Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients

Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we evaluated antiarrhythmic efficacy of carvedilol and flecainide in CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying different mutations in RYR2. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion and IA115 or V4653F mutation in RYR2 and of a healthy individual. Ca2+ kinetics and drug effects were studied with Fluo-4 AM indicator. Carvedilol abolished Ca2+ abnormalities in 31% of L4115F, 36% of V4653F, and 46% of exon 3 deletion carrying CPVT cardiomyocytes and flecainide 33%, 30%, and 52%, respectively. Both drugs lowered the intracellular Ca2+ level and beating rate of the cardiomyocytes significantly. Moreover, flecainide caused abnormal Ca2+ transients in 61% of controls compared to 26% of those with carvedilol. Carvedilol and flecainide were equally effective in CPVT iPSC-CMs. However, flecainide induced arrhythmias in 61% of control cells. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca2+ abnormalities, but they had the best response to drug therapies. According to this study, the arrhythmia-abolishing effect of neither of the drugs is optimal. iPSC-CMs provide a unique platform for testing drugs for CPVT.Peer reviewe

Seasonality and geographical spread of respiratory syncytial virus epidemics in 15 European countries, 2010 to 2016

Respiratory syncytial virus (RSV) is considered the most common pathogen causing severe lower respiratory tract infections among infants and young children. We describe the seasonality and geographical spread of RSV infection in 15 countries of the European Union and European Economic Area. We performed a retrospective descriptive study of weekly laboratory-confirmed RSV detections between weeks 40/2010 and 20/2016, in patients investigated for influenzalike illness, acute respiratory infection or following the clinician's judgment. Six countries reported 4,230 sentinel RSV laboratory diagnoses from primary care and 14 countries reported 156,188 non-sentinel laboratory diagnoses from primary care or hospitals. The median length of the RSV season based on sentinel and non-sentinel surveillance was 16 (range: 9-24) and 18 (range: 8-24) weeks, respectively. The median peak weeks for sentinel and non-sentinel detections were week 4 (range: 48 to 11) and week 4.5 (range: 49 to 17), respectively. RSV detections peaked later (r = 0.56; p = 0.0360) and seasons lasted longer with increasing latitude (r = 0.57; p = 0.0329). Our data demonstrated regular seasonality with moderate correlation between timing of the epidemic and increasing latitude of the country. This study supports the use of RSV diagnostics within influenza or other surveillance systems to monitor RSV seasonality and geographical spread

An attempt to understand exclusive pi+ electroproduction

Hard exclusive pi+ electroproduction is investigated within the handbag approach. The prominent role of the pion-pole contribution is demonstrated. It is also shown that the experimental data require a twist-3 effect which ensues from the helicity-flip generalized parton distribution H_T and the twist-3 pion wave function. The results calculated from this handbag approach are compared in detail with the experimental data on cross sections and spin asymmetries measured with a polarized target. It is also commented on consequences of this approach for exclusive \pi^0 and vector-meson electroproduction.Comment: 35 pages, 12 figures, using Latex, a number of additional comments have been included in the text, e.g. in paragraph above (3) or at end of sect.

Mark correlations: relating physical properties to spatial distributions

Mark correlations provide a systematic approach to look at objects both distributed in space and bearing intrinsic information, for instance on physical properties. The interplay of the objects' properties (marks) with the spatial clustering is of vivid interest for many applications; are, e.g., galaxies with high luminosities more strongly clustered than dim ones? Do neighbored pores in a sandstone have similar sizes? How does the shape of impact craters on a planet depend on the geological surface properties? In this article, we give an introduction into the appropriate mathematical framework to deal with such questions, i.e. the theory of marked point processes. After having clarified the notion of segregation effects, we define universal test quantities applicable to realizations of a marked point processes. We show their power using concrete data sets in analyzing the luminosity-dependence of the galaxy clustering, the alignment of dark matter halos in gravitational $N$-body simulations, the morphology- and diameter-dependence of the Martian crater distribution and the size correlations of pores in sandstone. In order to understand our data in more detail, we discuss the Boolean depletion model, the random field model and the Cox random field model. The first model describes depletion effects in the distribution of Martian craters and pores in sandstone, whereas the last one accounts at least qualitatively for the observed luminosity-dependence of the galaxy clustering.Comment: 35 pages, 12 figures. to be published in Lecture Notes of Physics, second Wuppertal conference "Spatial statistics and statistical physics

DVCS amplitude at tree level: Transversality, twist-3, and factorization

We study the virtual Compton amplitude in the generalized Bjorken region (q^2 -> Infinity, t small) in QCD by means of a light-cone expansion of the product of e.m. currents in string operators in coordinate space. Electromagnetic gauge invariance (transversality) is maintained by including in addition to the twist-2 operators 'kinematical' twist-3 operators which appear as total derivatives of twist-2 operators. The non-forward matrix elements of the elementary twist-2 operators are parametrized in terms of two-variable spectral functions (double distributions), from which twist-2 and 3 skewed distributions are obtained through reduction formulas. Our approach is equivalent to a Wandzura-Wilczek type approximation for the twist-3 skewed distributions. The resulting Compton amplitude is manifestly transverse up to terms of order t/q^2. We find that in this approximation the tensor amplitude for longitudinal polarization of the virtual photon is finite, while the one for transverse polarization contains a divergence already at tree level. However, this divergence has zero projection on the polarization vector of the final photon, so that the physical helicity amplitudes are finite.Comment: 34 pages, revtex, 1 eps figure included using epsf. Misprints corrected, one reference adde

The chirally-odd twist-3 distribution function e(x) in the chiral quark-soliton model

The chirally-odd twist-3 nucleon distribution e(x) is studied in the large-Nc limit in the framework of the chiral quark-soliton model at a low normalization point of about 0.6 GeV. The remarkable result is that in the model e(x) contains a delta-function-type singularity at x=0. The regular part of e(x) is found to be sizeable at the low scale of the model and in qualitative agreement with bag model calculations.Comment: 16 pages, 6 figures, revtex, Ref.[50] and footnote 3 adde

European all-cause excess and influenza-attributable mortality in the 2017/18 season: should the burden of influenza B be reconsidered?

Objectives Weekly monitoring of European all-cause excess mortality, the EuroMOMO network, observed high excess mortality during the influenza B/Yamagata dominated 2017/18 winter season, especially among elderly. We describe all-cause excess and influenza-attributable mortality during the season 2017/18 in Europe. Methods Based on weekly reporting of mortality from 24 European countries or sub-national regions, representing 60% of the European population excluding the Russian and Turkish parts of Europe, we estimated age stratified all-cause excess morality using the EuroMOMO model. In addition, age stratified all-cause influenza-attributable mortality was estimated using the FluMOMO algorithm, incorporating influenza activity based on clinical and virological surveillance data, and adjusting for extreme temperatures. Results Excess mortality was mainly attributable to influenza activity from December 2017 to April 2018, but also due to exceptionally low temperatures in February-March 2018. The pattern and extent of mortality excess was similar to the previous A(H3N2) dominated seasons, 2014/15 and 2016/17. The 2017/18 overall all-cause influenza-attributable mortality was estimated to be 25.4 (95%CI 25.0-25.8) per 100,000 population; 118.2 (116.4-119.9) for persons aged 65. Extending to the European population this translates into over-all 152,000 deaths. Conclusions The high mortality among elderly was unexpected in an influenza B dominated season, which commonly are considered to cause mild illness, mainly among children. Even though A(H3N2) also circulated in the 2017/18 season and may have contributed to the excess mortality among the elderly, the common perception of influenza B only having a modest impact on excess mortality in the older population may need to be reconsidered.Peer Reviewe