The accumulation of deficits approach to describe frailty

The advancing age of the participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study was the incentive to investigate frailty as a major parameter of ageing. The aim of this study was to develop a multidimensional tool to measure frailty in an ageing, free-living study population. The "accumulation of deficits approach" was used to develop a frailty index (FI) to characterize a sub-sample (N = 815) of the EPIC-Potsdam (EPIC-P) study population regarding the aging phenomenon. The EPIC-P frailty index (EPIC-P-FI) included 32 variables from the following domains: health, physical ability, psychosocial and physiological aspects. P-values were calculated for the linear trend between sociodemographic and life style variables and the EPIC-P-FI was calculated using regression analysis adjusted for age. The relationship between the EPIC-P-FI and age was investigated using fractional polynomials. Some characteristics such as age, education, time spent watching TV, cycling and a biomarker of inflammation (C-reactive protein) were associated with frailty in men and women. Interestingly, living alone, having no partner and smoking status were only associated with frailty in men, and alcohol use and physical fitness (VO2max) only in women. The generated, multidimensional FI, adapted to the EPIC-P study, showed that this cohort is a valuable source for further exploration of factors that promote healthy ageing

Dietary determinants of changes in waist circumference adjusted for body mass index - a proxy measure of visceral adiposity

Background Given the recognized health effects of visceral fat, the understanding of how diet can modulate changes in the phenotype “waist circumference for a given body mass index (WCBMI)”, a proxy measure of visceral adiposity, is deemed necessary. Hence, the objective of the present study was to assess the association between dietary factors and prospective changes in visceral adiposity as measured by changes in the phenotype WCBMI. Methods and Findings We analyzed data from 48,631 men and women from 5 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Anthropometric measurements were obtained at baseline and after a median follow-up time of 5.5 years. WCBMI was defined as the residuals of waist circumference regressed on body mass index, and annual change in WCBMI (¿WCBMI, cm/y) was defined as the difference between residuals at follow-up and baseline, divided by follow-up time. The association between energy, energy density (ED), macronutrients, alcohol, glycemic index (GI), glycemic load (GL), fibre and ¿WCBMI was modelled using centre-specific adjusted linear regression, and random-effects meta-analyses to obtain pooled estimates. Men and women with higher ED and GI diets showed significant increases in their WCBMI, compared to those with lower ED and GI [1 kcal/g greater ED predicted a ¿WCBMI of 0.09 cm (95% CI 0.05 to 0.13) in men and 0.15 cm (95% CI 0.09 to 0.21) in women; 10 units greater GI predicted a ¿WCBMI of 0.07 cm (95% CI 0.03 to 0.12) in men and 0.06 cm (95% CI 0.03 to 0.10) in women]. Among women, lower fibre intake, higher GL, and higher alcohol consumption also predicted a higher ¿WCBMI. Conclusions Results of this study suggest that a diet with low GI and ED may prevent visceral adiposity, defined as the prospective changes in WCBMI. Additional effects may be obtained among women of low alcohol, low GL, and high fibre intake

Prediction of circulating adipokine levels based on body fat compartments and adipose tissue gene expression

BACKGROUND: Adipokines are hormones secreted from adipose tissue (AT), and a number of them have been established as risk factors for chronic diseases. However, it is not clear whether and to what extent adiposity, gene expression, and other factors determine their circulating levels. OBJECTIVES: To assess to what extent adiposity, as measured by the amount of subcutaneous AT (SAT) and visceral AT (VAT) using magnetic resonance imaging, and gene expression levels in SAT determine plasma concentrations of the adipokines adiponectin, leptin, soluble leptin receptor, resistin, interleukin 6, and fatty acid-binding protein 4 (FABP4). METHODS: We performed a cross-sectional analysis of 156 participants from the EPIC Potsdam cohort study and analyzed multiple regression models and partial correlation coefficients. RESULTS: For leptin and FABP4 concentrations, 81 and 45% variance were explained by SAT mass, VAT mass, and gene expression in SAT in multivariable regression models. For the remaining adipokines, AT mass and gene expression explained <16% variance of plasma concentrations. Gene expression in SAT was a less important predictor compared to AT mass. SAT mass was a better predictor than VAT mass for leptin (partial correlation r = 0.81, 95% confidence interval 0.75–0.86, vs. r = 0.58, 95% confidence interval 0.46–0.67), while differences between AT compartments were small for the other adipokines. CONLUSIONS: While plasma levels of leptin and FABP4 can be explained in a large and medium part by the amount of AT and SAT gene expression, surprisingly, these predictors explained only little variance for all other investigated adipokines

Optimal Uncertainty Quantification

We propose a rigorous framework for Uncertainty Quantification (UQ) in which the UQ objectives and the assumptions/information set are brought to the forefront. This framework, which we call \emph{Optimal Uncertainty Quantification} (OUQ), is based on the observation that, given a set of assumptions and information about the problem, there exist optimal bounds on uncertainties: these are obtained as values of well-defined optimization problems corresponding to extremizing probabilities of failure, or of deviations, subject to the constraints imposed by the scenarios compatible with the assumptions and information. In particular, this framework does not implicitly impose inappropriate assumptions, nor does it repudiate relevant information. Although OUQ optimization problems are extremely large, we show that under general conditions they have finite-dimensional reductions. As an application, we develop \emph{Optimal Concentration Inequalities} (OCI) of Hoeffding and McDiarmid type. Surprisingly, these results show that uncertainties in input parameters, which propagate to output uncertainties in the classical sensitivity analysis paradigm, may fail to do so if the transfer functions (or probability distributions) are imperfectly known. We show how, for hierarchical structures, this phenomenon may lead to the non-propagation of uncertainties or information across scales. In addition, a general algorithmic framework is developed for OUQ and is tested on the Caltech surrogate model for hypervelocity impact and on the seismic safety assessment of truss structures, suggesting the feasibility of the framework for important complex systems. The introduction of this paper provides both an overview of the paper and a self-contained mini-tutorial about basic concepts and issues of UQ.Comment: 90 pages. Accepted for publication in SIAM Review (Expository Research Papers). See SIAM Review for higher quality figure

Molecular characterization of projection neuron subtypes in the mouse olfactory bulb

Projection neurons (PNs) in the mammalian olfactory bulb (OB) receive input from the nose and project to diverse cortical and subcortical areas. Morphological and physiological studies have highlighted functional heterogeneity, yet no molecular markers have been described that delineate PN subtypes. Here, we used viral injections into olfactory cortex and fluorescent nucleus sorting to enrich PNs for high-throughput single nucleus and bulk RNA deep sequencing. Transcriptome analysis and RNA in situ hybridization identified distinct mitral and tufted cell populations with characteristic transcription factor network topology, cell adhesion and excitability-related gene expression. Finally, we describe a new computational approach for integrating bulk and snRNA-seq data, and provide evidence that different mitral cell populations preferentially project to different target regions. Together, we have identified potential molecular and gene regulatory mechanisms underlying PN diversity and provide new molecular entry points into studying the diverse functional roles of mitral and tufted cell subtypes

Association of general and abdominal adiposity with postural changes in systolic blood pressure: results from the NAKO pretest and MetScan studies

The association between anthropometric measurements and postural changes in systolic blood pressure (SBP) has not been frequently reported. This study aimed to investigate the association of body mass index (BMI) and waist circumference (WC) with postural changes in SBP in two German cross-sectional studies. Data were derived from 506 participants of the population-based German National Cohort (NAKO) pretest and from 511 participants of the convenience sample-based MetScan studies. Linear regression models were used to estimate the association between BMI and WC with the difference between standing and sitting SBP (dSBP). Odds ratios (ORs) for an increase (dSBP > 10 mmHg) or decrease (dSBP ≤ −10 mmHg) in dSBP were calculated using logistic regression. The results were pooled by meta-analysis using an inverse variance model. In pooled analysis, a 5 kg/m(2) higher BMI was associated with a 1.46 mmHg (95% confidence interval (CI) 0.98–1.94) higher dSBP, while a 5 cm higher WC was associated with a 0.51 mmHg (95% CI 0.32–0.69) higher dSBP. BMI or WC were associated with a higher odds of an increase in dSBP (adjusted OR, 1.71; 95% CI 1.36–2.14 per 5 kg/m(2) higher BMI and 1.22; 95% CI 1.05–1.40 per 5 cm higher WC) but with a reduced odds of a decline in dSBP (adjusted OR, 0.67; 95% CI 0.44–1.00 per 5 kg/m(2) higher BMI and 0.84; 95% CI 0.72–0.99 per 5 cm higher WC). The associations between WC and dSBP were no longer statistically significant after BMI adjustments. In conclusion, higher BMI and higher WC were associated with higher postural increases in SBP; however, WC was not related to postural changes in SBP once adjusted for BMI

Circulating omentin as a novel biomarker for colorectal cancer risk: Data from the EPIC - Potsdam cohort study

Omentin is a novel biomarker shown to exert metabolic, inflammatory and immune-related properties, and thereby could be implicated in the risk of colorectal cancer (CRC). So far, the association between omentin and CRC risk has not been evaluated in prospective cohort studies. We investigated the association between pre-diagnostic plasma omentin concentrations and risk of CRC in a case-cohort comprising 251 incident CRC cases diagnosed over a mean follow-up time of 10.4 years and 2,295 persons who remained free of cancer in the European Prospective Investigation into Cancer and Nutrition-Potsdam study. Hazard ratios as a measure of relative risk (RR) and 95% confidence intervals (CI-s) were computed using a Prentice modified Cox regression. In a model adjusted for established CRC risk factors, age, sex, education, dietary and lifestyle factors, body mass index (BMI) and waist circumference, higher omentin concentrations were associated with a higher CRC risk (RRcontinuously per doubling of omentin concentrations=1.98, 95%CI: 1.45-2.73). Additional adjustment for metabolic biomarkers, including glycated hemoglobin, high-density lipoprotein cholesterol and C-reactive protein, did not alter the results. In stratified analyses, the positive association between omentin and CRC risk was retained in participants with BMI< 30 (RRcontinuously per doubling of omentin concentrations=2.26; 95%CI: 1.57-3.27), whereas among participants with BMI{greater than or equal to} 30 no association was revealed (RRcontinuously per doubling of omentin concentrations =1.07; 95%CI: 0.63-1.83; Pinteraction= 0.005). These novel findings provide the first lines of evidence for an independent association between pre-diagnostic omentin concentrations and CRC risk and suggest a potential interaction with the adiposity state of the individual

DEVELOPMENT OF A STRATEGIC BUSINESS DECISION-MAKING ENVIRONMENT FOR COMMERCIAL JET ENGINE SELECTION

Presented at the 41st AIAA Aerospace Sciences, Meeting and Exhibit, Reno, NV, January 6-10, 2003.In today?s business climate, aerospace companies are more than ever in need of rational methods and techniques that provide insights as to the best strategies which may be pursued for increased profitability and risk mitigation. However, the use of subjective, anecdotal decision-making remains prevalent due to the absence of analytical methods capable of capturing and forecasting future needs. Negotiations between airframe and engine manufacturers could benefit greatly from a structured environment that facilitates efficient, rational, decision-making. Creation of such an environment can be developed through a parametric physics-based, stochastic formulation that uses meta-models to expedite the process. This paper describes such an approach in order to demonstrate the types of insights that might be gained as an engine manufacturer tries to forecast the effects of uncertainties and future vehicle requirements on engine related characteristics for the design of a hypothetical regional business jet. Game theory concepts are suggested as a potential means by which one can attach business payoffs to the selection of any engine design point

Non-fasting lipids and risk of cardiovascular disease in patients with diabetes mellitus

The aim of this study was to examine the effect of postprandial time on the associations and predictive value of non-fasting lipid levels and cardiovascular disease risk in participants with diabetes. This study was conducted among 1,337 participants with diabetes from the Dutch and German (Potsdam) contributions to the European Prospective Investigation into Cancer and Nutrition. At baseline, total cholesterol, LDL- and HDL-cholesterol and triacylglycerol concentrations were measured and the ratio of total cholesterol/HDL-cholesterol was calculated. Participants were followed for incidence of cardiovascular disease. Lipid concentrations changed minimally with increasing postprandial time, except for triacylglycerol which was elevated just after a meal and declined over time (1.86 at 0.1 h to 1.33 at >6 h, p for trend <0.001). During a mean follow-up of 8 years, 116 cardiovascular events were documented. After adjustment for potential confounders, triacylglycerol (HR for third tertile compared with first tertile (HR(t)₃(to)₁), 1.73 [95% CI 1.04, 2.87]), HDL-cholesterol (HR(t)₃(to)₁, 0.41 [95% CI 0.23, 0.72]) and total cholesterol/HDL-cholesterol ratio (HR(t)₃(to)₁, 1.65 [95% CI 0.95, 2.85]) were associated with cardiovascular disease, independent of postprandial time. Cardiovascular disease risk prediction using the UK Prospective Diabetes Study risk engine was not affected by postprandial time. Postprandial time did not affect associations between lipid concentrations and cardiovascular disease risk in patients with diabetes, nor did it influence prediction of cardiovascular disease. Therefore, it may not be necessary to use fasting blood samples to determine lipid concentrations for cardiovascular disease risk prediction in patients with diabete