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Purpose: To examine the associations of accelerometer-derived steps volume and intensity with hospitalizations and all-cause mortality in older adults. Methods: This prospective cohort study involved 768 community-dwelling Spanish older adults (78.8 § 4.9 years, mean § SD; 53.9% females) from the Toledo Study for Healthy Aging (2012 2017). The number of steps per day and step cadence (steps/min) were derived from a hip-mounted accelerometer worn for at least 4 days at baseline. Participants were followed-up over a mean period of 3.1 years for hospitalization and 5.7 years for all-cause mortality. Cox proportional hazards regression models were used to estimate the individual and joint associations between daily steps and stepping intensity with hospitalizations and all-cause mortality. Results: Included participants walked 5835 § 3445 steps/day (mean § SD) with an intensity of 7.3 § 4.1 steps/min. After adjusting for age, sex, body mass index (BMI), education, income, marital status and comorbidities, higher step count (hazard ratio (HR) = 0.95, 95% confidence inter vals (95%CI: 0.90 1.00, and HR = 0.87, 95%CI: 0.81 0.95 per additional 1000 steps) and higher step intensity (HR = 0.95, 95%CI: 0.91 0.99, and HR = 0.89, 95%CI: 0.84 0.95 per each additional step/min) were associated with fewer hospitalizations and all-cause mortality risk, respectively. Compared to the group having low step volume and intensity, individuals in the group having high step volume and intensity had a lower risk of hospitalization (HR = 0.72, 95%CI: 0.52 0.98) and all-cause mortality (HR = 0.60, 95%CI: 0.37 0.98). Conclusion: Among older adults, both high step volume and step intensity were significantly associated with lower hospitalization and all-cause mortality risk. Increasing step volume and intensity may benefit older people.

Insulin signalling declines with increasing age and impacts skeletal muscle function and longevity in animal models. Our aim was to assess the relationships between insulin resistance (IR) and frailty and mortality in a unique community-dwelling cohort of older people. 991 non-diabetic subjects from the Toledo Study of Healthy Ageing (TSHA) cohort were included. IR was estimated by the homeostasis model assessment index (HOMA-IR) at baseline while frailty was determined by frailty phenotype (FP) and Frailty Trait Scale (FTS) at baseline and after 5-year follow-up. Deaths were also determined. Multivariate regression models were used to analyze the effects of HOMA-IR on outcomes. Age, gender, BMI, education level, cardio- and cerebro-vascular disease, glomerular filtration rate, and disability were included as potential confounding variables in progressive adjustment models. IR determined as increasing log HOMA-IR was inversely associated with risk of mortality. The association remained significant for all adjustment models (HR: 0.64–0.69). When we analyzed survival curves, the higher the HOMA-IR tertile, the lower the mortality rate (highest vs lowest tertile, p = 0.0082). In contrast, IR increased the risk of incident frailty determined by FP (OR 1.81 [1.14–2.87]) as well as deterioration of frailty status determined by worsening in FTS score (OR 1.28 [1.01–1.63]) at 5-year follow-up. In non-diabetic older subjects, IR significantly increases the risk for frailty and functional decline but decreased the risk of death at 5-year follow-up. This finding raises the need of assessing the effect of biomarkers on different outcomes before establishing their role as biomarkers of aging.

Visual impairment (VI) may lead to worsening functional status and disability. Although disability is very difficult to reverse, it is usually preceded by frailty that may be reverted more easily. It is possible that VI is also related to frailty. To assess the relationship between VI and worsening of the frailty status. Data were taken from the Toledo Study for Healthy Aging (TSHA), a cohort study of community-dwelling people older than 65 years living in one Spanish province who were followed for 5 years. 1181 participants were included. VI was self-reported and frailty was operationalized using the Fried’s phenotype adapted to a Spanish population. Models of multivariate logistic regression were built to assess the associations. The mean age was 73.9 (Standard Deviation (SD) = 5 years) and 58.5% were females. Pre-frailty/frailty prevalence at baseline and follow-up were 41.2/5% and 36.2/12.5%, respectively, and VI was reported by 14.1%. After adjusting for age, gender, education level, tobacco consumption, type 2 diabetes mellitus, high blood pressure, cardiovascular disease, depressive symptoms and cognitive status, odds ratios for the development of frailty by VI were 2.5 (95% Confidence Interval (CI) 1.5–4.4) for non-frail, 2.7 (95% CI 1.3–5.7) for pre-frail and 1.9 (CI 0.6–6.00) for robust participants. The frailty domains whose appearance was most increased by VI were slowness, low energy, low physical activity and weakness. Our findings support that VI worsens frailty in the early stages of its development (pre-frailty). VI impairs several frailty items at the same time. Our study highlights the need to assess both VI and frailty for the prevention of frailty and disability in older people.

Purpose Little is known about the economic burden that malnutrition or its risk imposes on community-dwelling older adults. Using cross-sectional and longitudinal analyses, we assessed the impact of malnutrition risk on healthcare utilization and costs in a cohort of older adults living in Spanish community. Patients and Methods Data from 1660 older (range 66-98 years), community-living adults participating in the Toledo Study on Healthy Ageing, waves 2 (year 2011-2013) and 3 (year 2015), were analyzed. Nutritional status categories were defined according to the Global Leadership Initiative on Malnutrition (GLIM) criteria, using a two-step approach. First, screening for malnutrition risk. Once positive, individuals were classified as malnourished according to some phenotypic (body mass index, grip strength, and unintentional weight loss) and etiologic (disease burden/inflammation and reduced food intake or assimilation) criteria. Outcomes assessed included healthcare resources (hospital admissions, number of hospitalizations, length of hospital stay per hospitalization, and number of medications). Results Fifteen percent of the population was found to be at risk of malnutrition, while 12.6% was malnourished. Overall, patients from both groups were older, had lower functional status, and had more comorbidities compared to well-nourished counterparts (p

Background/aim: A prospective evaluation of drug-induced liver injury (DILI) in two tertiary hospitals was conducted through a pharmacovigilance program from laboratory signals at hospital (PPLSH) to determine the principal characteristics of DILI in patients older than 65 years, a growing age group worldwide, which is underrepresented in the literature on DILI.Methods: All DILI in patients older than 65 years detected by PPLSH in two hospitals were followed up for 8 years in the La Paz Hospital and 2 years in the Getafe Hospital. A descriptive analysis was conducted that determined the causality of DILI and suspected drugs, the incidence of DILI morbidities, DILI characteristics, laboratory patterns, evolution and outcomes.Results: 458 DILI cases in 441 patients were identified, 31.0% resulting in hospitalisation and 69.0% developing during hospitalisation. The mean age was 76.61 years old (SD, 7.9), and 54.4% were women. The DILI incidence was 76.33/10,000 admissions (95%CI 60.78–95.13). Polypharmacy (taking >4 drugs) was present in 86.84% of patients, 39.68% of whom took >10 drugs. The hepatocellular phenotype was the most frequent type of DILI (53.29%), a higher proportion (65%) had a mild severity index, and, in 55.2% of the evaluated drugs the RUCAM indicated that the causal relationship was highly probable. The most frequently employed drugs were paracetamol (50-cases), amoxicillin-clavulanate (42-cases) and atorvastatin (37-cases). The incidence rate of in-hospital DILI per 10,000 DDDs was highest for piperacillin-tazobactam (66.96/10,000 DDDs). A higher risk of in-hospital DILI was associated with the therapeutic chemical group-J (antiinfectives for systemic use) (OR, 2.65; 95%CI 1.58–4.46) and group-N (central nervous system drugs) (OR, 2.33; 95%CI 1.26–4.31). The patients taking >4 medications presented higher maximum creatinine level (OR, 2.01; 95%CI 1.28–3.15), and the patients taking >10 medications had a higher use of group J drugs (OR, 2.08; 95%IC 1.31–3.32).Conclusion: The incidence rate of DILI in the patients older than 65 years was higher than expected. DILI in elderly patients is mild, has a good outcome, has a hepatocellular pattern, develops during hospitalisation, and prolongs the hospital stay. Knowing the DILI incidence and explanatory factors will help improve the therapy of the elderly population.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10−17), arthritis (GDF5 p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing., Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.

Objective To determine which of 8 commonly employed frailty assessment tools demonstrate the most appropriate characteristics to be employed in different clinical and social settings. Design Cross-sectional multicenter European-based study. Setting and Participants 1440 patients aged ≥75 years evaluated in geriatric inpatient wards, geriatric outpatient clinics, primary care clinics, and nursing homes. Methods The frailty instruments used were Frailty Phenotype, SHARE-FI, 3-item Frailty Trait Scale (FTS-3), 5-item Frailty Trait Scale (FTS-5), FRAIL, 35-item Frailty Index (FI-35), Gerontopole Frailty Screening Tool (GFST), and Clinical Frailty Scale (CFS). The settings were geriatrics wards, outpatient clinics, primary care, and nursing homes. Suitability was evaluated by considering the feasibility (patients with the test fully completed), administration time (time spent for administering the test), and interscale agreement (Cohen kappa index among instruments to detect frailty). Results The prevalence of frailty varied across settings and adopted tests. The scales with the mean highest feasibility were the FRAIL scale (99.4%), SHARE-FI (98.3%), and GFST (95.0%). The mean shortest administration times were obtained with CFS (24 seconds), GFST (72 seconds), and FRAIL scale (90 seconds). The interscale agreement between most of the tests was fair. CFS followed by FTS-5 agreed at least moderately with a greater number of scales overall and in almost all settings. Conclusions and Implications Based on feasibility, time to undertake the tool, and agreement with other scales, different scales would be recommended according to the setting considered. Our findings suggest that most of the tools evaluated are actually assessing different frailty constructs.

We used data from 3041 participants in four cohorts of community-dwelling individuals aged ≥65 years in Spain collected through a pre-pandemic face-to-face interview and a telephone interview conducted between weeks 7 to 15 after the beginning of the COVID-19 lockdown. On average, the confinement was not associated with a deterioration in lifestyle risk factors (smoking, alcohol intake, diet, or weight), except for a decreased physical activity and increased sedentary time, which reversed with the end of confinement. However, chronic pain worsened, and moderate declines in mental health, that did not seem to reverse after restrictions were lifted, were observed. Males, older adults with greater social isolation or greater feelings of loneliness, those with poorer housing conditions, as well as those with a higher prevalence of chronic morbidities were at increased risk of developing unhealthier lifestyles or mental health declines with confinement. On the other hand, previously having a greater adherence to the Mediterranean diet and doing more physical activity protected older adults from developing unhealthier lifestyles with confinement. If another lockdown were imposed during this or future pandemics, public health programs should specially address the needs of older individuals with male sex, greater social isolation, sub-optimal housing conditions, and chronic morbidities because of their greater vulnerability to the enacted movement restrictions, The Seniors-ENRICA-2 study was supported by Instituto de Salud Carlos III (Spain), State Secretary of R+D+I and FEDER/FSE research grants PI16/609, PI18/287, and 19/319; CIBERESP (16/01); and Cátedra de Epidemiología y Control del Riesgo Cardiovascular at UAM (#820024). ELS was supported by a Juan de la Cierva Contract from the Ministy of Universities. DMG and MSP were supported by supported by a “Ramon y Cajal”contract. Edad con Salud was funded by the Seventh Framework Programme (grant number 223071-COURAGE Study); the Insti tuto de Salud Carlos III (grants number PS09/00295(JMH), PS09/01845 (JLA), PI12/01490 (JMH), PI13/00059 (JLA), PI16/00212 (JMH), PI16/00218 (MM), PI16/01073 (JLA)); the European Regional Development Fund (ERDF) “A Way to Build Europe” (grant numbers PI12/01490, PI13/00059, PI16/00212 and PI16/01073);and CIBERSAM. EL was supported by the Sara Borrell postdoctoral programme (CD18/00099) from the Instituto de Salud Carlos III and co-funded by the European Union (FEDER/FSE, “Investing in your future”). BO was supported by the Miguel Servet programme (reference CP20/00040), funded by Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, "Investing in your future"). The Toledo Study for Healthy Ageing was funded by the Spanish Ministry of Economy, Industry and Competitiveness, cofinanced by FEDER (RD120001/0043), CIBERFES (CB16/10/00464) and DIABFRAIL-LATAM (contract number 825546, Horizon 2020). The Elderly EXERNET multicenter study was supported by the Ministerio de Economía, Industria y Competitividad (DEP2016-78309-R (GVR)), the Ministerio de Educación y Ciencia (Red EXERNET DEP2005-00046 JAC)), the High Council of Sports (Consejo Superior de Deportes) of the Ministe rio de Cultura y Deportes (09/UPB/19 (JAC) and 45/UPB/20 (JAC)), CIBERFES, the 4IE+ project (0499_4IE_PLUS_4_E (NG)) funded by the Interreg V-A España-Portugal (POCTEP) 2014-2020 pro gram, and FEDER funds from the European Union (CB16/10/00477 (IA)). The funding agencies had no role in study design, data collection and analysis, interpretation of results, manuscript preparation or the decision to submit this manuscript for publication

Frailty is considered a clinical marker of functional ageing. Telomere length (TL) has been proposed as a biomarker of biological age but its role in human ageing is controversial. The main aim of the study was to evaluate the longitudinal association of TL with incident frailty and mortality in two cohorts of Spanish community–dwelling older adults. TL was determined at baseline in blood samples from older adults included in Toledo Study for Healthy Aging and ENRICA cohorts while frailty was determined by frailty phenotype (FP) at baseline and at follow-up (3.5 years). Deaths occurring during follow-up were also recorded. Associations of TL with frailty and mortality were analysed by logistic regression with progressive adjustment. Data were separately analysed in the two cohorts and in all subjects by performing a meta-analysis. TL was not different between frail and non-frail subjects. Longer telomeres were not associated with lower risk of prevalent frailty. Similarly, TL at baseline failed to predict incident frailty (OR: 1.04 [0.88–1.23]) or even the development of a new FP criterion (OR: 0.97 [0.90–1.05]) at follow-up. Lack of association was also observed when analysing the development of specific FP criteria. Finally, while frailty at baseline was significantly associated with higher risk of death at follow-up (OR: 4.08 [1.97–8.43], p

Objective To evaluate the role of functional status along with other used clinical factors on the occurrence of death in patients hospitalized with COVID-19. Design Prospective Cohort study Setting Public University Hospital (Madrid) Participants and methods 375 consecutive patients with COVID-19 infection, admitted to a Public University Hospital (Madrid) between March 1 and March 31, 2020, were included in the Prospective Cohort study. Death was the main outcome. The main variable was disability in Activities of Daily Living (ADL) assessed with the Barthel index. Covariates included sex, age, severity index (Quick Sequential Organ Failure Assessment, qSOFA), polypharmacy (>5 drugs in the month before admission), and comorbidity (≥3 diseases). Multivariable logistic regression was used to identify risk factors for adverse outcomes. Estimated model coefficients served to calculate the expected probability of death for a selected combination of five variables: Barthel, sex, age, comorbidities and severity index (qSOFA). Results Mean age was 66 years (SD 15.33), 207 (55%) males. 74 patients died (19.8%). Mortality was associated to low Barthel index (OR per 5-point decrease 1.11; 95CI 1.03-1.20), male sex (0.23, 0.11-0.47), age (1.07, 1.03-1.10) and comorbidity (2.15; 1.08-4.30) but not to qSOFA (1.29, 0.87-1.93) or polypharmacy (1.54; 0.77-3.08). Calculated mortality risk ranged from 0 to 0.78. Conclusions and implications Functional status predicts death in hospitalized COVID-19 patients. Combination of five variables allows to predict individual probability of death. These findings provide useful information for the decision-making process and management of patients., Brief summary Functional status, assessed through the Barthel index, is an independent risk factor for death in patients hospitalized by COVID-19.

Background The purpose of this study was to evaluate the relationship of lower-limb muscle power with mortality and hospitalization. Methods A total of 1 928 participants from the Toledo Study for Healthy Aging were included. Muscle power was assessed with the 5-repetition sit-to-stand test and participants were classified into different groups of relative power (ie, normalized to body mass) according to sex-specific tertiles and their inability to perform the test. Mean follow-up periods for hospitalization and all-cause mortality were 3.3 and 6.3 years, respectively. Results Compared to the high relative muscle power group, men with low (HR [95% CI] = 2.1 [1.2–3.6]) and women with very low and low (HR [95% CI] = 4.7 [3.0–7.4] and 1.8 [1.2–2.7]) relative power had an increased age-adjusted risk of hospitalization. After adjusting for several covariates (age, physical activity, body mass index education, depression, comorbidities, disability, and handgrip strength), these effects were attenuated (men and women with very low relative power: HR [95% CI] = 1.6 [0.9–2.9] and 2.8 [1.6–4.9]). The very low relative muscle power group had also an increased all-cause mortality risk (age-adjusted) in both men and women (HR [95% CI] = 2.3 [1.4–3.9] and 2.9 [1.6–5.3]). After adjusting for all the covariates, a significantly increased mortality risk was observed only in men (HR [95% CI] = 2.1 [1.1–3.8]; women HR [95% CI] = 1.6 [0.8–3.2]), with very low levels of relative power. Conclusions Relative muscle power was independently and negatively associated with mortality and hospitalization in older adults. An augmented all-cause mortality risk was noted in the lowest group of relative muscle power.

Phenotype-specific omic expression patterns in people with frailty could provide invaluable insight into the underlying multi-systemic pathological processes and targets for intervention. Classical approaches to frailty have not considered the potential for different frailty phenotypes. We characterized associations between frailty (with/without disability) and sets of omic factors (genomic, proteomic, and metabolomic) plus markers measured in routine geriatric care. This study was a prevalent case control using stored biospecimens (urine, whole blood, cells, plasma, and serum) from 1522 individuals (identified as robust (R), pre-frail (P), or frail (F)] from the Toledo Study of Healthy Aging (R=178/P=184/F=109), 3 City Bordeaux (111/269/100), Aging Multidisciplinary Investigation (157/79/54) and InCHIANTI (106/98/77) cohorts. The analysis included over 35,000 omic and routine laboratory variables from robust and frail or pre-frail (with/without disability) individuals using a machine learning framework. We identified three protective biomarkers, vitamin D3 (OR: 0.81 [95% CI: 0.68-0.98]), lutein zeaxanthin (OR: 0.82 [95% CI: 0.70-0.97]), and miRNA125b-5p (OR: 0.73, [95% CI: 0.56-0.97]) and one risk biomarker, cardiac troponin T (OR: 1.25 [95% CI: 1.23-1.27]). Excluding individuals with a disability, one protective biomarker was identified, miR125b-5p (OR: 0.85, [95% CI: 0.81-0.88]). Three risks of frailty biomarkers were detected: pro-BNP (OR: 1.47 [95% CI: 1.27-1.7]), cardiac troponin T (OR: 1.29 [95% CI: 1.21-1.38]), and sRAGE (OR: 1.26 [95% CI: 1.01-1.57]). Three key frailty biomarkers demonstrated a statistical association with frailty (oxidative stress, vitamin D, and cardiovascular system) with relationship patterns differing depending on the presence or absence of a disability.

Introduction: The evidence that blood levels of the soluble receptor for advanced glycation end products (sRAGE) predict mortality in people with cardiovascular diseases (CVD) is inconsistent. To clarify this matter, we investigated if frailty status influences this association. Methods: We analysed data of 1,016 individuals (median age, 75 years) from 3 population-based European cohorts, enrolled in the FRAILOMIC project. Participants were stratified by history of CVD and frailty status. Mortality was recorded during 8 years of follow-up. Results: In adjusted Cox regression models, baseline serum sRAGE was positively associated with an increased risk of mortality in participants with CVD (HR 1.64, 95% CI 1.09–2.49, p = 0.019) but not in non-CVD. Within the CVD group, the risk of death was markedly enhanced in the frail subgroup (CVD-F, HR 1.97, 95% CI 1.18–3.29, p = 0.009), compared to the non-frail subgroup (CVD-NF, HR 1.50, 95% CI 0.71–3.15, p = 0.287). Kaplan-Meier analysis showed that the median survival time of CVD-F with high sRAGE (>1,554 pg/mL) was 2.9 years shorter than that of CVD-F with low sRAGE, whereas no survival difference was seen for CVD-NF. Area under the ROC curve analysis demonstrated that for CVD-F, addition of sRAGE to the prediction model increased its prognostic value. Conclusions: Frailty status influences the relationship between sRAGE and mortality in older adults with CVD. sRAGE could be used as a prognostic marker of mortality for these individuals, particularly if they are also frail.

Summary Background & aims Poor nutritional status leads to multiple adverse outcomes, but few studies have assessed its role as a risk factor for incident frailty and death in community-dwelling older adults. Hence, the aim of this paper is to assess the role of nutritional status using the Global Leadership Initiative on Malnutrition (GLIM) criteria in the risk of frailty and mortality in Spanish community-dwelling older adults. Methods We used data from two waves (waves 2 (2011–2013) and 3 (2015–2017)) from the Toledo Study of Healthy Ageing, which is an observational, prospective cohort (average follow-up = 3.18 years) of 1660 older (≥65 years) adults living in the community. Nutritional status categories were defined according to the GLIM criteria, which uses a two-step approach. First, screening for malnutrition risk. Once positive, individuals were classified as malnourished according to some phenotypic (body mass index, grip strength and unintentional weight loss) and etiologic (disease burden/inflammation and reduced food intake or assimilation) criteria. Frailty was assessed using both the Frailty Index (FI) and Frailty Trait Scale (FTS). Mortality data was obtained through the National Death Index. Results From the 1660 older adults, 248 participants (14.04%) were classified as ‘at malnutrition risk’ (AMR) and 209 (12.59%) as malnourished (MN). AMR and MN subjects were older and with worse functional status (frailer). Adjusted cross-sectional analysis showed an association between nutritional status and frailty by both FI and FTS. Adjusted longitudinal analyses showed that AMR was associated with higher risk of frailty, using both the FTS (OR: 1.262; 95% CI: 1.078–1.815) and the FI (OR: 1.116; 95% CI: 1.098–1.686), while being malnourished was associated with higher mortality risk (OR: 1.748; 95% CI: 1.073–2.849), but not with incident frailty at follow-up period. Conclusions Nutritional status, assessed through GLIM, predicts in a dose-dependent manner the risk of frailty and death. Being at malnutrition risk predicts the risk of becoming frail at follow-up period, whereas being malnourished predicts mortality. These findings highlight the importance of assessing the nutritional status of community-dwelling older adults to identify the ones at risk of developing frailty or death and inform targeted nutrition-focused interventions.

Background The associations between free-living physical activity (PA) and sedentary behaviour (SB) and sarcopenia in older people and its determinants are controversial. Self-reporting, the use of one-size-fits-all cut-points for intensity categorization when using accelerometers and the absence of a clear sarcopenia definition hampered explorations. The aim of this study is to describe the associations between objectively measured PA patterns and sarcopenia and its determinants. Methods Subjects aged >65 with valid accelerometry and sarcopenia-related measures from Toledo Study of Healthy Aging (TSHA) were included. Muscle mass (MM) was estimated by dual-energy X-ray absorptiometry. Handgrip strength (HS) was measured by dynamometry. Physical performance assessment relied on gait speed (GS). Sarcopenia presence was ascertained using Foundation for the National Institutes of Health (FNIH) criteria. PA and SB were estimated by ActiTrainer worn for 1 week and classified into time spent in SB and different PA intensity bands [light PA (LPA) and moderate-to-vigorous PA (MVPA)] using age-specific cut-points. Different multivariate linear and logistic regression models [(i) single-parameter, (ii) partition, and (iii) isotemporal substitution models] were used for estimating associations between PA, SB, and sarcopenia determinants and sarcopenia rates, respectively. All models adjusted for age, sex, co-morbidities (Charlson index), and functional ability (Katz and Lawton indexes). Results Five hundred twelve subjects from the TSHA had available data (78.08 ± 5.71 years of age; 54.3% women). FNIH sarcopenia assessment was performed in 497 subjects (23.3% were sarcopenic). In the linear regression, the singleparameter model showed an association between MVPA and all sarcopenia determinants. In the partition model, MVPA was associated with greater MM and GS. The isotemporal substitution showed that reallocating 1 h/day of MVPA displacing SB was associated with greater values in MM [β = 0.014; 95% confidence interval (CI) = 0.004, 0.024; P < 0.01], GS (β = 0.082; 95% CI = 0.054, 0.110; P < 0.001), and HS (β = 0.888; 95% CI = 0.145, 1.631; P < 0.05). In the logistic regression, the single-parameter model yielded a significant association between 1 h/day increase in MVPA and sarcopenia reduction [odds ratio (OR) = 0.522; 95% CI = 0.367, 0.726; P < 0.001], as did the partition model (OR = 0.555; 95% CI = 0.376, 0.799; P < 0.01). The reallocation of 1 h/day SB only yielded a significant lower sarcopenia risk by almost 50% when it was substituted with MVPA, whereas the substitution of 15 min/day yielded a significant lower sarcopenia risk by 15% (P < 0.001) but did not show any association when it was substituted with LPA. Conclusions An increase in MVPA replacing SB and LPA was associated with a reduction in sarcopenia prevalence and better performance across its determinants (MM, GS, and HS). LPA did not show any significant effect.

Introduction Frailty is a strong predictor of adverse health events, but its impact on cognitive function is poorly understood. Aim To assess cognitive performance in frailty and to identify the frailty stage where cognitive impairment begins. Methods Data were taken from 2044 people aged ≥65 years without cognitive impairment selected from the Toledo Study for Healthy Aging, a population-based cohort of older adults. Frailty status was assessed by 3 different scales: Frailty Phenotype (FP), Frailty Trait Scale (FTS), and Frailty Index (FI). Neuropsychological assessments of different cognitive domains included the Mini-Mental State Examination, Short and Long-Term Memory Recalling Test, the Boston Naming Test, Verbal Fluency Test, Digit Span Forward, Go/No-go Test, Luria Orders Test, Clock Drawing Test, and Serial Word Learning Test. The relationships between the score of the scales and frailty status (robust, prefrail, and frail for FP and quartiles for FTS and FI) were analyzed using multivariate linear regression models including age, sex, and educative level as possible confounders. Results Participants classified as the worst degree of frailty (frail in FP and fourth quartile of FTS and FI) presented more cognitive domains affected and to a higher extent than moderate frail (prefrail and second quartile and third quartile of FTS and FI) and robust (and first quartile of FTS and FI) participants. Conclusions Cognitive performance progressively declined across the frailty state, regardless of the instrument used to assess frailty. In prefrail participants, cognitive impairment may be an early marker of frailty-dependent cerebral involvement and could be already subject to interventions aimed at reducing the transition to frailty.

Objectives To assess the role of frailty in predicting death and incident disability in older adults with type 2 diabetes mellitus. Design Prospective cohort study. Setting Community dwelling. Participants A total of 1825 individuals ≥65 years old recruited between June 2006 and September 2009 were followed for a median of 5.5 years for mortality and 4.98 years for incident functional disability in activities of daily living. Self-reported diabetes, comorbidities (Charlson index), cardio- and cerebrovascular diseases, drug treatments, Frailty Trait Score (FTS) and Frailty Index (FI), activities of daily living, heart rate, and blood pressure among others were collected at baseline. Main outcome measures Survival analysis (Kaplan-Meier), adjusted Cox proportional-hazards models, and binary logistic regression were used to assess the relationship between frailty, comorbidity, and vascular diseases and time to death and incident disability. Results A total of 363 people had diabetes. Among them, 83 deaths and 84 cases of incident disability occurred during follow-up. People with diabetes died more frequently than those without diabetes [hazard ratio = 1.36, 95% confidence interval (CI) 1.06–1.75; P = .002], showing a poorer functional status at baseline. Survival analysis showed a relationship between frailty quartiles and the risk of death. In the adjusted Cox-models, only age and frailty indices, but not comorbidity or cardio/cerebrovascular diseases, were associated with the risk of death and incident disability after adjusting for measures of frailty. The hazard ratio for death was 1.51 (95% CI 1.28–1.77) and 1.83 (95% CI 1.49–2·26) for each 10 points increase in the FTS and FI; odds ratio for incident disability was 1·64 (95% CI 1.22–2.20) and 1·35 (95% CI 1.09–1.67) when using FI and FTS, respectively. Conclusions Frailty is an important risk factor for death and disability in older adults with diabetes, supporting the recent recommendations that frailty status should be routinely assessed in these patients.

Objectives To develop short versions of the Frailty Trait Scale (FTS) for use in clinical settings. Design Prospective population-based cohort study. Setting and Participants Data from 1634 participants from the Toledo Study for Healthy Aging. Methods The 12-item Frailty Trait Scale (FTS) reduction was performed based on an area under the curve (AUC) analysis adjusted by age, sex, and comorbidity. Items that maximized prognostic information for adverse events were selected. Each item score was done at the same time as the reduction, identifying the score that maximized the predictive ability for adverse events. For each short version of the FTS, cutoffs that optimized the prognostic information (sensitivity and specificity) were chosen, and their predictive value was later compared with a surrogate gold standard for frailty (the Fried Phenotype). Results Two short forms, the 5-item (FTS5) (range 0-50) and 3-item (FTS3) (range 0-30), were identified, both with AUCs for health adverse events similar to the 12-item FTS. The identified cutoffs were >25 for the FTS5 scale and >15 for the FTS3. The frailty prevalence with these cutoffs was 24% and 20% for the FTS5 and FTS3, respectively, whereas frailty according to Fried Phenotype (FP) reached 8% and prefrailty reached 41%. In general, the FTS5 showed better prognostic performance than the FP, especially with prefrail individuals, in whom the FTS5 form identified 65% of participants with an almost basal risk and 35% with a very high risk for mortality (OR: 4) and frailty (OR: 6.6-8.7), a high risk for hospitalization (OR: 1.9-2.1), and a moderate risk for disability (OR: 1.7) who could be considered frail. The FTS3 form had worse performance than the FTS5, showing 31% of false negatives between frail participants identified by FP with a high risk of adverse events. Conclusions and Implications The FTS5 is a short scale that is easy to administer and has a similar performance to the FTS, and it can be used in clinical settings for frailty diagnosis and evolution.

Dozens of scales and questionnaires have been used in the detection of frailty; however, a generalized method for its screening and diagnosis is still lacking in clinical settings. FRAILTOOLS´ main objective is to evaluate the usefulness of frailty scales in the detection of frailty in different clinical and social settings, and its integration in management algorithms for the frail older patient. FRAILTOOLS is an observational, longitudinal and prospective study with a follow-up of 6, 12 and 18 months. People older than 75 years old will be recruited from three separate clinical settings (acute geriatric wards, geriatric outpatient clinics and primary care) and one social setting (nursing homes). Exclusion criteria include Mini-mental State Examination

BACKGROUND the association between muscular strength, mortality and hospitalisation with ageing can change depending on sex and the body region analysed (e.g. upper and lower limb muscles). OBJECTIVE to determine the effect of measuring lower and upper extremities muscular strength on the relationship between strength, mortality and hospitalisation risk in elder men and women. DESIGN a population-based cohort study using data from the Toledo Study for Healthy Aging (TSHA). METHODS a Spanish population sample of 1,755 elders aged ≥65 years participated in this study. Upper (handgrip and shoulder) and lower limbs (knee and hip) maximal voluntary isometric strength was obtained using standardised techniques and equipment. Cox proportional hazards model was used to examine mortality and hospitalisation over 5.5 and 3 years of follow-up, respectively. RESULTS after adjustment for potential confounding factors, including co-morbidities and BMI, hazard ratio of death and hospitalisation was significantly lower in the stronger women and men, but showing regional- and sex-specific differences. That is shoulder, knee and hip muscle regions in women and handgrip and shoulder in men (all P < 0.05). There was a cumulative effect of measuring several muscle strengths over the risk of health events (P < 0.05), so that mortality hazard ratio increased by 45% in women and 25% in men per muscular strength (shoulder, grip, knee and hip) in the weaker strength quartile increase (P < 0.01). CONCLUSIONS regional muscle strength is a predictor of medium-term mortality and hospitalisation in elder men and women. Multiple strength measures including lower and upper body limb muscles are better predictors than a single strength measurement.

Visceral fat has a high metabolic activity with deleterious effects on health contributing to the risk for the frailty syndrome. We studied the association between waist to hip ratio (an indirect measure of visceral fat stores) on upper and lower extremities strength. 1741 individuals aged ≥65 participated in this study. The data was obtained from the Toledo Study for Healthy Aging. For each gender, we studied the relationship between the waist-to-hip ratio (WHR), body mass index (BMI) and regional muscle strength (grip, shoulder, knee and hip) using multivariate linear regression and kernel regression statistical models. WHR was higher in men than in women (0.98 ± 0.07 vs. 0.91 ± 0.08, respectively, P

This work has been supported by grants from the Instituto de Salud Carlos III (PI12/1166, PI11/01379, PI13/00288 and RD12/0043/0001 RETICEF) and the European Commission (FRAILOMIC Initiative FP7-HEALTH-2012-Proposal No: 305483-2)

The executive function is a complex set of skills affected during the aging process and translate into subclinical cerebrovascular disease. Postural instability or motor slowness are some clinical manifestations, being consubstantial with the frailty phenotype, genuine expression of aging. Executive dysfunction is also considered a predictor of adverse health events in the elderly. To study whether the executive dysfunction can be used as an early marker for frailty and the viability of use as a predictor of mortality, hospitalization and/or disability in a Mediterranean population. A population-based cohort study using data from the Toledo Study for Healthy Aging (TSHA). 1690 Spanish elders aged ≥65 years underwent a neuropsychological evaluation in order to measure executive function. To assess whether the accumulation of dysfunctions (in severity and amplitude) could increase the predictive value of adverse health events in relation to each dimension separately an executive dysfunction cumulative index was constructed. Cox proportional hazards model was used to examine mortality and hospitalization over 5.02 and 3.1 years of follow-up, respectively. Executive dysfunction is a powerful predictor of mortality, frailty and disability. Cumulative differences in executive function are associated with high risk of frailty and disability, thus, for each one point increment in the executive function index, the risk of death increased by 7 %, frailty by 13% and disability by 11% (P

Background Specific mechanisms underlying frailty syndrome are not well known. Frailty can be viewed as a loss of functional reserve resulting in increased vulnerability to stressors. We hypothesize that pathways regulating cellular response to stress are potential players in the development of frailty. The aim of this study was to evaluate the association of the expression of certain genes related to cellular response to stress with the presence of frailty in older patients. Methods A sample of 350 individuals aged 65 years or older (22% frail) was selected from the Toledo Study of Healthy Aging. RNA was extracted from blood and retro-transcribed into complementary DNA. TaqMan Low density Arrays were used for the measurement of expression of genes implicated in cellular response to oxidative stress, genes implicated in inflammation, genes implicated in vascular physiology, and genes related to hypoxia. For data analysis, a logistic regression model was used to assess the relationship of gene expression and frailty. Results Among the analyzed genes, lower expression of genes related to cellular response to hypoxia (hypoxia inducible factor-1α) or to cellular response to oxidative stress (nuclear factor erythroid 2-related factor 2 and its target genes heme oxygenase-2, thioredoxin reductase-1, and superoxide dismutase-2), but not to those related to inflammation or vascular physiology, were significantly associated with the presence of frailty after adjustment for age and sex. These associations remained significant after adjustment by type 2 diabetes and Charlson index of comorbidities. Lower expressions of genes involved in cellular response to stress were also associated with increased risk of functional impairment. Conclusions Reduced expression of several genes implicated in cellular response to oxidative stress or hypoxia is significantly associated with the presence of frailty. These results help to fill the gap of knowledge of this evolving field and provide targets for intervention to promote health and independence in the elderly.

a b s t r a c t Objectives: The aims of this study were to identify if the associations of physical activity (PA) and muscle strength may vary throughout the ageing process; to study the differences among genders in the rela- tionships between PA and strength in elderly people and to test whether these differences are explained by the hormonal, nutritional and inflammatory status. Study design: A total of 1741 people ≥65 years of age participated in this cross-sectional study. Main outcome measures: Upper- and lower-limbs maximal voluntary isometric strength was obtained using standardized techniques and equipment. PA was recorded by a validated questionnaire. The associations of PA with strength were assessed using generalized linear regression models with a Gamma- distributed dependent variable. Results: A significant gender by PA interaction was found for all strength-related variables (all P < 0.01). Moreover, when sexual hormones, albumin or C-Reactive protein were taken into account in the model, the results did not significantly change. In women, PA was positively associated with upper and lower- body strength; however in men, PA was only associated with grip and knee strength (both P < 0.01). Higher strength values were associated with higher levels of PA, especially in women. However, this tendency had a different pattern across the age range, showing a stronger association in the 'young' elderly compared with the 'old' elderly. Conclusion: Higher levels of PA are related to greater muscle strength, especially in women and those who were younger. © 2014 Elsevier Ireland Ltd. All rights reserved.

Aging is a process that involves a reduction in muscle strength and anabolic hormone concentrations, which impacts significantly on health.To study the hormone/total strength (H/TS) ratio as a proxy of anabolic insensitivity status in elders, and its relationship with disability, hospitalization, and mortality risk.A total of 1462 persons aged ≥65 years from the Toledo Study of Healthy Aging participated in this study. Serum concentrations of insulin like growth factor 1, total and free testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and 17β-estradiol were measured. Total maximal voluntary isometric strength was obtained (handgrip, shoulder, hip, and knee) using standardized techniques and equipment. Physical activity was recorded by physical activity scale for the elderly questionnaire. Associations of the H/TS ratio with hospitalization and mortality were assessed using logistic regression models, and participants stratified into quartiles for each H/TS ratio.In women, all individual ratio H/TS models showed a strong to moderate increased risk for death and hospitalization. In men, all models revealed a significant positive association of the ratio H/TS with mortality rate but not for hospitalization (P .01). Participants who have 2 or more H/TS ratios in the worst quartile increased the risk of hospitalization and mortality at least by 2-fold.We demonstrate the main role that muscle function plays in the relationship between the hormonal status and hospitalization and mortality risk; this could be taken into consideration as a way to classify patients for hormonal therapy.

Several studies have assessed the performance of the original frailty phenotype criteria (FPC) and the standardized version according to the characteristics of the population. No studies exist, however, evaluating the impact of this standardization on its predictive ability.To compare how the original FPC and the standardized-frailty phenotype criteria (S-FPC) estimate the prevalence of frailty and their ability to predict mortality, hospitalization, incident disability, and falls.Data were taken from the Toledo Study for Healthy Aging, a population-based, community-dwelling study conducted on 1645 individuals over 65. Frailty was operationalized in two ways: FPC, using the cut-off estimated in the Cardiovascular Health Study and S-FPC, using cut-off points fitted to the phenotypic characteristics of our study sample. Frailty prevalences were compared using chi-square statistic. Cox proportional hazard models and logistic regressions evaluated the predictive ability of both tools. Lastly, survival tests were applied.Frailty and prefrailty prevalences varied according to the tool used: 24.12% and 66.40%, respectively when we used FPC and 6.68% and 47.81% when we used S-FPC (P .01). Regarding their predictive ability, S-FPC, but not FPC, identified consistently the prefrail persons as an intermediate risk group between robust and frail people [death 1.57 (1.15-2.16); hospitalization 1.47 (1.16-1.85); and incident disability 1.96 (1.30-2.97); P.005]. Furthermore S-FPC predicted death and hospitalization at shorter times than FPC (P .05).FPC should be standardized according to the characteristics of the population in order to improve its predictive ability.

Resumen Objetivos Analizar los resultados del tratamiento de la isquemia cronica de miembros inferiores mediante la Endarterectomia iliofemoral retrograda transinguinal (FIRT). Pacientes y me;todos Entre 1986 y 1997 hemos indicado 138 E1RT en 120 pacientes. Edad media de 66 aios (r = 38-90), siendo el 94,2% varones. Las indicaciones fueron la isquemia critica de la extremidad en el 62,3% de los casos y la claudicacion incapacitante de la misma en el 37,7% restante. Obstruccion del eje iliofemoral en 74 casos (53,6%) y lesiones estenosantes significativas y difusas en los 64 restantes (46,4%). El procedimiento se realizo bajo control radiologico desde femoral comun, asociando en 67 casos profundoplastia. Se describen los resultados obtenidos precoces y tardios, asi como la permeabilidad y supervivencia acumuladas mediante el ana;lisis de tablas de vida. Resultados Precoces: En 13 casos no se pudo completar la te;cnica, por lo que se realizaron 125 casos. Permeabilidad acumulada 95,5%, morbimortalidad 8% (tres amputaciones, dos e;xitus por cardiopatin postoperatorios). Tardios: Permeabilidad acumulada del 82,9% y 79,1% a los 5 y 8 anos, respectivamente. Salvamento de extremidad y supervivencia actuarial a 8 aiios 85,9% y 88,7%. Conclusiones La EIRT es, en nuestra experiencia, una segura y va;lida alternativa quirurgica en el tratamiento de la isquemia cronica de miembros inferiores, en casos seleccionados.

The clinical and pathological findings in a patient with extrarenal angiomyolipoma arising in the perinephric space are presented. This location has been reported only rarely and sets forth some diagnostic and therapeutic difficulties that are also discussed.