Recurrence occurred within 1-year in 12.6%, 12.5%, 10.8% and 13.1% of CDI cases in "high virulence" 2003-2008 (n=527), "post-high virulence" 2008-2012 (n=252), "pre-pandemic" 2012-2020 (n=143) and "post-pandemic" 2020-2025 (n=110) periods respectively. The only factor with evidence of variation in its association with recurrence over time was surveillance classification (heterogeneity p=0.019; others p>0.05). Compared with hospital-onset cases, community-onset community-associated cases had increasing recurrence risks over time (subdistribution hazard ratios (SHRs)=2.05 (95% CI 1.27-3.31) in "post-pandemic" and 1.86 (1.16-2.98) in "pre-pandemic"), especially compared to the "high virulence" era of the early 2000s (SHR=0.81 (0.56-1.16)). This heterogeneity persisted after adjusting for baseline blood tests as a marker of severity (heterogeneity p=0.022). Conclusions Compared with hospital-onset hospital-associated cases, recurrence risks increased for community-onset community-associated CDI cases over time. Recurrence is a key contributor to overall CDI incidence and the underlying causes of increasing risks with community-onset community-associated cases should be explored further.

Seasonal Influenza and COVID-19 vaccination programmes are critical for reducing morbidity and mortality in older adults, yet uptake remains uneven across populations. We aimed to profile vaccination attitudes and examine predictors of COVID-19/influenza vaccination uptake among a UK participatory surveillance system - FluSurvey. We analysed FluSurvey data from participants aged [&ge;]65 years who were eligible for both vaccines in the 2023-2024 and 2024-2025 Autumn - Winter seasonal campaigns. Descriptive analyses examined self-reported attitudes to influenza vaccination. Logistic regression examined factors (age, sex, socioeconomic status, education, employment, transport, smoking and chronic conditions) associated with influenza and COVID-19 vaccination uptake in each season, adjusting for confounders. Belonging to a risk group and reducing risk of influenza were frequently reported motivations for influenza vaccination, while building natural immunity and concerns around safety and adverse effects were frequently reported barriers. Individuals vaccinated against COVID-19 were more likely to receive an influenza vaccination (aOR2023-2024=13.90 [9.28-21.17]; aOR2024-2025=8.54 [5.82-12.60]), and vice-versa (aOR2023-2024=13.91 [9.30-21.19]; aOR2024-2025=8.52 [5.81-12.58]). Lower educational attainment was associated with lower odds of COVID-19 vaccination (aOR2023-2024=0.59 [0.45-0.78], aOR2024-2025: 0.56 [0.39-0.79]). Other results were weaker or demonstrated variation by season. Our findings highlight recent attitudes and barriers to influenza and COVID-19 vaccination among the FluSurvey cohort, which may inform approaches to improve vaccination coverage in the population.

Importance Several influenza vaccine products are available for older adults, but evidence combining both their absolute effectiveness and head-to-head comparisons within the same large population remains scarce, limiting product-specific vaccination guidance for this high-risk group. Objective To estimate the relative and absolute effectiveness of influenza vaccines against influenza-related hospitalization and in-hospital mortality among older adults. Design, Setting, and Participants Nationwide cohort study using the French National Health Data System (SNDS), including all adults born in 1958 or earlier, living in metropolitan France, at the start of the 2023-2024 campaign. Relative effectiveness (rVE) was assessed using a landmark design with exposure fixed before epidemic onset. Absolute effectiveness (VE) was assessed using a sequential trial emulation with weekly matching of newly vaccinated individuals to yet unvaccinated controls. Follow-up ran from December 5, 2023 to April 19, 2024. Exposures Vaccination with a high-dose (Efluelda) or one of three standard-dose quadrivalent vaccines (Influvac, Fluarix, Vaxigrip), compared individually or by dosage category, and against no vaccination. Main Outcomes and Measures Hospitalization with a diagnosis of influenza and death during such hospitalization. Effectiveness was estimated as 1 minus the hazard ratio from weighted Cox models, with corresponding numbers needed to vaccinate to prevent one case. Results Among 13.8 million eligible individuals, 5.7 million (41%) were vaccinated at the beginning of follow-up. The high-dose vaccine showed greater rVE than standard-dose vaccines against hospitalization (27% [95%CI, 23 to 31%]) and in-hospital death (27% [95%CI,14 to 38%]). Absolute VE was 39% (95%CI, 38 to 41%) against hospitalization and 45% (95%CI, 40 to 49%) against in-hospital death, and was higher for the high-dose vaccine (50%) than standard-dose vaccines (36%) against hospitalization. This difference was most evident among adults 70 years and older, while overall effectiveness declined with age. Conclusions and Relevance In this study, influenza vaccination conferred moderate protection against severe outcomes in older adults, and high-dose vaccination was associated with significantly greater effectiveness than standard-dose vaccines, particularly among adults 70 years and older. These findings support product-level differentiation in vaccination strategy for this population.

Objective: To determine whether plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are elevated in hospitalised patients with delirium relative to patients with dementia and primary psychiatric disorders (PPD). Methods and analysis: This was a cross-sectional observational study conducted at the Royal Melbourne Hospital, Melbourne, Australia, between April and October 2024, with comparator samples from a research biobank. In Phase 1 (Delirium Discovery Cohort), we measured plasma NfL and GFAP using the Single molecule array (Simoa) platform in hospitalised patients with delirium and compared them with dementia and PPD groups. Biomarker concentrations were the primary outcome and were compared using general linear models adjusted for age, sex, and estimated glomerular filtration rate, with bootstrapped confidence intervals. Discriminative performance was assessed as a secondary outcome using receiver operating characteristic (ROC) curve analysis. In Phase 2, we applied this threshold to independent dementia and PPD groups. Results: In Phase 1 (n =176), inpatients with delirium showed higher concentrations of both NfL and GFAP than patients with dementia ({beta} = 0.78; 95% CI [0.37, 1.20] and {beta} = 0.39 [0.07, 0.73] respectively) or PPD groups ({beta} = 1.17; [0.69, 1.66] and {beta} = 0.83 [0.51, 1.24] respectively). ROC curve analysis for differentiating delirium from dementia and PPD groups yielded an optimal NfL threshold of 24.1 pg/mL (AUC = 0.89, 96% sensitivity, 70% specificity). In comparison, GFAP showed lower accuracy (AUC = 0.85), and combining NfL with GFAP (AUC = 0.90) did not significantly improve performance. In Phase 2 (n = 154), the NfL threshold of > 24 pg/ml maintained strong performance (AUC = 0.95, 96% sensitivity, and 77% specificity). Conclusions: Plasma NfL shows promise as a biomarker for delirium in hospitalised patients, distinguishing it with high sensitivity from patients with dementia and PPD. Larger multicentre studies are needed to refine cut-offs, evaluate temporal dynamics, and determine integration into acute hospital delirium pathways.

Background We examined whether two key housing quality indicators, energy efficiency and household overcrowding, were associated with lower respiratory tract infection (LRTI) hospital admissions in infants. Methods We used a cohort of all singleton births in Scotland 2010-2012, created through linked vital statistics and health data. LRTI admissions were characterised in hospital records. Overcrowding (defined using the national room standard) and median postcode-level energy efficiency were defined using maternal Census and postcode-level Energy Performance Certificate data linked to the cohort, respectively. We used logistic regression to model the odds of at least one infant LRTI admission. Results The cohort included 136,123 infants of whom 4.0% had at least one LRTI admission. Overcrowding was more common among infants of younger mothers and those in rented housing. Energy efficiency was lower among infants of older mothers, living in owner occupied homes, in less deprived areas. Compared with infants living in homes with excess rooms (under-occupied housing), those whose homes were below, or met, the minimum room standard had higher odds of LRTI admission (adjusted odds ratio 1.07, 95% CI 0.98-1.17; 1.10, 95% CI 1.03-1.17, respectively). Postcode-level energy efficiency was not associated with LRTI admission odds. Conclusion Overcrowding was more common in socioeconomically disadvantaged households and associated with increased risk of LRTI admission in infancy. Lower energy efficiency was associated with factors commonly linked to socioeconomic advantage and was not associated with LRTI admissions. Improving access to housing with adequate living space may reduce the burden of LRTIs in early life.

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

Residential environmental exposures might be associated with biological ageing, but evidence has largely focused on a limited set of single exposures. We investigated associations between the multidomain residential external exposome and epigenetic ageing in 3307 adults from the nationally representative UK Understanding Society study. We linked 30 exposures across six domains spanning social, built, physico-chemical, retail, health and weather environments, to residential postcodes and examined associations with first-, second- and third-generation epigenetic clocks. Across four complementary approaches capturing individual, joint, domain-level and clustered exposures, adverse social, built and physico-chemical environments showed the most consistent associations with biological ageing. Area deprivation, neighbourhood crime, lower social cohesion and greenness, air pollution and higher temperatures were associated with faster pace of ageing measured by third-generation clocks (particularly DunedinPACE) and, to a lesser extent, with PhenoAge. Greater distance to leisure services was associated with older biological age on Horvath s clock and PhenoAge. Clustering identified urban and rural exposure profiles, with faster ageing in the urban profile. Residential environmental exposures are associated with epigenetic ageing, with later-generation clocks appearing more sensitive to the biological imprint of the external residential exposome.