Frailty phenotypes in the elderly based on cluster analysis: a longitudinal study of two Danish cohorts. Evidence for a genetic influence on frailty

Frailty is a physiological state characterized by the deregulation of multiple physiologic systems of an aging organism determining the loss of homeostatic capacity, which exposes the elderly to disability, diseases, and finally death. An operative definition of frailty, useful for the classification of the individual quality of aging, is needed. On the other hand, the documented heterogeneity in the quality of aging among different geographic areas suggests the necessity for a frailty classification approach providing population-specific results. Moreover, the contribution of the individual genetic background on the frailty status is still questioned. We investigated the applicability of a cluster analysis approach based on specific geriatric parameters, previously set up and validated in a southern Italian population, to two large longitudinal Danish samples. In both cohorts, we identified groups of subjects homogeneous for their frailty status and characterized by different survival patterns. A subsequent survival analysis availing of Accelerated Failure Time models allowed us to formulate an operative index able to correlate classification variables with survival probability. From these models, we quantified the differential effect of various parameters on survival, and we estimated the heritability of the frailty phenotype by exploiting the twin pairs in our sample. These data suggest the presence of a genetic influence on the frailty variability and indicate that cluster analysis can define specific frailty phenotypes in each population.     

The ability of three different models of frailty to predict all-cause mortality: Results from the European Male Aging Study (EMAS)

Few studies have directly compared the ability of the most commonly used models of frailty to predict mortality among community-dwelling individuals. Here, we used a frailty index (FI), frailty phenotype (FP), and FRAIL scale (FS) to predict mortality in the EMAS. Participants were aged 40–79 years (n = 2929) at baseline and 6.6% (n = 193) died over a median 4.3 years of follow-up. The FI was generated from 39 deficits, including self-reported health, morbidities, functional performance and psychological assessments. The FP and FS consisted of five phenotypic criteria and both categorized individuals as robust when they had 0 criteria, prefrail as 1–2 criteria and frail as 3+ criteria. The mean FI increased linearly with age (r² = 0.21) and in Cox regression models adjusted for age, center, smoking and partner status the hazard ratio (HR) for death for each unit increase of the FI was 1.49. Men who were prefrail or frail by either the FP or FS definitions, had a significantly increased risk of death compared to their robust counterparts. Compared to robust men, those who were FP frail at baseline had a HR for death of 3.84, while those who were FS frail had a HR of 3.87. All three frailty models significantly predicted future mortality among community-dwelling, middle-aged and older European men after adjusting for potential confounders. Our data suggest that the choice of frailty model may not be of paramount importance when predicting future risk of death, enabling flexibility in the approach used.     

The stress of aging

Although the evolutionary theories of aging are quite well established, our knowledge about how we age is still very limited. The abundance and heterogeneity of available mechanistic theories of aging implicitly suggest that this phenomenon is overly complex and unlikely to be explained by a single pathway. Moreover, although aging remains a unique process, it is characterized by heterogeneous manifestations, not only determining inter-individual variations, but even intra-individual diversities. Such heterogeneity renders the inner nature of the aging process of difficult evaluation in older persons due to the potential biases introduced by multiple age-related social, biological, and clinical factors (and responsible for the evidence-based issue in geriatrics). Moving from the difficulties in translating anti-aging preclinical interventions into clinical trials, an alternative approach is illustrated. We encourage moving to a holistic evaluation of aging by adopting specific and consequent modifications in the design and conduction of clinical research. Such approach is today commonly applied in the clinical setting where the complexity of older patients often requires multidimensional interventions to adequately target the geriatric syndromes. Consistently, interventions targeting the aging process may result ineffective if too focused on a single underlying causal mechanism and/or failing to capture the complexity of the phenomenon. In this context, frailty (a geriatric syndrome characterized by age-related declines occurring across multiple physiologic systems) may indeed represent a clinically relevant threshold throughout the continuum of the aging process and a promising benchmark to test multidomain interventions against age-related conditions.     

恶性肿瘤与Rh血型系统各表型的相关性分析

目的：分析恶性肿瘤患者Rh血型表型的分布特点,并与正常对照组进行比较,查找恶性肿瘤与Rh血型表型相关性。方法：对120例恶性肿瘤患者（患者组）及100例正常健康人群（对照组）进行Rh血型表型测定,对其表型分布进行统计分析,采用χ2检验和相对危险度OR值来估计相对危险性。结果：恶性肿瘤患者组与对照组Rh血型表型CcDEe分布之间的差异有统计学意义（χ2=4.51,P〈0.05）。恶性肿瘤患者组Rh血型表型分布从高到低分别是CcDEe54例（45.00%）,CCDee39例（32.50%）,CcDee14例（11.67%）,ccDEE9例（7.50%）,ccDEe3例（2.50%）,CCDEe1例（0.83%）;对照组Rh血型表型分布从高到低分别是CCDee47例（47.00%）,CcDEe32例（32.00%）,ccDEE9例（9.00%）,CcDee6例（6.00%）,ccDEe5例（5.00%）,CCDEe1例（1.00%）;结论：恶性肿瘤的发生与Rh血型表型的分布有关,CcDEe（OR=1.82）、CcDee（OR=2.07）表型发病率明显高于其他表型。     

失智症护理研究共词聚类分析

目的分析2009-2019年失智症护理研究的热点，了解该领域研究现状及发展趋势。 方法检索Pubmed、Medline、Biosis Previews、Web of science数据库，检索词为"dementia"、"Alzheimers disease"，检索时间范围为2009-2019年，类别选项限定为护理。 结果共检索到2 883条文献记录，提取含关键词信息的文献共计2 560条。统计得出高频（≥85次）关键词38个，占总频次累计百分比为35.39%。共词聚类分析得到5个研究热点：失智症照护模式和管理、失智症疾病管理、失智症风险管理、失智症症状管理、失智症末期照护。 结论近10年来失智症相关护理研究集中探索了护理实践在失智症照护、干预、管理中的重要意义，为拓展失智症领域的护理实践和科研提供了理论基础。     

The association between frailty and quality of life when aging in place

Background and objectivesAdvanced age is often associated with frailty, which in turn is associated with low quality of life. This study explores to what extent multidimensional frailty is associated with multidimensional quality of life.Material and methodsA cross-sectional survey study was conducted in a sample of 336 Flemish older people aging in place. Data were collected between 2014 and 2016 using two multidimensional self-reporting instruments; the Comprehensive Frailty Assessment Instrument to assess frailty and the World Health Organization Quality of Life Instrument-Short Version to assess quality of life. Bivariate analyses were used to explore the relationship between quality of life, associated factors of quality of life and frailty.ResultsThe mean age of the respondents was 74.9 years and 71.7% were woman. An inverse correlation was found between frailty and quality of life (r = −.683) and the corresponding subdomains. Nevertheless, some respondents perceived their quality of life as high, although they were defined as mild to high frail. Further analysis indicated that neither socio-demographic factors nor being ill contributed to quality of life.Discussion and implicationsPsychological frailty contributed the most to quality of life. However, the results indicate that frailty does not inevitably leads to a lower quality of life and that other factors, besides frailty, play an important role in determining quality of life. Knowledge about these factors and their mutual relationship can help policymakers and services in providing client-centered care to increase or maintain the quality of life of people aging in place.     

A cluster analysis study of acetyl-l-carnitine effect on NMDA receptors in aging

Aging is associated with a reduction in the maximum density of n-methyl-d-aspartate (NMDA)-sensitive glutamate binding sites in the hippocampus of Fischer 344 rats. This study was designed to investigate the effect of acetyl-l-carnitine (ALCAR) on NMDA receptors in the old rat (24 months) after chronic or single-dose treatments. The number of NMDA receptors was significantly decreased in the old rat hippocampus by 19.5% compared with the young rat. A six-month treatment with ALCAR in the old rat attenuated the loss of NMDA binding sites in the hippocampus. A single-dose treatment with ALCAR in the old rat increased the B_max value by 35%, while no change was observed in the young group. We conclude that ALCAR can exert two actions: a trophic/neuro-preserving one when chronically administered during aging, and a stimulatory one when given at a single dose in the aged rat.     

Impact of complete lockdown on total infection and death rates: A hierarchical cluster analysis

Introduction and AimsRetarding the spread of SARS-CoV-2 infection by preventive strategies is the first line of management. Several countries have declared a stringent lockdown in order to enforce social distancing and prevent the spread of infection. This analysis was conducted in an attempt to understand the impact of lockdown on infection and death rates over a period of time in countries with declared lock-down.Material and methodsA validated database was used to generate data related to countries with declared lockdown. Simple regression analysis was conducted to assess the rate of change in infection and death rates. Subsequently, a k-means and hierarchical cluster analysis was done to identify the countries that performed similarly. Sweden and South Korea were included as counties without lockdown in a second-phase cluster analysis.ResultsThere was a significant 61% and 43% reduction in infection rates 1-week post lockdown in the overall and India cohorts, respectively, supporting its effectiveness. Countries with higher baseline infections and deaths (Spain, Germany, Italy, UK, and France-cluster 1) fared poorly compared to those who declared lockdown early on (Belgium, Austria, New Zealand, India, Hungary, Poland and Malaysia-cluster 2). Sweden and South Korea, countries without lock-down, fared as good as the countries in cluster 2.ConclusionLockdown has proven to be an effective strategy is slowing down the SARS-CoV-2 disease progression (infection rate and death) exponentially. The success story of non-lock-down countries (Sweden and South Korea) need to be explored in detail, to identify the variables responsible for the positive results.     

Skin aging parameters: A window to heart block

Background

Skin acts as a mirror to the internal state of the body.

Hypothesis

We tried to find the relation between skin aging parameters and the incidence of degenerative AV block.

Methods

This study included 97 patients divided into 2 groups; group D comprised 49 patients with advanced‐degree AV block, and group C comprised the 48 matched control group. All were subjected to full history taking, thorough clinical examination, calculation of intrinsic skin aging score, and resting 12‐lead surface electrocardiography (ECG). ECG for all patients assessed left ventricular end‐systolic diameter, left ventricular end‐diastolic diameter, ejection fraction, left atrium (LA) diameter, aortic root diameter, mitral annular calcification, aortic sclerosis. Coronary angiography was also performed when indicated for patients in group D.

Results

Patients in group D had a higher percentages of uneven pigmentation, fine skin wrinkles, lax appearance, seborrheic keratosis, total score > 7 (38 [77.55%] vs 10 [20.83%]), mitral annular calcification score of 33 (67.34%) vs 5 (10.41%), aortic sclerosis score of 21 (42.85%) vs 4 (8.33%), and mean LA diameter of 39.98 ± 5.52 vs 36.21 ± 3 mm (P < 0.001). Total score > 6 is the best cutoff value to predict advanced‐degree heart block with 89.79% sensitivity and 64.58% specificity. Seborrheic keratosis was the strongest independent predictor.

Conclusions

Any population with a total intrinsic skin aging score of >6 is at high risk for developing advanced‐degree AV block and should undergo periodic ECG follow‐up for early detection of any conduction disturbance in the early asymptomatic stages to minimize sudden cardiac death.     

Is atherosclerosis fundamental to human aging? Lessons from ancient mummies

Case reports from Johan Czermak, Marc Ruffer, and others a century or more ago demonstrated ancient Egyptians had atherosclerosis three millennia ago. The Horus study team extended their findings, demonstrating that atherosclerosis was prevalent among 76 ancient Egyptian mummies and among 61 mummies from each of the ancient cultures of Peru, the American Southwest, and the Aleutian Islands. These findings challenge the assumption that atherosclerosis is a modern disease caused by present day risk factors. An extensive autopsy of an ancient Egyptian teenage male weaver named Nakht found that he was infected with four parasites: Schistosoma haematobium, Taenia species, Trichinella spiralis, and Plasmodium falciparum. Modern day patients with chronic inflammatory disease such as rheumatoid arthritis, systemic lupus erythematosus, and human immunodeficiency virus experience premature atherosclerosis. Could the burden of chronic inflammatory disease have been a risk factor for atherosclerosis in these ancient cultures? The prevalence of atherosclerosis in four diverse ancient cultures is consistent with atherosclerosis being fundamental to aging. The impact of risk factors in modern times, and potentially in ancient times, suggests a strong gene-environmental interplay: human genes provide a vulnerability to atherosclerosis, the environment determines when and if atherosclerosis becomes manifest clinically.     

因子和聚类分析在继发性肺结核CT影像分类中的应用研究

目的　探讨联合应用因子分析与聚类分析统计方法在肺结核CT征象群分类的价值,为继发性肺结核病的CT分类研究提供依据。方法 将243例活动性肺结核(其中涂阳、涂阴肺结核分别为129例和114例)的肺内CT征象分为13种,应用因子分析(方差最大化正交旋转)与聚类分析相结合的方法对继发性肺结核进行影像分类.并比较在涂阳、涂阴肺结核诊断中的价值。结果 经因子分析后可形成5个公因子,即播散因子、实变因子、小叶中心正因子、小叶中心负因子、空洞因子。经聚类分析后继发性肺结核的影像类型分为5个类别,分别为空洞播散型59例(24.3%)、空洞为主型34例(14.0%)、气道播散型32例(13.2%)、实变为主型54例(22.2%)和结节型64例(26.3%)。涂阳、涂阴肺结核2组间类别构成有显著性差异(P<0.05)。其中涂阳组空洞播散型、实变型明显多于涂阴组;而涂阴组结节型明显多于涂阳组,均具有显著性差异(P<0.05)。结论 因子分析和聚类分析相结合可较好地对活动性肺结核的复杂CT征象进行科学分类,有助于活动性肺结核的诊断,特别是对涂阴肺结核的诊断具有重要价值。     

A single administration of human umbilical cord blood T cells produces long-lasting effects in the aging hippocampus

Neurogenesis occurs throughout life but significantly decreases with age. Human umbilical cord blood mononuclear cells (HUCB MNCs) have been shown to increase the proliferation of neural stem cells (NSCs) in the dentate gyrus (DG) of the hippocampus and the subgranular zone of aging rats (Bachstetter et al., BMC Neurosci 9:22, 2008), but it is unclear which fraction or combination of the HUCB MNCs are responsible for neurogenesis. To address this issue, we examined the ability of HUCB MNCs, CD4+, CD8+, CD3+, CD14+, and CD133+ subpopulations to increase proliferation of NSCs both in vitro and in vivo. NSCs were first grown in conditioned media generated from HUCB cultures, and survival and proliferation of NSC were determined with the fluorescein diacetate/propidium iodide and 5-bromo-2′-deoxyuridine incorporation assays, respectively. In a second study, we injected HUCB cells intravenously in young and aged Fisher 344 rats and examined proliferation in the DG at 1 week (study 2.1) and 2 weeks (study 2.2) postinjection. The effects of the HUCB MNC fractions on dendritic spine density and microglial activation were also assessed. HUCB T cells (CD3+, CD4+, and CD8+ cells) induced proliferation of NSCs (p < 0.001) and increased cell survival. In vivo, HUCB-derived CD4+ cells increased NSC proliferation at both 1 and 2 weeks while also enhancing the density of dendritic spines at 1 week and decreasing inflammation at 2 weeks postinjection. Collectively, these data indicate that a single injection of HUCB-derived T cells induces long-lasting effects and may therefore have tremendous potential to improve aging neurogenesis.     

Identifying young adults at high risk of cardiometabolic disease using cluster analysis and the Framingham 30-yr risk score

Background and aimsCurrent strategies to reduce cardiovascular disease (CVD) risk in young adults are largely limited to those at extremes of risk. In cohort studies we have shown cluster analysis identified a large sub-group of adolescents with multiple risk factors. This study examined if individuals classified at ‘high-risk’ by cluster analysis could also be identified by their Framingham risk scores.Methods and resultsRaine Study data at 17- (n = 1048) and 20-years (n = 1120) identified high- and low-risk groups by cluster analysis using continuous measures of systolic BP, BMI, triglycerides and insulin resistance. We assessed:- CVD risk at 20-years using the Framingham 30 yr-risk-score in the high- and low-risk clusters, and cluster stability from adolescence to adulthood.Cluster analysis at 17- and 20-years identified a high-risk group comprising, 17.9% and 21.3%, respectively of the cohort. In contrast, only 1.2% and 3.4%, respectively, met the metabolic syndrome criteria, all of whom were within the high-risk cluster. Compared with the low-risk cluster, Framingham scores of the high-risk cluster were elevated in males (9.4%; 99%CI 8.3, 10.6 vs 6.0%; 99%CI 5.7, 6.2) and females (4.9%; 99%CI 4.4, 5.4 vs 3.2%; 99%CI 3.0, 3.3) (both P < 0.0001). A score >8 for males and >4 for females identified those at high CVD risk with 99% confidence.ConclusionCluster analysis using multiple risk factors identified ～20% of young adults at high CVD risk. Application of our Framingham 30 yr-risk cut-offs to individuals allows identification of more young people with multiple risk factors for CVD than conventional metabolic syndrome criteria.     

一种新发现的线粒体DNA大片段缺失与衰老的关系初探

目的 在人外周血细胞中筛选新的线粒体DNA（mtDNA）大片段缺失突变,探讨mtDNA尤其在片段缺失突变与衰老的关系。方法 以人外周血细胞DNA为模板,进行聚合酶链反应（PCR）扩增,产物克隆、测序。用PCR半定量方法测定1条长达13．1kb的mtDNA缺失突变,＜60岁组和≥60岁组突变型与野生型的比例,差异有显著性。结论 该突变以前未见报道,可能是一种与衰老有关的缺失突变。     

Relationship between metastasis-associated phenotypes and N-glycan structure of surface glycoproteins in human hepatocarcinoma cells

Purpose: To study the relation of N-glycan structure on cell surface glycoproteins to the metastatic phenotypes. Methods: Two human hepatocarcinoma 7721 cell lines transfected with sense or antisense cDNA of GnT-V, named GnT-V/7721 and GnT-V-AS/7721, respectively, were adopted, because GnT-V can change the antennary number and the content of the β1,6 GlcNAc branch in N-glycans. The effects of over- and under-expression of GnT-V on the metastasis-associated phenotype of the transfected cells were investigated and compared with the cells mock-transfected with the plasmid vector. Results: In GnT-V/7721 cells, GnT-V activity was increased by 92% compared with the mock cells. HRP-labeled lectin staining of transfected cells showed elevated intensity with HRP-L-PHA and reduced intensity with HRP-ConA, suggesting the increased antennary number and content of the β1,6 GlcNAc branch in N- glycans. Analysis of the N-glycan structure of [³H]-labeled glycopeptides prepared from cell-surface [³H] glycoproteins using DSA-affinity chromatography also revealed the above change of the N-glycan structure in a more quantitative manner. GnT-V/7721 cells showed a suppressed cell attachment to fibronectin (Fn) or laminin (Ln), and increased cell migration and invasion through matrigel. In contrast, GnT-V-AS/7721 cells showed reduction of both GnT-V activity and content of the β1,6 branch in N-linked glycans, elevation of cell attachment to Fn or Ln, and decline of cell migration and invasion through matrigel. These changes were just the opposite to those in GnT-V/7721 cells. Conclusions: The alteration of N-glycan structure in surface glycoproteins resulting from the activity change of GnT-V contributes to the alterations in metastasis-associated phenotypes. The product of GnT-V, the β1,6 GlcNAc branch in N-linked glycans, is a structural factor of adhesion inhibition and invasion promotion. GnT-V is, therefore, closely related to cancer metastasis and its over-expression is an important molecular mechanism of metastasis. Received: 4 April 2000 / Accepted: 12 July 2000