Establishing the UHB doctor wellbeing group as a model for sustainable change in improving resident doctor wellbeing.

Significant wellbeing concerns have been reported nationally among resident doctors. A peer-led survey at University Hospitals Birmingham NHS Foundation Trust revealed high burnout risk and dissatisfaction. The Doctor Wellbeing Group (DWG) was established to address these multifaceted concerns by supporting resident doctors to run quality improvement projects to improve working conditions, with consultant supervision and regular reports to stakeholders.

Nitazene opioids and the heart: Identification of a cardiac ion channel target for illicit nitazene opioids.

The growing use of nitazene synthetic opioids heralds a new phase of the opioid crisis. However, limited information exists on the toxic effects of these drugs, aside from a propensity for respiratory depression. With restricted research availability of nitazenes, we used machine-learning-based tools to evaluate five nitazene compounds' interaction potential with the hERG potassium channel, a key drug antitarget in the heart.

Enhancing wellbeing in medical practice: Exploring interventions and effectiveness for improving the work lives of resident (junior) doctors: A systematic review and narrative synthesis.

Introduction: Globally, resident doctors face challenges like long work hours, critical decision-making stress, and exposure to death and distress, prompting concern for their wellbeing. This study addresses the need for interventions to improve their working conditions, vital for enhancing quality of life, patient care and retaining a skilled workforce.

Methods: Following PRISMA guidelines, a systematic literature review until 3 January 2024 explored interventions for resident Ddoctors pre- and post-COVID-19.

Modulation of Spontaneous Action Potential Rate by Inositol Trisphosphate in Myocytes from the Rabbit Atrioventricular Node.

The atrioventricular node (AVN) is a key component of the cardiac conduction system and takes over pacemaking of the ventricles if the sinoatrial node fails. IP (inositol 1,4,5 phosphate) can modulate excitability of myocytes from other regions of the heart, but it is not known whether IP receptor (IP-R) activation modulates AVN cell pacemaking. Consequently, this study investigated effects of IP on spontaneous action potentials (APs) from AVN cells isolated from rabbit hearts.

The key characteristics of cardiotoxicity for the pervasive pollutant phenanthrene.

The key characteristic (KCs) framework has been used previously to assess the carcinogenicity and cardiotoxicity of various chemical and pharmacological agents. Here, the 12 KCs of cardiotoxicity are used to evaluate the previously reported cardiotoxicity of phenanthrene (Phe), a tricyclic polycyclic aromatic hydrocarbon (PAH), and major component of fossil fuel-derived air pollution. Phe is a semi-volatile pollutant existing in both the gas phase and particle phase through adsorption onto or into particulate matter (PM).

Patient and health professional views on risk-stratified monitoring of immune-suppressing treatment in adults with inflammatory diseases.

Objective: To explore the acceptability of an individualised risk-stratified approach to monitoring for target-organ toxicity in adult patients with immune-mediated inflammatory diseases established on immune-suppressing treatment(s).

Methods: Adults (≥18 years) taking immune-suppressing treatment(s) for at-least six months, and healthcare professionals (HCPs) with experience of either prescribing and/or monitoring immune-suppressing drugs were invited to participate in a single, remote, one-to-one, semi-structured interview. Interviews were conducted by a trained qualitative researcher and explored their views and experiences of current monitoring and acceptability of a proposed risk-stratified monitoring plan.

Interactions between calcium-induced arrhythmia triggers and the electrophysiological-anatomical substrate underlying the induction of atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is sustained by spontaneous focal excitations and re-entry. Spontaneous electrical firing in the pulmonary vein (PV) sleeves is implicated in AF generation. The aim of this simulation study was to identify the mechanisms determining the localisation of AF triggers in the PVs and their contribution to the genesis of AF.

Motivation communication training programme for healthcare professionals to support adherence in patients with diabetic foot ulcers: Proof of concept study.

Patients with diabetic foot ulcers have poor adherence to treatment recommendations. However, the most effective way to support adherence in this population is unknown. This study aimed to assess the preliminary effectiveness of a motivation communication training programme for healthcare professionals working with these patients, using theory and evidence-based strategies.

In situ monolayer patch clamp of acutely stimulated human iPSC-derived cardiomyocytes promotes consistent electrophysiological responses to SK channel inhibition.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) represent an in vitro model of cardiac function. Isolated iPSC-CMs, however, exhibit electrophysiological heterogeneity which hinders their utility in the study of certain cardiac currents. In the healthy adult heart, the current mediated by small conductance, calcium-activated potassium (SK) channels (I) is atrial-selective.

New synthetic cannabinoids and the potential for cardiac arrhythmia risk.

Synthetic cannabinoid receptor agonists (SCRAs) have been associated with QT interval prolongation. Limited preclinical information on SCRA effects on cardiac electrogenesis results from the rapid emergence of new compounds and restricted research availability. We used two machine-learning-based tools to evaluate seven novel SCRAs' interaction potential with the hERG potassium channel, an important drug antitarget.

The Concise Guide to PHARMACOLOGY 2023/24: Transporters.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.

Evaluating pro-arrhythmogenic effects of the T634S-hERG mutation: insights from a simulation study.

A mutation to serine of a conserved threonine (T634S) in the hERG K channel S6 pore region has been identified as a variant of uncertain significance, showing a loss-of-function effect. However, its potential consequences for ventricular excitation and arrhythmogenesis have not been reported. This study evaluated possible functional effects of the T634S-hERG mutation on ventricular excitation and arrhythmogenesis by using multi-scale computer models of the human ventricle.

Development of a Motivation Communication Training to Aid Diabetes-Specialist Podiatrists With Adherence Discussions.

Diabetic foot ulcers (DFUs) impact a substantial proportion of patients with diabetes, with high recurrence rates, severe complications, and significant financial burden to health care systems. Adherence to treatment advice (e.g.

Global Air Pollutant Phenanthrene and Arrhythmic Outcomes in a Mouse Model.

Background: The three-ringed polycyclic aromatic hydrocarbon (PAH) phenanthrene (Phe) has been implicated in the cardiotoxicity of petroleum-based pollution in aquatic systems, where it disrupts the contractile and electrical function of the fish heart. Phe is also found adsorbed to particulate matter and in the gas phase of air pollution, but to date, no studies have investigated the impact of Phe on mammalian cardiac function.

Objectives: Our objectives were to determine the arrhythmogenic potential of acute Phe exposure on mammalian cardiac function and define the underlying mechanisms to provide insight into the toxicity risk to humans.

Inhibition of the hERG Potassium Channel by a Methanesulphonate-Free E-4031 Analogue.

()-encoded potassium channels underlie the cardiac rapid delayed rectifier (I) potassium current, which is a major target for antiarrhythmic agents and diverse non-cardiac drugs linked to the drug-induced form of long QT syndrome. E-4031 is a high potency hERG channel inhibitor from the methanesulphonanilide drug family. This study utilized a methanesulphonate-lacking E-4031 analogue, "E-4031-17", to evaluate the role of the methanesulphonamide group in E-4031 inhibition of hERG.

Left ventricular noncompaction cardiomyopathy and short QT syndrome due to primary carnitine deficiency.

We report the case of a 13-year-old female patient presenting with presyncope and palpitations. Her electrocardiogram revealed an abbreviation of the rate-corrected QT interval with imaging showing significant left ventricular dysfunction. Carnitine levels were measured as part of her diagnostic workup, discovering a rare, reversible cause of short QT syndrome (SQTS) and associated cardiomyopathy-primary carnitine deficiency (PCD) caused by a homozygous mutation in the SLC22A5 gene, leading to an in-frame deletion mutation (NP_003051.

Promoting Activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED): randomised controlled trial.

Objective: To determine the effectiveness of an exercise and functional activity therapy intervention in adults with early dementia or mild cognitive impairment compared with usual care.

Design: Randomised controlled trial.

Setting: Participants' homes and communities at five sites in the United Kingdom.

The facilitators and barriers to improving functional activity and wellbeing in people with dementia: a qualitative study from the process evaluation of Promoting Activity, Independence and Stability in Early Dementia (PrAISED).

Background: The PRomoting Activity, Independence and Stability in Early Dementia (PrAISED) study delivered an exercise and functional activity programme to participants living with dementia. A Randomised Controlled Trial showed no measurable benefits in activities of daily living, physical activity or quality of life.

Objective: To explore participants' responses to PrAISED and explain why an intervention that might be expected to have produced measurable health gains did not do so.

hERG agonists pose challenges to web-based machine learning methods for prediction of drug-hERG channel interaction.

Pharmacological blockade of the I channel (hERG) by diverse drugs in clinical use is associated with the Long QT Syndrome that can lead to life threatening arrhythmia. Various computational tools including machine learning models (MLM) for the prediction of hERG inhibition have been developed to facilitate the throughput screening of drugs in development and optimise thus the prediction of hERG liabilities. The use of MLM relies on large libraries of training compounds for the quantitative structure-activity relationship (QSAR) modelling of hERG inhibition.

Adherence to limiting weight-bearing activity in patients with diabetic foot ulcers: A qualitative study.

Patients with diabetic foot ulcers are advised to limit weight-bearing activity for ulcers to heal. Patients often disregard this advice although the reasons are not yet fully understood. This study explored (1) patients' experiences of receiving the advice and (2) factors influencing adherence to the advice.

A diverse diapsid tooth assemblage from the Early Triassic (Driefontein locality, South Africa) records the recovery of diapsids following the end-Permian mass extinction.

Mass extinctions change the trajectory of evolution and restructure ecosystems. The largest mass extinction, the end-Permian, is a particularly interesting case due to the hypothesized delay in the recovery of global ecosystems, where total trophic level recovery is not thought to have occurred until 5-9 million years after the extinction event. Diapsids, especially archosauromorphs, play an important role in this recovery, filling niches left vacant by therapsids and anapsids.

Palmitoylation regulates the magnitude of HCN4-mediated currents in mammalian cells.

The sinoatrial node (SAN) and subsidiary pacemakers in the cardiac conduction system generate spontaneous electrical activity which is indispensable for electrical and therefore contractile function of the heart. The hyperpolarisation-activated cyclic nucleotide-gated channel HCN4 is responsible for genesis of the pacemaker "funny" current during diastolic depolarisation. S-palmitoylation, the reversible conjugation of the fatty acid palmitate to protein cysteine sulfhydryls, regulates the activity of key cardiac Na and Ca handling proteins, influencing their membrane microdomain localisation and function.

Human atrial fibrillation and genetic defects in transient outward currents: mechanistic insights from multi-scale computational models.

Previous studies have linked dysfunctional arising from mutations to -encoded Kv4.3 and -encoded Kv4.2 to atrial fibrillation.