COVID-19 impact on medical education and the future post-pandemic era for medical students

The COVID-19 global emergency has brought about unexpected changes in the format and quality of undergraduate medical education in a short period of time. The impact of remote delivery on medical students learning, satisfaction, confidence, social relationships, communications and emotional wellbeing has been significant. The lack of direct patient and teacher contact is generating anxiety about their future competence. The ambivalence about urge to help without sufficient clinical skills and the fear of being either infected or becoming an asymptomatic carrier that puts patient safety at risk is of concern to them. Suggestions for enhancing pandemic or global emergency preparedness for the future are made. Strategies to manage the way in which remote learning is delivered need to be implemented as a matter of urgency should social distancing and quarantine regulations keep medical students away from hands-on clinical practice for long periods. Actions to maintain motivation and trust in the medical schools to meet their learning needs now and in the future are warranted

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Clinical, Genetic and Cellular Basis of Inherited Cardiovascular Disease

The inherited cardiovascular diseases are a complex group united by genetic underpinnings. This thesis synthesises new knowledge from clinical, genetic and cellular perspectives to improve the understanding and management of inherited cardiovascular disease. This is achieved through systematic review and meta-analysis, genome sequencing and induced pluripotent stem cell (iPSC) analysis with respect to the exemplar diseases: left ventricular non-compaction (LVNC), hypertrophic cardiomyopathy (HCM) and catecholaminergic polymorphic ventricular tachycardia (CPVT). These conditions comprise one emerging condition (LVNC) and one well-established disease (HCM). As such, it is anticipated the findings of this thesis will be applicable to a broader set of inherited cardiovascular diseases. In Chapter 2 a systematic review and meta-analysis finds that prevalence estimates were higher amongst LVNC cohorts diagnosed on cardiac magnetic resonance imaging (14.79%) compared with echocardiogram (1.28%). The results show that multiple diagnostic criteria are in use, there is a lack of a uniformly agreed disease definition and significant potential for overdiagnosis and overtreatment. Review of LVNC literature in Chapter 3 reveals associations with numerous comorbidities and ³70 genes. Comprehensive evaluation of 35 adults with LVNC in Chapter 4 reveals a genetic yield of 9%. Overall the genetic testing yield was low and most beneficial in LVNC associated with additional features or a significant family history. In Chapter 5, genetic assessment in people with HCM reveals causal variants in 40%. A total of 66% carried a non-unique variant. Eleven variants arose through independent mutation events and two were inherited from a common ancestor. In Chapters 6 and 7 a detailed literature review shows iPSC-cardiomyocyte phenotypes for the majority of inherited cardiovascular diseases. In Chapter 8 a repository of iPSCs is developed and utilised for this thesis and in collaborations to better understand inherited cardiovascular diseases. In Chapter 9, functional evidence is provided for the pathogenicity of a heterozygous CASQ2 variant in CPVT. A milder phenotype than that caused by an RYR2 variant is identified. The ultimate goal of the studies presented in this thesis is to improve the care of patients

Generation of an induced pluripotent stem cell line from a hypertrophic cardiomyopathy patient with a pathogenic myosin binding protein C (MYBPC3) p.Arg502Trp mutation

Hypertrophic cardiomyopathy is an inherited cardiomyopathy with a prevalence of up to 1 in 200, which can result in significant morbidity and mortality. An iPSC line was generated from peripheral blood mononuclear cells obtained from the whole blood of a 58-year-old male with hypertrophic cardiomyopathy who carries the heterozygous pathogenic myosin binding protein C mutation p.Arg502Trp. Induced pluripotent stem cells express pluripotency markers, demonstrate trilineage differentiation potential, and display a normal karyotype. This line is a useful resource for studying and modeling hypertrophic cardiomyopathy.Resource tableUnlabelled TableUnique stem cell line identifierMCCI0003i-HCMAlternative name(s) of stem cell lineIK1InstitutionCentenary InstituteContact information of distributorChristopher Semsarian; [email protected] of cell lineiPSCOriginHumanAdditional origin infoAge: 58Sex: maleEthnicity: North-west EuropeanCell sourcePeripheral blood mononuclear cellsClonalityClonalMethod of reprogrammingTransgene free (episomal vectors)Genetic modificationNAType of modificationNAAssociated diseaseHypertrophic CardiomyopathyGene/locusMYBPC3 c.1504C > T p.Arg502Trp, Chr11: 47364249 (on Assembly GRCh37)Method of modificationNAName of transgene or resistanceNAInducible/constitutive systemNADate archived/stock date2017Cell line repository/bankNAEthical approvalPatient informed consent obtained, and ethics review board-competent authority approval obtained through the Ethics Review Committee, Sydney Local Health District.Protocol No X13-0069 and HREC/13/RPAH/9

Generation of induced pluripotent stem cells (iPSCs) from a hypertrophic cardiomyopathy patient with the pathogenic variant p.Val698Ala in beta-myosin heavy chain (MYH7) gene

Induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) isolated from the whole blood of a 43-year-old male with hypertrophic cardiomyopathy (HCM) who carries the pathogenic variant p.Val698Ala in beta-myosin heavy chain (MYH7). Patient-derived PBMCs were reprogrammed using non-integrative episomal vectors containing reprogramming factors OCT4, SOX2, LIN28, KLF4 and L-MYC. iPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carry the pathogenic MYH7 variant p.Val698Ala, have a normal karyotype and no longer carry the episomal reprogramming vector. This line is useful for studying the link between variants in MYH7 and the pathogenesis of HCM

Peripheral blood derived induced pluripotent stem cells (iPSCs) from a female with familial hypertrophic cardiomyopathy

Induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) obtained from a 62-year-old female with familial hypertrophic cardiomyopathy (HCM). PBMCs were reprogrammed to a pluripotent state following transfection with non-integrative episomal vectors carrying reprogramming factors OCT4, SOX2, LIN28, KLF4 and L-MYC. iPSCs were shown to express pluripotency markers, possess trilineage differentiation potential, carry rare variants identified in DNA isolated directly from the patient's whole blood, have a normal karyotype and no longer carry episomal vectors for reprogramming. This line is a useful resource for identifying unknown genetic causes of HCM

Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is a genetically heterogeneous myocardial disease with >1000 causal variants identified. Nonunique variants account for disease in many families. We sought to characterize nonunique variants in Australian families and determine whether they arise from common ancestral mutations or recurrent mutation events. Genetic test results of 467 index patients from apparently unrelated families with hypertrophic cardiomyopathy were evaluated. Causal variants were found in 185 of 467 (40%) families. Nonunique variants accounted for 122 of 185 (66%) families. The most common single genetic cause of hypertrophic cardiomyopathy is the recurrent MYBPC3 (myosin-binding protein-C) variant c.1504C>T, p.Arg502Trp, which was found in 13 of 185 (7%) families with a causal variant identified. Thirteen variants in MYBPC3 and MYH7 (myosin heavy chain 7) were each identified >3 times and accounted for 78 of 185 (42%) hypertrophic cardiomyopathy families with a causal variant. Haplotype analysis of these 13 variants was performed on 126 individuals from 70 Australian families, and 11 variants arose through recurrent mutation events. Two variants, MYBPC3 c.1928-2A>G and MYH7 c.2681A>G, p.Glu894Gly, were found on 1 haplotype in 6 families each, supportive of a single mutation event inherited from a common ancestor. The majority of families with a causal variant identified have a nonunique variant. Discovery of the genetic origins of human disease forms a fundamental basis for improved understanding of disease pathogenesis and phenotype developmen