Association between endogenous plasma beta-hydroxy-beta-methylbutyrate levels and frailty in community-dwelling older people.

BACKGROUND: Frailty is a key element in healthy ageing in which muscle performance plays a main role. Beta-hydroxy-beta-methylbutyrate (HMB) supplementation has shown favourable effects in modulating protein synthesis, improving muscle mass and function in interventional studies. Decreased age-related endogenous HMB levels have been shown in previous studies. The aim of the present study is to assess whether there is an association between endogenous plasma HMB levels and frailty. METHODS: Data from 1290 subjects (56.98% women; mean ± standard deviation age 74.6 ± 5.95 years) from the Toledo Study for Healthy Aging were obtained. Participants had their frailty status qualified according to Fried's Frailty Phenotype (FFP) score and the Frailty Trait Scale in its 12-domain version (FTS-12). Plasma HMB levels were analysed by an ultrahigh-performance liquid chromatography tandem mass spectrometry. Differences between groups (frail vs. non-frail) were tested using Mann-Whitney U test, Kruskal-Wallis test and chi-squared test. The association between HMB and frailty was assessed by multivariate linear and logistic regressions when frailty was analysed as continuous and binary, respectively. Models were adjusted by age, gender, comorbidity, body composition and protein intake. RESULTS: HMB levels were lower in those aged ≥75 years than in those aged 65-74 years, with an inverse linear relationship between age and HMB levels (ß = -0.031; P = 0.018), mainly accounted by males (ß = -0.062; P = 0.002). HMB levels were higher in men (0.238 ± 0.065 vs. 0.193 ± 0.051 ng/mL; P ≤ 0.001). HMB levels were significantly lower in frail than in non-frail individuals: 0.204 ± 0.058 versus 0.217 ± 0.063 ng/dL (P = 0.001) according to the FFP and 0.203 ± 0.059 versus 0.219 ± 0.063 ng/mL (P < 0.001) according to FTS-12. These differences showed a dose-dependent profile when we compared them by quintiles of HMB (P for trend: 0.022; 0.012 and 0.0004, respectively, for FFP, FTS-12 binary and FTS-12 continuous). Variables associated with low HMB levels were body mass index, strength, exhaustion and weight loss. Frailty was associated with HMB levels in all the adjusted models, including the fully adjusted ones, no matter the tool used (odds ratio: 0.45 [0.26, 0.77] for FFP and 0.36 [0.20, 0.63] for FTS-12 binary; ß = -4.76 [-7.29, -2.23] for FTS-12 score). This association was also observed when the analyses were done by quintiles, showing such association since Q4 (FFP), Q2 (FTS-12 binary) and Q3 (FTS-12 score). The associations were observed in the whole sample and in each gender. CONCLUSIONS: There is an inverse association between HMB levels and frailty status. These findings support the design of targeted clinical trials to evaluate the effect of HMB supplementation in older frail people with low HMB levels.

Essential steps in primary care management of older people with Type 2 diabetes: an executive summary on behalf of the European geriatric medicine society (EuGMS) and the European diabetes working party for older people (EDWPOP) collaboration.

We present an executive summary of a guideline for management of type 2 diabetes mellitus in primary care written by the European Geriatric Medicine Society, the European Diabetes Working Party for Older People with contributions from primary care practitioners and participation of a patient's advocate. This consensus document relies where possible on evidence-based recommendations and expert opinions in the fields where evidences are lacking. The full text includes 4 parts: a general strategy based on comprehensive assessment to enhance quality and individualised care plan, treatments decision guidance, management of complications, and care in case of special conditions. Screening for frailty and cognitive impairment is recommended as well as a comprehensive assessment all health conditions are concerned, including end of life situations. The full text is available online at the following address: essential_steps_inprimary_care_in_older_people_with_diabetes_-_EuGMS-EDWPOP___3_.pdf.

Integrated health system to assess and manage frailty in community dwelling: Co-design and usability evaluation.

Objective: We aimed to co-create and evaluate an integrated system to follow-up frailty in a community dwelling environment and provide a multi-modal tailored intervention. Frailty and dependency among the older population are a major challenge to the sustainability of healthcare systems. Special attention must be paid to the needs and particularities of frail older persons as a vulnerable group. Methods: To ensure the solution fits all the stakeholders' needs, we performed several participatory design activities with them, such as pluralistic usability walkthroughs, design workshops, usability tests and a pre-pilot. The participants in the activities were older people; their informal carers; and specialized and community care professionals. In total, 48 stakeholders participated. Results: We created and evaluated an integrated system consisting of four mobile applications and a cloud server, which has been evaluated through a 6-months clinical trial, where secondary endpoints were both usability and user experience evaluation. In total, 10 older adults and 12 healthcare professionals participated in the intervention group using the technological system. Both patients and professionals have positively evaluated their applications. Conclusion: Both older adults and healthcare professionals have considered the resulted system easy to use and learn, consistent and secure. In general terms, they also would like to keep using it in the future.

Development and Validation of a Cutoff for the Chair Stand Test as a Screening for Mobility Impairment in the Context of the Integrated Care for Older People Program.

BACKGROUND: The 5-repetition chair stand test (CST) is increasingly being used to assess locomotion capacity in older adults. However, there is a lack of age-stratified cutoffs for adults aged ≥70 validated against a higher risk of functional loss. METHODS: We used 2 population-based studies (Study on global AGEing and adult health in Mexico [SAGE Mexico] and Toledo Study for Healthy Aging [TSHA]) and receiver operating characteristic (ROC) analyses to develop and cross-validate age-stratified chair stand cutoffs with activities of daily living (ADL) disability as the outcome. Then, we used data from an randomized controlled trial (RCT) (Multidomain Alzheimer Preventive Trial [MAPT]) and a frailty day-hospital for external validation with cross-sectional and longitudinal measures of ADL disability. The merged sample of SAGE Mexico and TSHA was n = 1 595; sample sizes for external validation were: MAPT n = 1 573 and Frailty day-hospital n = 2 434. The Cox models for incident disability in MAPT had a mean follow-up of 58.6 months. RESULTS: Cutoffs obtained were 14 second (ages 70-79) and 16 second (ages 80+). Those cutoffs identified older adults at higher odds of incident ADL disability odds ratio (OR) = 1.72 (95% confidence interval [CI] 1.06; 2.78) for ages 70-79 and odds ratio (OR) = 2.27 (95% CI 1.07; 4.80) in those aged 80+. Being a slow chair stander according to the cut points was associated with ADL disability in cross-sectional and longitudinal measures. CONCLUSIONS: Fourteen- and 16-second cut points for the CST are suitable to identify people at higher risk of functional decline among older adults in Mexico and Toledo, Spain. Adjusting the cut point from 14 to 16 second generally improved the psychometric properties of the test. The validation of these cutoffs can facilitate the screening for limited mobility and the implementation of the Integrated Care for Older People program.

FRAILTOOLS study protocol: a comprehensive validation of frailty assessment tools to screen and diagnose frailty in different clinical and social settings and to provide instruments for integrated care in older adults.

BACKGROUND: 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. METHODS: 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 < 20 points, and a Barthel index < 90 points, except in nursing home residents (< 40 points). The participants will be recruited in Spain, Italy, France, United Kingdom and Poland. The total sample size will be of 1.940 subjects, 97 subjects in each clinical setting by center. A personal interview with each participant will take place to register data on comorbidity (Charlson Index), functional (SPPB, Barthel and Lawton indexes), cognitive (MMSE) and frailty status (Fried Phenotype, Frailty Trait Scale - short version, SHARE-FI, 35-Items Rockwood Frailty Index, Clinical Frailty Scale, FRAIL scale and Gérontopôle Frailty Screening Tool) in the baseline visit, month 12 and month 18 visit of follow up. At 6 month a phone call will be made to assess whether there have been falls and to check the vital status. DISCUSSION: Currently, the usefulness of certain assessment tools in social and clinical settings have not been properly assessed, including their ability to predict the individual risk for different adverse outcomes, which is the main interest in daily practice. The FRAILTOOLS project concentrates on providing screening and diagnostic tools for frailty in those settings where its prevalence is the highest and where efforts in prevention could make a significant change in the trend towards disability. TRIAL REGISTRATION: Comprehensive validation of frailty assessment tools in older adults in different clinical and social settings (FRAILTOOLS), NCT02637518 (date of registration: 12/18/2015).

The Asia-Pacific Clinical Practice Guidelines for the Management of Frailty.

OBJECTIVE: To develop Clinical Practice Guidelines for the screening, assessment and management of the geriatric condition of frailty. METHODS: An adapted Grading of Recommendations, Assessment, Development, and Evaluation approach was used to develop the guidelines. This process involved detailed evaluation of the current scientific evidence paired with expert panel interpretation. Three categories of Clinical Practice Guidelines recommendations were developed: strong, conditional, and no recommendation. RECOMMENDATIONS: Strong recommendations were (1) use a validated measurement tool to identify frailty; (2) prescribe physical activity with a resistance training component; and (3) address polypharmacy by reducing or deprescribing any inappropriate/superfluous medications. Conditional recommendations were (1) screen for, and address modifiable causes of fatigue; (2) for persons exhibiting unintentional weight loss, screen for reversible causes and consider food fortification and protein/caloric supplementation; and (3) prescribe vitamin D for individuals deficient in vitamin D. No recommendation was given regarding the provision of a patient support and education plan. CONCLUSIONS: The recommendations provided herein are intended for use by healthcare providers in their management of older adults with frailty in the Asia Pacific region. It is proposed that regional guideline support committees be formed to help provide regular updates to these evidence-based guidelines.

Impact of frailty in older patients with diabetes mellitus: An overview / Efectos de la fragilidad en los pacientes mayores con diabetes: Una revisión

Diabetes and frailty are two conditions that frequently occur concurrently and are increasingly prevalent in the older patient. We review the concept, epidemiology and consequences of frailty, and the implications of the presence of frailty in the management of diabetes. Frailty is associated with decreased quality of life, a risk of falls, new or increased disability, hospitalization, and increased mortality. All of these factors affect the management of diabetes in older patients. It is important to rule out frailty in all diabetic patients aged >70 years; if frailty is suspected, a comprehensive and multidisciplinary medical and functional assessment of the patient should be conducted to develop an individualized treatment plan. This plan should include nutritional measures, physical activity, and education on self-care and diabetes; drugs should not be used without a clear indication. Antihyperglycemic drugs that may cause excessive weight loss and/or are associated with a high risk of hypoglycemia should be avoided (AU)

La diabetes y la fragilidad son 2 procesos que se producen a menudo simultáneamente y son cada vez más prevalentes en los pacientes mayores. Revisamos aquí el concepto, la epidemiología y las consecuencias de la fragilidad, y las implicaciones de la presencia de fragilidad en el tratamiento de la diabetes. La fragilidad se asocia con un empeoramiento de la calidad de vida, riesgo de caídas, aparición o aumento de la discapacidad, hospitalización y aumento de la mortalidad. Todos estos factores afectan al tratamiento de la diabetes en los pacientes de mayor edad. Es importante descartar la existencia de fragilidad en todos los pacientes diabéticos de más de 70 años de edad; si se sospecha fragilidad, debe efectuarse una valoración médica y funcional, exhaustiva y multidisciplinaria, del paciente para idear un plan de tratamiento individualizado. Este plan debe incluir medidas nutricionales, actividad física y educación sobre los cuidados personales y la diabetes; no deben utilizarse fármacos si no están claramente indicados. Deben evitarse los hipoglucemiantes que puedan causar una pérdida de peso excesiva o que se asocien con un riesgo elevado de hipoglucemia (AU)

Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease.

Skeletal muscle is recognized as vital to physical movement, posture, and breathing. In a less known but critically important role, muscle influences energy and protein metabolism throughout the body. Muscle is a primary site for glucose uptake and storage, and it is also a reservoir of amino acids stored as protein. Amino acids are released when supplies are needed elsewhere in the body. These conditions occur with acute and chronic diseases, which decrease dietary intake while increasing metabolic needs. Such metabolic shifts lead to the muscle loss associated with sarcopenia and cachexia, resulting in a variety of adverse health and economic consequences. With loss of skeletal muscle, protein and energy availability is lowered throughout the body. Muscle loss is associated with delayed recovery from illness, slowed wound healing, reduced resting metabolic rate, physical disability, poorer quality of life, and higher health care costs. These adverse effects can be combatted with exercise and nutrition. Studies suggest dietary protein and leucine or its metabolite ß-hydroxy ß-methylbutyrate (HMB) can improve muscle function, in turn improving functional performance. Considerable evidence shows that use of high-protein oral nutritional supplements (ONS) can help maintain and rebuild muscle mass and strength. We review muscle structure, function, and role in energy and protein balance. We discuss how disease- and age-related malnutrition hamper muscle accretion, ultimately causing whole-body deterioration. Finally, we describe how specialized nutrition and exercise can restore muscle mass, strength, and function, and ultimately reverse the negative health and economic outcomes associated with muscle loss.

A Multicomponent Exercise Intervention that Reverses Frailty and Improves Cognition, Emotion, and Social Networking in the Community-Dwelling Frail Elderly: A Randomized Clinical Trial.

BACKGROUND: Frailty can be an important clinical target to reduce rates of disability. OBJECTIVE: To ascertain if a supervised-facility multicomponent exercise program (MEP) when performed by frail older persons can reverse frailty and improve functionality; cognitive, emotional, and social networking; as well as biological biomarkers of frailty, when compared with a controlled population that received no training. DESIGN: This is an interventional, controlled, simple randomized study. Researchers responsible for data gathering were blinded for this study. SETTING: Participants from 2 primary rural care centers (Sollana and Carcaixent) of the same health department in Spain were enrolled in the study between December 2013 and September 2014. PATIENTS: We randomized a volunteer sample of 100 men and women who were sedentary, with a gait speed lower than 0.8 meters per second and frail (met at least 3 of the frailty phenotype criteria). INTERVENTIONS: Participants were randomized to a supervised-facility MEP (n = 51, age = 79.5, SD 3.9) that included proprioception, aerobic, strength, and stretching exercises for 65 minutes, 5 days per week, 24 weeks, or to a control group (n = 49, age = 80.3, SD 3.7). The intervention was performed by 8 experienced physiotherapists or nurses. Protein-calorie and vitamin D supplementation were controlled in both groups. RESULTS: Our MEP reverses frailty (number needed to treat to recover robustness in subjects with attendance to ≥50% of the training sessions was 3.2) and improves functional measurements: Barthel (trained group 91.6 SD 8.0 vs 82.0 SD 11.0 control group), Lawton and Brody (trained group 6.9 SD 0.9 vs 5.7 SD 2.0 control group), Tinetti (trained group 24.5 SD 4.4 vs 21.7 SD 4.5 control group), Short Physical Performance Battery (trained group 9.5 SD 1.8 vs 7.1 SD 2.8 control group), and physical performance test (trained group 23.5 SD 5.9 vs 16.5 SD 5.1 control group) as well as cognitive, emotional, and social networking determinations: Mini-Mental State Examination (trained group 28.9 SD 3.9 vs 25.9 SD 7.3 control group), geriatric depression scale from Yesavage (trained group 2.3 SD 2.2 vs 3.2 SD 2.0 control group), EuroQol quality-of-life scale (trained group 8.2 SD 1.6 vs 7.6 SD 1.3 control group), and Duke social support (trained group 48.5 SD 9.3 vs 41.2 SD 8.5 control group). This program is unique in that it leads to a decrease in the number of visits to primary care physician (trained group 1.3 SD 1.4 vs 2.4 SD 2.9 control group) and to a significant improvement in frailty biomarkers. CONCLUSIONS: We have designed a multicomponent exercise intervention that reverses frailty and improves cognition, emotional, and social networking in a controlled population of community-dwelling frail older adults. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT02331459.

Asymmetric dimethylarginine (ADMA) elevation and arginase up-regulation contribute to endothelial dysfunction related to insulin resistance in rats and morbidly obese humans.

KEY POINTS: The presence of insulin resistance (IR) is determinant for endothelial dysfunction associated with obesity. Although recent studies have implicated the involvement of mitochondrial superoxide and inflammation in the defective nitric oxide (NO)-mediated responses and subsequent endothelial dysfunction in IR, other mechanisms could compromise this pathway. In the present study, we assessed the role of asymmetric dimethylarginine (ADMA) and arginase with respect to IR-induced impairment of endothelium-dependent vasodilatation in human morbid obesity and in a non-obese rat model of IR. We show that both increased ADMA and up-regulated arginase are determinant factors in the alteration of the l-arginine/NO pathway associated with IR in both models and also that acute treatment of arteries with arginase inhibitor or with l-arginine significantly alleviate endothelial dysfunction. These results help to expand our knowledge regarding the mechanisms of endothelial dysfunction that are related to obesity and IR and establish potential therapeutic targets for intervention. ABSTRACT: Insulin resistance (IR) is determinant for endothelial dysfunction in human obesity. Although we have previously reported the involvement of mitochondrial superoxide and inflammation, other mechanisms could compromise NO-mediated responses in IR. We evaluated the role of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) and arginase with respect to IR-induced impairment of l-arginine/NO-mediated vasodilatation in human morbid obesity and in a non-obese rat model of IR. Bradykinin-induced vasodilatation was evaluated in microarteries derived from insulin-resistant morbidly obese (IR-MO) and non-insulin-resistant MO (NIR-MO) subjects. Defective endothelial vasodilatation in IR-MO was improved by l-arginine supplementation. Increased levels of ADMA were detected in serum and adipose tissue from IR-MO. Serum ADMA positively correlated with IR score and negatively with pD2 for bradykinin. Gene expression determination by RT-PCR revealed not only the decreased expression of ADMA degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH)1/2 in IR-MO microarteries, but also increased expression of arginase-2. Arginase inhibition improved endothelial vasodilatation in IR-MO. Analysis of endothelial vasodilatation in a non-obese IR model (fructose-fed rat) confirmed an elevation of circulating and aortic ADMA concentrations, as well as reduced DDAH aortic content and increased aortic arginase activity in IR. Improvement of endothelial vasodilatation in IR rats by l-arginine supplementation and arginase inhibition provided functional corroboration. These results demonstrate that increased ADMA and up-regulated arginase contribute to endothelial dysfunction as determined by the presence of IR in human obesity, most probably by compromising arginine availability. The results provide novel insights regarding the mechanisms of endothelial dysfunction related to obesity and IR and establish potential therapeutic targets for intervention.

Seasonal variance in serum levels of vitamin d determines a compensatory response by parathyroid hormone: study in an ambulatory elderly population in Quebec.

BACKGROUND: Although the seasonal variance in serum levels of vitamin D in the elderly is well known, its significance on parathyroid hormone (PTH) remains controversial. OBJECTIVE: To identify the variability and correlation between serum levels of vitamin D and PTH in a sample of community-dwelling elderly patients in the Province of Quebec, Canada, where vitamin D and calcium are supplemented in the food. METHODS: Cross-sectional study in an ambulatory elderly population in the Province of Quebec. Samples were analyzed at the Metabolic and Calcium Research Centre, Royal Victoria Hospital, Montreal, Quebec. 256 healthy men and women aged 65-94 (mean age +/- SD: 72.8 +/- 5.6) were analyzed. Serum levels of 25-hydroxyvitamin D (25(OH)D3) and PTH were determined between 1994 and 1999 using commercial radioimmunoassay kits to measure calciotropic hormones. We examined data in different seasons of the year and observed the behavior of the data through time. A cut-off level of 25 nmol/l for 25(OH)D3 was established to define vitamin D deficiency. A correlation between vitamin D levels vs. PTH levels was also obtained. RESULTS: There is a predominance of females with a 75% of the population. Among them, 32% showed levels of vitamin D <20 nmol/l as compared to 51% of the male population (p < 0.02). A seasonal variance in the levels of vitamin D was observed with the lower levels happening in early spring with a recovery at the end of the summer (p < 0.004). These low levels of vitamin D corresponded with an inverse pattern in the levels of PTH more importantly in early spring. CONCLUSION: This study not only confirms previous reports that despite vitamin D food supplementation a vitamin D deficiency is still a finding in elderly population in the Northern hemisphere, but also that a compensatory change in PTH levels concurrently occurs with a potential significance on bone strength and risk of fractures.