The Lancet Healthy Longevity

Purpose: Neurogenic dysphagia is prevalent in neurological inpatients and associated with adverse outcomes, yet its independent economic impact after adjustment for frailty and functional status remains poorly quantified. We aimed to estimate the independent effect of dysphagia on hospital length of stay (LOS) and costs, to test whether this effect differs between geriatric and non-geriatric patients, and to quantify the probability and magnitude of cost savings from improvements in swallowing function. Methods: We analysed 10,375 neurological inpatient cases (2021-2024) at a German university hospital. Dysphagia was defined by fiberoptic endoscopic evaluation of swallowing (FEES) or ICD-10 R13 coding (n = 1,382; 13.3%). Bayesian Gamma-log regression with informative priors from historical data and published literature was used to model LOS and total case costs (German DRG), adjusted for age, sex, Hospital Frailty Risk Score (HFRS, R13-adjusted), self-care index ("Selbstpflege-Index", SPI), stroke status, and emergency admission. A geriatric cohort was defined as age >=70 and adjusted HFRS >=5 (n = 2,053; 19.8%). Posterior predictive simulation estimated cost savings for hypothetical improvements of 1-3 points on the Functional Oral Intake Scale (FOIS). Results: After comprehensive adjustment, dysphagia was independently associated with 46.5% longer LOS (posterior ratio 1.465; 95% credible interval [CrI] 1.397-1.537) and 28.2% higher total case costs (ratio 1.282; CrI 1.213-1.354). The dysphagia x geriatric interaction was small but credible and ran in opposite directions: slightly attenuated for LOS (interaction ratio 0.908, CrI 0.837-0.986) but slightly amplified for costs (1.096, CrI 1.012-1.185), consistent with complexity-driven DRG grouping in geriatric patients. The absolute economic burden remained larger in the geriatric cohort due to higher baseline costs. In the geriatric cohort, a one-point FOIS improvement yielded a 74.3% posterior probability of LOS-based savings (mean EUR 555/case); at three points, this rose to 84.2% (mean EUR 1,115/case). The direct cost model confirmed high benefit probabilities from the payer's perspective (82.6% at dFOIS = 3). Conclusions: Neurogenic dysphagia is an independent and substantial driver of hospital LOS and costs in neurological inpatients, even after adjustment for frailty and functional status. The proportional effect on costs is slightly larger in geriatric patients, while the LOS effect is slightly smaller, consistent with the mechanics of the G-DRG system. Bayesian simulation indicates that improvements in swallowing function carry a high probability of generating cost savings, supporting the characterisation of dysphagia as a modifiable economic target with particular relevance to geriatric neurology.

BackgroundKCNT1-related disorders are a rare, severe neurogenetic disorder associated with early-onset, treatment-resistant seizures and significant developmental comorbidities. Currently there are no treatment-modifying therapeutics for this condition, and the condition necessitates complex, lifelong care that places a profound financial strain on affected families and healthcare systems. However, data quantifying this economic burden is sparse. ObjectiveTo evaluate the annual cost burden of KCNT1-related disorders in the United States using both caregiver-reported expenditures and electronic medical record (EMR) data, providing a comprehensive analysis of direct, indirect, and out-of-pocket expenses. MethodsA retrospective cohort analysis was conducted using two complementary data sources. In 2025, 34 U.S-based. caregivers from the KCNT1 Epilepsy Foundation registry completed a survey capturing insurance status, medical and non-medical expenses, and indirect costs. Separately, EMR data from 49 U.S.-based patients with KCNT1 variants were extracted from the Citizen Health database. Clinical services were mapped to CPT and HCPCS codes, and costs were calculated using Medicare fee schedules and other publicly available datasets. ResultsCaregiver-reported data revealed that all respondents possessed some form of insurance coverage, primarily through private insurance purchased independently or through their employer, or Medicaid. Nearly half of respondents (18/34) experienced financial hardship, citing high out-of-pocket expenses, medical debt, and loss of income due to caregiving responsibilities, and twelve percent of respondents delayed treatment due to financial strain (n=4). The estimated mean total annual medical cost per family--including direct, indirect, non-medical, and non-covered expenses--ranged from $355,474 to $797,727, based on upper and lower bounds of response categories from 10 respondents. EMR analysis, which only reported on direct medical costs, revealed that average first-year direct medical costs reached $154,389 per patient based on the records from 49 patients. This cost was primarily driven by hospitalizations, medications, and therapeutic procedures. Based on EMR data, direct medical costs declined once the patients reached two years of age and stabilized in subsequent years. Hospitalizations remained the most substantial cost contributor regardless of the age of the patient. ConclusionKCNT1-related disorders imposes a substantial economic burden on families and healthcare systems, particularly in the first year after diagnosis. This study highlights the need for rapid diagnostic procedures, targeted therapies, improved insurance coverage, and legislative support for families managing rare, high-burden conditions. Findings provide essential cost data to support drug development, healthcare planning, and rare disease policy reform. SignificanceThis is the first U.S.-based study to quantify both medical and non-medical costs associated with KCNT1-related disorders using combined caregiver and EMR data. The results highlight the urgency of disease-modifying treatments and equitable access to care, informing clinical trials and advocacy for systemic healthcare support.

Objective To examine the impact of acute illness on long-term health and describe any differences in these associations between socioeconomic and ethnic groups. Design Longitudinal population study. Setting Linked primary and secondary care data recorded in the Clinical Practice Research Datalink (CPRD). Participants Adults ([≥]18 years) residing in England registered with a primary care general practice (GP) between 1st January 2012 and 31st December 2022 who have not opted out of inclusion into CPRD and linked data sources. Socioeconomic deprivation was defined using the Index of Multiple Deprivation (IMD) and ethnicity by UK census 2011 definitions. Main outcome measures The primary outcome was new long-term disease and multimorbidity (two or more long-term diseases). We describe incidence of hospitalisation for acute illness as the exposure. Results We included 18,329,659 people, with 9,339,394 (51.0%) women, 7,430,555 (40.5%) people from the most deprived deciles (IMD 1-4) and 3,009,717 (16.4%) from a minority ethnic group. 6,038,272 (32.9%) people experienced hospitalisation for acute illness. Hospitalisation was associated with increased onset of long-term disease in those alive at the end of follow up (41.1% hospitalised vs 18.7% not hospitalised; adjusted HR 2.48 (2.47 to 2.48)). Compared to non-hospitalised, those who had been hospitalised were more likely to change from being disease free at baseline to having a new long-term disease (12.9% vs. 7.5%), develop multimorbidity (4.7% vs. 1.1%), or transition to multimorbidity if they had pre-existing disease (8.1% vs. 1.8%). Age-standardised hospitalisation rates were highest in the most deprived decile and in people with Black ethnicity. Comparative hospitalisation ratio for IMD 1 compared to IMD 10 ranging from 1.78 in 2018 to 1.96 in 2021 and for Black ethnicity compared to White ranging from 1.03 in 2017 to 1.08 in 2021. Conclusions Acute hospitalisation is a key stage in the development of long-term disease and may be an underutilised opportunity for intervention to change healthy life trajectory and reduce health inequality.

ImportanceRecent reports have highlighted an intense influenza activity related to the circulation of the influenza A(H3N2) subclade k variant. There is no data available on the impact of the emergence of H3N2 subclade k on the severity of the 2025-2026 epidemic or on the clinical phenotype of patients requiring admission to the intensive care unit (ICU). ObjectiveTo compare the clinical presentation, hospital mortality and virological characteristics of patients with laboratory-confirmed influenza infection included in French intensive care units during the 2025-2026 epidemic season with those of patients admitted during the 2024-2025 season. We also aimed at measuring the impact of the A(H3N2) subtype on hospital mortality during the 2025-2026 season. DesignProspective, multicenter, observational SEVARVIR cohort study including patients admitted during the 2024-2025 and 2025-2025 influenza seasons. SettingForty-two French ICUs ParticipantsAdult patients with laboratory-confirmed influenza infection Interventionsnone Main Outcomes and MeasuresThe primary outcome measure was in-hospital mortality. ResultsPatients admitted in intensive care units for influenza in 2024-2025 (n=360) and 2025-2026 (n=325) were included in the French nationwide prospective multicentre SEVARVIR study. There was no significant difference in day-28 mortality between the seasons (12.7%, n=45/355 vs 16.5% n=28/170; p=0.28). In the 2025-26 season, 49% had the A(H1N1) subtype and 51% the A(H3N2) subtype (k subclade: 77%). The univariable Cox analysis revealed that patients infected with A(H3N2) viruses were at greater risk of death over time. Multivariable Cox analysis revealed that during the 2025-2026 season, age (adjusted hazard ratio, aHR=1.05 [1.00;1.11]; p=0.046) and the clinical frailty scale (aHR=1.82 [1.26;2.72]; p=0.001) were associated with an increased risk of death. The A(H3N2) subtype was not associated with an increased risk of death (aHR=1.13 [0.32;4.51]; p=0.85). Phylogenetic analyses from our ICU cohort together with 300 contextual sequences from community-acquired influenza cases collected during the same period showed no clustering according to severity. Conclusions and RelevanceThis French national prospective observational study, found that the emergence of the influenza A(H3N2) subclade K was associated with an increased risk of death in univariable but not multivariable analysis, adjusting for host-related factors. Trial RegistrationNCT051625 Key PointsQuestion: What impact did the 2025-26 influenza epidemic and the A(H3N2) variant have on the mortality of patients admitted to intensive care units? Findings: In this prospective, nationwide cohort study of 685 patients admitted to intensive care units with severe influenza during the 2024-25 or 2025-26 seasons, no difference in hospital mortality was observed between the two seasons. Patients infected with the A(H3N2) virus, 77% of which corresponded to clade k, were at higher risk of death in univariable but not in multivariable analysis after adjusting for age and clinical frailty scale. Meaning: Patients in intensive care units with severe A(H3N2) infection during the 2025/2026 season were not at higher risk of death after adjusting for confounding variables.

Health visiting is England's universal home visiting programme for families with children under five and a key pillar of early intervention policy. Since the 2015 devolution of commissioning to Local Authorities (LAs), the service has faced sustained financial and workforce pressures, yet there is limited systematic evidence on whether resources and delivery have evolved differentially across areas and along the deprivation gradient. Using new Freedom of Information (FOI) data, we estimate how health visiting inputs (spending and workforce) and mandated contact delivery vary in levels and trajectories by baseline deprivation. FOI requests covered 147 English LAs (four pairs submitted joint returns), providing annual 2016-2021 Full-Time Equivalent (FTE) data on Health Visitors (HVs) and Clinical Skill Mix Staff (CSMS), which we link to DHSC Health Visitor Service Delivery Metrics reporting completion of the five mandated 0-5 reviews (New Birth Visits, 6-8 week reviews, 12-month reviews, 2-2.5 year reviews, and 2-2.5 year reviews completed with ASQ-3) and to LA revenue outturn expenditure on mandated and non-mandated 0-5 public health services (real-terms total and per child under five). Between 2016 and 2021, HV FTE fell by around one-fifth while CSMS expanded by roughly one-third, consistent with an overall contraction and a shift toward lower-band staff. To test whether these changes map onto underlying disadvantage, we stratify LAs into tertiles of baseline deprivation using the 2015 Income Deprivation Affecting Children Index (IDACI) and implement a three-part empirical strategy: (i) plotting tertile means over time, (ii) testing within-year cross-sectional differences using parametric and non-parametric methods with pairwise comparisons, and (iii) estimating LA fixed-effects regressions with Year x IDACI interactions under both a flexible year-by-year specification and a parsimonious linear-trend specification to assess differential trajectories. We find persistent cross-sectional gradients in per-child spending that are broadly progressive (more deprived LAs spend more per child on both mandated and non-mandated 0-5 services), while fixed-effects models show little evidence that spending trajectories differ systematically by deprivation. Workforce trends are more uneven: HV FTE declines more slowly and CSMS FTE grows more slowly in more deprived LAs in the linear-trend specification, while per-child HV trajectories show no differential trends. Despite these input differences, completion of mandated contacts is relatively stable across the deprivation gradient; the only consistent differential trend is faster improvement in the 6-8 week review in more deprived areas. Meanwhile, caseload pressure rises, increasing most sharply in the most deprived LAs in the pre-pandemic years, suggesting that completion-based performance measures may mask heterogeneities in service capacity and intensity. Finally, we quantify the resources required to restore recommended caseloads, implying the need for approximately 3,100 additional FTE staff and around 120 million GBP annually (plus training costs).

We evaluated 2024/25 KP.2 vaccine effectiveness (VE) against COVID-19 hospitalization among adults >60 years old eligible for publicly-funded vaccination during fall and/or spring campaigns in the province of Quebec, Canada. We included Quebec residents tested for COVID-19-compatible symptoms in an acute-care hospital between October 13, 2024 (epi-week 2024-42) and August 23, 2025 (2025-34), linking vaccine, hospital, chronic diseases and laboratory administrative records to assess VE through test-negative design. We compared the odds of being COVID-19 test-positive versus test-negative among vaccinated versus non-vaccinated participants, adjusting for sex, age, comorbidities, place of residence, and epidemiological week. Overall, 49,949 (43%) participants were vaccinated. Over an analysis period spanning up to ten months, including median time since vaccination of 16 weeks (interquartile range 9-24 weeks), VE was 34% overall, declining from 43% <8 weeks to negligible by the 32nd week post-vaccination. Findings confirm meaningful but short-lived COVID-19 vaccine protection against hospitalization in older adults.

OBJECTIVE: To evaluate the return on investment (ROI) of a community based Diabetes Self Management Program (DSMP) enhanced with health related social needs (HRSN) screening and referrals, implemented by the New York City (NYC) Department of Health and Mental Hygiene with three community based organizations in highly impacted, under resourced neighborhoods. RESEARCH DESIGN AND METHODS: A retrospective cost benefit analysis from a public sector payer perspective was conducted among 171 adults with type 2 diabetes who completed a six week, peer led DSMP delivered by community health workers (CHWs) in English, Spanish, and Korean during 2018 2019. A time driven, activity based costing model captured direct implementation costs, CHW workforce turnover, and administrative overhead. Monetized benefits included avoided diabetes related complications, reductions in self reported emergency department (ED) visits and hospitalizations, and quality adjusted life year (QALY) gains from improved medication adherence. Univariate sensitivity analyses tested robustness under conservative assumptions. RESULTS: Total program costs were $179,224; monetized benefits totaled $1,824,213, yielding a net benefit of $1,644,989 and an ROI of 918%, approximately $10 returned per $1 invested. Excluding QALY gains, ROI remained 551%. Self reported ED visits declined from 149 to 82 and hospitalizations from 93 to 24 in the six months following intervention. Over 80% of participants reported housing instability; 72% were Medicaid covered and 16% uninsured. Sensitivity analyses confirmed a positive ROI under all conservative scenarios. CONCLUSIONS: A CHW led, community based DSMP integrated with HRSN screening and referrals delivered substantial economic and public health value among adults facing housing instability and structural barriers to care. Findings support inclusion of DSMP as a covered benefit in Medicaid managed care, value based payment arrangements, and housing access initiatives to advance equitable diabetes outcomes.

ObjectiveSevere infections have been implicated in dementia risk, but their associations with detailed patterns of cognitive performance, and whether poorer cognition in turn increases risk for certain infections, remain unclear. We examined bidirectional associations between hospital-treated infections and domain-specific cognitive function in a cohort of older adults. MethodsWe analysed data from the English Longitudinal Study of Ageing Harmonised Cognitive Assessment Protocol (ELSA-HCAP), conducted in 2018 and linked to national inpatient records. Pre-HCAP hospital-treated infections were identified from 1997 to 2018; post-HCAP incident infections were ascertained from 2018 to 2024. Cognitive performance was assessed at HCAP using 21 standardised neuropsychological tests summarised into general and four domain-specific scores (executive function, memory, language, and visuospatial ability). Linear regression assessed associations between pre-HCAP hospital-treated infections and standardised cognitive scores; Cox models estimated associations between cognition and risk of incident hospital-treated infections after HCAP. All models were adjusted for sociodemographic, lifestyle, and health covariates. ResultsOf 1,159 participants aged [&ge;]65 at HCAP (631 [54.1%] female; mean [SD] age, 75.6 [7.2] years), 351 (30.3%) had a hospital-treated infection before HCAP. Prior hospitalisation for any infection was associated with lower general cognition ({beta} = -0.11 SD, 95% CI -0.21 to -0.02) and poorer executive function ({beta} = -0.19, -0.28 to -0.09), with similar patterns across infection types. Lower respiratory tract infections were additionally associated with poorer memory ({beta} = -0.20, -0.36 to -0.04). Cognitive scores were progressively lower among individuals with more frequent or prolonged infection-related hospitalisations, sepsis, or cardiovascular disease. Prospectively, over a mean (SD) 4.8 (1.9) years of follow-up, 271 incident hospital-treated infections occurred. Each 1-SD higher general cognition was associated with a 36% lower risk of any subsequent hospital-treated infection (HR 0.64, 0.53 to 0.78), and with consistent associations across cognitive domains for all-cause and bacterial infections. Executive function alone showed a strong association with viral infections, especially COVID-19 (HR 0.59, 0.44 to 0.80). ConclusionSevere infections were primarily associated with poorer executive function. Conversely, cognitive vulnerability across multiple domains was associated with increased susceptibility to infections requiring hospital care, while poorer executive function was specifically associated with viral infection risk. These findings support a reinforcing infection-cognition cycle in later life and cognitively tailored infection-prevention strategies.

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.

ObjectivesTo examine associations between cardiometabolic conditions and health-related quality of life (HRQoL) and to evaluate whether condition-associated HRQoL changed from 2001 to 2022. MethodsWe analyzed nationally representative data from U.S. adults aged [&ge;]18 years in the Medical Expenditure Panel Survey, 2001-2022. Survey years without BMI data (2017, 2019, 2021) were excluded. EQ-5D utilities were mapped from SF-12 scores using a validated algorithm. For each survey year, survey-weighted multivariable regression models estimated associations of sociodemographic characteristics, BMI, and cardiometabolic conditions (diabetes, heart disease, high blood pressure, high cholesterol, obesity, stroke) with HRQoL measured by EQ-5D. Temporal changes in condition-associated HRQoL decrements were assessed using meta-regression across years. Associations in recent survey years were summarized using pooled estimates from 2015, 2016, 2018, and 2022. ResultsOverall HRQoL improved from 2001 to 2022 across age groups, with the largest improvement among older adults. In pooled analyses, stroke was associated with the largest adjusted HRQoL decrement (-0.0714), followed by heart disease (-0.0503), diabetes (-0.0427), high blood pressure (-0.0328), obesity (-0.0305), and high cholesterol (-0.0236). Additional adjustment for BMI attenuated condition-associated decrements, most notably for obesity (-0.0305 to -0.0183), diabetes (-0.0427 to -0.0414), and high blood pressure (-0.0328 to -0.0316). Over time, diabetes- and heart disease-associated decrements attenuated linearly (diabetes: - 0.0489 in 2001 to -0.0406 in 2022; heart disease: -0.0591 to -0.0493). High blood pressure (-0.0337 in 2001, -0.0415 in 2012, -0.0306 in 2022) and obesity (-0.0305 in 2001, -0.0283 in 2012, -0.0367 in 2022) showed nonlinear patterns. ConclusionsCondition-associated HRQoL decrements varied over time, and recent-year utility estimates are recommended for population health research. HRQoL decrements for diabetes and heart disease attenuated, consistent with improvements in treatment and survival. High blood pressure-associated were lowest around 2012, and obesity-associated became more negative after 2012, consistent with worsening blood pressure control and obesity severity.

BackgroundWe investigated frailty progression after severe infections in adults ([&ge;]65 years) in the US and England. MethodsWe conducted parallel matched cohort studies using: US Veterans Aging Cohort Study (VACS-National, 2008-2019; median age 74 years; 98% male); and English Clinical Practice Research Datalink (2006-2019; median age 76 years; 45% male). Adults hospitalised primarily for infection (i.e., severe infection) were matched in calendar date order to individuals without severe infection on age, sex, care site, and US only, plus race and ethnicity. We measured frailty using VACS Index 2{middle dot}0 (US) and Electronic Frailty Index (eFI; England). We estimated annual conditional mean frailty differences between adults with versus without severe infection using linear regression adjusting for baseline frailty, demographics, lifestyle factors, infection history, and US only, comorbidities. ResultsMean baseline frailty was higher in those with severe infection than those without (US: 57 v 48; England: 0{middle dot}17 v 0{middle dot}12). At Year 1, adjusted mean frailty was higher among adults with severe infections than those without (US: VACS Index +2{middle dot}0, 95% CI 1{middle dot}9-2{middle dot}0; England: eFI +0{middle dot}005, 95% CI 0{middle dot}005-0{middle dot}006). At Years 2-5, adjusted mean frailty remained higher after severe infection; however, compared to Year 1, differences were smaller in US, and larger in England. Effects varied by infection type (strongest for lower respiratory tract infections, meningoencephalitis (UK only), urinary tract infections, and sepsis). InterpretationIndividuals with severe infections had higher frailty at baseline and follow up than those without. Preventing both frailty and infections is important for improving health in older age. FundingWellcome Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed (inception to October 27, 2025), for published articles evaluating the association between infections and frailty, with no language restrictions. We used the search terms [(infection OR infectious) AND (frailty OR frail)]. We found fifteen observational studies investigating associations between individual infections (including: HIV, cytomegalovirus, SARS-CoV-2, acute respiratory infection, urinary tract infection, and influenza) and frailty in adults. Frailty measures varied: eight studies used Frieds phenotype index, six used versions of the cumulative deficit index (i.e., Edmonton Frail Scale, FRAIL-NH Scale, Hospital Frailty Risk Score, Clinical Frailty Score, Veterans Affairs Frailty Index, Vulnerable Elders Survey-13), and one study used the Timed Up and Go Test. Results from identified studies were mixed, with nearly half (7/15) reporting a positive association between the infection studied and frailty, and the remaining eight finding no evidence of association. In cross-sectional analyses, HIV, SARS-CoV-2, cytomegalovirus, and urinary tract infection, were each associated with higher mean frailty scores or frailty prevalence. In longitudinal analysis, hospitalisation for acute respiratory infection was followed by higher mean hospital frailty risk scores two years post-discharge. SARS-CoV-2 infection was associated with early onset (i.e., higher hazard) of frailty over three years follow-up. However, other studies found no association between HIV, SARS-CoV-2, acute respiratory infection and influenza, and frailty prevalence, incidence, or transition between frailty states. These mixed findings may reflect methodological differences between the studies, including variation in frailty measures, and study limitations. Frailty exists along a continuum of vulnerability, and progression after infection may be an important outcome, yet current evidence is scarce. It remains unclear whether severe infections or different types of infection, are associated with faster frailty deterioration. Similarly, it is uncertain whether post-infection frailty risk varies by pathogen (bacterial, viral, parasitic, fungal), infection type (sepsis, urinary tract infection, skin and soft tissue infection, meningitis/encephalitis, lower respiratory tract, gastroenteritis), or by age, sex, social deprivation, and pre-existing comorbidities. Added value of this studyOur study compared frailty progression over a five-year period between adults aged [&ge;]65 years with severe infection (hospitalisation primarily due to infection) versus comparators without severe infection. We found higher baseline frailty at severe infection onset than in matched comparators. We saw evidence of increased frailty progression over time in people following severe infections compared to those without, however, these differences were small. We also saw higher risk of worsening frailty progression in older adults and those with dementia. Further, worsening frailty progression varied by infection type (strongest for lower respiratory tract infections, meningoencephalitis (UK only), urinary tract infections, and sepsis). Implications of all the available evidenceOur findings underscore the importance of both frailty and infection prevention in improving health in older age. Additional studies are required to explore other wider life-course influences on frailty, to guide the development of comprehensive preventive strategies.

BackgroundAgeing is associated with reduced resilience to physiological stressors such as infection and surgery. This reduced resilience is believed to be underpinned by the hallmarks of ageing, the key biological mechanisms driving the aged phenotype. Geroprotectors are drugs that are proposed to slow down the ageing process and promote longevity and healthspan. Despite this, mechanistic studies in healthy older adults are lacking. Methods and AnalysisThis trial will test the hypothesis that geroprotectors targeted towards biological mechanisms associated with poor resilience can reverse these pathways within a three-week period. Three geroprotectors with a good safety profile in older adults and evidence of effect on the hallmarks of ageing will be administered to 60 (30 female; 30 male) adults 70+. Participants will be randomised to one of three arms (Metformin MR 1500mg, Fisetin 100mg or Spermidine 15mg). Participants will be extensively clinically characterised at baseline. Blood, abdominal adipose tissue and stool samples will be taken at baseline and following the three-week intervention. The primary research question will answer whether a three-week course of Metformin, Spermidine, or Fisetin reduce the number of senescent cells as measured by SA-{beta}-GAL in adipose biopsies in healthy older volunteers. Additionally, there will be assessment of the effect of the geroprotectors on other hallmarks of ageing, including autophagy, immunosenescence, chronic inflammation, dysregulated mTOR signalling, epigenetic age, DNA damage, dysregulated metabolism, stem cell exhaustion and microbial composition. Ethics and DisseminationEthical approval is in place (24/LO/0549). The main trial report and any sub-studies will be published in high impact peer-reviewed gerontology journals, presented at academic conferences and through a series of public engagement events. Participants enrolled in the study will be informed of the results by a written summary. Trial RegistrationREPROGRAM was registered with ISRCTN on 10/09/24. ISRCTN47919839. Available at https://www.isrctn.com/search?q=47919839. Trial Registration Data Set O_TBL View this table: org.highwire.dtl.DTLVardef@1db6074org.highwire.dtl.DTLVardef@1997837org.highwire.dtl.DTLVardef@a39a11org.highwire.dtl.DTLVardef@d7e6eforg.highwire.dtl.DTLVardef@7a5b7f_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 1C_FLOATNO O_TABLECAPTIONTrial Registration Data Set C_TABLECAPTION C_TBL

Background Surgery is a widely used treatment option but the impact of surgery on long-term disease across socioeconomic groups is unknown. Methods Longitudinal population study using linked primary and secondary care data describing adults ([&ge;]18 years) in England recorded in the Clinical Practice Research Datalink (CPRD) between 1st January 2012 and 31st December 2021. Socioeconomic deprivation was defined using the Index of Multiple Deprivation (IMD). The exposure was surgery and primary outcome was long-term disease. Data are presented as n (%), median (IQR), and adjusted hazards ratios (HR) with 95% confidence intervals. Findings Of 18,329,659 people, 8,951,145 (48.8%) underwent surgery. 78.6% of index surgeries were elective (n=7,032,475), 21.4% were emergency (n=1,918,670). Amongst surgical patients, 4,741,188 (52.0%) were women, 3,540,136 (39.6%) from the most deprived deciles (IMD 1-4) and 994,595 (11.1%) from a minority ethnic group. Age-standardised rates of surgery were higher in deprived individuals (comparative rate ratio IMD 1 vs. IMD 10 elective: 1.11 (95% CI 1.11-1.11), emergency: 1.54 (1.54-1.54)). Age at first surgery was 42 (27-60) years for elective and 42 (25-65) years for emergency surgery overall, but lower for people from IMD 1-4 (elective: 39 (26-57) years, emergency: 38 (24-60) years). Rates of long-term disease increased following both elective (baseline 19.6%, three years 24.5%) and emergency surgery (baseline 10.3%, three years 12.3%). Risk of new long-term disease following surgery increased with increasing levels of deprivation (IMD 1 vs. IMD 10 elective: HR 1.46 (1.45-1.48), emergency: HR 1.46 (1.44-1.48)). Interpretation Surgical treatment is strongly associated with the onset of long-term disease and factors which limit healthy life expectancy. Surgery occurs at a younger age among socioeconomically deprived groups and may be linked to health inequalities. Similar but more complex patterns of inequality were seen in minority ethnic groups. Funding Barts Charity and UK Academy of Medical Sciences.

BackgroundOlder age is widely considered a risk factor for post-acute sequelae of SARS-CoV-2 infection (PASC), typically attributed to immunosenescence and inflammaging. However, whether this association reflects intrinsic biological ageing or accumulated comorbidity burden remains unclear, with implications for clinical risk stratification. MethodsWe conducted a retrospective cohort study using the Precision PASC Research Cohort (P2RC) from Mass General Brigham, comprising 133,792 COVID-19 patients from 12 hospitals and 20 community health centres in Massachusetts (March 2020-May 2024). PASC was ascertained using a validated computational phenotyping algorithm. We used generalised estimating equations with cluster-robust variance to model PASC risk, causal mediation analysis to decompose age effects through comorbidity burden and acute severity, and specification curve analysis across 768 analytical specifications to assess robustness. FindingsAfter adjustment for comorbidity burden, each decade of age was associated with 6% lower odds of PASC (OR 0.94; 95% CI 0.93-0.95). Causal mediation analysis revealed that comorbidities accounted for 145% of the total age effect, indicating inconsistent mediation wherein ages direct protective effect was masked by its indirect harm through chronic disease accumulation. This protection was age-dependent: adults younger than 65 years retained robust resilience independent of comorbidities (ADE:-0.0042, p<0.001), whereas adults 65 years and older showed complete loss of this protection (ADE: +0.0020, p=0.14). InterpretationLong COVID susceptibility is driven by physiological reserve rather than chronological age until approximately age 65, beyond which age-related protective mechanisms become exhausted. Risk stratification should prioritise comorbidity burden over birth year in younger adults. FundingNational Institute of Allergy and Infectious Diseases (NIAID).

Background: The 2025/2026 COVID-19 vaccine season introduced updated formulations targeting the LP.8.1 lineage. This study assessed the absolute vaccine effectiveness (aVE) of mRNA-1283 and BNT162b2 on COVID-19 outcomes in adults aged [&ge;]65 years. Methods: Background: The 2025/2026 COVID-19 vaccine season introduced updated formulations targeting the LP.8.1 lineage. This study assessed the absolute vaccine effectiveness (aVE) of mRNA-1283 and BNT162b2 on COVID-19 outcomes in adults aged [&ge;]65 years. Methods: This retrospective study used linked electronic health record and administrative claims data through Jan 31, 2026. Adults [&ge;]65 years who received the mRNA-1283 or BNT162b2 2025/2026 COVID-19 vaccine were matched to unvaccinated individuals. Inverse probability of treatment weighting was applied to matched cohorts of each vaccine to balance covariates. Each vaccine was evaluated independently against its own unvaccinated comparator group. aVE against COVID-19 related hospitalization and medically-attended COVID-19 was estimated using Cox proportional hazards models; aVE = 100 x (1 - hazard ratio [HR]). Results: We identified 233,072 mRNA-1283 recipients and 422,610 BNT162b2 recipients [&ge;]65 years. The aVE (95% confidence interval) of mRNA-1283 against COVID-19 related hospitalization and medically-attended COVID-19 was 59.3% (39.0%, 72.9%) and 42.0% (35.0%, 48.3%) among adults [&ge;]65 years and 66.9% (45.9%, 79.8%) and 50.2% (42.1%, 57.2%) in [&ge;]75 years, respectively. The aVE of BNT162b2 against COVID-19 related hospitalization and medically-attended COVID-19 was 48.3% (32.4%, 60.5%) and 41.2% (36.2%, 45.8%) in [&ge;]65 years and 45.9% (26.0%, 60.4%) and 44.0% (37.8%, 49.6%) in [&ge;]75 years, respectively. Conclusions: This is the first real-world evidence showing that mRNA-1283 prevents COVID-19-related hospitalizations and medically attended events in vulnerable older adults at highest risk of severe disease. These findings support mRNA-1283 as an important public health tool for reducing the ongoing burden of COVID-19.Results: We identified 233,072 mRNA-1283 recipients and 422,610 BNT162b2 recipients [&ge;]65 years. The aVE (95% confidence interval) of mRNA-1283 against COVID-19 related hospitalization and medically-attended COVID-19 was 59.3% (39.0%, 72.9%) and 42.0% (35.0%, 48.3%) among adults [&ge;]65 years and 66.9% (45.9 %, 79.8%) and 50.2% (42.1%, 57.2%) in [&ge;]75 years, respectively. The aVE of BNT162b2 against COVID-19 related hospitalization and medically-attended COVID-19 was 48.3% (32.4%, 60.5%) and 41.2% (36.2%, 45.8%) in [&ge;]65 years and 45.9% (26.0%, 60.4%) and 44.0% (37.8%, 49.6%) in [&ge;]75 years, respectively. Conclusions: This is the first real-world evidence showing that mRNA-1283 prevents COVID-19-related hospitalizations and medically attended events in vulnerable older adults at highest risk of severe disease. These findings support mRNA-1283 as an important public health tool for reducing the ongoing burden of COVID-19.

ObjectivesTo evaluate rates of treatment for depression and identify resident- and facility-level predictors of pharmacotherapy among long-term care (LTC) residents in the United States. DesignRetrospective, observational study. Setting and ParticipantsElectronic health record data from 1,675,873 LTC residents in the PointClickCare Life Sciences database (January-April 2025) were reviewed and 358,425 skilled nursing facility residents with a documented depression diagnosis were identified. MethodsResidents were classified as treated/untreated based on having a medication order for pharmacological depression treatment within medication classes recommended by the American Psychological Association. Descriptive analyses incorporated demographic and clinical characteristics, and multivariable logistic regression estimated odds of treatment. ResultsOverall, 81.7% of residents diagnosed with depression had [&ge;]1 pharmacological depression treatment order. Selective serotonin reuptake inhibitors (59.8%) and miscellaneous antidepressants (42.3%) were the most frequently used classes. Treatment rates were similar across depression diagnoses. Higher odds of receiving treatment were observed among residents also diagnosed with vascular dementia and those with hyperlipidemia medication orders. Lower odds were noted among residents who were Black or African American, had diabetes or hyperlipidemia diagnoses, or resided in facilities located in areas with poor socioeconomic status. Conclusions and ImplicationsMost residents with depression had at least one recommended pharmacologic therapy, although important disparities remain. Racial differences, comorbid conditions, and facility context continue to influence treatment access. These findings support the need for improved screening practices, greater attention to equity in prescribing, and strengthened clinical resources in socially vulnerable settings to enhance the quality of depression care in LTC facilities. Brief SummaryDepression is common in long-term care (LTC) and is associated with poor functional and clinical outcomes, however recent treatment patterns are not well understood. Using electronic health record data from 1,675,873 U.S. LTC residents between January and April 2025, 358,425 skilled nursing facility residents were identified with a documented depression diagnosis. The use of antidepressant medication was assessed based on medication order history and was aligned with American Psychological Association recommendations. Overall, 81.7% had at least one pharmacologic treatment order for depression; selective serotonin reuptake inhibitors (59.8%) and miscellaneous antidepressants (42.3%) were most frequently used. After adjusting for covariates, lower odds of treatment were observed among Black or African American residents and among residents in facilities located in more socioeconomically vulnerable areas. These findings highlight persistent inequities in depression pharmacotherapy in LTC and support efforts to strengthen depression assessment and ensure equitable access to evidence-informed treatment across facilities.

BackgroundOptimal rehabilitation dosing after ischaemic stroke remains contested. Linear assumptions underlying conventional regression models may mask clinically important threshold effects, whereby functional gains accelerate or plateau beyond specific intensity thresholds. This study applied panel threshold regression to Australian hospital administrative data to identify endogenous breakpoints in the dose-response relationship between rehabilitation intensity and functional recovery. MethodsWe used a retrospective longitudinal cohort derived from the Australian Stroke Clinical Registry (AuSCR) and the National Hospital Cost Data Collection (NHCDC) for fiscal years 2018-2019 to 2022-2023. The analytical sample comprised 18,742 hospitalised ischaemic stroke patients across 48 public hospitals in five Australian states. The primary exposure was daily rehabilitation intensity (minutes of physiotherapy, occupational therapy, and speech pathology per inpatient day). The primary outcome was change in the modified Rankin Scale (mRS) score from admission to discharge. We employed Hansens (1999) panel threshold regression framework to test for single, double, and triple threshold effects, using bootstrap p-values (n=500) to establish statistical significance. Fixed-effects estimation controlled for unobserved hospital heterogeneity. Secondary outcomes included acute length of stay and discharge destination. Cost-related parameters were benchmarked against published Australian cost-effectiveness data. ResultsThe panel threshold model identified two statistically significant breakpoints in the intensity-recovery relationship (p<0.001 for both). Below the first threshold (27.4 minutes/day; 95% CI: 24.8-29.6), each additional minute of daily rehabilitation was associated with a 0.008-point reduction in mRS score (beta = -0.008, 95% CI: -0.011 to -0.005, p<0.001). Between the two thresholds (27.4 to 54.7 minutes/day; 95% CI: 51.2-58.9), the marginal benefit approximately doubled (beta = -0.018, 95% CI: -0.022 to -0.013, p<0.001). Above the upper threshold (>54.7 minutes/day), the marginal effect diminished substantially (beta = -0.004, 95% CI: -0.009 to 0.002, p=0.186), suggesting a ceiling effect. These dose-response patterns were consistent across age subgroups, stroke severity strata, and hospital volume tertiles. ConclusionsRehabilitation intensity thresholds exist in stroke inpatient recovery and are non-linear. Patients receiving between 27 and 55 minutes of daily multidisciplinary therapy derive disproportionate functional benefit per unit of resource investment. Scheduling rehabilitation below the lower threshold represents a clinically and economically suboptimal allocation of inpatient resources. These findings have direct implications for workforce planning, clinical pathway design, and value-based commissioning in Australian public hospitals.

Background: The role of biological age acceleration (BioAgeAccel) in the dynamic progression from single cardiovascular-kidney-metabolic disease (CKMD) to multimorbidity, and subsequently to dementia and mortality remains elusive. Methods: We conducted a longitudinal study with data of 433,911 UK Biobank participants. Cardiovascular-kidney-metabolic multimorbidity (CKMM) was defined as the coexistence of two or more CKMDs, including cardiovascular disease (CVD), stroke, type 2 diabetes (T2D), and chronic kidney disease. Biological aging was measured via PhenoAge and KDM-BA. Multistate models examined the association between BioAgeAccel and disease transitions, ranging from healthy to the first occurrence of CKMD (FCKMD), then progression to CKMM, dementia, and mortality. Restricted mean survival time estimated the disease transition time or life expectancy between states. Results: BioAgeAccel was significantly associated with increased risks across all disease transitions. Specifically, during CKMM progression, the hazard ratios (HRs) of the transition from healthy to FCKMD were 1.24 [95%CI 1.23-1.25] for PhenoAgeAccel and 1.16 [1.15-1.17] for KDM-BA-Accel. For subsequent transition to CKMM, the HRs were 1.20 [1.18-1.22] and 1.19 [1.17-1.21], respectively. In dementia-related transitions, PhenoAgeAccel showed the higher risk for CKMM to dementia (HR=1.13 [1.04-1.22]) than for the transition from healthy or from FCKMD to dementia. These associations were further moderated by age, physical activity, educational, and lifestyle factors. BioAgeAccel also accelerated disease progression and reduced life expectancy; for example, during CKMM progression, BioAgeAccel shortened the time between disease transitions by about 1.09 years from healthy to FCKMD, and an additional 1.75 years to CKMM. Regarding life expectancy, individuals with CKMM experienced an average reduction of about 1.36 years under PhenoAge, while those with dementia showed a decrease of about 0.77 years. Among individuals with CVD or T2D as the initial diagnosis, the impact of BioAgeAccel on progression to CKMM or dementia was stronger. Conclusions: BioAgeAccel exerts significant promotive role in the onset of CKMD and their subsequent progression to CKMM, dementia, and mortality, helping identify high-risk individuals. Implementing biological age assessments and health lifestyle interventions in middle-aged populations serves as an effective strategy for alleviating the burden of CKMDs and dementia.

ObjectivesAn update to the NICE Type 2 diabetes (T2DM) guideline in February 2022 recommended an SGLT2 inhibitor be offered to people with cardiovascular disease (CVD) or heart failure (HF) as comorbidities and considered for people at high CVD risk. We report uptake of this guideline in England 18 months after its publication. DesignObservational cohort study. SettingGeneral practices contributing to the Clinical Practice Research Data Link, linked to hospital admission records. Participants587,826 people aged over 18 years with T2DM on 1st September 2023, stratified according to their CVD category (CVD only; HF only; CVD and HF; high CVD risk score; low CVD risk score) and chronic kidney disease (CKD) status, and further by age, gender, ethnicity, deprivation, and T2DM diagnosis duration. Main outcome measuresPercentage of patients with a current SGLT2 inhibitor prescription; odds ratios for association between patient characteristics and a current prescription. ResultsIn people with T2DM, the percentage with a current SGLT2 inhibitor prescription was 19.5% for people with CVD, 29.4% for people with HF, 30.5% for people with both CVD and HF, and 19.9% and 20.2% respectively for people at high and low CVD risk. In age-stratified analyses, uptake ordered from lowest to highest was as follows: low CVD risk score, high CVD risk score, CVD only, HF only, CVD and HF. In models adjusted for clinical and patient characteristics uptake was lower in people aged >60, women, Black people, and people living in areas of higher deprivation. ConclusionsWhilst prescribing of SGLT2 inhibitors continues to rise in England, an opportunity remains to increase uptake and to reduce inequalities in people with T2DM in 2026. We report inequalities by ethnicity and deprivation, and lower uptake for people with CVD without HF than people with HF, despite an equal guideline recommendation for these two groups. Additional evidence is needed on the effectiveness of SGLT2 inhibitors in frailer populations. What is already known on this topic?O_LIIn 2020 approximately 10% of people with type 2 diabetes (T2DM) and cardiovascular disease (CVD) and 14% of people with T2DM but without CVD in England had a current SGLT2 inhibitor prescription. C_LIO_LIIn February 2022 NICE recommended that an SGLT2 inhibitor should be offered to people with T2DM with heart failure or CVD, and considered for people with T2DM at high risk of CVD; network meta-analyses have found 10% to 40% lower odds of cardiovascular mortality with treatment in these groups. C_LIO_LIUptake of NICE guidelines in general practice has historically been variable, although higher when accompanied by pay-for-performance schemes such as the Quality and Outcomes Framework. C_LI What this study addsO_LIBy September 2023 the percentage of people with T2DM with a current SGLT2 inhibitor prescription had reached 19.5% in those with CVD as a comorbidity, 30.5% in those with heart failure, and 19.9% in those at high risk of CVD. C_LIO_LIWomen, people of Black ethnicity, and people living in areas of high deprivation had lower odds of a current prescription in analyses adjusted for age, gender, cardiovascular comorbidity, and renal function. C_LI How might these results change the focus of research or clinical practice?O_LIThe results highlight the need for ongoing surveillance of uptake of NICE-recommended treatments for T2DM, and consideration of actions to address barriers to uptake. This is particularly important in the context of broader eligibility for SGLT2 inhibitor treatment in type 2 diabetes in England from 2026. C_LIO_LIThese results support the development of initiatives and quality improvement programmes to improve evidence-based prescribing and address inequalities between clinical and demographic subgroups. C_LI

Frailty is a multisystem clinical syndrome closely linked to cognitive aging, yet its cerebral underpinnings and co-contribution to adverse outcomes remain poorly understood. In 63,509 dementia-free UK Biobank participants (aged 65.0{+/-}7.7), higher frailty index (FI) was associated with multiple neuroimaging markers, including reduced hippocampal volume, decreased cortical thickness, greater white matter hyperintensities burden, and impaired brain diffusion metrics. FI and neuroimaging markers additively increased the risks of incident dementia and mortality. An extreme gradient boosting with accelerated failure time framework highlighted FI and key regional neuroimaging features in dementia risk prediction (nested C-index=0.825, iAUC=0.759). Integrating the top 10 predictors into a novel point-based cerebral frailty risk score (CFRS) showed strong performance in predicting dementia onset (optimism-corrected C-index=0.838, iAUC=0.778), and was robust to the competing risk of mortality. These findings highlight the potential utility of a CFRS framework that integrates cumulative systemic and cerebral vulnerabilities for dementia risk stratification.