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Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study.
AIMS: Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital-twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM. METHODS AND RESULTS: Computational models of human HCM cardiomyocytes, tissue and ventricles were used to simulate outcomes of phase 1A acute myocardial ischaemia. Cellular response predictions were validated with patch-clamp studies of human HCM cardiomyocytes (n=12 cells, N=5 patients). Ventricular simulations were informed by typical distributions of subendocardial/transmural ischaemia as analysed in perfusion scans (N=28 patients). S1-S2 pacing protocols were used to quantify arrhythmic risk for scenarios in which regions of septal obstructive hypertrophy were affected by (i) ischaemia, (ii) ischaemia and impaired repolarisation, and (iii) ischaemia, impaired repolarisation, and diffuse fibrosis.HCM cardiomyocytes exhibited enhanced action potential and abnormal effective refractory period shortening to ischaemic insults. Analysis of c.a. 75,000 re-entry induction cases revealed that the abnormal HCM cellular response enabled establishment of arrhythmia at milder ischaemia than otherwise possible in healthy myocardium, due to larger refractoriness gradients that promoted conduction block. Arrhythmias were more easily sustained in transmural than subendocardial ischaemia. Mechanisms of ischaemia-fibrosis interaction were strongly electrophysiology dependent. Fibrosis enabled asymmetric re-entry patterns and break-up into sustained ventricular tachycardia. CONCLUSIONS: HCM ventricles exhibited an increased risk to non-sustained and sustained re-entry, largely dominated by an impaired cellular response and deleterious interactions with the diffuse fibrotic substrate.
Recruitment, Retention, and Training of Citizen Scientists in Translational Medicine Research: A Citizen Science Initiative on Non-Alcoholic Fatty Liver Disease.
Citizen science is a participatory science approach in which members of the public (citizens) collaborate with scientists and professional researchers and become involved in research and innovation activities, resulting in the co-creation of scientific knowledge and innovation. Citizen science has been widely applied in research, particularly in the social sciences, environmental sciences, information and communication technologies, and public health. However, the application of this approach in clinical sciences, particularly in translational medicine research, is still nascent. This exploratory study involved members of the public (citizen scientists) in a translational medicine experiment on non-alcoholic fatty liver disease that incorporated a lifestyle and weight-loss intervention. The aim of this paper is to report successful methods and approaches for the recruitment, retention, and training of citizen scientists. For the citizen scientists' recruitment, online calls placed on the websites of our research project and biomedical research center and targeted emails were the most helpful. Of the 14 members of the public who expressed interest in our study, six were recruited as citizen scientists. Citizen scientists were mostly female (n = 5, 83%), white (n = 3, 50%), over 50 years of age (n = 4, 67%), educated to postgraduate level (n = 5, 83%), and either retired or not in employment (n = 5, 83%). The retention rate was 83% (n = 5), and the dropout rate was 17% (n = 1). We arranged instructor-led interactive online training sessions (an hour-long one-on-one session and two-hour group sessions). Research skills training covered ethics in research and qualitative and quantitative data analysis. Citizen scientists were given several incentives, such as reimbursement of travel and care costs, selection as citizen scientists of the month, publications of their blogs and perspective articles, and co-authorship and acknowledgement in papers and project deliverables. To conclude, members of the public (particularly middle-aged white women with postgraduate education) are interested in becoming citizen scientists in translational medicine research. Their retention rate is higher, and they can contribute to different research activities. However, they need training to develop their research skills and expertise. The training should be simple, comprehensive, and flexible to accommodate the schedules of individual citizen scientists. They deserve incentives as they work on a voluntary basis.
Interstitial pneumonitis following mitozantrone, chlorambucil and prednisolone (MCP) chemotherapy.
We describe two cases of interstitial lung disease in patients with non-Hodgkin's lymphoma who were treated with combination chemotherapy including mitozantrone. In both we had radiological and histological evidence of interstitial lung disease, with patterns of organizing pneumonia and hypersensitivity without a clear aetiological agent. Clinical resolution occurred on withdrawal of chemotherapy. One patient required a course of corticosteroid treatment. To date, both patients are well and in remission, and there has been no recurrence of their respiratory disease. We postulate that these observations are hitherto undescribed pulmonary abnormalities secondary to mitozantrone therapy.