Generation of a heterozygous Calsequestrin 2 F189L iPSC line (UMGi158-B) by CRISPR/Cas9 genome editing to investigate the cardiac pathophysiology of Takotsubo Syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia.

Takotsubo Syndrome (TTS) is a potentially life-threatening disease characterized by a transient left ventricular apical akinesia in response to β-adrenergic overstimulation. Since a genetic predisposition is assumed, we generated an iPSC-line carrying a p.F189L mutation in the calcium buffering protein Calsequestrin 2 (CasQ2).

Na1.8 as Proarrhythmic Target in a Ventricular Cardiac Stem Cell Model.

The sodium channel Na1.8, encoded by the gene, has recently emerged as a potential regulator of cardiac electrophysiology. We have previously shown that Na1.

Acute Gastroenteritis Outbreak Among Colorado River Rafters and Backpackers in the Grand Canyon, 2022.

Introduction: From April 1 to May 31, 2022, Grand Canyon National Park received increased acute gastroenteritis reports. Pooled portable toilet specimens identified norovirus genogroups I and II. We sought to determine outbreak transmission contributors and individual risk factors while rafting or backpacking in the park.

Generation of a pluripotent stem cell line (UMGi270-A) and a corresponding CRISPR/Cas9 modified isogenic control (UMGi270-A-1) from a patient with sudden onset dilated cardiomyopathy harboring a FLNC p.R2187P mutation.

Filamin C (FLNC) is a highly important actin crosslinker and multi-adaptor protein in striated skeletal and cardiac muscle. Mutations have been linked to a range of cardiomyopathy types. Here, we generated induced pluripotent stem cells (iPSC) from a patient with dilated cardiomyopathy (DCM) harboring a new, unique heterozygous FLNC mutation p.

Optimal test procedures for multiple hypotheses controlling the familywise expected loss.

We consider the problem of testing multiple null hypotheses, where a decision to reject or retain must be made for each one and embedding incorrect decisions into a real-life context may inflict different losses. We argue that traditional methods controlling the Type I error rate may be too restrictive in this situation and that the standard familywise error rate may not be appropriate. Using a decision-theoretic approach, we define suitable loss functions for a given decision rule, where incorrect decisions can be treated unequally by assigning different loss values.

Molecular and Functional Relevance of Na1.8-Induced Atrial Arrhythmogenic Triggers in a Human Knock-Out Stem Cell Model.

In heart failure and atrial fibrillation, a persistent Na current (I) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that Na1.8 contributes to arrhythmogenesis by inducing a I.

Outbreak of Acute Gastroenteritis Among Rafters and Backpackers in the Backcountry of Grand Canyon National Park, April-June 2022.

On May 11, 2022, the National Park Service (NPS) Office of Public Health (OPH) and Coconino County Health and Human Services (CCHHS) in Flagstaff, Arizona contacted CDC about a rising number of acute gastroenteritis cases among backcountry visitors to Grand Canyon National Park (Grand Canyon). The agencies reviewed illness report forms, assessed infection prevention and control (IPC) practices, and distributed a detailed survey to river rafters and hikers with backcountry permits (backpackers) who visited the Grand Canyon backcountry. During April 1-June 17, a total of 191 rafters and 31 backpackers reported symptoms consistent with acute gastroenteritis.

Rationale for the update algorithm of the graphical approach to sequentially rejective multiple test procedures.

The graphical approach by Bretz et al. is a convenient tool to construct, visualize and perform multiple test procedures that are tailored to structured families of hypotheses while controlling the familywise error rate. A critical step is to update the transition weights following a pre-specified algorithm.

Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients.

Cancer therapies with anthracyclines have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of B-cell lymphoma and to examine whether doxorubicin (DOX)-treated ACT-iPSC cardiomyocytes (CM) can recapitulate the clinical features exhibited by patients, and thus help uncover a DOX-dependent pathomechanism. ACT-iPSC CM generated from individuals with CD20 B-cell lymphoma who had received high doses of DOX and suffered cardiac dysfunction were studied and compared to control-iPSC CM from cancer survivors without cardiac symptoms.

Generation of homozygous Na1.8 knock-out iPSC lines by CRISPR Cas9 genome editing to investigate a potential new antiarrhythmic strategy.

The sodium channel Na1.8, encoded by SCN10A, is reported to contribute to arrhythmogenesis by inducing the late I and thereby enhanced persistent Na current. However, its exact electrophysiological role in cardiomyocytes remains unclear.

Detrimental proarrhythmogenic interaction of Ca/calmodulin-dependent protein kinase II and Na1.8 in heart failure.

An interplay between Ca/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na current (I) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform Na1.8 for CaMKIIδc-dependent proarrhythmia.

Spreading of Isolated Mutant Basal Cell Carcinoma Precursors Is Physiologically Suppressed and Counteracts Tumor Formation in Mice.

Basal cell carcinoma (BCC) originate from Hedgehog/Patched signaling-activated epidermal stem cells. However, the chemically induced tumorigenesis of mice with a -mediated biallelic loss of the Hedgehog signaling repressor Patched also induces BCC formation. Here, we identified the cellular origin of -targeted BCC progenitors as rare Keratin 5 epidermal cells and show that wildtype offspring of these cells spread over the hair follicle/skin complex with increasing mouse age.

Major changes in grapevine wood microbiota are associated with the onset of esca, a devastating trunk disease.

Esca, a major grapevine trunk disease in old grapevines, is associated with the colonization of woody tissues by a broad range of plant pathogenic fungi. To identify which fungal and bacterial species are involved in the onset of this disease, we analysed the microbiota from woody tissues of young (10-year-old) grapevines at an early stage of esca. Using meta-barcoding, 515 fungal and 403 bacterial operational taxonomic units (OTUs) were identified in woody tissues.

Vaccine hesitancy : Report of a student study group.

In summer 2019 an extracurricular activity was started at the Medical University of Vienna (MUW) with the title: "Esoterism in Medicine", where different chapters were evaluated by students. Here we present the subheading "Vaccine Hesitancy". Three students formulated arguments from sceptic, hesitant or anti-vaccine groups and discussed the scientific literature to rebut it.

Generation of iPSC-lines from two independent Takotsubo syndrome patients with recurrent Takotsubo events.

The Takotsubo syndrome (TTS) is characterized by acute transient left ventricular dysfunction in the absence of obstructive coronary lesions. An enhanced β-adrenergic signaling and higher sensitivity to catecholamine-induced-toxicity were identified as mechanisms associated with TTS. It is still elusive, whether TTS patients with recurrent events show similar underlying signaling pathomechanism.

Analysis of Resistance of Ebola Virus Glycoprotein-Driven Entry Against MDL28170, An Inhibitor of Cysteine Cathepsins.

Ebola virus (EBOV) infection can cause severe and frequently fatal disease in human patients. The EBOV glycoprotein (GP) mediates viral entry into host cells. For this, GP depends on priming by the pH-dependent endolysosomal cysteine proteases cathepsin B (CatB) and, to a lesser degree, cathepsin L (CatL), at least in most cell culture systems.

Controlling the type I error rate in two-stage sequential adaptive designs when testing for average bioequivalence.

In a 2×2 crossover trial for establishing average bioequivalence (ABE) of a generic agent and a currently marketed drug, the recommended approach to hypothesis testing is the two one-sided test (TOST) procedure, which depends, among other things, on the estimated within-subject variability. The power of this procedure, and therefore the sample size required to achieve a minimum power, depends on having a good estimate of this variability. When there is uncertainty, it is advisable to plan the design in two stages, with an interim sample size reestimation after the first stage, using an interim estimate of the within-subject variability.

Adaptive designs: The Swiss Army knife among clinical trial designs?

There has been considerable progress in the development and implementation of adaptive designs over the past 30 years. A major driver for this class of novel designs is the possibility to increase the information value of clinical trial data to enable better decisions, leading to more efficient drug development processes and improved late-stage success rates. In the first part of this article, we review the development of adaptive designs from different perspectives.

A unified framework for weighted parametric multiple test procedures.

We describe a general framework for weighted parametric multiple test procedures based on the closure principle. We utilize general weighting strategies that can reflect complex study objectives and include many procedures in the literature as special cases. The proposed weighted parametric tests bridge the gap between rejection rules using either adjusted significance levels or adjusted p-values.

The importance of the patient voice in vaccination and vaccine safety-are we listening?

Much has been written about the patient-physician relationship over the years. This relationship is essential in maintaining trust in the complex arena of modern diagnostic techniques, treatment and prevention, including vaccines and vaccine safety. However, a great deal of this material was written from the viewpoint of clinicians and academics.

Preprocedural Assessment for Sedation in Gastrointestinal Endoscopy.

The role of the anesthesia service in sedation for gastrointestinal endoscopy (GIE) has been steadily increasing. The goals of preprocedural assessment are determined by the specific details of the procedure, the issues related to the illness that requires the endoscopy, comorbidities, the goals for sedation, and the risk of complications from the sedation and the endoscopic procedure. Rather than consider these issues as separate entities, they should be considered as part of a continuum of preparation for GIE.

Multiplicity in confirmatory clinical trials: a case study with discussion from a JSM panel.

An invited panel session was conducted in the 2012 Joint Statistical Meetings, San Diego, California, USA, to stimulate the discussion on multiplicity issues in confirmatory clinical trials for drug development. A total of 11 expert panel members were invited and 9 participated. Prior to the session, a case study was previously provided to the panel members to facilitate the discussion, focusing on the key components of the study design and multiplicity.