Multivariate frailty models for two types of recurrent events with a dependent terminal event: Application to breast cancer data

Individuals may experience more than one type of recurrent event and a terminal event during the life course of a disease. Follow‐up may be interrupted for several reasons, including the end of a study, or patients lost to follow‐up, which are noninformative censoring events. Death could also stop the follow‐up, hence, it is considered as a dependent terminal event. We propose a multivariate frailty model that jointly analyzes two types of recurrent events with a dependent terminal event. Two estimation methods are proposed: a semiparametrical approach using penalized likelihood estimation where baseline hazard functions are approximated by M‐splines, and another one with piecewise constant baseline hazard functions. Finally, we derived martingale residuals to check the goodness‐of‐fit. We illustrate our proposals with a real dataset on breast cancer. The main objective was to model the dependency between the two types of recurrent events (locoregional and metastatic) and the terminal event (death) after a breast cancer.     

Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty

Frailty is an important geriatric syndrome that predicts disability and mortality. Substantial evidence suggests inflammation marked by elevated IL-6 levels as a key pathophysiologic factor that contributes to frailty. CXCL-10, a potent pro-inflammatory chemokine, has increased levels with age and is implicated in several inflammatory conditions. To better understand molecular mechanisms of inflammation activation in frailty, we evaluated monocytic expression of CXCL-10 and other inflammatory pathway genes by pathway-specific gene array analysis and quantitative RT-PCR. Frailty status was determined by the validated criteria. Sixteen pairs of community-dwelling frail and age-, race-, and sex-matched non-frail participants (mean age 83 years, range 72–94) completed the study. Here we report that frail participants had higher CXCL-10 expression levels than matched non-frail controls (1.05 ± 0.88 versus 0.53 ± 0.39, p = 0.04). CXCL-10 expression correlated with IL-6 levels only in frail participants (Spearman correlation coefficient r = 0.52, p = 0.03). Furthermore, frailty-associated CXCL-10 upregulation was highly correlated with IL-6 elevation, both measured by frail-over-non-frail ratios (r = 0.93, p < 0.0001). These findings suggest upregulated monocytic expression of CXCL-10 as an important molecular mechanism that contributes to inflammation activation in frail older adults. Therapeutic implications include potential development of CXCL-10-based interventional strategies for the prevention and treatment of frailty in older adults.     

The NAD World: A New Systemic Regulatory Network for Metabolism and Aging—Sirt1, Systemic NAD Biosynthesis,and Their Importance

For the past several years, it has been demonstrated that the NAD-dependent protein deacetylase Sirt1 and nicotinamide phosphoribosyltransferase (Nampt)-mediated systemic NAD biosynthesis together play a critical role in the regulation of metabolism and possibly aging in mammals. Based on our recent studies on these two critical components, we have developed a hypothesis of a novel systemic regulatory network, named “NAD World”, for mammalian aging. Conceptually, in the NAD World, systemic NAD biosynthesis mediated by intra- and extracellular Nampt functions as a driver that keeps up the pace of metabolism in multiple tissues/organs, and the NAD-dependent deacetylase Sirt1 serves as a universal mediator that executes metabolic effects in a tissue-dependent manner in response to changes in systemic NAD biosynthesis. This new concept of the NAD World provides important insights into a systemic regulatory mechanism that fundamentally connects metabolism and aging and also conveys the ideas of functional hierarchy and frailty for the regulation of metabolic robustness and aging in mammals.     

Perfil clínico y mortalidad a 90 días de los pacientes centenarios atendidos en servicios de urgencias hospitalarios

ObjectivesTo determine the clinical profile and to develop a model to predict 90-day mortality in centenarian patients attended in emergency departments (ED).MethodologyThis was an observational, retrospective, multicentre cohort study including patients > 99 years attended in 5 ED in the Community of Madrid from January to December 2012. Demographic variables were recorded, as well as, comorbidities, cognitive, functional, social basal status, geriatric syndromes, acute episode, and hospital and social resources use, and 90-day mortality.ResultsThe study included 209 patients aged 101 years (SD 1.7) of whom 161 (77.0%) were female. Sixty four (32.5%) had severe comorbidity (Charlson index ≥ 3), 101 (49.8%) on multiple medication, 100 (52.6%) had cognitive impairment, 82 (42.3%) had severe functional dependence, 85 (40.7%) were institutionalised, and 190 (94.5%) had a geriatric syndrome. Dyspnoea (26.8%), followed by falls (12.4%) were the most common causes of attendance. One hundred and eighteen (56.5%) were admitted, and 58 out of 174 (33.3%) died in the first 90 days. The model to predict 90-day overall mortality included male sex (OR 2.42 95% CI = 0.97-6.04; P = .059), emergency care in the previous 3 months (OR 4.08 95% CI = 1.26-13.16; P = .019) and the hospitalization by index event (OR 8.63 95% CI = 3.25-22.9; P < .001) and this model had an area under ROC curve of 0.776 (95% CI = 0.70-0.85; P < .001).ConclusionsCentenarian patients attended in ED had a significant frailty and one in three cases died in the first 90 days after being attended, and this was associated with male sex, emergency care in the previous 3 months, and hospitalisation.     

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.

Frecuencia de envejecimiento exitoso y fragilidad. Factores de riesgo asociados

Objective

To determine the frequency of successful aging (SA) and its relationship with frailty in an elderly population.

Bayesian semiparametric proportional odds models

Methodology for implementing the proportional odds regression model for survival data assuming a mixture of finite Polya trees (MPT) prior on baseline survival is presented. Extensions to frailties and generalized odds rates are discussed. Although all manner of censoring and truncation can be accommodated, we discuss model implementation, regression diagnostics, and model comparison for right-censored data. An advantage of the MPT model is the relative ease with which predictive densities, survival, and hazard curves are generated. Much discussion is devoted to practical implementation of the proposed models, and a novel MCMC algorithm based on an approximating parametric normal model is developed. A modest simulation study comparing the small sample behavior of the MPT model to a rank-based estimator and a real data example is presented.