Journal of the American Geriatrics Society

Burn trauma disproportionately impacts older adults, yet existing burn severity models emphasize age, total body surface area (TBSA), and inhalation injury without accounting for geriatric-specific vulnerabilities such as frailty. We conducted a retrospective cohort study of 326 geriatric patients admitted with burn injuries between 2020 and 2024 to evaluate how TBSA, burn location, inhalation injury, renal insufficiency, comorbidities, and functional dependence in activities of daily living (ADLs) and instrumental activities of daily living (IADLs) affect in- hospital mortality and discharge disposition. Based on multivariable logistic regression and chi- square analyses, TBSA, as expected, emerged as the strongest predictor across models. Each 1% increase in TBSA was associated with a 7% increase in the odds of in-hospital mortality (p=0.006) and a 12 to 19% increase in odds of post-acute care placement (p<0.001). Inhalation injury and renal insufficiency were also independently associated with increased odds of both mortality and post-acute care disposition, whereas respiratory comorbidity predicted mortality alone. Functional status demonstrated outcome-specific prognostic value: ADL dependence predicted mortality, while IADL dependence predicted discharge disposition. Patients with some ADL dependence had five-fold higher odds of in-hospital mortality (p=0.011), while some (OR=2.48, p= 0.039) and full IADL dependence (OR=2.61, p=0.025) were associated with higher odds of post-acute care placement. Integrating structured functional assessments that distinguish basic from instrumental limitations alongside established burn severity metrics may enhance prognostication and guide individualized care planning for older adults with burn injuries.

Background: Advance care planning (ACP) documentation, including living wills and durable power of attorney (DPOA), is intended to support goal concordant end of life care. However, it is unknown if comprehensive documentation confers additional benefits, and how these associations vary across clinical contexts. Methods: We used 2010 to 2022 Health and Retirement Study exit interview data to examine associations between ACP documentation and end of life care among U.S. adults aged 50 years and older. Documentation was categorized as none, one document (living will or DPOA), or two documents (both). Outcomes included intensive care unit (ICU) use, life sustaining treatment, hospice enrollment, and out-of-hospital death. Modified Poisson regression models were used to estimate adjusted risk ratios (aRRs), and temporal trends in documentation were assessed using joinpoint regression. Results: Among 5,622 decedents representing 23.2 million individuals, 42.7% had two documents and 28.9% had none, documentation increased substantially around 2014. Compared with no documentation, having any documentation was associated with lower likelihood of life-sustaining treatment (aRR=0.85, 95% CI: 0.74 to 0.98) and higher likelihood of hospice enrollment (aRR=1.43, 95% CI: 1.28 to 1.60) and out-of-hospital death (aRR=1.11, 95% CI: 1.06 to 1.18), but not ICU use. Having two documents showed similar patterns, with modest differences compared with one document after adjustment. Associations were stronger among decedents with expected death and attenuated among those with unexpected death. Conclusions: Comprehensive ACP documentation is associated with less aggressive end of life care and greater hospice use, though the incremental benefits of two documents are modest. Findings highlight the importance of documentation within care planning processes and the clinical context.

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.

Postoperative resilience varies widely among older adults, yet the biological drivers of recovery remain unclear. We evaluated whether preoperative immune profiles, measured in plasma and through ex vivo whole blood stimulation, predict resilience to the acute stress of total knee arthroplasty. A total of 152 adults (greater or equal to 60 years) in the PRIME KNEE cohort underwent elective total knee arthroplasty and had available blood samples for measurement of 45 immune biomarkers, quantified in plasma and in whole blood stimulated ex vivo for 24 hours with lipopolysaccharide (LPS) or influenza antigen (FLU). Resilience was assessed using Expected Recovery Differential (ERD) and Resilience Trajectory (RT) across pain severity, pain interference, lower extremity physical activities of daily living (LE PADLs), and step counts. An exploratory stability selection framework using LASSO identified biomarker predictors of postoperative outcomes. Plasma and stimulated biomarkers showed broadly similar predictive performance. A shared set of biomarkers, including LBP, leptin, TNFR1, CD30, and LIF, was consistently selected across models. Immune predictors explained ~12-24% of the variance in resilience outcomes. Distinct immune signatures emerged for pain versus functional recovery: pain related predictors mapped to local inflammatory and neuroimmune pathways, whereas function related predictors reflected systemic inflammatory load and cytokine signaling. Preoperative immune biomarkers, whether measured in plasma or after ex vivo stimulation, capture meaningful variance in postoperative resilience. The divergence between pain related and function related immune signatures highlights biologically distinct pathways underlying different dimensions of recovery and supports further development of immune based perioperative risk assessment.

The VACS 2.0 Frailty Index was developed using the VA health records system to identify frailty and predict mortality in older Veterans that were living with HIV. Systemic inflammatory indices have been associated with frailty, but little is known about the association between frailty and immunosenescence. We aim to investigate the potential link between soluble inflammatory indices, T cell expression of exhaustion and senescence markers, and frailty as measured by the VACS 2.0 index. We analyzed a one-time blood draw for plasma levels of inflammatory indices, T cell subsets and expression of exhaustion and senescence markers, and calculated VACS 2.0 index scores in a cohort of 30 older (>65 years) Veteran participants. We found that VACS 2.0 scores correlated with the number of prescribed medications in the older Veterans. Soluble TNF receptor levels strongly correlated with VACS 2.0 frailty scores. How these soluble TNF receptors are generated and whether they mechanistically contribute to frailty warrants further investigation.

Objectives: Cardiovascular disease (CVD) is a leading cause of mortality and disability in older populations. This study aimed to identify CVD risk factors in community-dwelling older adults and to examine whether frailty-related factors (sarcopenia and nutritional status) interact with chronic kidney disease (CKD). Methods: This cross-sectional study included 307 community-dwelling Japanese adults aged [&ge;]65 years between September 2024 and March 2025. CVD history was assessed based on self-reported physician diagnoses obtained through a structured questionnaire. Lifestyle-related factors included hypertension, diabetes, dyslipidemia, and body mass index (BMI). Frailty-related factors included sarcopenia (Asian Working Group for Sarcopenia 2019 criteria), nutritional status (Mini Nutritional Assessment-Short Form), and physical activity (International Physical Activity Questionnaire-Short Form). CKD was defined using the estimated glomerular filtration rate (eGFR): non-CKD ([&ge;]60 mL/min/1.73 m2) and CKD (<60 mL/min/1.73 m2). Multivariable logistic regression identified independent correlates of CVD, and interactions between CKD and frailty-related factors were tested. Results: The prevalence of CVD was 17.9%. Independent correlates included CKD (aOR 5.0), hypertension (aOR 4.0), male sex (aOR 3.1), undernutrition (aOR 2.7), sarcopenia (aOR 2.7), and low physical activity (aOR 2.5). No significant interactions were observed between CKD and sarcopenia (p = 0.70) or nutritional status (p = 0.40). Conclusions: CKD, sarcopenia, undernutrition, and low physical activity were independently associated with CVD, with no interaction between CKD and frailty factors. These findings suggest that integrated management addressing both renal function and frailty-related factors may be important for CVD prevention in older adults.

Delirium, a dynamic neuropsychiatric condition associated with morbidity and mortality, remains underdiagnosed due to reliance on subjective, intermittent screening tools. Objective and potentially continuous identification is needed to improve clinical care. We developed and validated an analytic framework for delirium classification based on automatically extracted video features. In this prospective cohort study, patients ([&ge;] 18 years) admitted to the inpatient medical or neurological ward of a tertiary academic center between August 2020 and March 2022 with an expected stay longer than one night were enrolled. Daily structured delirium assessments and brief video recordings were performed in consenting patients. Videos were analyzed using deep learning pose estimation to extract keypoints and calculate behavioral features based on eye, face, and limb postures and movements. Four machine learning models (logistic regression, gradient boosting, support vector machines, and random forests) were trained to predict delirium status from extracted features. Model performance was evaluated on 20 repetitions of three-fold cross-validation using the area under the curve of the receiver operating characteristics curve (AUC ROC). The cohort included 109 videos from 25 male and 25 female participants (median age: 72, IQR: 63.25-78). Twenty videos (18%) were from patients with delirium. Keypoints for this dataset were more accurately extracted using a customized ResNet-101 model developed with DeepLabCut (sensitivity 0.94, specificity 0.89, compared to human-labeled gold standards) than using off-the-shelf models. Keypoints were then used to generate behavioral features summarizing movement and postures throughout the video. A support vector machine model achieved an average delirium classification AUC ROC of 0.79 (SD {+/-} 0.09), sensitivity of 0.71 (SD {+/-} 0.16), and specificity of 0.78 (SD {+/-} 0.07). This study demonstrates the feasibility of identifying delirium using brief videos in clinically heterogeneous cohorts and reveals novel features for objective identification. Author SummaryDelirium is a sudden change in attention and awareness that commonly affects hospitalized patients. It is linked with longer hospital stays, cognitive decline, and death. Patients with delirium often show changes in movements and behaviors such as slowed movement, restlessness, or excessive scanning of the environment. Since current screening tools rely on intermittent human interactions, they can be subjective and miss the fluctuating nature of delirium, leading to underdiagnosis. We sought to explore whether short video recordings could be used to detect delirium automatically. In our study, we enrolled 50 hospitalized patients and conducted daily delirium assessments and video recordings. We used a machine learning model to analyze patients eye movements, facial expressions, and body postures. We found that video-derived features could be used to identify delirium in a small clinical cohort. While needing further validation in outside cohorts, this study shows an important proof-of-concept for objective delirium monitoring in heterogeneous clinical contexts without adding burden to clinical staff.

BackgroundPrediabetes is highly prevalent in older adults and is characterized by heterogeneous clinical trajectories, including regression to normoglycemia and progression to diabetes. While prediabetes has been associated with impaired physical function and frailty, the longitudinal impact of both a single diagnosis and dynamic glycemic transitions on functional outcomes remains unclear. We aimed to evaluate associations between baseline prediabetes and glycemic transitions over time with trajectories of functional capacity and frailty in older adults. MethodsWe conducted a pooled analysis of harmonized data from five nationally representative longitudinal aging cohorts (MHAS, HRS, CHARLS, ELSA, CRELES) within the Gateway to Global Aging Data, including adults aged [&ge;]50 years with [&ge;]1 HbA1c measurements. Prediabetes was defined per ADA criteria (HbA1c 5.7-6.4%). Functional outcomes included activities of daily living (ADL), instrumental ADL (IADL), and frailty assessed using Fried phenotype, FRAIL scale, and a deficit-accumulation Frailty Index (FI). Mixed-effects Poisson models estimated incidence rate ratios (IRRs) for baseline prediabetes, while generalized estimating equations assessed time-varying glycemic status and transition trajectories. Models were adjusted for age, sex, cohort, and time-varying covariates, with sensitivity analyses including BMI, smoking, and alcohol intake. FindingsAmong 18,571 participants (median follow-up 13.6 years), baseline prediabetes was associated with increased progression of functional deficits and frailty compared with normoglycemia, including higher FI values and accelerated FI progression. Prediabetes was associated with higher incidence of ADL, IADL, and multimorbidity deficits from early follow-up, although time-dependent changes in incidence rates were not significant. In time-varying analyses (n=7,840), both prediabetes and diabetes were associated with higher incidence of functional deficits compared with normoglycemia, with diabetes showing the strongest effects across all outcomes. Diabetes was associated with greater FI burden and accelerated progression, whereas prediabetes showed a smaller increase, with attenuation over time. Among individuals with baseline prediabetes, regression to normoglycemia occurred in 20.8% and was associated with increased incidence of ADL and frailty deficits. In contrast, progression to diabetes occurred in 24.3%, and was associated with lower risk of incident ADL and Fried frailty deficits compared to stable prediabetes. InterpretationPrediabetes is associated with increased risk of functional decline, frailty, and deficit accumulation in older adults, independent of progression to diabetes. Regression to normoglycemia was associated with higher risk of functional deterioration. These findings suggest that prediabetes reflects a state of metabolic vulnerability linked to biological aging rather than solely a precursor to diabetes and highlights a need to reframe its clinical significance in older populations. FundingThis research was supported by Instituto Nacional de Geriatria in Mexico. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed up to April 1, 2026, using the terms ("prediabetes") AND ("frailty" OR "functional decline" OR "activities of daily living" OR "mortality") AND ("older adults" OR "aging" OR "longitudinal" OR "cohort"). Existing evidence from predominantly single-country and cross-sectional studies suggests that prediabetes is associated with increased risk of frailty, disability, and adverse health outcomes in older adults. However, findings have been inconsistent, particularly regarding incident versus prevalent outcomes and the role of competing risks in aging populations. Importantly, few studies have used harmonized multinational longitudinal data, incorporated repeated measures of glycemic status, or evaluated multiple complementary frailty constructs. The impact of dynamic glycemic transitions, including regression to normoglycemia and progression to diabetes, on functional trajectories remains poorly understood. Added value of this studyThis study leverages harmonized longitudinal data from five nationally representative aging cohorts from Mexico, England, China, Costa Rica and the United States to examine both baseline prediabetes and time-varying glycemic status in relation to trajectories of functional decline and frailty. By integrating multiple validated measures of functional capacity and frailty, and applying longitudinal modeling strategies, we provide a comprehensive assessment of the relationship between prediabetes and age-related outcomes. We further characterize glycemic transition trajectories and show that regression to normoglycemia among older adults with prediabetes is associated with increased risk of frailty, while progression to diabetes does not uniformly confer additional risk beyond stable prediabetes. Implications of all the available evidenceOur results support a reconceptualization of prediabetes in older adults as a marker of systemic vulnerability rather than solely a precursor to diabetes. Glycemic status in later life appears to also reflect underlying physiological reserve, with dynamic changes potentially signaling deterioration rather than improvement. Our findings suggest a need to incorporate glycemic markers into geriatric risk stratification and to interpret their changes in the context of aging biology. Future research should focus on elucidating the mechanisms linking dysglycemia with frailty and functional decline, including the roles of sarcopenia, inflammation, and multimorbidity, and on evaluating interventions tailored to older populations across diverse global contexts.

Background: Despite the growing global burden of multimorbidity, the patterns of disease combinations, have not been extensively categorized. We aimed to explore the predictors, health consequences, and patterns of discordant and concordant multimorbidity. Methods: We used the 2018 China Health and Retirement Longitudinal Study (CHARLS), a representative database of adults aged >45 years from China. We conducted logistic regression analyses to assess the likelihood of having discordant (conditions from different disease systems) versus concordant (only cardiometabolic, or only respiratory diseases) multimorbidity, and to compare the health status and healthcare utilization between patients with discordant and concordant multimorbidity. Latent class analysis (LCA) was applied to both the entire sample and to patients with discordant multimorbidity to identify clusters of disease combinations. Results: The sample included 1668 patients with concordant (mainly cardiometabolic), and 7306 patients with discordant, multimorbidity. Female patients, patients living in rural settings, former and current smokers, and patients engaging in high-intensity physical activity, were more likely to have discordant instead of concordant multimorbidity. Depression, limitations in daily activities, poor self-reported health, and frequent healthcare use were more common in patients with discordant than concordant multimorbidity. The LCA identified five clusters when all multimorbid patients were included (cardiometabolic, arthritis-digestive, respiratory, multisystem, and arthritis-hypertension classes), and four clusters when restricted to discordant multimorbidity (digestive, arthritis-cardiometabolic, respiratory, and multisystem classes). Conclusion: Discordant multimorbidity is associated with poorer health and increased use of healthcare. Cardiometabolic diseases, arthritis, and digestive diseases have a central role in defining disease patterns.

Background: Wheeled walkers can improve safety during walking, but improper use may increase fall risk among frail older adults. No suitable tool exists to assess safe indoor wheeled walker use in this population. This study aimed to develop and validate a video-based expert assessment tool. Methods: Based on the literature and expert consensus, seven problematic indoor situations were identified, and an assessment tool with five safety criteria per situation was developed (maximum score = 35). Fifty participants (mean age 83.9 years, 64% women) from a geriatric rehabilitation clinic and a nursing home were video-recorded while using a rollator. Expert ratings were compared with nursing staff ratings, self-ratings, and the Timed Up and Go test to evaluate validity. Intra- and inter-rater reliability were determined from independent ratings by two physiotherapists and a repeated expert rating after seven days. Sensitivity to change was assessed after two weeks of rehabilitation, and feasibility by the time required for assessment. Results: The expert score of rater 1 at baseline was 28.5 points, and assessment required a mean of 17.5 minutes. Intra-rater reliability was excellent (ICC = 0.98) and inter-rater reliability was good (ICC = 0.80). Validity analyses showed the strongest association with nursing staff assessments (r = 0.74) and a moderate association with the Timed Up and Go test (r = -0.45). After two weeks, patients improved by an average of 2.38 points (8.4% of baseline score). Conclusions: The new instrument demonstrated high reliability, acceptable validity, sensitivity to change, and good feasibility for assessing safe wheeled walker use in frail older adults. Trial registration number and date of registration: DRKS00038358, 07/11/2025

Background Insomnia symptoms are common in older adults. While observational studies suggest physical activity (PA) timing affects health outcomes, its effect on sleep remains unclear. We compared morning versus evening PA effects on insomnia severity and sleep quality in older adults with insomnia symptoms. Methods Eligible participants were aged 60 to 80 years with (sub)clinical insomnia (Insomnia Severity Index [ISI] score [&ge;]10). In a randomized cross-over trial, participants engaged in coached PA in the morning (10:00 - 11:00) or evening (19:30 - 20:30) for 14 days each. ISI scores were assessed post-intervention. Objective sleep parameters; duration, latency, efficiency, and timing, were assessed with a Withings Sleep Analyzer under the mattress. Subjective sleep quality was reported daily via smartphone app. Salivary dim light melatonin onset (DLMO) was measured on the final day of each intervention. Results Of 37 participants (mean ISI 14.3 {+/-} 3.3), 27 completed the study (mean age 69.8 {+/-} 5; 63% women). ISI scores improved after both morning ({Delta} - 2.5; 95% CI: - 1.14, - 3.83) and evening ({Delta} - 2.0; 95% CI: - 0.63, - 3.38) activity relative to baseline, but were not different between interventions. Compared to evening activity, sleep midpoint occurred earlier with morning activity (03:40 vs 04:00; {Delta} - 20 min; 95% CI: - 31, - 8). No differences in subjective sleep quality or DLMO were found. Exploratory analyses suggested insomnia scores improved specifically in late chronotypes following morning activity. Conclusions While morning vs. evening PA timing did not impact most sleep quality measures, it influenced sleep timing. Larger studies are needed to define optimal and personalized PA timing for improving sleep.

Background: LLMs enable patient-facing conversational agents, creating a pathway toward digital twins that capture older adults' lived experiences and behavioral responses across time. A central barrier is personality drift---inconsistent trait expression across repeated interactions---which undermines reliability of generated trajectories and intervention-response simulation in geriatric care. Objective: To develop ELDER-SIM, a multi-role elderly-care conversational platform for building personality-stable digital twin agents, and to propose a psychometric validation framework for quantifying personality consistency in LLM-based agents. Methods: ELDER-SIM was implemented via n8n workflow orchestration with local LLM inference (Ollama/vLLM), integrating (1) Big Five (OCEAN) trait specifications, (2) a Cognitive Conceptualization Diagram (CCD) grounded in Beck's CBT framework, and (3) a MySQL-based long-term memory module. Ablation studies across four conditions---Baseline, +Memory, +CCD, and +LoRA (fine-tuned on 19,717 instruction pairs from CHARLS)---were evaluated via Cronbach's $\alpha$, ICC, and role discrimination accuracy. Results: Personality measurement reliability was acceptable to excellent across conditions (Cronbach's : 0.70-0.94), with consistently high test-retest stability (ICC: 0.85- 2 0.96). Role discrimination improved stepwise from 83.3% (Baseline) to 88.9% (+Memory), 94.4% (+CCD), and 97.2% (+LoRA). CCD produced the largest gain in internal consistency (mean 0.702[-&gt;]0.892), while LoRA achieved the highest overall internal consistency ( 0.940) and ICC (0.958). Conclusions: ELDER-SIM provides a psychometrically validated approach for constructing personality-consistent elderly digital twin agents. Structured cognitive modeling and domain adaptation reduce personality drift, supporting reliable longitudinal simulation for elderly mental health care and reproducible in silico evaluation before clinical deployment.

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.

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

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.

OBJECTIVE: Bladder cancer (BC) is predominantly a disease of older, comorbid adults, and radical cystectomy (RC), which is the gold standard treatment, carries considerable morbidity. We sought to determine the impact of baseline dementia and frailty on the care trajectory beyond the immediate postoperative period. We hypothesized that frail patients and those with dementia undergoing RC for BC will have poorer care trajectories. METHODS AND MATERIALS: We identified Medicare beneficiaries [&ge;] 66 years old who underwent RC for BC in 2017 with 12 months of pre- and post-RC enrollment. Frailty and dementia were characterized using validated, claims-based measures. Associations between baseline frailty and dementia with postoperative care trajectory outcomes were determined using Fine-Gray competing risk models. RESULTS: We identified 3,600 beneficiaries of whom 11.6% were frail and 3.4% met criteria for dementia. Patients with dementia were more likely to be frail, comorbid, and not receive standard-of-care neoadjuvant chemotherapy. Frailty was independently associated with [&ge;] 2 transitions in care level after index discharge from RC and skilled nursing facility (SNF) admissions within 1 year of RC, exposure to intensive post-RC interventions, including dialysis and feeding tube placement, and poorer survival. Dementia remained associated with SNF admissions regardless of frailty level. CONCLUSIONS: Among a contemporary cohort of older adults undergoing RC for BC, preoperative dementia and frailty were independently associated with poorer care trajectory beyond the immediate postoperative period after RC. Our work highlights a role for preoperative geriatric assessment in identifying and optimizing patients at greatest risk.

Background: Sleep problems are common in older people and have been associated with increased fall risk, but the mechanisms underlying this relationship remain unclear. Gait quality reflects balance control and neurological function and may provide insight into pathways linking sleep health and falls. Methods: Data from 758 community-dwelling older people ([&ge;]65 years; mean age 75.8 years, 69.3% women) were analysed. Sleep problems were assessed at baseline using a self-reported item (Patient Health Questionnaire-9, question 3). Daily-life gait quality and habitual walking speed were derived from one week of wearable sensor monitoring. Falls and injurious falls were prospectively recorded over 12 months. Associations between sleep problems, gait quality, and fall incidence were examined using regression models adjusted for demographic, pain and cognitive factors, and use of sleeping medication. Results: Sleep problems were reported by 43.9% of participants. Sleep problems were not associated with habitual walking speed, but were associated with lower gait quality in daily life (adjusted {beta} = -0.15, 95% CI -0.27 to -0.03). Participants reporting sleep problems had higher incidence rates of total falls (adjusted IRR = 1.42, 95% CI 1.07 to 1.90) and injurious falls (adjusted IRR = 1.50, 95% CI 1.07 to 2.10). Conclusions: Self-reported sleep problems were associated with impaired real-world gait quality and substantially higher rates of falls and injurious falls in older people. These findings suggest that sleep problems may increase fall risk by altering balance control rather than by reducing walking speed. Sleep should be considered when managing fall risk, and fall risk should be considered in older people with sleep complaints.

BackgroundEarly recognition of dementia-related changes is critical for timely intervention. The AD8 Dementia Screening Interview (AD8) detects subtle cognitive and functional changes, yet its broader associations with health and wellbeing among Chinese-speaking older adults remain underexplored. MethodsA cross-sectional study was conducted with 144 community-dwelling Chinese older adults (mean age 73.1 years; 81.3% female). Participants completed sociodemographic, health, functional, and psychosocial measures, including the AD8 and the Geriatric Depression Scale (GDS-15). Exploratory Factor Analysis (EFA) assessed the dimensionality of the AD8, and binary logistic regression examined associations between AD8 items and demographic, health, functional, and psychosocial outcomes. ResultsChronic disease was prevalent (68.1 percent), and 13.2 percent reported a mental health disorder. EFA identified three domains: memory impairment, executive and interest decline, and functional recall difficulties, explaining 61.7 percent of the variance. Logistic regression showed predictive roles for judgment problems (AD8_1), repetition (AD8_3), financial difficulties (AD8_6), tool-use difficulties (AD8_4), and daily memory problems (AD8_8). Financial and executive difficulties were associated with age and mobility challenges, while repetition predicted psychological disorders and hopelessness. Judgment problems were linked to lower life satisfaction and happiness but greater helplessness. Worthlessness was predicted by financial, tool-use, and memory difficulties, whereas intact temporal recall (AD8_5) was protective. Several outcomes including boredom, low energy, and staying home were not significant. ConclusionDistinct AD8 items predicted vulnerabilities across physical, psychological, and social domains. Findings highlight the multidimensional value of the AD8 as a culturally relevant screening and risk stratification tool for community-based assessments of Chinese older adults. Summary Statement Implications for PracticeO_ST_ABSWhat does this research add to existing knowledge in gerontology?C_ST_ABSThis study shows that specific AD8 items identify early multidimensional vulnerability among community-dwelling Chinese-speaking older adults. Difficulties with judgment, repetition, financial management, tool use, and daily memory were associated with functional limitations and psychosocial distress, extending the AD8 beyond dementia screening alone. The identification of three AD8 domains supports a broader understanding of early cognitive change as involving cognitive, functional, and emotional processes. The findings contribute culturally specific evidence from an under-researched population in gerontological research. What are the implications of this new knowledge for nursing care with older people?For nursing practice, the AD8 provides a brief, feasible tool to support holistic assessment in community and aged care settings. Key AD8 indicators can guide nurses in identifying older people at risk of functional decline and emotional vulnerability, enabling earlier, person-centred interventions. The findings highlight the importance of culturally and linguistically appropriate assessment when caring for diverse ageing populations. How could the findings be used to influence policy or practice or research or education?The results support integrating brief cognitive screening into routine nursing assessments and community-based aged care services to promote early identification and ageing in place. Nursing education should emphasise interpreting cognitive screening within psychosocial and cultural contexts. Longitudinal research is needed to assess intervention effectiveness. Key Points[tpltrtarr] Early cognitive changes matter for older Chinese-speaking adults, because difficulties with judgment, repetition, financial management, and tool use (AD8 domains) were consistently linked to poorer functional and psychosocial outcomes. [tpltrtarr]Beyond dementia screening, the AD8 proved useful for detecting vulnerabilities in wellbeing and daily functioning, extending its role beyond diagnostic sensitivity. [tpltrtarr]A cultural focus is vital, as this study is among the first to examine AD8 associations in older Chinese-speaking adults, underscoring the need for culturally tailored screening. [tpltrtarr]The psychosocial impact of cognitive changes was evident, with strong associations to helplessness, worthlessness, and reduced life satisfaction, reinforcing the overlap between cognitive and emotional health. [tpltrtarr]In practice, integrating AD8 screening into community and primary care could help identify at-risk individuals early and support targeted interventions in culturally and linguistically diverse populations.

BackgroundPoor physical function has been associated with higher cardiovascular disease (CVD) risk. However, the association between physical function and atrial fibrillation (AF) remains understudied. The comprehensive investigation of the association between physical function and incident AF risk could highlight a novel target for AF prevention. MethodsA total of 4,803 participants without diagnosed AF from the Atherosclerosis Risk in Communities (ARIC) Study cohort with physical function assessed in 2011-2013 were studied. Physical function was measured using Short Physical Performance Battery (SPPB), 4-meter walk time, and grip strength. Hospital discharge codes and death certificates were used to ascertain incident AF through 2022, and through 2020 for participants from Jackson. Cox regression was used to assess the association between physical function and incident AF risk, adjusting for multiple covariates. Z-score transformations were performed to identify the physical function measure most strongly associated with incident AF risk, and SPPB component analysis was performed to identify the most influential SPPB component. ResultsMean age of the study participants was 75.1 {+/-} 5.0 years, with 41.2% being male participants and 22.2% being black participants. During a median follow-up of 9.2 years, there were 809 incident AF events. SPPB (HR: 0.93, 95% CI: 0.90-0.96, per 1-point increase) and grip strength (HR: 0.87, 95% CI: 0.78-0.96, per 10kg increase) were inversely associated with incident AF risk, while 4-meter walk time (HR: 1.08, 95% CI: 1.03-1.13, per 1-second increase) was positively associated with incident AF risk. SPPB had the strongest association with incident AF risk. Within SPPB, only the chair stand component was significantly associated with incident AF risk. ConclusionsThe findings suggest that better physical function is associated with reduced incident AF risk, with higher SPPB having the strongest association. Given the modifiable nature of physical function, these findings highlight a potential novel target for AF prevention in aging populations. What is KnownO_LIPhysical function has been associated with cardiovascular diseases, however, the relationship between physical function and incident atrial fibrillation (AF) remains understudied. C_LI What the Study AddsO_LIThis study found that better Short Physical Performance Battery (SPPB), 4-meter walk time, and grip strength were all independently associated with reduced risk of incident AF. C_LIO_LIIn this study, higher SPPB was most strongly associated with reduced risk of incident AF, implying the importance of multi-domain measures of physical function. C_LIO_LIThis study found that within SPPB, higher chair stand component score was the only component significantly associated with reduced risk of incident AF, highlighting the critical role of muscle strength in the association between physical function and risk of incident AF. C_LIO_LIThe results suggest that physical function may be a novel modifiable target for AF prevention. C_LI

Objective: Alzheimer's disease (AD) is a leading cause of death and disability, and treatment options for Alzheimer's disease and related dementias (ADRD) remain limited. We applied a data-driven, mechanism-agnostic Medication-Wide Association Study Plus (MWAS+) framework to identify candidate medications associated with ADRD using longitudinal electronic health record data and explainable artificial intelligence (AI). Methods: We used Veterans Health Administration electronic health record data from January 1999 to May 2022. The initial study population comprised 8,424,715 Veterans aged 65 years or older. Cases were defined by ADRD-related diagnosis codes or ADRD-related medication prescriptions, and controls were free of ADRD diagnosis and ADRD-related medication use. After exclusions and matching on sex, race, age at first encounter, and duration of follow-up, the primary analytic cohort included 505,817 matched case-control pairs (1:1; 1,011,634 Veterans). Longitudinal features were extracted from historical data up to 1 year before the index date and aggregated into 1-year intervals. We developed an upgraded Hybrid Value-Aware Transformer (HVAT 2.0) to jointly learn from longitudinal and nonlongitudinal clinical data while incorporating numerical values associated with clinical concepts, including cumulative medication dose. To enhance interpretability, we applied a medication-specific impact score method to estimate model-derived associations between medication exposure and ADRD risk. Findings: The model demonstrated stable performance across data partitions, with area under the receiver operating characteristic curve values of 0.791 in the training set, 0.772 in the validation set, and 0.775 in the testing set. Metolazone and varenicline were identified as the top 2 candidate medications with negative impact scores, suggesting potentially protective associations with new-onset ADRD. The impact score was -0.196 per unit of cumulative dose for metolazone (1800 mg) and -0.134 per unit for varenicline (280 mg). Although individual-level impact scores varied, most exposed patients had negative scores, including 12,020 of 12,480 metolazone users (96%) and 8,341 of 8,786 varenicline users (95%). Implications: This study demonstrates the feasibility of combining a medication-wide association framework, longitudinal dose-aware modeling, and explainable AI to identify candidate medications for ADRD from real-world electronic health record data. The findings should be interpreted as signals for hypothesis generation rather than evidence of causality. This framework may support prioritization of repurposing candidates for expert review, follow-up cohort validation, and future clinical investigation.