To have maximal benefit, Alzheimer's disease-modifying treatments might need to be started before the onset of clinical symptoms. Mutations of the PSEN1 gene are inherited as fully penetrant, autosomal-dominant traits, which almost always result in the clinical onset of Alzheimer's disease before the age of 65 years. We aimed to evaluate the efficacy, including possible delayed emergence of cognitive impairment, and safety of crenezumab, an anti-amyloid monoclonal antibody, in cognitively unimpaired carriers of the PSEN1Glu280Ala mutation at high imminent risk of developing symptoms due to Alzheimer's disease. This 5-8-year common-close, double-blind, placebo-controlled, single-centre trial screened kindred members aged 30-60 years from the main health-care site in Medellín, Colombia. Participants who were cognitively unimpaired and carried the PSEN1Glu280Ala autosomal-dominant mutation were randomly assigned 1:1 to receive placebo or subcutaneous crenezumab (investigators and participants were masked to treatment allocation), with an initial 300 mg dose every 2 weeks that increased to 720 mg every 2 weeks, and a later optional increase to 60 mg/kg intravenously every 4 weeks. Randomisation was stratified by age, education, APOE ɛ4 carrier status, and baseline Clinical Dementia Rating. Mutation non-carriers received placebo and were included in a 1:2 ratio of non-carriers to carriers to maintain genotype masking and include a genetic kindred control. Dual primary outcomes were the annualised rates of change in the Alzheimer's Prevention Initiative (API) preclinical autosomal-dominant Alzheimer's disease (ADAD) composite test total score and Free and Cued Selective Reminding Test-Cueing Index (FCSRT-CI) assessed in randomised participants who received at least one dose of the study drug, according to treatment assignment. Primary endpoints were assessed with a random coefficient regression model with a missing-at-random assumption adjusting for randomisation factors. Safety endpoints for mutation carriers were assessed in randomised participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT01998841) and is completed. 619 Colombian API registrants were prescreened, 315 were assessed for eligibility, and 252 were enrolled (crenezumab-carrier, n=85; placebo-carrier, n=84; placebo-non-carrier, n=83; 160 [63%] women and 92 [37%] men) between Dec 20, 2013, and Feb 27, 2017. 237 (94%) completed the trial, with final data collection on March 22, 2022. The annualised rate of change in the API ADAD composite was -1·10 (SE 0·29) in the crenezumab group and -1·43 (0·29) in the placebo group (between-group difference 0·33 [95% CI -0·48 to 1·13]; p=0·43). The annualised rate of change in FCSRT-CI was -0·03 (0·00) in the crenezumab group and -0·04 (0·00) in the placebo group (between-group difference 0·01 [0·00 to 0·02]; p=0·16). All participants had at least one adverse event; serious adverse events occurred in 23 (27%) of 84 in the crenezumab group and 21 (25%) of 84 in the placebo group. No fatalities occurred. Crenezumab therapy administered for 5-8 years did not result in significant benefits on our primary clinical outcomes in cognitively unimpaired participants predisposed to developing ADAD dementia; secondary and exploratory outcomes also showed no significant effect on removal of amyloid plaques or other clinical or biomarker outcomes. Together with the results of other anti-amyloid β trials, robust fibrillar amyloid removal appears necessary for clinical efficacy in people with elevated brain amyloid. This study will further inform the biomarker, cognitive, and clinical trajectory of preclinical ADAD, the risk of clinical progression in amyloid-positive and amyloid-negative mutation carriers, and the size and design of future secondary and primary prevention trials. US National Institute on Aging (NIA), Banner Alzheimer's Institute, Genentech, F Hoffmann-La Roche.
Lower respiratory infections (LRIs) remain the world's leading infectious cause of death. This analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides global, regional, and national estimates of LRI incidence, mortality, and disability-adjusted life-years (DALYs), with attribution to 26 pathogens, including 11 newly modelled pathogens, across 204 countries and territories from 1990 to 2023. With new data and revised modelling techniques, these estimates serve as an update and expansion to GBD 2021. Through these estimates, we also aimed to assess progress towards the 2025 Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD) target for pneumonia mortality in children younger than 5 years. Mortality from LRIs, defined as physician-diagnosed pneumonia or bronchiolitis, was estimated using the Cause of Death Ensemble model with data from vital registration, verbal autopsy, surveillance, and minimally invasive tissue sampling. The Bayesian meta-regression tool DisMod-MR 2.1 was used to model overall morbidity due to LRIs. DALYs were calculated as the sum of years of life lost (YLLs) and years lived with disability (YLDs) for all locations, years, age groups, and sexes. We modelled pathogen-specific case-fatality ratios (CFRs) for each age group and location using splined binomial regression to create internally consistent estimates of incidence and mortality proportions attributable to viral, fungal, parasitic, and bacterial pathogens. Progress was assessed towards the GAPPD target of less than three deaths from pneumonia per 1000 livebirths, which is roughly equivalent to a mortality rate of less than 60 deaths per 100 000 children younger than 5 years. In 2023, LRIs were responsible for 2·50 million (95% uncertainty interval [UI] 2·24-2·81) deaths and 98·7 million (87·7-112) DALYs, with children younger than 5 years and adults aged 70 years and older carrying the highest burden. LRI mortality in children younger than 5 years fell by 33·4% (10·4-47·4) since 2010, with a global mortality rate of 94·8 (75·6-116·4) per 100 000 person-years in 2023. Among adults aged 70 years and older, the burden remained substantial with only marginal declines since 2010. A mortality rate of less than 60 deaths per 100 000 for children younger than 5 years was met by 129 of the 204 modelled countries in 2023. At a super-regional level, sub-Saharan Africa had an aggregate mortality rate in children younger than 5 years (hereafter referred to as under-5 mortality rate) furthest from the GAPPD target. Streptococcus pneumoniae continued to account for the largest number of LRI deaths globally (634 000 [95% UI 565 000-721 000] deaths or 25·3% [24·5-26·1] of all LRI deaths), followed by Staphylococcus aureus (271 000 [243 000-298 000] deaths or 10·9% [10·3-11·3]), and Klebsiella pneumoniae (228 000 [204 000-261 000] deaths or 9·1% [8·8-9·5]). Among pathogens newly modelled in this study, non-tuberculous mycobacteria (responsible for 177 000 [95% UI 155 000-201 000] deaths) and Aspergillus spp (responsible for 67 800 [59 900-75 900] deaths) emerged as important contributors. Altogether, the 11 newly modelled pathogens accounted for approximately 22% of LRI deaths. This comprehensive analysis underscores both the gains achieved through vaccination and the challenges that remain in controlling the LRI burden globally. Furthermore, it demonstrates persistent disparities in disease burden, with the highest mortality rates concentrated in countries in sub-Saharan Africa. Globally, as well as in these high-burden locations, the under-5 LRI mortality rate remains well above the GAPPD target. Progress towards this target requires equitable access to vaccines and preventive therapies-including newer interventions such as respiratory syncytial virus monoclonal antibodies-and health systems capable of early diagnosis and treatment. Expanding surveillance of emerging pathogens, strengthening adult immunisation programmes, and combating vaccine hesitancy are also crucial. As the global population ages, the dual challenge of sustaining gains in child survival while addressing the rising vulnerability in older adults will shape future pneumonia control strategies. Gates Foundation.
Few studies comprehensively examined women's life-course reproductive patterns and the risk of dementia. This study aims to examine the association between women's reproductive life sequence and dementia, and to explore the potential role of intrinsic capacity (IC) on such association. This study used data of 153,909 women who were post-menopause and free of dementia at baseline from the UK Biobank. We conducted sequence analysis and cluster analysis to identify women's life-course reproductive sequence and its potential patterns based on self-reported single reproductive factors. Women's IC at baseline comprised four functional domains: psychology, sensory, vitality, and locomotion. Participants were followed from baseline to the onset of dementia, death, or the end of follow-up (September 1, 2023). Fine and Gray's subdistribution hazard models were used to examine the associations between reproductive life sequences, IC, and dementia. During a median follow-up of 14.5 years, 2,940 dementia (including 1,509 Alzheimer's disease and 577 vascular dementia) cases were documented. Patterns of reproductive life sequences identified were: standard sequence (46.4%), early childbearing and oophorectomy menopause (6.5%), short reproductive span with natural menopause (17.7%), early childbearing and hysterectomy menopause (11.4%), and high parity with long birth span (18.1%). Compared to the standard sequence, short reproductive span with natural menopause (hazard ratio [HR] = 1.30, 95% confidence interval [CI] = 1.18-1.44), early childbearing and hysterectomy menopause (HR = 1.17, 95% CI = 1.04-1.32), and high parity with long birth span (HR = 1.13, 95% CI = 1.03-1.25) were associated with a higher risk of dementia. These associations would be strengthened when combining with IC impairment. For example, women with the combined sequence of short reproductive span with natural menopause and IC impairment had 2.40-fold (1.77-3.24) increased risk of dementia, compared to those with the standard sequence and no IC impairment. The associations between reproductive life patterns and dementia risk were stronger among women with more impairment items of IC. Our study showed cumulative associations of women's life-course reproductive factors with the risk of dementia in later life, and IC impairment could strengthen such associations. These results suggest the need to prioritize women with high-risk reproductive sequences, with special focus on their IC, in the prevention strategies for dementia.
Birthweight readily measurable marker of fetal growth that may influence health across the lifespan. We aimed to investigate the potential causal association between birthweight and healthy aging and to identify the mediating roles of subsequent socioeconomic, behavioral, functional, and disease-related factors to inform life-course strategies to promote healthy aging and reduce health inequities. We performed two-sample Mendelian randomization analyses in European-ancestry participants to estimate the effect of birthweight (n = 298,142-423,683) on two robust, composite healthy aging phenotypes (genetically independent phenotype of aging (aging-GIP) and multivariate aging-related genetic factor (mvAge)) and six individual aging phenotypes, including healthspan, resilience, parental lifespan, self-rated health, phenotypic age deceleration, and 90th percentile self-longevity (n = 34,710-1,958,774), and screened for 100 candidate mediators (n = 14,267-1,812,017) using a two-step mediation analysis. Genetically determined each 1-SD higher birthweight was associated with higher aging-GIP (β [95% CI] in different models ranging from 0.131 [0.066-0.196] to 0.162 [0.089-0.235] SDs) and mvAge (0.036 [0.010-0.063] to 0.045 [0.024-0.067]), independent of later-life obesity indicators; also with more interpretable benefits, including 12%-16% higher odds of longer healthspan, a 0.079-0.089 SD improvement in resilience, and a 1.22-1.74 year increase in parental lifespan. Of 100 candidates, 26 and 25 mediated the effect of birthweight on aging-GIP and mvAge, respectively, including socioeconomic indicators (education, household income, occupational attainment; individual mediation proportion: 12.72%-27.79%); behaviors (e.g., cheese intake, age at first sex; 10.38%-29.56%); physical functions (e.g., blood pressure, grip strength; 7.57%-42.65%); and cardiometabolic diseases (e.g., type 2 diabetes, cardiovascular diseases; 25.02%-70.11%). Higher birthweight within the normal range directly promotes healthy aging, mediated by multifaceted modifiable factors. Our findings advocate adopting a life-course approach to foster healthy aging, starting with optimal birthweight and extending to interventions that enhance socioeconomic status, promote healthy behaviors, strengthen physical functions, and prevent cardiometabolic diseases.
To map and characterise major transnational initiatives in geriatrics education and training, and explore complementarities as a basis for a more integrated and equitable global framework. A mapping exercise and expert consultation were undertaken by the European Geriatric Medicine Society (EuGMS) Special Interest Group on Education and Training between January and October 2025, including a meeting of international experts during the Twenty-First EuGMS Congress in Reykjavík. Eligible initiatives operated across national borders with an explicit mandate in education and training related to geriatrics and were not confined to a specific topic or subspecialty. Each initiative was profiled by scope, target audience, and contributions, and classified within a three-tier framework: (1) foundational capacity-building, (2) professional and interprofessional development, and (3) leadership and specialist advancement. Seventeen initiatives were identified. Tier 1 included the International Federation on Ageing (IFA), International Institute on Ageing, United Nations-Malta (INIA), PAHO's ACAPEM (Basic), ASEAN's Centre for Active Ageing and Innovation (ASEAN-ACAI), IAGG's e-Training in Gerontology and Geriatrics (e-TRIGGER) programmes, WHO's Integrated Care for Older People (WHO ICOPE approach), and AfriAGE. Tier 2 included the IAGG, EuGMS, EICA, PROGRAMMING CA2112, Victorian Geriatric Medicine Training Programme (VGMTP), and ACAPEM (Intermediate); and Tier 3 was represented by leadership academies (EAMA, ALMA, MEAMA/MENAAA, and AAMA), and UEMS-GMS. Collectively, these programmes form a considerably disjointed but potentially complementary global ecosystem for geriatrics education. Greater mutual awareness and alignment, anchored in equity and interprofessional inclusion, could enhance efficiency and sustainability in developing the global geriatrics workforce.
The Novara Cohort Study (NCS) was established to investigate the biological, psychological and social factors that influence ageing in the general population. The study aims to identify early risk factors for frailty, allostatic load and cognitive decline, and to uncover molecular and functional markers of accelerated biological ageing. NCS addresses the need for detailed life-course data from Southern Europe to support personalised prevention and early diagnosis, and to promote healthy longevity. NCS is a population-based, longitudinal cohort in the Novara province (Northern Italy), originally enrolling adults aged 35 and older. The inclusion criteria were later expanded to encompass all residents aged 18 and over, facilitating the study of ageing trajectories from early adulthood onward. As of mid-2025, about 1000 participants have been enrolled, and recruitment is ongoing. The cohort's diversity in age, employment status and health conditions enhances its value for life-course analysis. Following a pilot phase in 2022-2023, the whole study protocol now includes detailed demographic, clinical, behavioural, cognitive and psychosocial data, along with biological samples stored in the UPO Biobank. The protocol incorporates validated tools, comprehensive physical and cognitive assessments, and over 90 laboratory biomarkers covering inflammation, metabolism, hormonal function and coagulation. Additionally, a subset of participants underwent advanced inflammatory profiling by simultaneous measurement of 92 immune-related proteins and comprehensive genomic profiling using Illumina Single Nucleotide Polymorphism (SNP) arrays, capturing common genetic variation across multiple biological domains. Preliminary results demonstrate the feasibility of integrating deep phenotyping, reveal the roles of frailty in ageing and show initial evidence of age-related changes in inflammatory proteins. NCS plans to enrol at least 10 000 participants and will conduct long-term follow-up using both passive methods, such as linking with clinical records and administrative health databases, and active in-person reassessments. Future phases will integrate clinical, behavioural and cognitive data with large-scale omics analyses, including genomics, proteomics, metabolomics and transcriptomics. Machine learning techniques will be employed to model biological age, identify early signs of age-related decline and develop personalised prevention strategies. By combining high-resolution phenotyping with multidimensional data, NCS aims to find modifiable risk factors and molecular signatures of ageing, supporting national and European research efforts and encouraging collaborative studies through open data-sharing frameworks.
The Total or Partial Knee Arthroplasty Trial (TOPKAT) aimed to evaluate the difference between total knee replacement (TKR) and partial (unicompartmental) replacement (PKR) for treatment of late-stage medial compartment knee osteoarthritis. As longevity is a key issue for joint replacement, extended follow-up periods are required to fully evaluate the long-term efficacy. In this analysis, we report the 10-year follow-up of the TOPKAT trial. TOPKAT was a multicentre, randomised, pragmatic comparative effectiveness trial including an expertise component. Patients with medial compartment knee osteoarthritis were enrolled from 27 UK National Health Service (NHS) hospitals and randomly assigned (1:1) to receive PKR or TKR by surgeons who were either expert in and willing to perform both surgeries or by a surgeon with particular expertise in the allocated procedure. Neither surgeons, patients, nor follow-up assessors were masked to allocation, but the implant type was not highlighted at any stage. The primary long-term endpoint was the Oxford Knee Score (OKS) in the intention-to-treat population at 10 years. Cost effectiveness was also assessed. Individuals with relevant lived experience were involved in the study design. This trial is registered with ISRCTN03013488 and ClinicalTrials.gov, NCT01352247, and is complete. Between Jan 18, 2010, and Sept 30, 2013, of 962 patients assessed for eligibility, 528 patients (306 [58%] male, 222 [42%] female, mean age 65 years [SD 8·7]) were randomly assigned (PKR n=264; TKR n=264). Follow-up primary outcome response rate for eligible patients (excluding those who had died or withdrew) at 10 years was 326 (73%) of 444. Both operations provided good outcome. The between-group estimates ruled out any individually clinically meaningful differences in mean OKS scores (mean difference 0·27, 95% CI -1·59 to 2·13) or cumulatively over 10 years in the area under the curve analysis (mean difference 0·45, 95% CI -0·98 to 1·88). At 10 years, by treatment received, complications were 53 (22%) of 245 for PKR and 74 (27%) of 270 for TKR, reoperations (including revision) were 21 (9%) for PKR and 23 (9%) for TKR, and revision rates were 15 (6%) for PKR and 11 (4%) for TKR. By treatment allocated, for PKR and TKR respectively, complication occurred in 55 (21%) of 263 and 72 (29%) of 252, reoperations in 20 (8%) and 24 (10%), with revisions in 13 (5%) and 13 (5%) patients. PKR was more cost-effective compared with TKR, being associated with increased health benefits (mean difference in quality-adjusted life years of 0·322, 95% CI -0·069 to 0·712) and lower health-care costs (mean difference in cost -£731, 95% CI -1352 to -110). 10-year results comparing TKR and PKR show similar clinical outcomes, reoperation rates, and revision rates, but cost effectiveness is in favour of PKR. National Institute for Health and Care Research Health Technology Assessment Programme.
BackgroundPrevious studies investigating associations between adverse experiences across the life-course and dementia consider a narrow range of experiences and use sum scores which assume each experience has the same impact on dementia risk.ObjectiveTo develop a greater understanding of how patterns of adversity influence associations with dementia through consideration of timing, type and cumulation of adverse experiences.MethodsThe English Longitudinal Study of Ageing measured adverse life experiences in a life history interview. Cox proportional hazard models were used to investigate associations between dementia and three types of exposure: sum scores, individual experiences, and categories of similar experiences. We used linear hypothesis testing to assess whether associations between each experience and dementia differed significantly.ResultsA linear relationship between dementia and number of adult adverse experiences (HR:1.09, 95% CI:1.01-1.16), but not total or childhood experiences, was observed. When adverse experiences were considered separately, child abuse was associated with a 74% higher hazard of dementia (HR:1.74, 95% CI:1.25-2.43) and adult economic hardship was associated with a 32% higher hazard of dementia (HR:1.32, 95% CI:1.06-1.66). Associations between dementia and adverse experiences in childhood were heterogenous, showing greater variability than expected about a common hazard ratio (p = 0.01).ConclusionsAdulthood adverse experiences associate with dementia in a cumulative risk manner. In childhood, only abuse was associated with dementia. Use of sum scores to operationalize adverse experiences throughout the life-course may oversimplify associations with dementia. Both type and timing of experience influence the association. Work to prevent adverse experiences must span the life-course.
To examine the associations of life-course stressful life events (SLEs) with intrinsic capacity in older adults from the US, England and China. Prospective cohort study. A total of 6241 older adults from the US Health and Retirement Study (HRS), 2857 from the English Longitudinal Study on Ageing (ELSA), and 5829 the China Health and Retirement Longitudinal Study (CHARLS). Childhood and adulthood SLEs were self-reported by participants and were categorised into four groups: none, childhood only, adulthood only, and both. Intrinsic capacity consisted of five domains: locomotion, vitality, sensory, psychology and cognition. The level of each domain was converted into z-score by subtracting the mean and dividing the standard deviation. The composite z-score of intrinsic capacity referred to the mean of the z-scores of each domain. The mean (±standard deviation) age of the participants were 75.2 (±7.2), 70.5 (±7.5) and 67.5 (±6.1) years in HRS, ELSA and CHARLS. In three studies, there were 2672 (42.8%), 293 (10.3%) and 655 (11.2%) experiencing both childhood and adulthood SLEs, respectively. Older adults exhibited a decline in intrinsic capacity with increasing age. Compared to no SLEs, experiencing both childhood and adulthood SLEs was associated with significantly lower intrinsic capacity [β = -0.128 (95% CI = -0.159 to -0.097), relative risk (RR) = 1.25 (95% CI = 1.14 to 1.37) in HRS; β = -0.142 (95% CI = -0.189 to -0.095), RR = 1.28, (95% CI = 1.16-1.42) in ELSA; β = -0.156 (95% CI = -0.191 to -0.120), RR = 1.24 (95% CI = 1.16-1.33) in CHARLS]. Exposure to stressful life events, either in childhood or in adulthood or both, were associated with lower intrinsic capacity in late life. Individuals with SLEs during their life span should prioritised in prevention of functional decline and changing the environmental context and promoting social support can be a prominent strategy for reducing adulthood adversity.
Kelp forests throughout many temperate zones are in decline due to various human stressors, chiefly marine warming. Conservation measures including restoration are presently of great interest and focus on both historical and novel methodologies. Of paramount importance for these efforts is an understanding of the mechanics of kelp decline to identify the factors and triggers leading to stepwise declines and thus support the development and spatial prioritization of strategic intervention to facilitate resilience. Here, we utilized a unique dataset documenting the demographic dynamics of giant kelp, Macrocystis pyrifera, in response to multiple disturbances across >40 years off San Diego (California, USA). The recruitment and life history of >14,000 individuals were used to evaluate cohort structure, size, and longevity forced by algal community structure and disturbance. Cohort dynamics varied spatially by depth and study subregion, thus aiding identification of areas to prioritize intervention to foster resilience. Five algal assemblages were characterized providing context for cohort dynamics in response to physical disturbances and sea urchin grazing. A trend of decreasing cohort size and resilience was observed over time accentuated by the marine heat wave of 2014-2015 (MHW) after which competition with understory canopies increasingly interfered with giant kelp cohort development and plant size structure. Cohort recruitment ranged on a continuum from discrete ("pulsed") to more gradual ("trickled") episodes. Pulsed cohorts mainly produced single cohort-dominated age stands punctuated by major disturbances. Pulsed events were more common than trickled recruitment, especially at deeper sites. Trickled cohorts resulted in relatively mixed age stands, especially when individual cohorts overlapped within sites. Trickled recruitment increased over time as understory dominance increased. Cohort longevity was highly variable among sites and among cohorts within a site, with high first-year mortality mostly due to warming, waves, or their combination. Longevity was inversely related to temperature and sea urchin density, and was greatest at deeper sites, especially after the MHW. The downward trend of single cohort dominance and individual plant size over time and its step downward after the MHW suggest that deeper areas should be prioritized for restoration. Regardless, understory canopies will increasingly dominate Southern California with continued warming.
Stressful life events significantly influence the development and course of mental disorders in children and adolescents. The Stressful Life Events Schedule (SLES) is an instrument designed to evaluate these events. This study aims to validate the Spanish version of the SLES (Spanish SLES) for children, adolescents and parents by analysing its psychometric properties and discriminant validity. Participants were recruited from two cohorts. Cohort I comprised 188 offspring aged 6-17 years (50.0% female), including 114 offspring of patients with bipolar disorder or schizophrenia (high-risk group) and 74 offspring of control subjects (control group). Cohort II included 35 adolescents aged 14-18 years with a first-episode psychosis (FEP group) (62.9% female). The psychometric properties of the SLES were assessed, including internal consistency (IC) and test-retest reliability, discriminant validity across groups, and concurrent validity. The Spanish SLES demonstrated robust psychometric properties. In adolescents, IC was 0.87 for the total event count and 0.88 for interference with intraclass correlation coefficients (ICCs) of 0.74 and 0.70, respectively. In children, IC was also high (α=0.83 for events and α=0.85 for interference) with ICCs of 0.61 for both measures. In parents, IC was 0.78-0.86 for events and 0.78-0.87 for interference with ICCs of 0.80-0.84 and 0.75-0.82, respectively. Adolescents in the FEP group reported significantly more stressful events (p<0.001, ηp2=0.156) and greater interference (p<0.001, ηp2=0.190) compared with both the high-risk and control groups. Additionally, moderate correlations were found between parent and adolescent reports, with lower concordance observed in the child sample. These findings underscore the importance of integrating multiple informants when assessing stressful life events in clinical practice. The Spanish SLES is a valid and reliable instrument for assessing stressful life events in children, adolescents and their parents. It is an accessible and easy-to-administer tool, suitable for use in both clinical practice and research settings.
Early-life growth adversity is important to later-life health, but precision assessment in adulthood is challenging. We evaluated whether the difference between attained and genotype-predicted adult height ("height-GaP") would associate with prospectively ascertained early-life growth adversity and later-life all-cause and cardiovascular mortality. Data were first analyzed from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4582; 56/43% female/male) and UKBiobank (n = 483,385; 54/46% female/male). Genotype-predicted height was calculated using a multi-ancestry polygenic height score. Height-GaP was calculated as the difference between measured and genotype-predicted adult height. Early-life growth conditions were ascertained prospectively via standardized procedures (ALSPAC) and mortality via death register (UKBiobank). Regression models examined: (i) adult height-GaP as the outcome with early-life growth conditions as predictors; and (ii) mortality as the outcome with adult height-GaP as predictor. All models were adjusted for age, sex, genotype-predicted height and genetic ancestry. Analyses were replicated in the Dunedin Multidisciplinary Health and Development Study (DMHDS; n = 855; 49/51% female/male) and the Multi-Ethnic Study of Atherosclerosis (MESA; n = 6352; 52/48% female/male). Here we show that among ALSPAC participants (median [IQR] age: 24 [18-25] years at height-GaP assessment), lower gestational age at birth, greater pre- and post-natal deprivation indices, tobacco smoke exposure and less breastfeeding are associated with larger adult height-GaP deficit (p < 0.01). Among UKBiobank participants (mean ± SD age: 56 ± 8 years at height-GaP assessment), height-GaP deficit is associated with death from all-causes (adjusted hazard ratio comparing highest-to-lowest height-GaP deficit quartile [aHR]: 1.25 95%CI: 1.21-1.29), atherosclerotic cardiovascular disease (aHR: 1.32 95%CI: 1.23-1.42) and coronary heart disease (aHR: 1.64 95%CI: 1.49-1.81). Early- and later-life height-GaP associations replicate in DMHDS and MESA. This study introduces a precision index of early-life growth adversity deployable in adulthood to investigate the developmental origins of longevity and improve health equity across the life course. Early-life exposures that adversely affect body growth have been implicated in later-life health, but assessment in adulthood is challenging. We tested whether the difference between one’s standing height in adulthood and one’s genetically predicted adult height (“height-GaP”) would be a suitable method for assessing cumulative exposure to early-life growth adversity and predicting later-life health. In two early-life studies that followed children into adulthood, pre-natal and post-natal exposure to tobacco smoke, poverty, less breast feeding and poor nutrition were associated with larger adult height-GaP deficit. In two adult studies, larger height-GaP deficit was associated with death from all-causes and from heart disease. This study introduces a precision measure of early-life growth adversity that can be deployed in adulthood to investigate the developmental origins of health and disease.
Traumatic brain injury is a progressive and potentially persistent pathophysiological condition affecting multiple cognitive domains. Large-scale brain networks, particularly those supporting attention, are closely linked to these cognitive impairments. Additionally, functional network connectivity, which captures statistical dependencies among network time courses, has revealed disrupted coupling between attentional networks. However, longitudinal evidence on how functional network connectivity changes over time and whether such changes are related to structural connectivity or cognitive outcomes remains limited. To address these gaps, this study investigated functional and structural connectivity among the default mode network, dorsal attention network, and ventral attention network in 41 patients with mild traumatic brain injury (mean age: 48.7 ± 15.8 years) and 35 matched controls (mean age: 44.6 ± 12.8 years). Both groups underwent brain imaging, clinical and neuropsychological assessments, and two cognitive tasks, including the Wisconsin Card Sorting Test and Digit Span Test, during the baseline (<1 month) and follow-up (>3 months) phases. Functional networks were defined using the Schaefer atlas and structural connectivity was constructed using these networks as nodes. Diffusion metrics, including fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity, were assessed. Clinically, symptom scores of depression, symptom severity, and quality of life improved over the three-month period (P < 0.001), whereas outcomes assessed by the Korean version of the Montreal Cognitive Assessment and the Frontal Assessment Battery showed limited change (P > 0.05). Cognitive performance was generally comparable between groups, except for a significant main effect of group in the backward Digit Span Test, with the mild traumatic brain injury group showing poorer performance than controls. In the baseline phase, functional network connectivity between the default mode network and dorsal and ventral attention network was significantly reduced in the mild traumatic brain injury group, correlating with impaired attentional control but not with working memory capacity. These disruptions were no longer observed at the follow-up assessment. Structural connectivity remained largely stable throughout the period. Diffusion metrics in controls were associated with attentional performance but not with working memory performance. Positive associations were observed between attentional performance and fractional anisotropy only during the follow-up phase in the mild traumatic brain injury group, possibly reflecting shifts in the association over time. In contrast, working memory performance was consistently linked to diffusion metrics in the mild traumatic brain injury group. Taken together, these findings highlight a temporal dissociation between early functional disconnection and later structure-cognitive coupling following mild traumatic brain injury and highlight the value of multimodal longitudinal imaging in understanding post-injury recovery.
Effective management of biological age (or slowing down the aging process) is a rapidly developing field that seeks not only to increase life expectancy but also to improve quality of life in old age, prolonging the period of active longevity. Medical rehabilitation plays a fundamental and critical role in managing biological age and promoting health, especially in the context of achieving healthy longevity. The most effective and scientifically proven tool in medical rehabilitation for managing biological age are therapeutic physical factors capable of activating primary and secondary protective and adaptive mechanisms aimed at restoring impaired self-regulation and slowing down the processes of biological aging. To evaluate the effectiveness of the integrated use of pathogenetically oriented medical rehabilitation methods on biological age indicators and patient quality of life. The study was conducted at the B.V. Sechenov Russian Scientific Center of Surgery. The Petrovsky Clinical Hospital involved 125 participants with an average age of 57.3±0.37 years. All patients received basic therapy (BT), including a course of physical exercise, a reduced-calorie diet, and vitamin therapy. Using a simple fixed randomization method, the entire cohort of patients was divided into 3 groups: a control group (n=42), a comparison group (n=41), and a main group (n=42). Patients in the control group received BT only. In the comparison group, in addition to BT, patients received a course of complex physiotherapy, including whole-body air cryotherapy, hypoxic-hyperoxygen therapy, and dry carbon dioxide baths. The main group of patients, in addition to the comparison group, received a course of binaural therapy. A comprehensive patient examination included anthropometric measurements (body mass index), biochemical (blood lipid profile, blood glucose levels, oxidative stress and systemic inflammation markers), and hormonal (insulin, cortisol, serotonin) parameters, as well as an assessment of biological age according to V.P. Voitenko and the aging rate coefficient. Patients' quality of life was also assessed using the SF-36 psychometric questionnaire and the EQ VAS questionnaire. The use of a physiotherapy program, supplemented by a course of binaural therapy, resulted in the maximum corrective effect, manifested by positive changes in anthropometric and laboratory parameters, as well as a decrease in biological age and the aging rate coefficient to normal values. The most significant improvement in quality-of-life indicators was also noted in the study group. An integrative comparative assessment of the effectiveness of medical rehabilitation for patients between the selected groups using a correlation adaptometry algorithm revealed that the greatest decrease in the weight of the correlation graph - a quantitative indicator that collectively reflects the strength of correlations-was observed in the study group. This finding reflects a weakening of the correlational cooperation between various variables, characteristic of an increased level of the body's functional reserves. The developed non-drug technology, based on the use of therapeutic physical factors, reduces biological age and the aging rate coefficient by activating secondary sanogenetic processes, which have a corrective effect on the systemic mechanisms of aging. The observed combination of changes in various physiological and regulatory systems is aimed at increasing the functional reserves and adaptive capacity of the human body, which ultimately results in an improved quality of life for patients. Эффективное управление биологическим возрастом (или замедление процессов старения) представляет собой активно развивающуюся область, которая стремится не просто увеличить продолжительность жизни, но и улучшить качество жизни в старшем возрасте, продлевая период активного долголетия. Фундаментальную и критически важную роль в управлении биологическим возрастом и укреплении здоровья, особенно в контексте достижения здорового долголетия, играет медицинская реабилитация. Наиболее эффективным и научно обоснованным инструментом при проведении медицинской реабилитации в целях управления биологическим возрастом выступают лечебные физические факторы, способные активировать первичные и вторичные защитно-приспособительные механизмы, направленные на восстановление нарушенной саморегуляции и замедление процессов биологического старения организма. Оценка эффективности комплексного применения патогенетически ориентированных методов медицинской реабилитации на показатели биологического возраста и качество жизни пациентов. Исследования выполнены на базе ФГБНУ «РНЦХ им. акад. Б.В. Петровского» с участием 125 человек, средний возраст которых составил 57,3±0,37 года. Все пациенты получали базовую терапию (БТ), включающую курс физических упражнений, диетотерапию со сниженной калорийностью и витаминотерапию. Методом простой фиксированной рандомизации вся когорта пациентов была разделена на 3 группы: контрольную (42 пациента), группу сравнения (41 пациент) и основную (42 пациента). Пациенты контрольной группы получали только БТ. В группе сравнения дополнительно к БТ пациенты получали курсовое комплексное физиотерапевтическое воздействие, включающее общую воздушную криотерапию, гипокси-гиперокситерапию и сухие углекислые ванны. Основная группа пациентов дополнительно к комплексу группы сравнения получала курс бинауральной терапии. Комплексное обследование пациентов включало определение антропометрических данных с расчетом индекса массы тела, биохимических (липидный спектр крови, уровень гликемии, маркеры оксидативного стресса и системного воспаления) и гормональных (инсулин, кортизол, серотонин) показателей, а также оценку биологического возраста по В.П. Войтенко и коэффициента скорости старения. Дополнительно определяли уровень качества жизни пациентов, используя психометрический опросник SF-36 и опросник EQ VAS. Использование физиотерапевтического комплекса, дополненного курсом бинауральной терапии, сопровождалось развитием максимального корригирующего эффекта, проявившегося положительной динамикой антропометрических и лабораторных показателей, а также снижением биологического возраста и коэффициента скорости старения до нормальных значений. Наиболее выраженный прирост показателей качества жизни пациентов также был отмечен в основной группе. Проведение интегративной сравнительной оценки эффективности медицинской реабилитации пациентов между выделенными группами с помощью алгоритма корреляционной адаптометрии позволило установить, что максимальное снижение веса корреляционного графа — количественного показателя, суммарно отражающего силу корреляционных зависимостей, — было выявлено в основной группе. Отмеченный факт отражает ослабление корреляционной кооперации между разными переменными, характерное для возросшего уровня функциональных резервов организма. Разработанная нелекарственная технология на основе использования лечебных физических факторов снижает биологический возраст и коэффициент скорости старения за счет активирующего влияния на вторичные саногенетические процессы, оказывающие корригирующее влияние на системные механизмы старения. Наблюдаемая при этом совокупность изменений различных физиологических и регуляторных систем направлена на повышение функциональных резервов и адаптивных возможностей организма человека, что в конечном итоге проявляется повышением уровня качества жизни пациентов.
The problem of increasing the duration of active longevity is being solved with great difficulty, since there is still no clear understanding of the predictors of premature aging, their validity, informativeness and effectiveness of various corrective programs. The priority in this direction remains for special statistical methods, among which regression analysis and correlation adaptometry stand out. Despite the fact that the effectiveness of complex physiotherapy for various pathological reactions of premature aging has been proven, however, verification of this process from the perspective of using various methods to assess the dynamics of life expectancy has not yet been carried out. To analyze the validity and informativeness of statistical methods of premature aging and predictors of the effectiveness of combined physiotherapy. The research was conducted on the basis of the Scientific and Clinical Center 1 of the Russian National Research Center named after BV. Petrovsky Academy with the participation of 40 patients (19 men and 21 women) aged from 20 to 90 years. After signing a voluntary informed consent to conduct a special study with the processing of their personal data, all patients underwent a comprehensive clinical, laboratory and functional examination, patients with moderate physical activity, reduced calorie intake and vitamin therapy received a physiotherapy complex 2 times a year, which included multimodal effects using the Alpha LED Ohu Light-Spa device, hyper-hypoxytherapy, pressotherapy, dry carbon dioxide baths. The preventive courses were repeated twice with an interval of 6 months. All studies were conducted before and 6, 12 and 18 months after the completion of each preventive course. Multiple linear regression analysis was used to identify the predictors. It was found that active longevity is determined by telomere length, inhibited by an increasing index of insulin resistance and a high concentration of malondialdehyde in the blood, although correlation adaptometry largely identified the index of insulin resistance and the coefficient of atherogenicity as predictors of premature aging. An analysis of the predictors of the effectiveness of combined physiotherapy associated with the dynamics of biological age showed that their role is mostly claimed by the insulin resistance index, atherogenicity coefficient, malondialdehyde; the index of systemic inflammation and the relative length of telomeres. It has been proven that insulin resistance, atherogenicity coefficient, and telomere length reduction are the leading predictors of premature aging, which emphasizes the importance of optimizing hormonal regulation of carbohydrate and lipid metabolism and, ultimately, energy supply for sanogenetic processes that characterize premature aging in patients. The analysis of dynamic processes in the application of combined physiotherapy has expanded the number of predictors of the effectiveness of inhibiting premature aging, apparently due to the polymodal therapeutic effect of factors of various physical nature. Проблема увеличения сроков активного долголетия решается с большим трудом, поскольку до настоящего времени нет четкого понимания предикторов преждевременного старения, их валидности, информативности и эффективности корригирующих программ. Приоритет в этом направлении остается за специальными статистическими методами, среди которых выделяются регрессионный анализ и корреляционная адаптометрия. Несмотря на то что доказана эффективность комплексной физиотерапии на патологические реакции преждевременного старения, верификация этого процесса с позиции применения разных методов оценки динамики продолжительности жизни до настоящего времени не проводилась. Анализ валоидности и информативности статистических методов преждевременного старения и предикторов эффективности комбинированной физиотерапити. Исследования были проведены на базе Научно-клинического центра №1 ФГБНУ «РНЦХ им. акад. Б.В. Петровского» при участии 40 пациентов (19 мужчин и 21 женщина) в возрасте от 20 до 90 лет. Все пациенты прошли комплексное клинико-лабораторное и функциональное обследование и на фоне умеренной физической нагрузки, снижения калорийности питания и витаминотерапии получали 2 раза в год физиотерапевтический комплекс, в состав которого входили мультимодальные воздействия с использованием аппарата Alpha LED Оху Light-Spa, гипер-гипокситерапия, прессотерапия, сухие углекислые ванны. Профилактические курсы повторяли дважды с интервалом 6 мес. Исследования проводили до и через 6, 12 и 18 мес после завершения каждого профилактического курса. Для выявления предикторов применяли множественный линейный регрессионный анализ. Установлено, что активное долголетие определяется длиной теломер, тормозится возрастающим индексом инсулинорезистентности и высокой концентрацией в крови малонового диальдегида, хотя корреляционная адаптометрия в большей степени выделяла в качестве предикторов преждевременного старения индекс инсулинорезистентности и коэффициент атерогенности. Анализ предикторов эффективности комбинированной физиотерапии, ассоциированных с динамикой биологического возраста, показал, что на их роль в большей степени претендуют индекс инсулинорезистентности, коэффициент атерогенности, малоновый диальдегид, индекс системного воспаления и относительная длина теломер. Доказано, что инсулинорезистентность, коэффициент атерогенности и уменьшение длины теломер являются ведущими предикторами преждевременного старения, что подчеркивает роль важности оптимизации гормональной регуляции метаболизма углеводов и липидов и в конечном счете энергетического обеспечения саногенетических процессов, характеризующих преждевременное старение пациентов. Анализ динамических процессов при применении комбинированной физиотерапии расширил количество предикторов эффективности торможения преждевременного старения, по-видимому, за счет полимодального терапевтического эффекта факторов разной физической природы.
Structured educational programs for physicians in healthy longevity medicine (HLM) remain scarce. No published data yet document the impact of longevity-focused medical education on physicians. This study assesses the ramifications of the HLM curriculum, certified by the American Council for Continuing Medical Education, on physicians' confidence in their knowledge of HLM and clinical practice. This study aimed to evaluate the impact of accredited HLM education on physicians' confidence in knowledge and practice patterns, examining self-reported integration of HLM principles, professional attitudes, and career trajectories to determine the translational value of structured curricula in the emerging medical discipline. A cross-sectional online survey was conducted between March and April 2024 among physicians who had completed accredited HLM courses between January 2023 and February 2024. Invitations were sent globally to 590 eligible physicians; trainees and students were excluded. A total of 113 (19.2%) respondents completed the survey and were included in the analysis. The survey assessed self-reported changes in clinical implementation, confidence in HLM-related knowledge, and professional attitudes following course completion. Descriptive statistics and logistic regression analyses were performed (P<.05). Respondents represented 42 nationalities and were primarily trained in family medicine (n=31, 27.4%) and internal medicine (n=18, 15.9%). Overall, 96.5% (n=99) of the respondents reported increased confidence in HLM-related knowledge, with 47.8% (n=55) indicating substantial improvement. More than half of the respondents (n=63, 55.8%) reported integrating HLM principles into routine patient assessments, and 80.5% (n=91) of the respondents reported more frequent discussions related to health span-focused care. In addition, 23% (n=26) of the respondents initiated aging biomarker testing, 48.7% (n=55) increased the testing frequency, 52.2% (n=59) reported a shift in their perspective on aging, and 73.5% (n=83) anticipated full integration of HLM into mainstream medicine. Physicians practicing in specialized care demonstrated higher odds of reporting increased confidence in HLM knowledge compared with those in primary and preventive care (odds ratio 4.46, 95% CI 1.55-12.79; P=.005). Accredited education in HLM is associated with enhanced confidence in HLM knowledge, increased clinical engagement with HLM practices, and a shift in aging-related care paradigms. These findings underscore the critical role of structured HLM curricula in bridging the translational gap between geroscience and everyday medical practice. Nevertheless, systemic health care barriers impede widespread implementation, warranting policy-level strategies to support health span-oriented education and care models.
Current primary prevention guidelines recommend estimation of long-term cardiovascular disease (CVD) risk among younger adults to enable preventive efforts earlier in the life course. However, conceptualizing absolute risk estimates over this time horizon is challenging for both clinicians and patients. Framing risk relative to peers (ie, "population-based percentiles") as complementary information may have utility for risk communication. We sought to develop population-based age- and sex-specific percentiles of 30-year absolute risk estimates for CVD, atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF) with the PREVENT (Predicting Risk of CVD EVENTs) equations. We used data from a nationally representative sample of U.S. adults aged 30 to 59 years without prevalent CVD in the National Health and Nutrition Examination Survey (NHANES) 2011 to March 2020. We calculated 30-year risk estimates with PREVENT for eligible participants and derived age- and sex-specific percentiles at each age (using rolling windows of ±5 years) for each outcome of CVD, ASCVD, and HF. Among 8,686 NHANES participants, representing approximately 91 million U.S. adults aged 30 to 59 years in the final sample, mean age was 44.8 ± 0.2 years among female participants and 44.2 ± 0.2 years among male participants. The median 30-year absolute CVD risk in the overall sample was 13.1%. Then, corresponding percentile values were developed and evaluated for each age among women and men aged 30 to 59 years for 30-year risk of CVD, ASCVD, and HF. For example, at age 45 years, the 50th percentile of 30-year CVD risk for was 9.9% for women and 16.2% for men, and the 75th percentile was 14.7% for women and 21.2% for men at that age. Similar patterns were observed for ASCVD and HF, with higher 30-year absolute risk in men compared with women. An online tool was developed to present risk percentiles alongside absolute 30-year risk for CVD, ASCVD, and HF. Population-based age- and sex-specific percentiles for 30-year CVD risk with PREVENT may offer a complementary tool for clinicians and patients in addition to communicating absolute CVD risk estimates. Prospective studies should test whether this approach improves risk perception or decision-making in younger adults.
Personal Views of Aging (VoA) encompass different constructs capturing individuals' perceptions, attitudes, and expectations regarding their aging self, which are well-established influences of health-related and longevity outcomes over the adult life course. The present study aimed to investigate the associations among personal VoA facets, namely subjective age, Attitudes Toward Own Aging (ATOA), and Awareness of Age-Related Change (AARC), and their joint contribution in explaining mood and cognitive functioning in midlife and older age. A sample of 350 community-dwelling individuals aged 40 to 92 years reported their mental felt age and completed the Attitudes Toward Own Aging scale (ATOA) and the Awareness of Age-Related Change questionnaire (AARC), assessing perceptions of age-related gains (AARC-Gains) and losses (AARC-Losses) in various functioning domains. They were also administered a working memory and a mood measure. Structural equation models were used to examine the associations between personal VoA, cognitive and mood outcomes. Results revealed that AARC is more likely to act as a mediator between the global personal VoA facets and the mood outcome but not the cognitive one. Specifically, more positive ATOA scores were associated with high AARC-Gains and low AARC-Losses, and AARC-Losses were in turn associated with better mood functioning. Moreover, a youthful mental felt age was associated with higher ATOA and AARC-Gains scores, whereas greater AARC-Gains and AARC-Losses were associated with a poorer working memory performance. These findings suggest a complex interplay between facets of personal VoA and further highlight their contributions to explaining particularly mood outcomes in midlife and older age.
Total hip replacement is a successful operation that aims to restore function and quality of life to millions of people globally. Knowing how long a total hip replacement might last is important for patients, surgeons, and health-care institutions for planning and resource allocation. Over the past 20 years, the use of contemporary bearing surfaces for total hip replacement has substantially altered implant wear and, possibly, longevity. To date, there has been no large-scale study that examines survivorship of these modern implants. We aimed to determine the survivorship of contemporary total hip replacements and bearing materials. We focused solely on the assessment of modern bearing surfaces: highly cross-linked polyethylene versus metal or third-generation and fourth-generation ceramic heads and ceramic-on-ceramic primary total hip replacement in adult patients. We conducted a search of MEDLINE and Embase from database inception to June 13, 2024, including articles that reported a minimum of 10 years of survivorship, irrespective of fixation method or surgical approach. We then conducted a meta-analysis combining data from eight national joint registries assessing all-cause revision within the various bearing combinations. We extrapolated the extracted data to estimate survivorship to 30 years, using the multivariable random-effects model from the registry data. The primary outcome was survivorship of the hip replacement, defined as time from primary total hip replacement to first all-cause revision, expressed as a percentage of unrevised implants at specific timepoints. This study is registered with PROSPERO (CRD42024572518). We identified 1 904 237 total hip arthroplasties across 29 clinical studies (n=5203) and eight national joint registries (n=1 899 034). Pooled analysis of the included studies showed an all-cause implant survivorship of 0·97 (0·96-0·98) under the random-effects model. Survivorship estimate based on joint registry data was at 93·6% (95% CI 92·3-94·7) at 20 years. Extrapolating these data indicates a predicted survivorship of 92·8% (91·2-94·2) at 25 years and 92·1% (90·1- 93·7) at 30 years. The estimated 92% 30-year survivorship of contemporary total hip replacement suggests that advances in bearing surface technology have greatly improved the long-term durability of total hip replacements and might influence patient counselling, health-care planning, and device regulation. None.
Prior research has shown that high composite biological health scores (BHS, based on the allostatic load theory of multisystem physiological dysregulation) are associated with mortality. However, most of this work remains cross-sectional and does not explore the implications of long-term biological health changes, although this is an essential perspective for a better understanding of ageing and health span. To explore the relationship between BHS-at two time points and longitudinally-and mortality, we analysed waves six (2007-08) and seven (2015-16) of the Tromsø Study linked with all-cause mortality data from the Norwegian Population Registry up to 2022. Using 10 biomarkers from 8117 individuals, we created 2-category (low/high) Tromsø6-BHS, Tromsø7-BHS, and longitudinal BHS measures. Cox proportional hazard regression analysis adjusted for confounders revealed that both higher Tromsø6-BHS and Tromsø7-BHS were significant predictors of mortality 15 and 7 years later, respectively (Tromsø6-BHS: HR = 1.20 [0.99-1.45]; Tromsø7-BHS: HR = 1.26 [1.05-1.52]), and that the 7-year mortality risk was more pronounced for the longitudinal BHS (1.30 [1.09-1.56]). Corresponding sex- and age-adjusted median survival was lowered by 0.71, 1.69, and 1.84 years in participants with a high versus low Tromsø6-BHS, Tromsø7-BHS and longitudinal-BHS, respectively. These results indicate that both historical elevations of BHS and their cumulation over time play a role in determining mortality risk. Our findings underline the importance of monitoring biological health over the life course as a preventive measure and suggest that individuals with high BHS levels may benefit from dynamic monitoring from mid-adulthood to mitigate the risk of premature mortality.