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Aims: The effects of vericiguat vs. placebo on high-sensitivity C-reactive protein (hsCRP) and serum uric acid (SUA) were assessed in patients with heart failure with reduced ejection fraction (HFrEF) in the Phase 2 SOCRATES-REDUCED study (NCT01951625)., Methods and Results: Changes from baseline hsCRP and SUA values at 12 weeks with placebo and vericiguat (1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg, respectively) were assessed. The probability of achieving an hsCRP value of ≤3.0 mg/L or SUA value of <7.0 mg/dL at week 12 was tested. Median baseline hsCRP and SUA levels were 3.68 mg/L [interquartile range (IQR) 1.41-8.41; n = 335] and 7.80 mg/dL (IQR 6.40-9.33; n = 348), respectively. Baseline-adjusted mean percentage changes in hsCRP were 0.2%, -19.5%, -24.3%, -25.7% and -31.9% in the placebo and vericiguat 1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg groups, respectively; significance vs. placebo was observed in the vericiguat 10.0 mg group (P = 0.035). Baseline-adjusted mean percentage changes in SUA were 5.0%, -1.3%, -1.1%, -3.5% and -5.3% in the placebo, and vericiguat 1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg groups, respectively; significance vs. placebo was observed in the 5.0 mg and 10.0 mg groups (P = 0.0202 and P = 0.004, respectively). Estimated probability for an end-of-treatment hsCRP value of ≤3.0 mg/L and SUA value of <7.0 mg/dL was higher with vericiguat compared with placebo. The effect was dose-dependent, with the greatest effect observed in the 10.0 mg group., Conclusions: Vericiguat treatment for 12 weeks was associated with reductions in hsCRP and SUA, and a higher likelihood of achieving an hsCRP value of ≤3.0 mg/L and SUA value of <7.0 mg/dL., (© 2020 Bayer AG Pharmaceuticals. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: During preclinical drug development, monitoring of the electrocardiogram (ECG) is an important part of cardiac safety assessment. To detect potential pro-arrhythmic liabilities of a drug candidate and for internal decision-making during early stage drug development an in vivo model in small animals with translatability to human cardiac function is required., Methods: Over the last years, modifications/improvements regarding animal housing, ECG electrode placement, and data evaluation have been introduced into an established model for ECG recordings using telemetry in conscious, freely moving guinea pigs. Pharmacological validation using selected reference compounds affecting different mechanisms relevant for cardiac electrophysiology (quinidine, flecainide, atenolol, dl-sotalol, dofetilide, nifedipine, moxifloxacin) was conducted and findings were compared with results obtained in telemetered Beagle dogs., Results and Conclusion: Under standardized conditions, reliable ECG data with low variability allowing largely automated evaluation were obtained from the telemetered guinea pig model. The model is sensitive to compounds blocking cardiac sodium channels, hERG K(+) channels and calcium channels, and appears to be even more sensitive to β-blockers as observed in dogs at rest. QT interval correction according to Bazett and Sarma appears to be appropriate methods in conscious guinea pigs. Overall, the telemetered guinea pig is a suitable model for the conduct of early stage preclinical ECG assessment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Menopause-associated thermoregulatory dysfunction can lead to symptoms such as hot flushes severely impairing quality of life of affected women. Treatment effects are often assessed by the ovariectomized rat model providing time series of tail skin temperature measurements in which circadian rhythms are a fundamental ingredient. In this work, a new statistical strategy is presented for analyzing such stochastic-dynamic data with the aim of detecting successful drugs in hot flush treatment. The circadian component is represented by a nonlinear dynamical system which is defined by the van der Pol equation and provides well-interpretable model parameters. Results regarding the statistical evaluation of these parameters are presented.

DNA aneuploidy has been identified as a prognostic factor for epithelial malignancies. Further understanding of the translation of DNA aneuploidy into protein expression will help to define novel biomarkers to improve therapies and prognosis. DNA ploidy was assessed by image cytometry. Comparison of gel-electrophoresis-based protein expression patterns of three diploid and four aneuploid colorectal cancer cell lines detected 64 ploidy-associated proteins. Proteins were identified by mass spectrometry and subjected to Ingenuity Pathway Analysis resulting in two overlapping high-ranked networks maintaining Cellular Assembly and Organization, Cell Cycle, and Cellular Growth and Proliferation. CAPZA1, TXNL1, and HDAC2 were significantly validated by Western blotting in cell lines and the latter two showed expression differences also in clinical samples using a tissue microarray of normal mucosa (n=19), diploid (n=31), and aneuploid (n=47) carcinomas. The results suggest that distinct protein expression patterns, affecting TXNL1 and HDAC2, distinguish aneuploid with poor prognosis from diploid colorectal cancers., (© Springer Basel AG 2011)

Background: Measuring propofol concentration in plasma (c(P)PL) and in exhaled alveolar gas (c(P)G) during constant infusion provides information about their respective time courses. In the present study, we compared these time courses in patients undergoing cardiac surgery from the beginning of propofol anaesthesia until eye opening upon awakening., Methods: The c(P)G was measured before, during, and after continuous infusion of propofol for general anaesthesia in 12 patients at two randomly allocated doses (3 or 6 mg kg(-1) h(-1)). Gas samples were collected on Tenax tubes. After thermodesorption, c(P)G was measured by gas chromatography mass spectrometry. Simultaneously with exhaled gas, arterial blood was sampled for measuring c(P)PL by reversed-phase high-performance liquid chromatography with fluorescence detection. In order to compare the time courses of c(P)PL and c(P)G as dimensionless values directly, each gas and plasma value was normalized by relating it to the corresponding value at the end of the initial infusion after 40 min., Results: The c(P)G ranged between 2.8 and 22.5 ppb, whereas the corresponding c(P)PL varied between 0.3 and 3.3 microg ml(-1). Normalized concentration values showed a delayed increase in c(P)G compared with c(P)PL under constant propofol infusion before the onset of cardiopulmonary bypass, and a delayed decrease after stopping the propofol at the end of anaesthesia., Conclusions: Propofol can be measured in exhaled gas from the beginning until the end of propofol anaesthesia. The different time courses of c(P)PL and c(P)G have to be considered when interpreting c(P)G.

Mutual information (MI) is a robust nonparametric statistical approach for identifying associations between genotypes and gene expression levels. Using the data of Problem 1 provided for the Genetic Analysis Workshop 15, we first compared a quantitative MI (Tsalenko et al. 2006 J Bioinform Comput Biol 4:259-4) with the standard analysis of variance (ANOVA) and the nonparametric Kruskal-Wallis (KW) test. We then proposed a novel feature selection approach using MI in a classification scenario to address the small n - large p problem and compared it with a feature selection that relies on an asymptotic chi2 distribution. In both applications, we used a permutation-based approach for evaluating the significance of MI. Substantial discrepancies in significance were observed between MI, ANOVA, and KW that can be explained by different empirical distributions of the data. In contrast to ANOVA and KW, MI detects shifts in location when the data are non-normally distributed, skewed, or contaminated with outliers. ANOVA but not MI is often significant if one genotype with a small frequency had a remarkable difference in the average gene expression level relative to the other two genotypes. MI depends on genotype frequencies and cannot detect these differences. In the classification scenario, we show that our novel approach for feature selection identifies a smaller list of markers with higher accuracy compared to the standard method. In conclusion, permutation-based MI approaches provide reliable and flexible statistical frameworks which seem to be well suited for data that are non-normal, skewed, or have an otherwise peculiar distribution. They merit further methodological investigation.