The Lancet Healthy Longevity

ImportanceEcological and observational studies have shown a protective association between herpes zoster (HZ) vaccination and dementia risk, yet many had methodological limitations or examined the live HZ vaccine that is no longer available in the US. Improved access to linked electronic health records for patients receiving post-acute care and long-term care permit robust comparisons of dementia risk in adults eligible to receive the recombinant HZ vaccine. ObjectiveEmulate a randomized trial in observational data to estimate the association of the recombinant HZ vaccine (RZV) with incident dementia risk among older adults newly admitted for post-acute or long-term care in nursing homes (NHs). DesignRetrospective cohort study with target trial emulation and the clone censor approach. SettingU.S. NHs that use PointClickCare as their electronic health record. ParticipantsIndividuals who were admitted to a NH between 01/01/2017-12/31/2022; Medicare fee-for-service beneficiaries; did not have prevalent dementia; and eligible to receive RZV as of admission. ExposuresReceive one or more RZV doses within one year of admission vs. do not receive any RZV over four years of follow-up. ResultsWe identified 509,926 eligible NH residents (mean age 79 years; 36% men). Among those alive, uncensored, and without dementia at 12 months of follow-up, 8,843 received one or more doses of RZV. Receipt of RZV within one year of NH admission was associated with a 5.8% lower absolute risk (95%CI: -3.9% to -7.5%) of newly diagnosed dementia over four years (risk ratio [RR] = 0.76 [95%CI: 0.69-0.84]; cumulative incidence in 1+ RZV vs. no RZV: 18.8% vs. 24.6%). Associations were smaller in men (RR=0.82 [95%CI: 0.68-1.01]) and those with prior live HZ vaccination (RR=0.86 [95%CI: 0.65-1.09]). Bias analyses based on two negative control outcomes (NCOs) attenuated, but did not fully explain, the main effect of RZV on dementia risk (bias-adjusted RR = 0.82 [wellness visit NCO] and RR = 0.88 [hip fracture NCO]). Conclusions and RelevanceAdministering RZV within 1 year of NH admission may reduce dementia risk. As RZV uptake was low overall, new NH residents would benefit from increased RZV vaccination uptake. KEY POINTSO_ST_ABSQuestionC_ST_ABSDoes the recombinant herpes zoster vaccine (RZV) reduce dementia risk among older adults? FindingsIn this cohort and trial emulation study of 509,926 patients newly admitted to skilled nursing or long-term care, we found that [≥]1 RZV dose within a year was associated with a 24% relative and 6% absolute reduction in 4-year dementia risk. Effects were robust to bias analyses and were stronger in women and those without prior vaccination with the live HZ vaccine. MeaningUsing causal inference methods, this observational study provides evidence that some cases of dementia may be prevented through vaccination with RZV.

BackgroundDelirium is strongly associated with subsequent dementia, but this is often assumed to reflect underlying associations of baseline health with dementia. We examined the associations of delirium on admission with incident dementia across the spectrum of multimorbidity. MethodsRetrospective population-based cohort study using linked primary care and hospital data for emergency admissions aged [≥]65 years in Lothian, Scotland, from 1 Apr 2017 to 1 Apr 2020. Delirium on admission was assessed at the bedside for all patients using the 4AT (www.the4AT.com). Associations of delirium, multimorbidity, and their interaction with incident dementia and mortality were examined using Fine-Gray competing-risks regression and Cox proportional hazards models. ResultsOf 23,558 people without pre-existing dementia (mean age 78.9 years, 54% female), 4135 (18%) had an admission with delirium. Delirium was associated with higher incident dementia risk. The relative risk was highest in those without multimorbidity (adjusted Hazard Ratio (aHR) 3.38, 95% CI 2.46-4.63) and decreased with an increasing number of long-term conditions. Delirium was also associated with increased mortality, regardless of multimorbidity. In those without multimorbidity, delirium was associated with higher early mortality ([≤]90 days: aHR 4.23, 95% CI 3.27 to 5.49) and late mortality (>90 days: aHR 1.64, 95% CI 1.33 to 2.03). ConclusionDelirium is strongly associated with incident dementia in older adults across the multimorbidity spectrum, with the highest relative risk in people without multimorbidity. Findings support routine delirium assessment on hospital admission for all older adults and highlight need to further investigate neurodegenerative mechanisms in delirium.

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 [≥]50 years with [≥]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.

PurposeThe emergence of antibiotic-resistant bacteria represents a considerable threat to human health, particularly for vulnerable populations such as those living in residential aged care. However, antimicrobial resistance (AMR) carriage and modes of transmission remain incompletely understood. The Generating evidence on antimicrobial Resistance in the Aged Care Environment (GRACE) study was established to determine principal risk factors of AMR carriage and transmission in residential aged care facilities (RACF). ParticipantsBetween March 2019 and March 2020, 279 participants were recruited from five South Australian RACFs. The median age was 88.6 years, the median period in residence was 681 days, and 71.7% were female. A dementia diagnosis was recorded in 54.5% and more than two thirds had moderate to severe cognitive impairment (68.8%). Sixty-one percent had received at least one course of antibiotics in the 12 months prior to enrolment. Findings to dateTo investigate the representation of the GRACE cohort to Australians in residential aged care, its characteristics were compared to a subset of the historical cohort of the Registry of Senior Australians (ROSA). This included 142,923 individuals who were permanent residents of RACFs on June 30th, 2017. GRACE and ROSA cohorts were similar in age, sex, and duration of residential care, prevalence of health conditions, and recorded dementia diagnoses. Differences were observed in care requirements and antibiotic exposure (both higher for GRACE participants). GRACE participants had fewer hospital visits compared to the ROSA cohort, and a smaller proportion were prescribed psycholeptic medications. Future plansParticipant and built environment metagenomes will be used to determine microbiome and resistome characteristics. Individual and facility risk exposures will be aligned with metagenomic data to identify principal determinants for AMR carriage. Ultimately, this analysis will inform measures aimed at reducing the emergence and spread of antibiotic resistant pathogens in this high-risk population. Strengths and limitations of this studyO_LIThe GRACE study captured a diverse array of data; demographics, medications, personal and medical care, RACF management practices, as well as oropharyngeal, intestinal, and environmental metagenomic data, allowing detailed analysis of exposure-resistome relationships. C_LIO_LIA high rate of participant recruitment (75% of eligible residents) was achieved, representing the spectrum of resident characteristics and care needs. This included a representative proportion of individuals with moderate or severe cognitive impairment. C_LIO_LIThe main limitation of this cohort resulted from the early cessation of recruitment, due to stringent facility access regulations resulting from the COVID-19 pandemic. While a high recruitment rate partially compensated in terms of cohort size, we were unable to complete recruitment at our fifth site or begin recruitment at two further sites. C_LIO_LIEthnic and linguistic data was not captured and so could not be compared between cohorts. C_LI

BackgroundPre-frailty and frailty prevalence is increasing in the Western Pacific, resulting in substantial morbidity and mortality in older populations. Modelling frameworks are required to estimate the prevalence of frailty and potential impacts of ongoing population-level nutritional interventions. MethodsUsing a microsimulation sociodemographic model of 3,353,032 individuals from 1990 to 2050, and data from the Singapore Longitudinal Ageing Study 2 of 3,270 participants, we developed a Bayesian multistate model of robust, pre-frailty and frailty stages with estimated transition probabilities by age, ethnicity, and gender for each body-mass index (BMI) category. We then explored four scenarios where weight management interventions are applied that modify the annual distribution of underweight, normal weight, overweight, obese I and obese II individuals. FindingsBetween 2011 and 2050, the overall prevalence of pre-frailty and frailty increased from 44{middle dot}2% to 46.9%, and from 3{middle dot}2% to 11{middle dot}3% respectively. Reductions of 811 pre-frail individuals (95% CrI: 624-1,127) and 36,202 frail individuals (22,109- 41,124) were estimated when underweights shifted to normal weights, 5,787 (3,670- 7,707) and 55,777 (32,683-80,941) when obese II moved to obese I, and 22,045 (18,430-23,487) and 62,847 (40,165-91,517) when both groups shifted respectively. Total healthcare utilization decreases by 6{middle dot}9% (4.3%-8{middle dot}1%) with the latter intervention. InterpretationFrailty prevalence is projected to substantially increase by 2050 where large-scale weight management interventions could be utilised to avert cases of both pre-frailty and frailty in older individuals. FundingThis research was supported by the Population Health Metrics and Analytics project, the Ministry of Health and National Innovation Challenge (NIC Ageing), Healthy Longevity Catalyst Awards (HLCA) MOH-HLCA22Feb-0007.

BackgroundDue to severe outcomes, elderly adults 60 years or older are prioritized for COVID-19 vaccination but accumulated SARS-CoV-2 infection and vaccination likely modifies their risk. We estimated vaccine effectiveness against omicron-associated hospitalisation among elderly adults, by number of doses, prior infection history and time since last immunological event. MethodsWe conducted a test-negative case-control study among symptomatic elderly adults tested for SARS-CoV-2 in Quebec, Canada during BA.1-, BA.2- and BA.4/5-dominant periods. Relative to unvaccinated, infection-naive participants, we compared COVID-19 hospitalisation risk by mRNA vaccine dose and/or prior infection (pre-omicron or omicron) history. FindingsDuring BA.1, BA.2 and BA.4/5 periods, two- vs. four-dose vaccine effectiveness alone against hospitalisation was: 78% (95%CI:75-80) vs. 96% (95%CI:93-98); 60% (95%CI:50-97) vs. 84% (95%CI:81-87); and 40% (95%CI:30-49) vs. 68% (95%CI:63-72), respectively, consistent with longer median time since second vs fourth dose. By respective period, effectiveness of pre-omicron vs. omicron infection alone against hospitalisation was: 93% (95%CI:80-97) vs. [not estimable]; 88% (95%CI:50-97) vs. 96% (95%CI:68-99); and 69% (95%CI:30-85) vs. 90% (95%CI:79-95). Regardless of doses (2-5) or prior infection type, hybrid protection was [≥]90%, lasting at least 6-8 months during the BA.4/5 period. Prior omicron infection alone reduced BA.4/5 hospitalisation risk by >80% for at least 6-8 months. InterpretationElderly adults with history of both prior SARS-CoV-2 infection and [≥]2 vaccine doses appear well-protected for a prolonged period against omicron hospitalisation, including BA.4/5. Ensuring infection-naive older adults remain up-to-date with vaccination may further reduce COVID-19 hospitalisations most efficiently. FundingMinistere de la Sante et des Services sociaux du Quebec.

BackgroundWe investigated frailty progression after severe infections in adults ([≥]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 [≥]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.

Background Evidence on frailty progression following severe infections is limited. We compared rates of transition to greater frailty or death between adults with and without severe infection in England. Methods We conducted a matched-cohort study among adults aged [≥]65 years (1,452,117: median age 76 years, 45% male) in Clinical Practice Research Datalink Aurum (2006-2019). Adults with severe infection (hospitalised primarily due to infection) were matched on calendar time to individuals without severe infection on age, sex, and primary care practice. The admission date was used as index date and same was assigned to matched unexposed adults. We measured frailty using Electronic Frailty Index, a proportion of 36 health deficits in validated categories (Fit 0-0.12, Mild >0.12-0.24, Moderate >0.24-0.36, Severe >0.36). In a time-varying Markov multistate model, we focused on forward transitions from baseline or intermediate frailty states to higher states or death. For each transition, we used Cox regression to estimate cause-specific transition hazard ratios (HR) with 95% confidence intervals (CIs), comparing adults with and without severe infection. We adjusted for baseline frailty score, age, sex, deprivation, harmful alcohol use, smoking, and primary care infection history 5 years before index date. We estimated state occupancy probabilities, and expected length of stay (ELOS) in each state at year five among adults with and without severe infection. We explored effect modification by infection type. Results Across all transitions, severe infection was associated with higher adjusted hazards of transitioning to worsening frailty or death, HR, 95% CI: (fit to: mild[1.56, 1.54-1.58], moderate[2.51, 1.79-3.51], death[4.57, 4.50-4.65]; mild to: moderate[1.52, 1.50-1.53], severe[1.90, 1.43-2.52], death[2.67, 2.64-2.70]; moderate to: severe[1.40, 1.38-1.42], death[1.87, 1.85-1.90]; severe to death[1.48, 1.46-1.50]). Transition hazard ratios were strongest for lower respiratory tract infections, followed by sepsis, urinary tract infections, meningitis/encephalitis, gastroenteritis, and skin and soft tissue infections. At five years, adults with severe infection had higher probabilities of transitioning to greater frailty or death across all transitions and lower ELOS in each frailty state than those without severe infection. Interpretation Severe infections may accelerate frailty deterioration in older age. Prevention through vaccination, early detection, and prompt management may help mitigate this decline.

IntroductionThis study aims to explore the impact of COVID-19 vaccination on critical care by examining associations between vaccination and admission to critical care with COVID-19 during Englands Delta wave, by age group, dose, and over time. MethodsWe used linked routinely-collected data to conduct a population cohort study of patients admitted to adult critical care in England for management of COVID-19 between 1 May and 15 December 2021. Included participants were the whole population of England aged 18 years or over (44.7 million), including 10,141 patients admitted to critical care with COVID-19. The intervention was vaccination with one, two, or a booster/three doses of any COVID-19 vaccine. ResultsCompared with unvaccinated patients, vaccinated patients were older (median 64 years for patients receiving two or more doses versus 50 years for unvaccinated), with higher levels of severe comorbidity (20.3% versus 3.9%) and immunocompromise (15.0% versus 2.3%). Compared with patients who were unvaccinated, those vaccinated with two doses had a relative risk reduction (RRR) of between 90.1% (patients aged 18-29, 95% CI, 86.8% to 92.7%) and 95.9% (patients aged 60-69, 95% CI, 95.5% to 96.2%). Waning was only observed for those aged 70+, for whom the RRR reduced from 97.3% (91.0% to 99.2%) to 86.7% (85.3% to 90.1%) between May and December but increased again to 98.3% (97.6% to 98.8%) with a booster/third dose. ConclusionImportant demographic and clinical differences exist between vaccinated and unvaccinated patients admitted to critical care with COVID-19. While not a causal analysis, our findings are consistent with a substantial and sustained impact of vaccination on reducing admissions to critical care during Englands Delta wave, with evidence of waning predominantly restricted to those aged 70+.

Mortality among patients admitted to intensive care with coronavirus disease 2019 (COVID-19) remains substantial despite advances in management. The contribution of pre-admission medication profiles to long-term survival is poorly defined. We analysed 497 adults with confirmed COVID-19 admitted to six intensive care units in southern Sweden between May 2020 and May 2021. Clinical and laboratory data were combined with prescription information from the national drug registry; drugs dispensed at least twice within eight months before admission were classified by Anatomical Therapeutic Chemical code. Polypharmacy was defined as the use of five or more medications. An XGBoost survival model with a Cox partial-likelihood objective was trained to predict one-year mortality and interpreted using SHapley Additive exPlanations (SHAP). The model achieved a concordance index of 0.74. Age was the strongest predictor of mortality, followed by the number of medications per patient, which ranked above the Charlson Comorbidity Index and Clinical Frailty Scale. Proton pump inhibitors were the only individual drug class among the top predictors, showing a modest positive association with mortality, whereas angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers had negligible contributions. These findings identify cumulative medication burden as an independent and clinically relevant marker of vulnerability in critical COVID-19.

BackgroundNon-specific live vaccine effects have been described in paediatric populations. We investigated whether non-specific effects are observed in older adults with live shingles (Zostavax(R)) immunisation. MethodsA population-based cohort study was performed using primary- and secondary-care data from the Clinical Practice Research Datalink in England. Shingles vaccine eligible individuals aged 70 years and over who had received pneumococcal immunisation were included. All-cause death, all-cause hospitalisation, and infection-associated hospitalisation rates were compared between live shingles vaccinated and unvaccinated person-time using time-to-first-event Cox regression and recurrent events modelling. Live shingles vaccine exposure was included as a time-varying exposure. The models were run on an overlap-weighted pseudo-population to minimise confounding. FindingsBetween September 2013 and June 2019 314,618 participants aged 70 years and over who had received pneumococcal immunisation prior to study entry were identified, of which 55% had live shingles vaccine exposure. The overlap weighted pseudo-population consisted of 60021 lives shingles vaccine unexposed and 60245{middle dot}6 exposed participants. Live shingles vaccine exposure in the overlap pseudo-population was associated with a reduction in all-cause death (hazard ratio 0{middle dot}64; 95% confidence interval 0{middle dot}62, 0{middle dot}66), a reduction in recurrent all-cause hospitalisation (hazard ratio 0{middle dot}83 (0{middle dot}79, 0{middle dot}87)), and a reduction in first and recurrent infection-associated hospitalisation (hazard ratio for first event 0{middle dot}81 (0{middle dot}79, 0{middle dot}83), and for recurrent events 0.75 (0.73, 0.77)). Protective vaccine effects were observed for at least five years post-immunisation. InterpretationsReceipt of live shingles vaccine associates with lower mortality and morbidity in older adults in England. The potential for causal linkage should be validated in robust prospective studies, with major implications for national immunisation policies. FundingNo specific funding for this project. KD was supported by an NIHR academic clinical fellowship. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSA body of research exists demonstrating an association between live vaccines and a reduction in mortality and illness unrelated to the vaccine target. This has been termed non-specific vaccine effects for which heterologous immune programming has been proposed as a possible mechanism. To date, non-specific vaccine effects have largely been demonstrated in paediatric populations in relation to live measles, oral polio, and Bacillus Calmette-Guerin (BCG) immunisation. Added value of this studyThis is the first study to evaluate mortality and hospitalisation effects in an older adult population with live shingles immunisation. Older adults are a growing population in many settings worldwide and require cost-effective interventions to reduce morbidity and mortality. This study finds a reduction in all-cause death, all-cause hospitalisation, and infection-associated hospitalisation in over 70-year-olds in England associated with live shingles vaccine exposure. These findings were not explained by any measurable confounding effect of age, socio-economic status, comorbidity, nor health-seeking behaviour. Implications of all the available evidenceThis work and other emerging reports advocate for studies with an experimental design to provide definitive evidence of non-specific vaccine effects to guide policy makers and to evaluate the possible immune mechanisms in an older immunosenescent population. There is potential for very significant benefits relating to both use of shingles vaccine and type of vaccine that needs clarity.

Background: Existing electronic frailty indices (eFI) are typically based on structured data and designed for older adults. We developed an eFI that integrates structured and unstructured electronic health records (EHRs) across adulthood and assessed its longitudinal trajectories and associations with adverse outcomes. Methods: We used longitudinal EHR data from 193629 individuals aged 35-103 in the Wellbeing Services County of Central Finland (2010-2023) and constructed a 53-item eFI including diagnosis codes, laboratory tests and items extracted from free-text clinical notes using deep-learning-based natural language processing. Associations with all-cause mortality, severe infections, fractures, and healthcare utilization were assessed using Cox and count models. Predictive performance was compared with Hospital Frailty Risk Score (HFRS) and Charlson Comorbidity Index (CCI). Findings: eFI trajectories accelerated notably from age 65 onwards. Using the eFI as a categorical variable, severe frailty was associated with higher risks of mortality (hazard ratio [HR] 7.31, 95% confidence interval [CI] 6.83-7.83), severe infections (HR 9.22, 95%CI 8.52-9.98), fractures (HR 2.75, 95%CI 2.52-3.01) and increased healthcare utilization (odds ratio [OR] 3.15, 95%CI 2.96-3.35) compared with non-frail. The risks were relatively greater in younger age groups and persisted when using the continuous eFI restricted to non-frail individuals. Across all outcomes, the eFI showed greater model discrimination than HFRS and CCI. Interpretation: An eFI using structured and unstructured EHR data improves risk stratification even in younger adults and at very low levels of frailty. Funding: Research Council of Finland, Instrumentarium Science Foundation, Sigrid Juselius Foundation and Samfundet Folkhalsan.

BackgroundReceiving fewer COVID-19 vaccine doses than recommended ("undervaccination") may increase risks of death, severe COVID-19, and post-COVID condition. However, population-scale evidence from Italy remains limited. We aimed to characterise determinants of undervaccination in Lombardy and to quantify its association with mortality, severe COVID-19, and long COVID outcomes. MethodsWe conducted a population-based study including all residents of Lombardy aged [&ge;]30 years who were alive on June 1, 2022 (n=6,836,566), and followed them until Dec 31, 2024. Vaccine deficit was defined as the difference between age-specific recommended doses (three for <60 years; four for [&ge;]60 years) and doses received, and was modelled as a time-varying exposure. Outcomes were all-cause mortality, severe COVID-19 (hospitalisation or COVID-19-related death), and long COVID defined using symptom-based ICD codes recorded [&ge;]1 month after infection. Determinants of undervaccination were assessed using multivariable logistic regression. Age-stratified Cox models estimated adjusted hazard ratios (HRs). Counterfactual vaccination scenarios were simulated using fitted survival models. ResultsOn June 1, 2022, 1,668,014 individuals (24{middle dot}4%) were not up to date with recommended vaccination. Undervaccination was more frequent in younger adults, women, individuals born outside Europe, rural residents, and those with high comorbidity burden. During follow-up, 265,383 deaths, 52,121 severe COVID-19 events, and 23,780 long COVID events occurred. In adults aged [&ge;]60 years, increasing vaccine deficit was associated with progressively higher risks of mortality (HR up to 1{middle dot}63) and severe COVID-19 (HR up to 2{middle dot}16). Associations were weaker in younger adults. For long COVID, effect estimates were modest and sensitive to outcome definition. Simulated universal booster coverage in adults [&ge;]60 years was associated with substantial reductions in expected deaths and severe COVID-19 events. ConclusionAbout one in four adults in Lombardy was undervaccinated by mid-2022. An increasing vaccine deficit was associated with a higher risk of severe COVID-19 and mortality, particularly in older adults. Sustaining booster uptake in high-risk groups remains central to mitigating the COVID-19 burden.

Dementia affects tens of millions of people worldwide, yet disease-modifying treatments remain strikingly limited. Although the recombinant zoster vaccine Shingrix has been associated with reduced dementia incidence, its potential influence on individuals already living with dementia is unknown. Here, we followed a propensity-score matched cohort of 68,960 US dementia patients using a nationwide electronic health record network, comparing Shingrix recipients within two years of diagnosis to recipients of any other vaccine. Shingrix was associated with substantially reduced all-cause mortality across the first three years of follow-up (hazard ratios 0.74, 0.88, and 0.89; P[&le;]0.006), robust across multiple sensitivity analyses. Furthermore, within-individual subgroup analyses of repeated Mini-Mental State Examinations conducted 3-6 years apart revealed significantly divergent cognitive decline rates across groups (time-by-group interaction P=0.002). Interval vaccination was associated with more stable cognition, contrasting with steeper declines in unvaccinated individuals. These findings support prospective evaluation of recombinant zoster vaccination as a potential strategy to improve outcomes in patients with established dementia.

BackgroundTo inform future preventive measures including repeated vaccinations, we have searched for a clinically useful immune correlate of protection against fatal Covid-19 among nursing homes residents. MethodsWe performed repeated capillary blood sampling with analysis of S-binding IgG in an open cohort study with inclusion of nursing home residents in Sweden. We analyzed immunological and registry data collected from September 2021 with end of follow-up 31 August 2022. The study period included implementation of the 3rd and 4th mRNA monovalent vaccine doses and Omicron virus waves. FindingsA total of 3012 nursing home residents with median age 86 were enrolled. The 3rd mRNA dose elicited a 99-fold relative increase of S-binding IgG among 2606 blood-sampled individuals and corresponding increase of neutralizing antibodies. The 4th mRNA vaccine dose boosted the levels 3.8-fold. Half-life of S-binding IgG was 72 days. A total 528 residents acquired their first SARS-CoV-2 infection after the 3rd or the 4th vaccine dose and the 30-day mortality was 9.1%. We found no indication that levels of vaccine-induced antibodies protected against infection with Omicron VOCs. In contrast, the risk of death was inversely correlated to levels of S-directed IgG below the 20th percentile. The risk plateaued at population average above lower 35th percentile of S-binding IgG. InterpretationIn the absence of neutralizing antibodies that protection from infection, quantification of S-binding IgG post vaccination may be useful to identify the most vulnerable for fatal Covid-19 among the oldest and frailest. This information is of importance for future strategies to protect vulnerable populations against neutralization resistant variants of concern. FundingSwedish Research Council, SciLife, Knut and Alice Wallenberg Foundation and Vinnova.

We estimated risk of death in vaccinated compared to unvaccinated COVID-19 cases. Cases vaccinated with 1 dose of BNT162b2 had 44% reduced risk of death, 55% with 1 dose of ChAdOx1, and 69% with 2 doses of BNT162b2. This is on top of the protection provided against becoming a case.

ObjectivesPersistent critical illness (PerCI, [&ge;]10 days in Intensive Care Unit [ICU]) is defined as the time from ICU admission when patients antecedent characteristics define their mortality rather than the admission aetiology. Patients with frailty and without COVID-19 have a higher risk of developing and dying from PerCI. We aimed to investigate the impact of frailty on critically ill patients with COVID-19 experiencing PerCI. MethodsWe conducted a retrospective multicentre cohort study including 103 Australian and New Zealand ICUs over two years, investigating the impact of frailty, measured with Clinical Frailty Scale (CFS), in patients with COVID-19, between patients with and without PerCI. ResultsThe prevalence of PerCI was similar between patients with and without frailty (25.4% vs. 27.9%; p=0.44). Hospital mortality was higher in patients with PerCI than without (28.8% vs. 9.3%; p<0.001), with mortality rising with increasing CFS (p<0.001). Frailty independently predicted hospital mortality, but when adjusted for ANZROD and sex, its impact was no different in patients with and without PerCI (odds ratio [OR]=1.30 [95%-CI: 1.14-1.49] vs. OR=1.46 [95%-CI: 1.29-1.64]). ConclusionsThe presence of frailty independently predicted hospital mortality in patients with PerCI, but frailty did not have a different impact on patients with and without PerCI.

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.

BackgroundPost-pandemic years are characterized by widespread previous population immunisation against COVID-19. Whether and for whom SARS-CoV-2 vaccinations are still justified is unclear. We use nationwide estimates of IFR and literature derived estimates of vaccine effectiveness (VE) to calculate numbers needed to vaccinate to prevent one COVID-19 death (NNV) and for one life-year saved (LYS) in Austria in 2024. MethodsIn this retrospective analysis we calculate SARS-CoV-2 IFR during 2024 in Austria according to previously published wastewater-based infection estimates and available mortality data. Using literature derived VE estimates we calculate NNV to prevent one COVID-19 death and for one LYS in strata according to age groups, nursing home residency and vaccination in 2024. We repeat analyses with sensitivity range values of parameters. ResultsIn 2024, total IFR was 0.048%. NNV (LYS) in the age groups 0-19, 20-39, 40-59, 60-74 and 75-84 years were very high: e.g. 5,497,526 (151,570), 2,432,498 (92,614), 415,714 (24,777), 35,925 (3,748), and 4,882 (1,009), respectively, in community dwellers. In the 85+ years age group, IFRs of unvaccinated/vaccinated were 0.91%/0.77% for community dwellers, and 1.22%/1.04% for nursing home residents. The 85+ year age group had NNV estimates of 1,215 and 907 (LYS: 525 and 1,896) in community dweller and nursing home residents, respectively. Sensitivity analyses yielded LYS<1,000 only under some favourable assumptions in the 75-84 and 85+ years old age strata. ConclusionsIn 2024 SARS-CoV-2 IFR was low and NNV and LYS of COVID-19 vaccinations correspondingly non-favourably high, even for very old individuals.

BackgroundExtreme heat exposure is a growing public health threat, particularly for older adults. While air pollution is a recognized modifiable risk factor for dementia, the role of sustained high heat exposure remains underexplored. This study investigates the association between cumulative extreme heat exposure and the prevalence of Alzheimers disease and related dementias (ADRD) and mild cognitive impairment (MCI) in adults. MethodsData were drawn from the All of Us Research Program (n = 286 767). High heat exposure was calculated using the CDCs National Environmental Public Health Tracking Network based on the number of extreme heat days within multi-day events from 2019 to 2023. Exposure was measured using daily maximum temperature and heat index. Diagnoses were identified from electronic health records. Logistic regression models estimated associations between heat exposure and ADRD/MCI, adjusting for demographic, health, behavioral, and socioeconomic variables. Stratified and interaction models assessed differences by age and sex. FindingsEvery 10 extreme heat days were associated with a 4{middle dot}0% increase in ADRD/MCI odds using maximum temperature (OR=1{middle dot}040, 95% CI: 1{middle dot}026-1{middle dot}051) and a 6{middle dot}0% increase using heat index (OR=1{middle dot}058, 95% CI: 1{middle dot}044-1{middle dot}071). Using age-stratified analysis the effect was stronger among adults aged [&ge;]70, with odds increasing by 7{middle dot}8% versus 3{middle dot}9% among those <70 using heat index. A significant interaction by age was observed (p<0{middle dot}001). Odds ratios were slightly higher in females, but sex did not significantly modify the association. Area deprivation accounted for 8{middle dot}6%-9{middle dot}6% of the association, while education and social isolation were not significant mediators. InterpretationCumulative high heat exposure is associated with increased odds of ADRD/MCI, especially among adults aged 70 and older. These findings underscore the need for climate adaptation strategies targeting older and socioeconomically disadvantaged populations. FundingThis research was supported by the All of Us Research Program, and funded by the National Institutes of Health. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and Google Scholar for studies published between January 2005 and April 2025 using combinations of the terms "extreme heat," "heat exposure," "heat waves," "dementia," "Alzheimers disease," "cognitive impairment," and "older adults." While many studies have shown that older adults face increased mortality and morbidity during extreme heat events, few have explored cognitive outcomes. Research specifically linking heat exposure to Alzheimers disease and related dementias (ADRD) is scarce. Most existing studies focus on short-term heat events and general health or mortality outcomes, rather than dementia. Although some evidence suggests temporary cognitive effects from heat, robust studies on diagnosed ADRD are lacking. Only one study has assessed the impact of cumulative extreme heat on cognitive function, and it did not examine clinical diagnoses or adjust for comorbid conditions. Added value of this studyTo our knowledge, this is the first national-level study in the United States to examine the association between cumulative high heat exposure and diagnosed ADRD or mild cognitive impairment (MCI) using detailed individual-level electronic health records. Our study used five years of environmental exposure data (2019-2023) and two distinct metrics--maximum temperature and maximum heat index--linked to a large, diverse cohort from the All of Us Research Program. We adjusted for demographic, clinical, behavioral, and social factors and explored interactions by age and sex. We also assessed mediation of the relationship by area deprivation, education, and social isolation. Our findings reveal that cumulative heat exposure is associated with increased odds of ADRD/MCI and that risk is more pronounced among individuals aged 70 and older. Implications of all the available evidenceCumulative high heat exposure may contribute to neurocognitive risk in later life, particularly among older adults. Our findings suggest that neighborhood-level socioeconomic disadvantage partly explains this association, underscoring the influence of structural and environmental conditions on dementia risk. This research supports the integration of heat-related vulnerability into dementia prevention frameworks and climate adaptation strategies. As climate change intensifies, understanding how environmental stressors such as heat affect cognitive ageing is essential for public health planning and policy. Targeted interventions and protective measures for older adults may help mitigate these long-term cognitive impacts.