StatSeq Systems Genetics Benchmark

Description of published synthetic Systems Genetics datasets.The StatSeq benchmark dataset is meant to be used for training and evaluating algorithms and techniques for the inference of networks from systems genetics data. The goal is to comprehend which methodology has the best overall inferring performance, and which eventually performs better under particular conditions (i.e. population size, large or small marker distances, high or low heritability, network size). This short document describes how the data have been generated through SysGenSIM. Detailed information is provided about the construction of the gene networks, the simulation of the genotype and of the gene expression, and the submission and evaluation of the predictions

From Knockouts to Networks: Establishing Direct Cause-Effect Relationships through Graph Analysis

Background: Reverse-engineering gene networks from expression profiles is a difficult problem for which a multitude of techniques have been developed over the last decade. The yearly organized DREAM challenges allow for a fair evaluation and unbiased comparison of these methods. Results: We propose an inference algorithm that combines confidence matrices, computed as the standard scores from single-gene knockout data, with the down-ranking of feed-forward edges. Substantial improvements on the predictions can be obtained after the execution of this second step. Conclusions: Our algorithm was awarded the best overall performance at the DREAM4 In Silico 100-gene network subchallenge, proving to be effective in inferring medium-size gene regulatory networks. This success demonstrates once again the decisive importance of gene expression data obtained after systematic gene perturbations and highlights the usefulness of graph analysis to increase the reliability of inference

Prognostic Implications of Baroreflex Sensitivity in Heart Failure Patients in the Beta-Blocking Era

ObjectivesThis study investigated the clinical correlates and prognostic value of depressed baroreceptor-heart rate reflex sensitivity (BRS) among patients with heart failure (HF), with and without beta-blockade.BackgroundAbnormalities in autonomic reflexes play an important role in the development and progression of HF. Few studies have assessed the effects of beta-blockers on BRS in HF.MethodsThe study population consisted of 103 stable HF patients, age (median [interquartile range]) 54 years (48 to 57 years), with New York Heart Association (NYHA) functional class ≥III in 22, and with a left ventricular ejection fraction (LVEF) of 30% (24% to 36%), treated with beta-blockers; and 144 untreated patients, age 55 years (48 to 60 years), with NYHA functional class ≥III in 47%, and an LVEF of 26% (21% to 30%). They underwent BRS testing (phenylephrine technique).ResultsIn both treated and untreated patients, a lower BRS was associated with a higher (≥III) NYHA functional class (p = 0.0002 and p < 0.0001, respectively); a more severe (≥2) mitral regurgitation (p = 0.007 and p = 0.0002), respectively; a lower LVEF (p = 0.0004 and p = 0.001, respectively), baseline RR interval (p = 0.0004 and p = 0.0002, respectively), and SDNN (p < 0.0001, p = 0.002, respectively); and a higher blood urea nitrogen (p = 0.004, p < 0.0001, respectively). Clinical variables explained only 43% of BRS variability among treated and 36% among untreated patients. During a median follow-up of 29 months, 17 of 103 patients and 55 of 144 patients, respectively, experienced a cardiac event. A depressed BRS (<3.0 ms/mm Hg) was significantly associated with the outcome, independently of known risk predictors and beta-blocker treatment (adjusted hazard ratio: 3.0 [95% confidence interval: 1.5 to 5.9], p = 0.001).ConclusionsBaroreceptor-heart rate reflex sensitivity does not simply mirror the pathophysiological substrate of HF. A depressed BRS conveys independent prognostic information that is not affected by the modification of autonomic dysfunction brought about by beta-blockade

Are multiple-choice questions a good tool for the assessment of clinical competence in Internal Medicine?

There are many feasible tools for the assessment of clinical practice, but there is a wide consensus on the fact that the simultaneous use of several different methods could be strategic for a comprehensive overall judgment of clinical competence. Multiple-choice questions (MCQs) are a well-established reliable method of assessing knowledge. Constructing effective MCQ tests and items requires scrupulous care in the design, review and validation stages. Creating high-quality multiple-choice questions requires a very deep experience, knowledge and large amount of time. Hereby, after reviewing their construction, strengths and limitations, we debate their completeness for the assessment of professional competence

Clinical and haemodynamic correlates of heart rate turbulence as a non-invasive index of baroreflex sensitivity in chronic heart failure

HRT (heart rate turbulence), describing the heart rate changes following a premature ventricular contraction, has been regarded as an indirect index of baroreflex function. However, limited data are available on its relationship with invasive assessment by phenylephrine injection (Phe-slope). In the present study, we therefore compared these methodologies in a series of patients with HF (heart failure) in which both measures together with clinical and haemodynamic data were available. HRT parameters [TO (turbulence onset) and TS (turbulence slope)] were measured from 24-h Holter recordings obtained within 1 week of baroreflex sensitivity assessment and right heart haemodynamic evaluation (Swan-Ganz catheter). HRT was computable in 135 out of 157 (86%) patients who had both a phenylephrine test and haemodynamic evaluation. TO and TS significantly correlated with Phe-slope (r=−0.39, P<0.0001 and r=0.66, P<0.0001 respectively). Age, baseline heart rate, LVEF (left ventricular ejection fraction), PCP (pulmonary capillary pressure), CI (cardiac index) and sodium were significant and independent predictors of Phe-slope, accounting for 51% of its variability. Similarly, age, baseline heart rate and PCP, and NYHA (New York Heart Association) classes III–IV were independent predictors for TS and explained 48% of its variability, whereas only CI and LVEF were found to be significantly related to TO and explained a very limited proportion (20%) of the variability. In conclusion, these results suggest that HRT may be regarded as a surrogate measure of baroreflex sensitivity in clinical and prognostic evaluation in patients with HF

X=Y–ZH compounds as potential 1,3-dipoles. Part 64: Synthesis of highly substituted conformationally restricted and spiro nitropyrrolidines via Ag(I) catalysed azomethine ylide cycloadditions

1,3-Dipolar reactions of imines of both acyclic and cyclic α-amino esters with a range of nitroolefins using a combination of AgOAc or Ag2O with NEt3 are described. In most cases the reactions were highly regio- and stereospecific and endo-cycloadducts were obtained in good yield. However, in a few cases the initially formed cycloadducts underwent base catalysed epimerisation. The stereochemistry of the cycloadducts was assigned from NOE data and established unequivocally in several cases by X-ray crystallography

Prevalence and Persistence of Breathing Disorders in Chronic Heart Failure Patients: Preliminary Results from Home Telemonitoring in the HHH Study

In this paper we present preliminary results of the European Community multicountry trial HHH (Home or Hospital in Heart Failure), which assessed the prevalence and persistence of nocturnal breathing disorders in mild-to-moderate CHF patients. All subjects (465) carried out a baseline respiratory recording in the hospital, followed by 12 recordings (one per month) at home. The latter were totally self-managed by the patients, and data were transmitted to the referring hospital through telephone lines. We found that 43 % of the patients had a periodic breathing pattern (PB, waxing and waning of ventilation with or without apneas) during the night lasting ≥ 1 hour, and the apnea-hypopnea index (AHI) was ≥ 5 events/hour in 51 % of them. During the 1-year follow-up, a PB ≥ 1 hour and an AHI ≥ 5 events/hour were persistent (i.e., occurred in&gt; 50 % of the recordings) in 43 % and 52 % of the patients. These findings confirm the high prevalence of nocturnal breathing disorders in CHF patients and show that in a large proportion of patients they tend to persist over time. 1