Viscosity of fluorine-doped silica glasses

The viscous behavior of fluorine-doped synthetic silica is studied using collapsing experiments with different fluorine-doped tubes on a modified chemical vapor deposition (MCVD) lathe. The principles, techniques, and evaluations of this method are the same as the ones demonstrated previously in detail with pure and doped silica. The present investigations provide information about the influence of fluorine doping up to a concentration of about 10 mol% F (3.4 wt% F) in a temperature range between 1600°C and 2000°C. Fluorine doping leads to a systematic decrease in the viscosity, combined with a decrease of the activation energy of the viscous flow and a certain increase of the pre-exponential factor. In summary, this demonstrates the weakening influence of fluorine on the glass network, similar to the incorporation of hydroxyl or chlorine

Functional genomics of abiotic environmental adaptation in lacertid lizards and other vertebrates

Understanding the genomic basis of adaptation to different abiotic environments is important in the context of climate change and resulting short-term environmental fluctuations. Using functional and comparative genomics approaches, we here investigated whether signatures of genomic adaptation to a set of environmental parameters are concentrated in specific subsets of genes and functions in lacertid lizards and other vertebrates. We first identify 200 genes with signatures of positive diversifying selection from transcriptomes of 24 species of lacertid lizards and demonstrate their involvement in physiological and morphological adaptations to climate. To understand how functionally similar these genes are to previously predicted candidate functions for climate adaptation and to compare them with other vertebrate species, we then performed a meta-analysis of 1,100 genes under selection obtained from -omics studies in vertebrate species adapted to different abiotic factors. We found that the vertebrate gene set formed a tightly connected interactome, which was to 23% enriched in previously predicted functions of adaptation to climate, and to a large part (18%) involved in organismal stress response. We found a much higher degree of identical genes being repeatedly selected among different animal groups (43.6%), and of functional similarity and post-translational modifications than expected by chance, and no clear functional division between genes used for ectotherm and endotherm physiological strategies. In total, 171 out of 200 genes of Lacertidae were part of this network. These results highlight an important role of a comparatively small set of genes and their functions in environmental adaptation and narrow the set of candidate pathways and markers to be used in future research on adaptation and stress response related to climate change

Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3

AIMS: Clinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). beta-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease. METHODS AND RESULTS: We studied effects of autonomic modulation on arrhythmias in vivo and in vitro and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (DeltaKPQ) in the Scn5a gene coding for the cardiac sodium channel and increased late sodium current (LQT3 mice). Cholinergic stimulation by carbachol provoked bigemini and TdP in freely roaming LQT3 mice. No arrhythmias were provoked by physical stress, mental stress, isoproterenol, or atropine. In isolated, beating hearts, carbachol did not prolong action potentials per se, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. beta-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. beta-Adrenoceptor density was reduced in LQT3 hearts. Acute beta-adrenoceptor blockade by esmolol, propranolol or chronic propranolol in vivo did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all P < 0.05). CONCLUSION: Cholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. beta-Adrenoceptor density is reduced, and beta-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and beta-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.status: publishe

MRI-detected brain lesions in AF patients without further stroke risk factors undergoing ablation - a retrospective analysis of prospective studies

Abstract Background Atrial fibrillation (AF) without other stroke risk factors is assumed to have a low annual stroke risk comparable to patients without AF. Therefore, current clinical guidelines do not recommend oral anticoagulation for stroke prevention of AF in patients without stroke risk factors. We analyzed brain magnetic resonance imaging (MRI) imaging to estimate the rate of clinically inapparent (“silent”) ischemic brain lesions in these patients. Methods We pooled individual patient-level data from three prospective studies comprising stroke-free patients with symptomatic AF. All study patients underwent brain MRI within 24–48 h before planned left atrial catheter ablation. MRIs were analyzed by a neuroradiologist blinded to clinical data. Results In total, 175 patients (median age 60 (IQR 54–67) years, 32% female, median CHA2DS2-VASc = 1 (IQR 0–2), 33% persistent AF) were included. In AF patients without or with at least one stroke risk factor, at least one silent ischemic brain lesion was observed in 4 (8%) out of 48 and 10 (8%) out of 127 patients, respectively (p > 0.99). Presence of silent ischemic brain lesions was related to age (p = 0.03) but not to AF pattern (p = 0.77). At least one cerebral microbleed was detected in 5 (13%) out of 30 AF patients without stroke risk factors and 25 (25%) out of 108 AF patients with stroke risk factors (p = 0.2). Presence of cerebral microbleeds was related to male sex (p = 0.04) or peripheral artery occlusive disease (p = 0.03). Conclusion In patients with symptomatic AF scheduled for ablation, brain MRI detected silent ischemic brain lesions in approximately one in 12 patients, and microbleeds in one in 5 patients. The prevalence of silent ischemic brain lesions did not differ in AF patients with or without further stroke risk factors

How to use implantable loop recorders in clinical trials and hybrid therapy

Epidemiological studies show that atrial fibrillation (AF) is associated with a doubling of mortality, even after adjustment for confounders. AF can be asymptomatic, but this does not decrease the thromboembolic risk of the patient. Office ECGs, occasional 24-h Holter recordings and long-term ECG event recording might not be sensitive and accurate enough in patients with AF, especially in those with paroxysmal episodes. In one study, 7 days of continuous monitoring with event recorders detected paroxysmal AF in 20 of 65 patients with a previous negative 24-h Holter recording. Over the last decade, enormous improvements have been made in the technology of implantable devices, which can now store significant information regarding heart rhythm. The first subcutaneous implantable monitor (Reveal XT, Medtronic) was validated for continuous AF monitoring by the XPECT study. The dedicated AF detection algorithm uses irregularity and incoherence of R–R intervals to identify and classify patterns in ventricular conduction. Its sensitivity in identifying patients with AF is >96%. Numerous clinical data from continuous monitoring of AF have recently been published. The first applications of this technology have been in the field of surgical and catheter AF ablation. With regard to cryptogenic stroke, an international randomized trial is ongoing to compare standard care with standard care plus the implantable cardiac monitor for AF detection in patients discharged with the diagnosis of cryptogenic stroke: the Crystal AF trial. Continuous AF monitoring provides an optimal picture of daily AF burden, both symptomatic and asymptomatic. Implantable cardiac monitors have high sensitivity, enable better assessment of therapy success and may guide further AF therapy

Regulation of APD and Force by the Na+/Ca2+ Exchanger in Human-Induced Pluripotent Stem Cell-Derived Engineered Heart Tissue

The physiological importance of NCX in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is not well characterized but may depend on the relative strength of the current, compared to adult cardiomyocytes, and on the exact spatial arrangement of proteins involved in Ca2+ extrusion. Here, we determined NCX currents and its contribution to action potential and force in hiPSC-CMs cultured in engineered heart tissue (EHT). The results were compared with data from rat and human left ventricular tissue. The NCX currents in hiPSC-CMs were larger than in ventricular cardiomyocytes isolated from human left ventricles (1.3 ± 0.2 pA/pF and 3.2 ± 0.2 pA/pF for human ventricle and EHT, respectively, p 0.05). Force was increased by the NCX block in rat ventricle (by 31 ± 5.4%, p < 0.05) and EHT (by 20.8 ± 3.9%, p < 0.05), but not in human left ventricular preparations. In conclusion, hiPSC-CMs possess NCX currents not smaller than human left ventricular tissue. Robust NCX block-induced APD shortening and inotropy makes EHT an attractive pharmacological model.publishedVersionPeer reviewe

Characteristics of patients initiated on edoxaban in Europe:baseline data from edoxaban treatment in routine clinical practice for patients with atrial fibrillation (AF) in Europe (ETNA-AF-Europe)

Background: Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have substantially improved anticoagulation therapy for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The available routine care data have demonstrated the safety of different NOACs; however, such data for edoxaban are scarce. Here, we report baseline characteristics of 13,638 edoxaban-treated patients with AF enrolled between November 2016 and February 2018. Methods: ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study conducted in 825 sites in 10 European countries. Patients will be followed up for four years. Results: Overall, 13,980 patients were enrolled of which 342 patients were excluded from the analysis. Mean patient age was 73.6 years with an average creatinine clearance of 69.4 mL/min. 56.6% were male. The calculated CHA2DS2-VASc and HAS-BLED mean scores were 3.1 and 2.6, respectively. Overall, 3.3, 14.6 and 82.0% of patients had low (CHA2DS2-VASc = 0), intermediate (CHA2DS2-VASc = 1) and high (CHA2DS2-VASc≥2) risks of stroke, respectively. High-risk patients (those with prior stroke, prior major bleeding, prior intracranial bleed or CHA2DS2-VASc ≥4) comprised 38.4% of the overall population. For 75.1% of patients edoxaban was their first anticoagulant prescription, whilst 16.9% switched from a VKA and 8.0% from another NOAC. A total of 23.4% of patients in ETNA-AF-Europe received the reduced dose of edoxaban 30 mg. Overall, 83.8% of patients received an edoxaban dose in line with the criteria outlined in the label. Conclusion: Edoxaban was predominantly initiated in older, often anticoagulation-naïve, unselected European patients with AF, with a good overall adherence to the approved label. Trial registration: NCT02944019; Date of registration: October 24, 2016