Ventricular Arrhythmia Classification Using Similarity Maps and Hierarchical Multi-Stream Deep Learning.

Objective: Ventricular arrhythmias are the primary arrhythmias that cause sudden cardiac death. We address the problem of classification between ventricular tachycardia (VT), ventricular fibrillation (VF) and non-ventricular rhythms (NVR).

Methods: To address the challenging problem of the discrimination between VT and VF, we develop similarity maps - a novel set of features designed to capture regularity within an ECG trace.

Innovative approaches to cardiovascular safety pharmacology assessment.

This editorial prefaces the annual themed issue on safety pharmacology (SP) methods which has been published since 2004 in the Journal of Pharmacological and Toxicological Methods (JPTM). Here we highlight content derived from the 2023 Safety Pharmacology Society (SPS) meeting held in Brussels, Belgium. The meeting generated 138 abstracts, reproduced in the current volume of JPTM.

Safety pharmacology 2023 and implementation of the ICH E14/S7B Q&A guidance document.

This editorial prefaces the annual themed issue on safety pharmacology (SP) methods published since 2004 in the Journal of Pharmacological and Toxicological Methods (JPTM). We highlight here the content derived from the recent 2022 Safety Pharmacology Society (SPS) and Canadian Society of Pharmacology and Therapeutics (CSPT) joint meeting held in Montreal, Quebec, Canada. The meeting also generated 179 abstracts (reproduced in the current volume of JPTM).

The effect of combined β-lactoglobulin supplementation and resistance exercise training prior to limb immobilisation on muscle protein synthesis rates in healthy young adults: study protocol for a randomised controlled trial.

Background: The decline in skeletal muscle mass experienced following a short-term period (days to weeks) of muscle disuse is mediated by impaired rates of muscle protein synthesis (MPS). Previous RCTs of exercise or nutrition prehabilitation interventions designed to mitigate disuse-induced muscle atrophy have reported limited efficacy. Hence, the aim of this study is to investigate the impact of a complex prehabilitation intervention that combines β-lactoglobulin (a novel milk protein with a high leucine content) supplementation with resistance exercise training on disuse-induced changes in free-living integrated rates of MPS in healthy, young adults.

Similarity Maps for Ventricular Arrhythmia Classification.

Ventricular arrhythmias are the primary arrhythmias that cause sudden cardiac death. In current clinical and preclinical research, the discovery of new therapies and their translation is hampered by the lack of consistency in diagnostic criteria for distinguishing between ventricular tachycardia (VT) and ventricular fibrillation (VF). This study develops a new set of features, similarity maps, for discrimination between VT and VF using deep neural network architectures.

Safety pharmacology in 2022: Taking one small step for cardiovascular safety assay development but one giant leap for regulatory drug safety assessment.

The 2021 Annual Safety Pharmacology (SP) Society (SPS) meeting was held virtually October 4-8, 2021 due to the continuing COVID-19 global pandemic. This themed issue of J Pharmacol Toxicol Methods comprises articles arising from the meeting. As in previous years the manuscripts reflect various areas of innovation in SP including a perspective on aging and its impact on drug attrition during safety assessments, an integrated assessment of respiratory, cardiovascular and animal activity of in vivo nonclinical studies, development of a dynamic QT-rate correction method in primates, evaluation of the "comprehensive in vitro proarrhythmia assay" (CiPA) ion channel protocol to the automated patch clamp, and best practices regarding the conduct of hERG electrophysiology studies and an analysis of secondary pharmacology assays by the FDA.

Planning experiments: Updated guidance on experimental design and analysis and their reporting III.

Scientists who plan to publish in British Journal of Pharmacology (BJP) must read this article before undertaking a study. This editorial provides guidance for the design of experiments. We have published previously two guidance documents on experimental design and analysis (Curtis et al.

Safety pharmacology during the COVID pandemic.

This editorial summarizes the content of the current themed issue of J Pharmacol Toxicol Methods derived from the 2020 Annual Safety Pharmacology Society (SPS) meeting that was held virtually September 14-17, 2020 due to the ongoing COVID-19 global pandemic. A selection of articles arising from the virtual meeting is summarized. Like previous years they continue to reflect current areas of innovation in SP including new methodologies to predict human safety, best practices for IKr current measurement, and best practice considerations for the conduct of in vivo nonclinical QT studies.

The COVID-19 Pandemic and Coronary Angiography for ST-Elevation Myocardial Infarction, Use of Mechanical Support, and Mechanical Complications in Canada: A Canadian Association of Interventional Cardiology National Survey.

Background: As a result of the COVID-19 pandemic first wave, reductions in ST-elevation myocardial infarction (STEMI) invasive care, ranging from 23% to 76%, have been reported from various countries. Whether this change had any impact on coronary angiography (CA) volume or on mechanical support device use for STEMI and post-STEMI mechanical complications in Canada is unknown.

Methods: We administered a Canada-wide survey to all cardiac catheterization laboratory directors, seeking the volume of CA use for STEMI performed during the period from March 1 2020 to May 31, 2020 (pandemic period), and during 2 control periods (March 1, 2019 to May 31, 2019 and March 1, 2018 to May 31, 2018).

GEORGE®: A Pilot Study of a Smartphone Application for Huntington's Disease.

Background: Current Huntington's disease (HD) measures are limited to subjective, episodic assessments conducted in clinic. Smartphones can enable the collection of objective, real-world data but their use has not been extensively evaluated in HD.

Objective: Develop and evaluate a smartphone application to assess feasibility of use and key features of HD in clinic and at home.

Is there a role for the no observed adverse effect level in safety pharmacology?

In nonclinical toxicology the highest dose or exposure without test article-related adverse effects, known as the No Observed Adverse Effect Level (NOAEL), is a variable that may be determined. In safety pharmacology the vast majority of the endpoints measured are quantitative numeric functional endpoints such as changes in heart rate, blood pressure or respiratory frequency, endpoints that are usually not assessed using a defined framework of adversity. Therefore, we asked the question: is there a role for the NOAEL in safety pharmacology? To help answer this question, we conducted a survey via the Safety Pharmacology Society.

Twenty years of safety pharmacology model validation and the wider implications of this to drug discovery.

This editorial summarizes the content of the current themed issue of J Pharm Tox Methods derived from the 2019 Annual Safety Pharmacology Society (SPS) meeting held in Barcelona, Spain, and reflects on 20 years of innovation in the elaboration of methods for evaluating adversity, particularly during the nonclinical research phase. Given the success of safety pharmacology (SP) in the last 20 years, we propose that the rubric for SP method invention and validation be examined in more detail to explore whether it may have wider relevance to the drug discovery process. Articles arising from the Barcelona meeting are summarized here.

The application of electrophysiological methods to characterize AMPA receptors in dissociated adult rat and non-human primate cerebellar neurons for use in neuronal safety pharmacology assessments of the central nervous system.

Introduction: Pre-clinically, safety risk assessment of a drug is primarily tested in vivo using functional evaluation of adult animals while the mechanistic etiology of drug-induced CNS adverse effects is often uncharacterized. In vitro electrophysiology may provide a better understanding of drug effects without additional animal use. However, in vitro protocols are typically designed for using embryonic or juvenile animals.

Characterisation of mexiletine's translational therapeutic index for suppression of ischaemia-induced ventricular fibrillation in the rat isolated heart.

The 'translational therapeutic index' (TTI) is a drug's ratio of nonclinical threshold dose (or concentration) for significant benefit versus threshold for adversity. In early nonclinical research, discovery and safety studies are normally undertaken separately. Our aim was to evaluate a novel integrated approach for generating a TTI for drugs intended for prevention of ischaemia-induced ventricular fibrillation (VF).

Methodological and technological advances in safety pharmacology - New or simply nuanced?

This editorial previews and summarizes the content of the current themed issue of J Pharm Tox Methods derived from the recent 2018 Annual Safety Pharmacology Society (SPS) meeting held in Washington, DC. The papers highlight improvements in methods and study endpoints used in non-clinical safety pharmacology (SP) to enhance clinical translatability. Articles cover areas including the SP assessment of oligonucleotides and gene therapy, core battery clinical translation case studies, next generation non-opiate pain management strategy, aspects of cardio-oncology that extend the traditional objectives of an SP assessment, real-world advanced imaging techniques used in preclinical safety, in silico approaches including mathematical modeling, machine learning, and bioinformatics and how secondary SP studies impact clinical trial interpretation and design.

Methods for Improved Discrimination Between Ventricular Fibrillation and Tachycardia.

Differentiating between ventricular tachycardia and ventricular fibrillation in clinical and preclinical research is based on subjective definitions that have yet to be validated using objective criteria. This is partly due to shortcomings in the discrimination ability of current objective approaches, typified by the algorithms that perform cardiac rhythm classification using low-dimensional feature representations of electrocardiogram (ECG) signals. These identify ventricular tachyarrhythmias, but do not discriminate between ventricular tachycardia and ventricular fibrillation.

Experimental design and analysis and their reporting II: updated and simplified guidance for authors and peer reviewers.

This article updates the guidance published in 2015 for authors submitting papers to British Journal of Pharmacology (Curtis et al., 2015) and is intended to provide the rubric for peer review. Thus, it is directed towards authors, reviewers and editors.

Facilitation of ischaemia-induced ventricular fibrillation by catecholamines is mediated by β and β agonism in the rat heart in vitro.

Background And Purpose: Antiarrhythmic β-blockers are used in patients at risk of myocardial ischaemia, but the survival benefit and mechanisms are unclear. We hypothesized that β-blockers do not prevent ventricular fibrillation (VF) but instead inhibit the ability of catecholamines to facilitate ischaemia-induced VF, limiting the scope of their usefulness.

Experimental Approach: ECGs were analysed from ischaemic Langendorff-perfused rat hearts perfused with adrenoceptor antagonists and/or exogenous catecholamines (CATs: 313 nM noradrenaline + 75 nM adrenaline) in a blinded and randomized study.

The Safety Pharmacology Society salary survey.

Introduction: Safety pharmacology is a growing discipline with scientists broadly distributed across international geographical regions. This electronic salary survey is the first to be distributed amongst the entire Safety Pharmacology Society (SPS) membership. An electronic survey was sent to all members of the Society.

Safety pharmacology methods and models in an evolving regulatory environment.

This editorial prefaces the annual themed issue on safety pharmacology (SP) methods published in the Journal of Pharmacological and Toxicological Methods (JPTM). We highlight here the content derived from the recent 2016 Safety Pharmacology Society (SPS), Canadian Society of Pharmacology and Therapeutics (CSPT), and Japanese Safety Pharmacology Society (JSPS) joint meeting held in Vancouver, B.C.