Survival analysis for AdVerse events with VarYing follow-up times (SAVVY) -- estimation of adverse event risks

The SAVVY project aims to improve the analyses of adverse event (AE) data in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). Although statistical methodologies have advanced, in AE analyses often the incidence proportion, the incidence density, or a non-parametric Kaplan-Meier estimator (KME) are used, which either ignore censoring or CEs. In an empirical study including randomized clinical trials from several sponsor organisations, these potential sources of bias are investigated. The main aim is to compare the estimators that are typically used in AE analysis to the Aalen-Johansen estimator (AJE) as the gold-standard. Here, one-sample findings are reported, while a companion paper considers consequences when comparing treatment groups. Estimators are compared with descriptive statistics, graphical displays and with a random effects meta-analysis. The influence of different factors on the size of the bias is investigated in a meta-regression. Comparisons are conducted at the maximum follow-up time and at earlier evaluation time points. CEs definition does not only include death before AE but also end of follow-up for AEs due to events possibly related to the disease course or the treatment. Ten sponsor organisations provided 17 trials including 186 types of AEs. The one minus KME was on average about 1.2-fold larger than the AJE. Leading forces influencing bias were the amount of censoring and of CEs. As a consequence, the average bias using the incidence proportion was less than 5%. Assuming constant hazards using incidence densities was hardly an issue provided that CEs were accounted for. There is a need to improve the guidelines of reporting risks of AEs so that the KME and the incidence proportion are replaced by the AJE with an appropriate definition of CEs

CNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2

Background: Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle. We hypothesize that antiarrhythmic effects of CNP are mediated by PDE2 (phosphodiesterase 2), which has the unique property to be stimulated by cGMP to primarily hydrolyze cAMP. Thus, CNP might promote beneficial effects of PDE2-mediated negative crosstalk between cAMP and cGMP signaling pathways. Methods: To determine antiarrhythmic effects of cGMP-mediated PDE2 stimulation by CNP, we analyzed arrhythmic events and intracellular trigger mechanisms in mice in vivo, at organ level and in isolated cardiomyocytes as well as in human-induced pluripotent stem cell-derived cardiomyocytes. Results: In ex vivo perfused mouse hearts, CNP abrogated arrhythmia after ischemia/reperfusion injury. Upon high-dose catecholamine injections in mice, PDE2 inhibition prevented the antiarrhythmic effect of CNP. In mouse ventricular cardiomyocytes, CNP blunted the catecholamine-mediated increase in arrhythmogenic events as well as in ICaL, INaL, and Ca2+spark frequency. Mechanistically, this was driven by reduced cellular cAMP levels and decreased phosphorylation of Ca2+handling proteins. Key experiments were confirmed in human iPSC-derived cardiomyocytes. Accordingly, the protective CNP effects were reversed by either specific pharmacological PDE2 inhibition or cardiomyocyte-specific PDE2 deletion. Conclusions: CNP shows strong PDE2-dependent antiarrhythmic effects. Consequently, the CNP-PDE2 axis represents a novel and attractive target for future antiarrhythmic strategies

Die Politik der Sowjetischen Militäradministration in Deutschland (SMAD): Kultur, Wissenschaft und Bildung 1945-1949. Ziele, Methoden, Ergebnisse. Dokumente aus russischen Archiven

This edition provides an introduction to the wide range of policies applied in the Soviet Occupation Zone (SBZ) with respect to the areas of culture, education and science. Carefully selected and translated documents shed light on the relationship between the occupational forces and the traditions and institutions of the emerging German Democratic Republic. It represents the initial result of a joint German-Russian research project on the history of the SMAD made possible by the recent release of the original sources in Russian archives