Age and Ageing

Background: In the UK, over 36 million contacts are made annually by people living with dementia (PLWD) to either primary or secondary community mental health services. As dementia progresses, PLWD may experience increased distress and resort to 999 calls for an ambulance, which may in turn result in conveyance to Accident & Emergency (A&E). Nearly 1 million A&E attendances are made by PLWD. This trend is set to rise sharply as the prevalence rates of dementia increase over time and as the condition progresses, with associated healthcare costs impacting overall care delivery. This may lead to reduced resource allocation for dementia emergency services, negatively affecting the experiences of both providers and service users. Aim(s): To explore ways to improve access and quality of care to emergency crisis care for PLWD from the perspective of healthcare staff providing this type of support. Methods: This qualitative study explored (1) the experiences, resources, and needs of healthcare professionals in emergency and community settings to support access for PLWD, and (2) the mechanisms influencing dementia crisis response. The COREQ Checklist was used to improve transparency, credibility, and reproducibility. Inter-rater reliability was calculated. PPIE contributors co-developed recommendations for healthcare professionals, and study findings informed a comic-based dissemination resource shared with third-sector organisations to support community awareness and engagement. Results: Fifteen interviews were held with emergency services staff. Inter-rater reliability was substantial between two raters (k = 0.62). Four overarching themes, with associated subthemes, were identified relating to crisis care delivery, barriers to effective response, and strategies employed to address these challenges. Additional themes captured decision-making processes at key points in the care pathway, including initial crisis response, during intervention, and at discharge from emergency and community services. Decision-making was characterised by the need to balance patient safety with autonomy in determining care in the best interests of PLWD and their informal carers. Discussion: This exploratory study reveals frontline staff perspectives on challenges and actionable strategies for dementia crisis care. Findings support targeted service improvements, cross-sector collaboration, and co-produced resources to enhance outcomes for PLWD and their informal carers.

Background: People affected by dementia experience intersecting care inequalities. We explored relationships between ethnicity and health and social care resource use among people with dementia in an ethnically diverse urban region. Methods: We conducted a retrospective observational cohort study using Discover-NOW, including patients with dementia between 1.4.2015 and 1.4.2025. We calculated ethnic density as the percentage of the Middle Layer Super Output Area (SOA) population self-identifying with the same ethnic group. Regression models, clustered by Local SOA, tested whether ethnic density moderated relationships between ethnicity and primary care, outpatient, inpatient, emergency and social care service use, controlling for sociodemographic characteristics, deprivation, comorbidities and time of diagnosis. Findings: We included 30,704 people with dementia. People from Black and Mixed ethnic groups used more primary care, and those from Asian ethnic groups less primary and secondary care, than White ethnic groups. Rates of local authority social care packages were similar across ethnic groups. High ethnic density predicted fewer GP consultations in Black ethnic groups, but more in South Asian groups. Interpretation: Among Black ethnic groups, primary care use was relatively high, especially in areas of low ethnic density, perhaps reflecting greater needs among communities at risk of racism and isolation. The trend towards increased primary care use among South Asian people in areas of higher ethnic density may reflect communities mitigating help-seeking hesitancy related to cultural and language barriers. Greater care integration could reduce care inequalities among minority ethnic communities who may experience fewer barriers to social relative to health care.

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 [≥] 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 [≥] 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: 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 Low-level systemic inflammation has been associated with late-life depressive symptoms. Whether individuals with higher inflammation derive preventive benefit from low-dose aspirin therapy is unknown. Methods We performed a post-hoc analysis of the ASPiring in Reducing Events in the Elderly (ASPREE) randomised, double-blind, placebo-controlled trial. Baseline C-reactive protein (hsCRP) was measured in plasma and depressive symptoms were assessed annually using the Center for Epidemiologic Studies Depression 10 Scale with elevated symptoms defined as CES-D-10 >= 8. Participants with elevated depressive symptoms at baseline were excluded. We fitted population-averaged logistic generalised estimating equation models adjusted for baseline sociodemographic and lifestyle covariates, including an hsCRP x treatment interaction to test effect modification by aspirin. Results Higher baseline hsCRP was associated with increased odds of elevated depressive symptoms during follow-up (OR 1.07 per SD increase in hsCRP, 95% CI 1.03-1.11). Low-dose aspirin allocation did not modify the hsCRP-depressive symptoms association (interaction OR 1.02, 95% CI 0.94-1.10). Findings were similar after additional adjustment for comorbidity and other covariates. Conclusions In community-dwelling older adults during the ASPREE randomised trial period, higher baseline hsCRP was modestly associated with elevated depressive symptoms. There was no evidence that low-dose aspirin was associated with reduced risk of depressive symptoms among participants with higher baseline inflammation.

Background. The emergency department in the United States of America functions as a residual access point for healthcare and social services for populations including rural communities, the uninsured, mental health and addiction patients, and the unhoused. The workforce variable that determines unit function (experience density, the concentration of accumulated clinical judgment within a unit workforce) is not measured in hospital accounting systems. Objective. To document workforce composition changes in U.S. emergency nursing across the 2018 and 2022 cycles of the National Sample Survey of Registered Nurses (NSSRN), and to specify falsifiable predictions for the 2026 cycle. Methods. We analyzed NSSRN public-use files using a four-way ED definition extending Castner et al. (2024) and a hospital-bedside-restricted comparator. Variance estimation used jackknife replicate weights for 2018 and Successive Differences Replication for 2022. Burnout was operationalized using the Norful et al. (2023) leaving-reasons proxy across cycles, with sensitivity analysis using the 2022 direct burnout item. Results. A 15-year trajectory (2008-2022) documents progressive experience-density compression: the ED's 15+ year veteran cohort fell from 41.9% to 28.0% over the decade preceding the pandemic, a loss of nearly a third of the senior cohort and a 19.6% decline in mean experience density, before recovering modestly to 33.3% as veteran nurses remained through the pandemic acute phase, leaving the ED as the youngest hospital setting throughout. Hospital non-ED bedside nurses lost senior tenure between cycles (mean 15.65[-&gt;]14.06 years since first licensure; 15+ year share 43.5%[-&gt;]38.7%), while ED nurses retained their senior tail (mean 11.60[-&gt;]12.58). Burnout endorsement rose sharply in both populations (non-ED 27.3%[-&gt;]46.0%; ED 34.2%[-&gt;]61.2%), with the ED-vs-non-ED gap more than doubling. Controlling for tenure, ED status was not independently associated with burnout in 2018 (OR 1.15, 95% CI 0.83-1.59) but was strongly associated in 2022 (OR 1.92, 95% CI 1.44-2.55; p<.001). The direct burnout item showed a parallel pattern (OR 2.92, 95% CI 1.62-5.28). Conclusions. A pandemic-era setting-specific burnout effect emerged in emergency nursing that workforce-composition controls cannot explain. The 2022 cycle establishes a pre-exit baseline against which the 2026 NSSRN will serve as the falsifiable test of post-Omicron veteran exit. Nursing pipeline replacement lag exceeds the interval before 2026 data arrives; the consequences of inaction fall on populations dependent on ED-based residual access.

Background Slow walking in older adults with mild parkinsonian signs (MPS) is a complex, multifactorial phenomenon arising from the cumulative burden of subclinical age-associated pathologies. This decline reflects age-associated neuronal loss in the dopaminergic system. A recent study suggests that levodopa treatment may enhance gait parameters. The goal of this small pilot study is to explore the effect of levodopa treatment on slow walking gait in older adults with MPS. Method This study was a randomized, placebo-controlled clinical pilot trial. Slow walking older adults without clinical evidence of PD were recruited and randomized into 2 groups (active treatment group or placebo control group). Participants in the active group were pre-treated with carbidopa for three days, followed by carbidopa-levodopa for seven days. Spatiotemporal gait parameters were evaluated at baseline and post-intervention. Results Gait factor analysis identified three main factors explaining gait characteristics at baseline, which included gait efficiency, gait rhythmicity, and gait turning.No effect of treatment was observed in the placebo group (p=0.111, p=0.616), no group difference was observed between the placebo and active group at baseline ({beta}=0.310, p=0.547), but a strong trend for a treatment-related increase was observed in the active treatment group ({beta}=0.506, p=0.076). Conclusion Our preliminary data suggest that sustained levodopa treatment (one week) in conjunction with carbidopa pre-treatment and concomitant carbidopa supplementation is feasible in slow walking older adults with MPS. Moreover, the data indicate potential efficacy, showing improvements in cadence, and step durations.

Background Chronic pain is common in adults aged 85 years and older (85+) and is associated with detrimental outcomes. Chronic pain guidelines advise first line management with non-pharmacological measures; paracetamol and non-steroidal anti-inflammatory drugs are the preferred analgesics. Challenges in accessing non-pharmacological therapies for adults aged 85+, and the presence of multimorbidity and polypharmacy, mean that opioid medication is often prescribed for chronic pain despite the potential for opioid-related adverse effects and guidance identifying long-term opioids for chronic pain as a potentially inappropriate prescription. Aim This study aims to explore patient, caregiver, and healthcare professional perspectives on the prescription of opioid medications for pain management for chronic pain in adults aged 85+ to support development of resources for optimising opioid prescribing. Design and Setting In this qualitative study, participants were recruited through primary care, in the community or in care home settings. Method 36 semi-structured interviews were conducted with care home residents and community dwellers aged 85+ (n=12), caregivers (informal and care home staff) (n=12), and healthcare professionals (n=12). Interviews were transcribed and analysed using reflexive thematic analysis. Results Four themes were developed: contextual complexity, satellite influences, balancing act, and pragmatic prescribing. Using opioids in adults aged 85+ is a balancing act to support patients best possible quality of life within their unique circumstances whilst using the pain management tools available. Conclusion Opioids continue to have an important role in pain management in adults aged 85+ largely due to paucity of alternatives and the drive to support quality of life.

INTRODUCTION Severe acute brain injury (stroke, traumatic brain injury or hypoxic-ischemic encephalopathy; SABI) is increasingly recognized as a chronic condition with care and communication needs beyond the initial hospitalization. This study aimed to characterize post-acute care patterns among SABI survivors, focusing on healthcare utilization and outpatient communication. METHODS Data were collected from a prospective cohort of hospitalized SABI patients using surveys, chart reviews, and the ED Information Exchange database. Socioeconomic disadvantage was assessed using the Area Deprivation Index (ADI), and qualitative analysis of outpatient notes examined conversations around palliative care needs and goals-of-care. RESULTS Two-thirds of patients (140/222) survived until discharge, primarily to nursing facilities (39%) or inpatient rehabilitation (38%). Among 109 with one-year follow-up, there were 89 hospitalizations, 104 ED visits, and 28 deaths. Patients from the most disadvantaged neighborhoods had significantly higher odds of rehospitalization or ED use within 30 days (OR 3.37, p=0.036). ADI was not linked to one-year utilization. seen outpatient by primary care (40%), neurology/neurosurgery (57%), and palliative care (1%), but conversations rarely revisited prognosis or goals-of-care. CONCLUSIONS Our findings highlight the need for improved long-term care planning and communication, particularly for socioeconomically disadvantaged survivors of SABI.

Objectives To explore caregiver and clinicians perspectives on implementing mental health conversations and supports for caregivers of children with chronic conditions in paediatric outpatient clinics. Specifically, views were sought on (a) screening approaches and measures (phase 1) and (b) how feedback and support could be provided to caregivers experiencing mental health difficulties (phase 2). Methods Caregivers and clinicians from two outpatient clinics (neuromuscular and diabetes) at a tertiary paediatric hospital in Melbourne, Australia participated in online focus groups in July and August 2024. Caregivers were recruited from outpatient clinics and clinicians were recruited via email. Both groups were combined for phase 1 before separating into breakout rooms for phase 2. Two authors conducted reflexive thematic analysis of transcripts using NVivo. Results Sixteen participants (caregivers n = 8; and clinicians n = 8) took part in in two semi-structured focus groups. Analysis generated two overarching domains, each comprising multiple themes. Domain 1, Addressing caregiver mental health, captured themes of overwhelm and invisibility, diverse caregiving roles, and the need for time and resources to support wellbeing conversations. Domain 2, Housing the mental health conversation, encompassed themes of screening preferences, caregiver agency in confidentiality, delivery of feedback, and access to tailored supports. Conclusions Caregivers and clinicians support routine caregiver mental health discussions in paediatric outpatient settings. Caregivers favour screening at diagnosis and key transitions, with clear, and actionable feedback delivered away from the child. Questions about record-keeping warrant further exploration, as do the perspectives of fathers.

Background and Objectives: Arts and cultural engagement may contribute to well-being in later life. However, evidence from longitudinal studies from Asia, including Japan, remains limited. This study examined the association of arts and cultural engagement with subsequent multidimensional well-being among older adults in Japan, one of the fastest-aging countries. Research Design and Methods: This longitudinal study used panel data from 354 individuals aged 60 and older (mean age 74.0 years; 78.6% women) who completed self-administered questionnaires by mail between 2022 and 2024. The PERMA-Profiler was used to assess five multifaceted aspects of psychological well-being: positive emotion, engagement, relationships, meaning, and accomplishment. Frequencies of arts and cultural engagement at baseline were measured for active (e.g., activities by individuals and participation in groups, such as music and painting) and receptive (e.g., visiting museums, galleries, and theaters) forms. Results: Multivariable linear regression analysis, adjusted for the covariates including baseline PERMA scores, showed that higher frequencies of active engagement were positively associated with higher PERMA scores for all domains. Higher frequencies of receptive engagement were associated with the domains of positive emotion, meaning, and accomplishment, but not clearly associated with engagement and relationships. Restricted cubic spline analyses suggested clearer positive frequency-response patterns for active engagement than for receptive engagement. Discussion and Implications: Arts and cultural engagement, both active and receptive forms, was associated with subsequent multiple aspects of well-being in later life. These findings suggest the importance of ensuring access to arts and cultural opportunities for older adults to create, participate, and connect.

Cultural engagement is associated longitudinally with better mental health and reduced depression incidence, but evidence has largely relied on self-reported symptoms and diagnoses, leaving uncertainty about clinically recorded disorders, and residual confounding remains a concern. Here, we examined whether cultural engagement (including going to cinemas, museums, galleries, exhibitions, theatre, concerts, or opera) predicts hospital-treated mental disorders in 8,274 adults aged 50 years or older from the English Longitudinal Study of Ageing. Participant records were linked to ICD-10 diagnoses in Hospital Episode Statistics and mortality records with follow-up of up to 20 years. In fully adjusted Cox models accounting for sociodemographic, lifestyle, and social factors and multiple testing, frequent cultural engagement was associated with lower risk of any mental disorders (HR 0.71, 95% CI 0.62-0.82, FDR adjusted P value<0.001), dementia (0.71, 0.56-0.89, FDR adjusted P value=0.010), substance misuse (0.75, 0.59-0.95,FDR adjusted P value=0.040), and mood disorders (0.73, 0.56-0.95, FDR adjusted P value=0.044), but not neurotic disorders. Associations persisted after excluding early incident cases and adjusting for baseline depressive symptoms and cognition, and showed robustness to unmeasured confounders. To further probe causality, eye disease, ear disease, and traumatic brain injury, which share similar socio-demographic profiles to mental disorders, were prespecified as negative control outcomes. Cultural engagement was not associated with any negative control outcomes. These findings provide triangulated statistical data to suggest that cultural engagement is associated with reduced risk of several clinically recorded mental disorders and support further testing of cultural engagement as a population mental health strategy.

Objective To map national Parkinsons disease (PD) research capability to inform an inclusive delivery strategy for a large-scale clinical trial. Background Few people with PD participate in clinical trials, particularly from under-served populations. The Edmond J Safra Accelerating Clinical Trials in PD initiative (EJS ACT-PD) aims to deliver an inclusive multi-arm multi-stage (MAMS) disease modification PD trial. Methods A survey disseminated to National Health Service (NHS) hospitals assessed PD research capability regarding trial experience, rater expertise, trial facilities and specialist investigations. A process was developed to categorise sites into 3 tiers, with tier 1 having the least PD-research capability or experience, and tier 3 being experienced specialist centres. We mapped tiers to PD prevalence, social deprivation and ethnic diversity to identify infrastructure gaps. We developed trial delivery strategies to facilitate rapid and inclusive recruitment. Results Out of 97 survey responses, 43 sites were categorised as tier 1, 33 as tier 2 and 21 as tier 3. Diversity and social deprivation index were higher for tier 3 sites (predominantly urban). A greater proportion of tier 1 and 2 sites were situated in areas of higher PD prevalence (predominantly rural). Ninety one percent of sites reported experience with remote trial delivery methods. Our delivery strategy included: initial trial set-up at tier 3 sites to enable rapid and ethnically diverse recruitment; core funded staff within strategic sites to develop regional solutions for inclusive trial participation and to enable research opportunity provision in areas where currently very little exists, and a hybrid delivery model of in-person and remote study visits, ensuring maximal acceptability and deliverability. Conclusions The mapping of current PD research delivery capability has allowed us to develop a trial delivery strategy that will broaden the provision of research participation opportunity to under-served groups. It has also enabled existing infrastructure to be maximised while mitigating identified gaps.

Background: Occupational therapists can improve stroke survivors hand and arm movement and participation in daily activities through action observation (AO). AO involves watching another persons hand or arm complete a movement or task. While research generally supports the use of AO with stroke survivors, there are limited AO videos are available to occupational therapists which makes applying AO challenging. Objective: The purpose of this work is to develop structured and widely accessible tool to support access to AO for stroke survivors, occupational therapists, and researchers. Methods: To develop an AO video library for stroke rehabilitation, functional and non-functional upper limb task deficits were first identified through clinical observations and clinician interviews to establish a prioritized list of daily activities. In collaboration with media production specialists, healthy adult volunteers were recruited and filmed performing these tasks from both first- and third-person perspectives. The recorded videos were then systematically edited, enhanced with instructional title slides, and distributed via a public YouTube channel for clinical application and a categorized digital repository for research purposes. Results: Initial assessments revealed a complete lack of familiarity, awareness, and utilization of AO resources among local occupational therapists, despite high perceived clinical utility. To address this gap, a final library of 150 tasks was established, resulting in the production of 419 finalized, standardized videos featuring six healthy volunteers. For clinical application, these videos were hosted on a free, public YouTube channel organized into 18 functional playlists, while a parallel set was structured into distinct movement categories for research repository storage. Conclusion: By providing a structured and highly accessible tool, this repository enables clinicians, researchers, and caregivers to readily implement evidence-based action observation interventions in both clinical and home settings.

Background Electronic health record documentation patterns may reflect workflow complexity, monitoring intensity, and operational strain in intensive care settings. However, documentation-derived features can be sensitive to local documentation culture, data capture systems, and outcome definitions. Retrospective validation across multiple datasets is therefore needed before these signals are used in workflow intelligence or clinical AI governance tools. Objective To evaluate whether documentation-density and documentation-timing features show reproducible retrospective signal for ICU workflow complexity and long-stay proxy outcomes across de-identified critical care datasets, while distinguishing workflow and long-stay associations from unsupported claims about mortality prediction, burden reduction, or deployment readiness. Methods We synthesized retrospective validation results from de-identified ICU and workflow datasets generated through a prespecified documentation-density validation program. Feature families included Documentation Burden Score style features, Shift-End Documentation Rate style features, documentation reliability style metadata, and all-documentation feature sets where available. Outcomes included long ICU length of stay proxies, mortality where available, and workflow proxy endpoints. Models compared baseline feature sets with enhanced models containing documentation-density or workflow features. Performance was summarized using area under the receiver operating characteristic curve, Brier score where reported, delta AUROC, bootstrap confidence intervals where reported, and label-shuffle controls where available. Results The strongest external long-stay proxy evidence came from the NWICU chartevents analysis, which included 28,612 ICU stays, 20,267 stays with chart events, and 9,619,759 chart events. For ICU length of stay greater than the median, baseline AUROC was 0.5252. Enhanced AUROC was 0.9512 for Documentation Burden Score features, 0.9214 for Shift-End Documentation Rate features, 0.8470 for documentation reliability style features, and 0.9517 for all documentation features. Corresponding label-shuffle enhanced AUROCs were near random, ranging from 0.4897 to 0.5064. For ICU length of stay greater than the 75th percentile, baseline AUROC was 0.5155. Enhanced AUROC was 0.9433 for Documentation Burden Score features, 0.9194 for Shift-End Documentation Rate features, 0.8118 for documentation reliability style features, and 0.9427 for all documentation features, with label-shuffle enhanced AUROCs from 0.4836 to 0.4999. Additional retrospective support was observed in eICU workflow analyses, HiRID first-24-hour documentation-density analyses, MIMIC-IV HF ICU internal analyses, MIMIC-IV-Note metadata extensions, and nursing-chart or lab density proxy analyses. However, cross-institution discrimination transfer was weak without recalibration, and several analyses remained proxy validations rather than final clinical validations. Conclusions Documentation-density and documentation-timing features show promising retrospective signal for ICU workflow complexity and long-stay proxy outcomes, especially in NWICU chartevents and selected internal dataset-specific analyses. These findings support further preregistered, prospective, silent-mode validation of documentation-derived workflow intelligence. They do not establish prospective clinical performance, mortality reduction, clinician burden reduction, autonomous deterioration prediction, or deployment readiness.

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent and debilitating in Alzheimer's disease (AD). Existing pharmacologic treatments are often ineffective and associated with serious adverse events. Identifying modifiable risk factors (MRFs) is critical for prevention and treatment. METHODS: Capitalizing on data from 14,497 individuals with AD from the National Alzheimer's Coordinating Center (NACC) database, we examined longitudinal associations between modifiable risk factors, APOE genotype and NPI-Q-assessed NPS using Cox proportional hazards models adjusted for demographics. RESULTS: Diabetes, alcohol consumption, smoking, and TBI were associated with an increased risk of specific NPS in AD. APOE{varepsilon}4 carrier status was linked to multiple NPS, showing a dose-response relationship. Education, LDL-C, and corrective lenses were protective; hypertension showed no associations. CONCLUSION: These findings strongly suggest that individual MRFs are associated with specific NPS in line with a complex etiology underlying these symptoms. Early detection and management of vascular, lifestyle and sensory factors could reduce NPS.

Background. Blood-based biomarkers are increasingly proposed for identifying high-risk individuals before clinical disease and for making prevention-oriented trials more efficient. Prognostic enrichment can increase event rates, but trial efficiency also depends on whether the intervention effect is preserved in the enriched population. Methods. Using the UK Biobank Pharma Proteomics Project, we trained disease-specific proteomic risk scores (ProRS) from 2,916 plasma proteins with elastic-net Cox models. We compared ProRS, polygenic risk scores (PRS), and combined PRS--ProRS scores across ten incident diseases. We estimated cumulative incidence and theoretical two-arm time-to-event trial sample sizes across risk strata. To evaluate effect preservation, we examined six intervention-analogue exposure--outcome pairs spanning genetic (PCSK9/coronary artery disease, APOE/Alzheimer's disease, PPARG/type 2 diabetes, IL23R/Crohn's disease), behavioural (physical activity/all-cause mortality), and pharmacological (RAAS inhibitors versus calcium channel blockers/coronary artery disease) examples. Results. ProRS outperformed PRS for 9 of 10 diseases (median C-index 0.75 versus 0.61). ProRS and PRS were weakly correlated (median Pearson |r| = 0.04), and joint PRS--ProRS stratification identified groups with higher observed incidence than either score alone for several endpoints. In the top risk quartile, combined-score enrichment reduced theoretical required sample sizes by 32--74\% under a fixed 20\% relative hazard reduction. These gains were not always preserved when stratum-specific intervention-analogue effects were used. Effects were broadly preserved for APOE/Alzheimer's disease and physical activity/mortality. The PPARG/type 2 diabetes effect attenuated toward the null under all three score types, showing that event-rate enrichment does not guarantee effect preservation. For IL23R/Crohn's disease and the antihypertensive comparison, point estimates differed across score types -- preserved under polygenic but attenuated under proteomic enrichment -- but confidence intervals were wide and overlapping. Conclusions. Proteomic risk scores can identify high-event-rate populations for prevention-oriented trials, but event-rate enrichment alone is insufficient for trial design. Biomarker-guided enrichment should evaluate mechanism-specific effect preservation and may be preferable as a stratification or adaptive-design variable rather than as a restrictive eligibility criterion.

Background: It is an everyday observation that people of the same chronological age differ with respect to their physical and mental capacity. However, assessing these differences in biological age remains challenging. Methods: Here, we aggregate 89 age-associated variables from the Berlin Aging Study II (BASE-II, n=1,631) to generate MultiAge, a new marker of biological age that summarizes information from ten domains reflecting organ health and global biological age. We then used methylation data obtained from an Illumina MethylationEPIC array and supervised machine learning to translate MultiAge into a DNA methylation signature, MultiAgeEpi (309 CpGs), which was subsequently validated in four independent external validation cohorts (KORA FF4, KORA Age, SHIP-TREND, BiDirect, total n=4,339). MultiAgeEpi results were compared with previously published epigenetic clocks (GrimAge, DunedinPACE, SystemsAge). Results: We report that MultiAgeEpi showed similar, and in several cases, stronger associations with age-associated outcomes such as diabetes, metabolic syndrome, multimorbidity, frailty and mortality (q < 0.05) compared to the other clocks. Conclusions: MultiAge and MultiAgeEpi thus provide a comprehensive assessment of biological age through aggregation of numerous age-associated variables and the use of the high-resolution methylomics data makes transfer of this marker to other cohorts possible.

Introduction Indigenous peoples in Canada face persistent health inequities rooted in colonialism, systemic racism, discrimination and social exclusion, all of which operate with particular intensity within healthcare institutions. Despite a growing qualitative literature documenting the discrimination and stigmatisation of Indigenous people by healthcare professionals, no validated instrument existed in the Canadian context to measure the stigmatizing attitudes and behaviors of clinicians toward this population. Aim This study aimed to co-develop and validate an instrument using clinical case vignettes designed to capture the affective, cognitive, and behavioral dimensions of stigmatization of indigenous peoples. Method Following Boateng et al.'s three-phase scale development approach, a multidisciplinary team including Indigenous patient partners, researchers, clinicians, and measurement experts generated 244 items across three paired clinical vignettes addressing type 2 diabetes, chronic back pain, and depressive disorder. Each vignette was developed in two versions, one featuring an Indigenous patient (test) and one featuring a non-Indigenous patient (control), distinguished solely by name and origin. Content validity was assessed by an expert committee using a Content Validity Index. The instrument was subsequently administered to a sample of nurses and physicians from two canadian health institutions using a twelve-arm randomization design. Analyses were carried to assess the internal structure of the instrument, convergent and concurrent validity as well as internal consistency. Results Our results show that the instrument developed has good psychometric qualities, particularly in terms of internal consistency, concurrent validity and factor structure, which reflects the theoretical structure assumed. Concurrent validity of the tool with the M-PATAS scale demonstrated weak to moderate significant correlations. Developed through a participatory process centering Indigenous expertise and lived experience, this instrument constitutes a significant methodological advance in the study of racialized stigmatization in Canadian healthcare.

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.