Shifting trends in modes of death in the Intensive Care Unit.

PURPOSE: To describe the way patients die in a Spanish ICU, and how the modes of death have changed in the last 10 years. MATERIALS AND METHODS: Retrospective observational study evaluating all patients who died in a Spanish tertiary ICU over a 10-year period. Modes of death were classified as death despite maximal support (D-MS), brain death (BD), and death following life-sustaining treatment limitation (D-LSTL). RESULTS: Amongst 9264 ICU admissions, 1553 (16.8%) deaths were recorded. The ICU mortality rate declined (1.7%/year, 95% CI 1.4-2.0; p = 0.021) while ICU admissions increased (3.5%/year, 95% CI 3.3-3.7; p < 0.001). More than half of the patients (888, 57.2%) died D-MS, 389 (25.0%) died after a shared decision of D-LSTL and 276 (17.8%) died due to BD. Modes of death have changed significantly over the past decade. D-LSTL increased by 15.1%/year (95% CI 14.4-15.8; p < 0.001) and D-MS at the end-of-life decreased by 7.1%/year (95% CI 6.6-7.6; p < 0.001). The proportion of patients diagnosed with BD remained stable over time. CONCLUSIONS: End-of-life practices and modes of death in our ICU have steadily changed. The proportion of patients who died in ICU following limitation of life-prolonging therapies substantially increased, whereas death after maximal support occurred significantly less frequently.

Relation Between Genetic Factors and Frailty in Older Adults.

OBJECTIVES: Frailty is a geriatric syndrome that identifies individuals at higher risk of disability, institutionalization, and death. We previously reported that frailty is related to oxidative stress and cognitive impairment-related biomarkers. The aim of this study was to determine whether frailty is associated with genetic variants. DESIGN: Longitudinal population-based cohort of 2488 community-dwelling people from Toledo, Spain, aged 65 years or older. SETTING AND PARTICIPANTS: We obtained blood samples from 78 individuals with frailty and 74 nonfrail individuals who were nonfrail (according to Fried criteria) from the Toledo Study of Healthy Ageing and extracted DNA using the Chemagic DNA blood kit. MEASURES: Sample genotyping was carried out by means of Axiom Exome 319 Genotyping Array (Thermo Fisher Scientific), which contains 295,988 markers [single-nucleotide polymorphisms (SNPs) and rare variants], and transferred to the GeneTitan Instrument (Affymetrix). RESULTS: We found 15 SNPs (P < .001), 18 genes (P < .005), and 4 pathways (P < .05) related to cytokine-cytokine receptor interaction, natural killer cell-mediated cytotoxicity, regulation of autophagy, and renin-angiotensin system as the most strongly associated with frailty. CONCLUSIONS/IMPLICATIONS: The specific genetic features related to energy metabolism, biological processes regulation, cognition, and inflammation highlighted by this preliminary analysis offer useful insights for finding biologically meaningful biomarkers of frailty that allow early diagnosis and treatment. Further research is needed to confirm our novel findings in a larger population. Indeed, the EU-funded FRAILOMICS research effort will address this question.

Identificación de polimorfismos de un solo nucleótido relacionados con la fragilidad / Identification of single nucleotide polymorphisms related to frailty

Introducción: La búsqueda de biomarcadores que permitan la detección y el posible tratamiento precoz de la fragilidad se ha convertido en uno de los objetivos primordiales de la comunidad científica geriátrica. El objetivo del presente estudio fue identificar polimorfismos de un solo nucleótido ([SNP] del inglés single nucleotide polymorphisms) relacionados con la fragilidad. Material y métodos: El estudio se llevó a cabo en 152 sujetos de la cohorte del Estudio de Toledo (de 65 a 95 años de edad), clasificados como frágiles (n=78), y no frágiles (n=74), según los criterios de Fried. Tras la extracción de sangre se aisló y amplificó el ADN para el análisis de SNP mediante la tecnología AxiomTMGenotyping de Affymetrix. Los análisis estadísticos fueron realizados mediante el programa Plink y la biblioteca de R library SNPassoc para Windows. Resultados: Los resultados del análisis mostraron 15 SNP con un valor de p inferior a 0,001. Destacamos aquellos implicados en procesos relacionados con la fragilidad, como el metabolismo energético, la regulación de procesos biológicos, la motilidad e integridad celular y la cognición. Conclusiones: Los resultados sugieren que las variaciones genéticas identificadas en individuos frágiles y que están implicadas en procesos biológicos relacionados con la fragilidad podrían constituir biomarcadores que contribuyan a la detección precoz de la misma

Introduction: The search for biomarkers that can lead to the early diagnosis and thus, early treatment of frailty, has become one of the main challenges facing the geriatric scientific community. The aim of the present study was to identify single nucleotide polymorphisms (SNPs) related to frailty. Material and methods: The study was conducted on 152 subjects from the Toledo Study for Healthy Aging (65 to 95 years of age), and classified as frail (n=78), and non-frail (n=74), according to Fried's criteria. After blood collection, DNA was isolated and amplified for the analysis of SNPs using AxiomTM Genotyping technology (Affymetrix). Statistical analyses were performed using the Plink program and library SNPassoc. Results: The results of the study showed 15 SNPs with a P<.001. Those SNPs involved in processes related to frailty, such as energy metabolism, regulation of biological processes, cell motility and integrity, and cognition are highlighted. Conclusions: These results suggest that the genetic variations identified in frail individuals that are involved in biological processes related to frailty may be considered as biomarkers for the early detection of frailty

[Identification of single nucleotide polymorphisms related to frailty]. / Identificación de polimorfismos de un solo nucleótido relacionados con la fragilidad.

INTRODUCTION: The search for biomarkers that can lead to the early diagnosis and thus, early treatment of frailty, has become one of the main challenges facing the geriatric scientific community. The aim of the present study was to identify single nucleotide polymorphisms (SNPs) related to frailty. MATERIAL AND METHODS: The study was conducted on 152 subjects from the Toledo Study for Healthy Aging (65 to 95 years of age), and classified as frail (n=78), and non-frail (n=74), according to Fried's criteria. After blood collection, DNA was isolated and amplified for the analysis of SNPs using AxiomTM Genotyping technology (Affymetrix). Statistical analyses were performed using the Plink program and library SNPassoc. RESULTS: The results of the study showed 15 SNPs with a P<.001. Those SNPs involved in processes related to frailty, such as energy metabolism, regulation of biological processes, cell motility and integrity, and cognition are highlighted. CONCLUSIONS: These results suggest that the genetic variations identified in frail individuals that are involved in biological processes related to frailty may be considered as biomarkers for the early detection of frailty.

Impact of pharmacogenetics on CNS side effects related to efavirenz.

AIM: This article evaluates which genetic factors are involved in CNS toxicity related to long-term treatment with efavirenz (EFV) standard doses and their relationship with plasma concentrations. PATIENTS & METHODS: A total of 119 HIV-positive patients, in which 1350 EFV plasma concentrations, 68 SNPs and 14 EFV-related adverse effects (AEs) were analyzed. RESULTS: Overall, 32.77% of patients reported CNS toxicity and 8.40% had concentrations above the therapeutic range. A correlation was mainly found between patients with global CNS AEs and high EFV maximum steady-state plasma concentration (p = 1.47 × 10(-6)). A preliminary analysis confirmed that CYP2B6*6 (516G>T and 785A>G) was the most highly correlated (p = 0.005) with AEs and high plasma concentrations. In a second analysis adjusting for maximum steady-state plasma concentration, suggestive genetic associations were found between BCRP 421C>A, MRP1 816G>A, 5-HT2A 102C>T and different AEs. CONCLUSION: The finding of the involvement of these SNPs in EFV toxicity opens the door for further studies to confirm their validity and for their application in the future clinical practice. Original submitted 18 February 2013; Revision submitted 17 May 2013.