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.

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.

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.

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.

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.

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.

Aims: The risks of dementia, stroke, and mortality increase from normoglycemia to prediabetes and type 2 diabetes (T2D). Blood pressure variability (BPV) is associated with adverse vascular and neurological outcomes, but its role in glycemia-associated risks remains unclear. We examined the interplay between glycemia, BPV, and these outcomes. Methods and Results: In a large prospective cohort, visit-to-visit BPV was quantified using absolute and directional measures of systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse pressure (PP). Glycemic status was defined as normoglycemia, prediabetes, and T2D. Time-updated Cox models estimated outcome associations, adjusting for confounders and mean blood pressure. We evaluated the joint and independent associations of BPV and glycemic status with outcomes, effect modification, and attenuation of glycemia-associated risks after BPV adjustment. Among 57,611 participants (median follow-up, 5.1 years; IQR, 3.3-9.5 years), compared with normoglycemia and low BPV, T2D with high SBP variability was associated with higher risks of all-cause mortality (HR 2.80, 95% CI 2.12-3.69) and nominally higher risk of all-cause dementia (HR 2.46, 95% CI 1.37-4.42). All absolute BPV measures were independently associated with mortality, while DBP and MAP variability were associated with overall stroke after FDR correction. Additional adjustment for BPV minimally attenuated glycemia-associated risk, and no multiplicative interaction remained significant after multiple-testing correction. Conclusions: Absolute BPV was associated with mortality, and DBP and MAP variability with overall stroke, after accounting for glycemic status and mean blood pressure. Additional BPV adjustment changed the glycemic association only minimally.

Background: When intravenous insulin is stopped in critically ill patients, the basal insulin dose that balances rebound hyperglycemia against hypoglycemia is uncertain, because randomized trials were small and not designed to quantify this trade-off. We examined how the first glargine dose, relative to the preceding intravenous insulin requirement, was associated with both outcomes. Methods: In this retrospective cohort study of the Medical Information Mart for Intensive Care IV database (2008-2022), we included transitions from intravenous insulin infusions of at least 6 hours to subcutaneous glargine in adults without diabetic ketoacidosis or hyperosmolar hyperglycemic state. The exposure was the ratio of the first glargine dose to 24 times the mean infusion rate over the final 6 hours. The primary outcomes, rebound hyperglycemia (glucose >180 mg/dL within 24 hours) and hypoglycemia (glucose <70 mg/dL within 48 hours) during intensive care unit follow-up, were analyzed with multivariable Cox models after multiple imputation. Results: Among 6,220 transitions in 5,924 patients (87.5% after cardiac surgery), the median ratio was 0.41 (interquartile range 0.30-0.46). Kaplan-Meier cumulative incidences were 44.4% for rebound hyperglycemia (2,109 events) and 6.4% for hypoglycemia (211 events). Each 0.1 increase in the ratio was associated with less rebound hyperglycemia (hazard ratio 0.96, 95% confidence interval 0.93-0.99) and more hypoglycemia (1.11, 1.04-1.18), consistently across 21 sensitivity analyses. Rebound within the first 6 hours (57.6% of events) was not associated with the ratio (0.99, 0.95-1.02), whereas later rebound was (0.91, 0.86-0.96). Standardized to the cohort, a ratio of 0.60 versus 0.40 corresponded to 2.7 (0.6-4.9) fewer rebound and 1.7 (-0.2 to 3.5) more hypoglycemia episodes per 100 transitions. In secondary analyses, rebound was less frequent with glargine given at least 2 hours before discontinuation (0.86, 0.77-0.96) and more frequent with an oral diet (1.49, 1.30-1.71). Conclusions: In critically ill adults, mostly after cardiac surgery, higher glargine doses relative to the preceding intravenous requirement were associated with less rebound hyperglycemia after the first 6 hours and more hypoglycemia, a gradual trade-off. Which basal fraction is preferable depends on the weight given to each outcome; a randomized trial including the guideline-implied fraction of about 0.30 is warranted.

Introduction: This study compared the health and economic impact of the 21-valent pneumococcal conjugate vaccine (aPCV21) vs the 20-valent pneumococcal conjugate vaccine (PCV20) on invasive pneumococcal disease (IPD) and post-meningitis sequelae (PMS) among adults aged 65 years and older in the United Kingdom (UK). Methods: A published Markov model was used to simulate a single-cohort of vaccine-naive adults who became eligible for age-based vaccination at age 65 years, with uptake occurring over time. The cohort was followed until a maximum age of 100 years. Model inputs were derived from publicly available national health data and published reports. Outcomes were discounted at 3.5% annually, and costs were adjusted to the 2024 Great Britain Pound ({pound}). Additional analyses explored the impact of changing the age-based recommendation from 65 years to 75 years. Scenarios involving instantaneous vaccine uptake rates were included as part of the sensitivity analyses. A deterministic sensitivity analysis was performed on the incremental direct medical costs between vaccinating with aPCV21 vs PCV20 under the age-based recommendation of 65 years. Results: Using an age-based recommendation of 65 years, aPCV21 led to fewer cases, deaths, and costs than PCV20. Compared with PCV20, aPCV21 averted an additional 138 IPD cases, 1 PMS case, and 22 IPD deaths, saving {pound}1.2 million in direct medical costs. Raising the age-based recommendation from 65 to 75 years and using aPCV21 (or PCV20, respectively), resulted in 120 (92) additional IPD cases, 2 (1) additional PMS case(s), 19 (14) additional IPD death(s), and an extra {pound}1.1 ({pound}0.8) million in direct medical costs. The deterministic sensitivity analysis showed that aPCV21 reduced direct medical costs across all parameter ranges. Conclusions: Compared with PCV20, aPCV21 prevented more IPD cases, IPD deaths, and direct medical costs among older adults in the UK. Changing the age-based recommendation from age 65 to 75 resulted in worse health and economic outcomes. Key words. Pneumococcal infections; pneumococcal vaccines; vaccines, conjugate; serotype; United Kingdom; health costs

Objective: To test the hypothesis that selected SIRS and SOFA criteria measured at ICU admission have divergent associations with (1) the development of new culture-confirmed infections and (2) early empiric broad-spectrum antibiotic receipt in critically ill patients with cirrhosis. Design: Retrospective, observational study using electronic health record (EHR) data. Setting: Both community and academic ICUs within a five-hospital health system between July 2017 and December 2025. Subjects: Adult patients >18 years of age diagnosed with cirrhosis admitted to the ICU within 96 hours of hospital admission. Patients transferred from outside facilities and those with positive cultures collected >24 hours before ICU admission were excluded. Interventions: None. Measurements: Multivariable logistic regression tested the association of the most aberrant values in nine SIRS/SOFA vital sign and laboratory parameters measured during the 24 hours prior to ICU admission with (1) the development a newly positive culture collected during the 24 hours before through the 96 hours after ICU admission and (2) receipt of broad-spectrum antibiotics during the 24 hours before through the 24 hours after ICU admission. Main Results: The presence of hyperthermia, hypothermia, hypoxia, or hypotension at ICU admission was associated with both culture positivity and antibiotic receipt. The presence of leukocytosis was associated with antibiotic receipt but not culture positivity. Among patients in the 21.6% of encounters with newly positive cultures, normothermia and normal WBC were common (respectively present in 97.2% and 77.5% of encounters) and associated with antibiotic omission at ICU admission despite the subsequent development culture positivity. Conclusions: Traditional physiologic markers of infection are often absent in critically ill patients with cirrhosis who develop new culture-confirmed infections at ICU admission, possibly contributing to delayed antibiotics. There may be opportunities to improve antibiotic delivery and stewardship at ICU admission in this high-risk population.

Background: Previous studies indicated that regional fluctuations in COVID-19 impact were associated with socioeconomic, demographic and environmental factors early in the pandemic. It is unclear whether factors associated with regional COVID-19 mortality and SARS-CoV-2 infections changed over the course of the pandemic. Methods: We evaluated the association of ecological factors with municipality-specific COVID-19 mortality in the national population of Austria between January 2020 and June 2023. Analyses were conducted separately per calendar year and pooled across years via random-effects meta-analysis. Outcomes were analysed using univariable and multivariable zero-inflated negative binomial (ZINB) regression, including annually averaged environmental exposome exposure (including air pollution and UV radiation), socioeconomic, demographic and infection dissemination predictors with significance threshold set to p<0.005. Secondary analysis modelled SARS-CoV-2 infections using of negative-binomial model (NB). Two additional approaches for smaller predictor set selection were applied as sensitivity analyses. Results: Within the entire observation period 18,430 COVID-19 deaths were reported. In univariable analyses (pooled RR (99.5% CI)), COVID-19 mortality was significantly associated with the proportion of commuters (0.79 (0.73-0.86)), residents aged 75-84 (1.18 (1.01-1.37)) and [&ge;]85 years (1.29 (1.04-1.60)), residents with at most compulsory education (1.15 (1.02-1.29)), employed residents aged 15-64 (0.89 (0.85-0.93)), and homeowners (0.91 (0.83-0.99)), as well as with precipitation (0.94 (0.89-0.99)) and the average time with a mean temperature of 5-15 C (0.95 (0.90-0.99)). In multivariable analyses the share of population aged 85 or older (1.30 (1.09-1.54)) and home ownership (0.92 (0.87-0.98)) were independently significant. Mortality predictor estimates were relatively stable across pandemic years. Across 5,963,882 documented SARS-CoV-2 infections share of employed in 15- to 64-year-olds (1.01 (1.01-1.02)), part-time employment rate (1.01 (1.00-1.02)) and district level nursing care allowance recipiency (0.97 (0.95-0.98)) were associated with detected infections. Overnight stays, population 85 or older, income, compulsory education or less and air pollution all had multiple significant estimates with opposite directionality, leading to non-significant overall associations. Sensitivity analyses outcomes mirrored main analyses outcomes. Conclusions: Throughout the pandemic in Austria, demographic and socioeconomic factors were associated with COVID-19 mortality and infections, but many associations, especially for infections, were unstable over time. These findings underscore the importance of structural vulnerabilities in epidemic impact.

Objectives: To evaluate change in physical function and probable sarcopenia following a 36-week community multicomponent exercise programme (Vivifrail model) across two consecutive cycles, and to assess the consistency of this change between cohorts. Study design: Quasi-experimental, single-arm, repeated-measures service evaluation. Ninety-two older adults (2025-2026 cohort; mean age 75.9 years, 88.0% women) completed baseline and post-intervention assessments; an independent 2024-2025 cohort (n = 86) was analysed jointly for replication (n = 178). Main outcome measures: Short Physical Performance Battery (SPPB) score (primary); Timed Up and Go (TUG), handgrip strength, 6-metre walk time and Mini-Mental State Examination (MMSE) (secondary); probable sarcopenia (EWGSOP2), SPPB-based frailty category, and a fall-risk indicator computed identically in both cohorts. Results: SPPB improved by a mean of 1.33 points (Cohen's d = 0.96; p < .001), with concordant improvement in all four secondary outcomes (all q < .005). 72.8% reached the substantial minimal clinically important difference. Probable sarcopenia fell from 17.4% to 5.4% (p = .006), and frailty category shifted toward higher functional levels (p < .001). Effect sizes were consistent between cohorts for SPPB, handgrip and 6-metre walk; the Time x Cohort interaction was significant for TUG only. In the pooled sample, elevated fall risk fell from 19.7% to 11.2% (p = .002). Conclusions: A 36-week multicomponent exercise programme was associated with clinically meaningful, reproducible improvement in physical function and a reduction in probable sarcopenia across two independent cohorts. The single-arm design precludes causal inference.

ObjectivesRespiratory Syncytial Virus (RSV) vaccine policies have varied globally since their approval in 2023. In the UK, policy has adapted in line with National evidence generation such that from Autumn 2026 at-risk persons [&ge;]65 years old will become eligible for vaccination. Immunosuppressed persons <65 years will still not be offered protection. The objective of this study is to investigate the relative burden of RSV infection by age and immunosuppressed status (IC). DesignRetrospective observational cohort study using routine healthcare data from North West London Integrated Care System. ParticipantsPatients with a confirmed diagnosis of a respiratory viral infection (RSV, Influenza A and B, SARS-CoV2) between October 2021 and July 2025. Main outcomes measuresPrevalence and severity of RSV infection in immunosuppressed persons <65 years old, and to provide a comparative analysis with Influenza and SARS-CoV2 in a sub-cohort tested using a 4-in-1 combined rapid PCR test. ResultsDuring the study period, 1226 patients were diagnosed with RSV of whom 596 (48.6%) were <65 years old. In 1091 patients with clinical data, 341 (31.3%) were IC. Fifty (9.9%) patients <65 years old had severe infection (ICU admission or death within 28 days of diagnosis), of whom 14 (28.0%) were IC. Proportionally, 16.7% of all RSV-associated deaths and 55.1% of all ICU RSV-admissions occurred in adult patients <65 years old. RSV accounted for 665 (10.1%) infections confirmed by 4-in-1 viral PCR testing. Eight-nine (13.4%), 172 (9.3%) and 448 (12.0%) patients with RSV, Influenza A and SARS-COV2 experienced severe infection, of whom 32 (36.0%), 82 (47.7%) and 156 (34.8%) were <65 years old respectively. Eight (25.0%), 20 (24.4%) and 52 (33.3%) of patients <65 years old with severe infection were IC. On adjusted analysis, having an immunosuppressive condition increased the odds of a severe SARS-CoV2 infection, OR (95% CI) 1.36 (1.08-1.71) but not a severe RSV or Influenza infection. ConclusionsSevere RSV infections occur in persons <65 years old, with a significant proportion of patients having an immunosuppressive condition. Urgent research is needed to investigate the potential benefit of extending the current UK RSV vaccine policy to protect younger immunosuppressed adults.

Objective To examine the association between patient-reported shared decision-making (SDM) and documented advance care planning (ACP) among adults with Alzheimer disease and related dementias (ADRD), and to assess whether this association differed between adults with and without ADRD. Design Retrospective observational study using linked survey and electronic health record (EHR) data. Setting and Participants Participants aged [&ge;]50 years in the All of Us Research Program who completed a patient-reported SDM measure and had linked EHR records. The primary analytic cohort included 3,635 adults with ADRD; 123,681 adults without ADRD comprised a secondary comparison cohort. Methods SDM was measured by how often clinicians asked participants about their opinions or preferences regarding medical care or treatment and was categorized as high (always/most of the time) or low (some of the time/ None of the time). Documented ACP was identified within 3 years before or after the SDM assessment. Modified Poisson regression with robust variance estimated prevalence ratios (PRs) and adjusted PRs (aPRs). Results Among adults with ADRD, 60.6% reported high SDM. Documented ACP prevalence was 5.1% among participants with high SDM and 3.6% among those with low SDM (P=0.027). High SDM was associated with greater ACP prevalence in the unadjusted model (PR, 1.44; 95% CI, 1.04-1.99); the association remained positive but was attenuated after full adjustment (aPR, 1.28; 95% CI, 0.93-1.77). Among adults without ADRD, high SDM was associated with documented ACP (aPR, 1.17; 95% CI, 1.03-1.33). Conclusions and Implications Among adults with ADRD, high SDM was associated with greater ACP prevalence in unadjusted analyses, although the fully adjusted association was not statistically significant. In contrast, higher SDM remained significantly associated with ACP among those without ADRD. The low prevalence of ACP highlights an important opportunity to expand discussions of current and future care preferences as a routine component of patient-centered care.

Background: Vitamin D deficiency has been associated with mortality and chronic disease. In a recent study of Israeli Leumit Health Services (LHS) and US TriNetX populations, severe deficiency was reproducibly associated with mortality and multisystem morbidity, while longitudinal supplementation reconstructed from pharmacy dispensing was associated with lower risk. Methods: We sought to reproduce these associations and address a wide range of potential confounders in the deeply phenotyped UK Biobank. Baseline circulating 25-hydroxyvitamin D [25(OH)D] was standardized to a common late-winter nadir using an eight-harmonic model, and participants were categorized according to nadir-equivalent 25(OH)D as <5, 5-10, 10-15, 15-20, or [&ge;]20 ng/mL. Primary survival analyses used one-year delayed entry and complete-case multivariable adjustment. Results: Analyses included 412,020 participants and 31,197 deaths. Mortality hazard ratios were 2.03 (95% CI 1.90-2.18), 1.34 (1.29-1.39), 1.08 (1.04-1.11), respectively, for <5, 5-10 and 10-15, versus [&ge;]20 ng/mL. Associations previously observed in LHS and TriNetX were reproduced, notably for diabetes, myocardial infarction, cerebrovascular disease, dementia, diabetic retinopathy, and end-stage renal disease, whereas skin malignancies showed the opposite gradient, consistent with greater ultraviolet exposure. DAG-informed causal analyses using generalized overlap weighting achieved acceptable balance across measured covariates; weighted 10-year mortality was 9.7% with very severe deficiency versus 4.8% with [&ge;]20 ng/mL, supporting a causal interpretation. Estimates remained stable with landmark lags extending to 5 years after measurement. Conclusions: Seasonally normalized 25(OH)D identifies a reproducible state of systemic vulnerability while reducing exposure misclassification caused by calendar timing of measurement. An interactive implementation of the normalization model is available: https://vitamind.medil.ai.

Background and objectives: Industrialisation is associated with lower gut microbial richness. The ecological insurance hypothesis proposes that richer communities buffer disturbance via overlapping functions, possibly affecting infection susceptibility. We state predictions, audit the evidence, and test the richness-infection relationship in Gambian children. Methodology: We analysed 452 children aged 6-35 months with Day 85 stool 16S profiles and dated infections over 113 days. Diversity used Hill numbers (q = 0, 1, 2); redundancy was inferred from reference-genome gene content. We examined associations with illness during follow-up and infections after Day 85, adjusting for earlier illness. Results: Richness was lower in children with any infection (93.9 vs 103.1; d = 0.36; adjusted odds ratio 0.989 per species, p = 0.019); abundance-weighted diversity was not. Most illness preceded sampling (295 of 315); the difference lay in common and intermediate-prevalence species. Richness was lowest around recent illness. Higher richness was associated with fewer later infections (rate ratio 0.69 per SD, 95% CI 0.51-0.93; q = 0.11). Redundancy correlated with richness at q = 0 (rho = 0.93); at q = 1-2 estimates indicated lower infection rates but none survived correction (smallest FDR q = 0.14). Conclusions and implications: Richness and infection were associated in both directions: children who had been ill had lower richness, and greater Day 85 diversity preceded fewer infections. Redundancy was directionally aligned with reduced infection at higher diversity orders, but FDR control and collinearity limit inference. Cohorts sampled before illness, with shotgun data, are needed.

Background Type 2 diabetes (T2D) disproportionately affects socioeconomically disadvantaged communities. Evidence on the feasibility and effectiveness of prevention and self-management strategies in complex contexts remains limited. Objective To report effectiveness outcomes from a feasibility trial comparing the SMART2D intervention with routine primary care for T2D prevention and control in two neighbourhoods in Stockholm. Methods A cluster-randomized feasibility trial with hybrid type 1 design was conducted in two neighbourhoods among individuals at high risk of T2D (n=84) or with diagnosed T2D (n=58), allocated to an integrated care arm (n=70; personal coaching and community outreach) or facility-only arm (n=72; routine care). Primary outcomes were glycaemic control (participants with T2D) and HbA1c reduction (participants at high risk of T2D); secondary outcomes were retention to care and diabetes incidence (participants at high risk of T2D). Analysis used intention-to-treat principles: difference-in-differences with mixed-effects models for HbA1c reduction, and modified Poisson regression (IRR, 95% CI) for other outcomes. Results Among participants with T2D, glycaemic control (adjusted IRR=0.92, 95% CI=0.89-0.95) and retention to care (adjusted IRR=0.91, 95% CI=0.91-0.92) were significantly lower in the integrated care arm. Among participants at high risk of T2D, integrated care showed a marginally significant, greater HbA1c reduction (adjusted 2.02, 0.20-3.84) and significantly higher retention to care (adjusted IRR=1.22, 1.15-1.29), plus fewer incident diabetes cases (0 vs. 2 in facility-only). Conclusions Integrated care (personal coaching, community outreach) benefited HbA1c reduction and retention among participants at high risk of T2D, whereas facility-only care improved glycaemic control and retention among participants with T2D.

OBJECTIVE: Sepsis-associated encephalopathy (SAE) and sepsis-associated delirium (SAD) lack confirmatory laboratory tests or biomarkers. We evaluated whether the Th17/interleukin (IL)-17 axis or neuroglial-injury biomarkers reflect acute brain dysfunction beyond systemic inflammation and whether biomarker profiles differ between these phenotypes. DATA SOURCES: EMBASE, MEDLINE/PubMed, and the Cochrane Library from inception to August 1, 2026, supplemented by backward and forward citation searching, following PRISMA 2020. STUDY SELECTION: Observational studies of adults with sepsis classified by SAE or SAD status and reporting circulating biomarker concentrations by neurological group or biomarker-outcome associations. Eighteen studies (2,388 participants; 1,863 with sepsis) were included. DATA EXTRACTION: Two reviewers independently extracted study, phenotype, assay, and outcome data. Risk of bias was assessed with the Newcastle-Ottawa Scale and certainty with GRADE. DATA SYNTHESIS: Random-effects models pooled standardized mean differences (SMDs) separately against non-septic and septic controls and odds ratios (ORs) for biomarker-outcome associations. IL-6 was the only mediator elevated in both comparative frameworks and associated with outcomes (non-septic controls: SMD, 0.54 [0.25-0.82]; septic controls: SMD, 1.05 [0.51-1.59]; OR, 1.85 [1.50-2.29]). S100B, neuron-specific enolase, IL-10, tumor necrosis factor; and interferon-gamma; were elevated versus septic controls, whereas IL-17 was modestly elevated only versus non-septic controls (SMD, 0.37 [0.01-0.73]). The IL-6 septic-control effect was concentrated in SAE (p<0.0001) and remained robust in leave-one-out and risk-of-bias sensitivity analyses. Certainty was low to very low, and all 14 computable prediction intervals included the null. CONCLUSIONS: IL-6 emerges as the leading circulating candidate biomarker of sepsis-associated brain dysfunction, while S100B and NSE capture neuroglial injury beyond sepsis. Current evidence does not establish a discriminating role for the Th17 axis. Future studies require standardized neurological phenotyping and appropriately matched septic controls to establish diagnostic value.

BackgroundSocial isolation (SI) is an established risk factor for chronic disease and mortality. How people travel, including the modes of transportation they use, may shape opportunities for social interaction and influence the impacts of SI. This study assessed heterogeneity of the association between SI and mortality across primary modes of non-commute transportation. MethodsWe analyzed cohort data from the UK Biobank, following participants aged 40-69 years from 2006 to 2022. SI at baseline was derived from three items and dichotomized. Cox models were used to estimate the association between SI and mortality, adjusting for socioeconomic factors, health behaviours, and comorbidities. Effect modification by participants primary mode of non-commute transportation was assessed using interaction terms with SI. ResultsThere were 490,114 participants with complete baseline exposure data. SI was associated with increased hazard of all-cause (Hazard Ratio [HR] = 1.34, 95% Confidence Interval [CI]: 1.31-1.38) and cardiovascular mortality (HR = 1.49, CI: 1.41-1.57). The association with cardiovascular mortality was stronger among participants who only used public transport compared with those who only used a car (interaction HR = 1.17, CI: 1.00-1.37). In contrast, using a car alongside active or public transport, compared to using a car alone, attenuated the association between SI and all-cause mortality (interaction HR = 0.93, CI: 0.87-0.99). ConclusionMixed transport, including a car, showed the greatest reduction in the association between SI and all-cause mortality. Our findings motivate further exploration of the role of transportation modes in enhancing social connection, mobility, and health.