Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2.

Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1-3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4-11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication-transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.

Microstructural and Microvascular Phenotype of Sarcomere Mutation Carriers and Overt Hypertrophic Cardiomyopathy.

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups-overt, either genotype-positive (G+LVH+) or genotype-negative (G-LVH+), and subclinical (G+LVH-) HCM-exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G-LVH+), 77 patients with G+LVH-, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P<0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P<0.001). Patients with G-LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G- patients (100% [51/51] versus 82% [41/50]; P=0.001). Patients with G+LVH- compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P<0.001), and MVD (reduced stress myocardial blood flow [P=0.015] with perfusion defects in 28% versus 0 healthy volunteers [P=0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P=0.01; stress myocardial blood flow: odds ratio, 2.8, P=0.015; subclinical: fractional anisotropy odds ratio, 4.0, P=0.001; myocardial perfusion reserve odds ratio, 2.2, P=0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G- patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.

Mitral Annulus Disjunction: A Comprehensive Cardiovascular Magnetic Resonance Phenotype and Clinical Outcomes Study.

BACKGROUND: Clinical importance of mitral annulus disjunction (MAD) is not well established. PURPOSE: Characterize a population of MAD all-comers diagnosed by cardiac magnetic resonance imaging (MRI). STUDY TYPE: Retrospective. POPULATION: MAD confirmed in 222 patients, age of 49.2 ± 19.3 years, 126 (56.8%) males. FIELD STRENGTH/SEQUENCE: 1.5 T and 3 T/steady-state free precession and inversion recovery. ASSESSMENT: Clinical history, outcomes, imaging, and arrhythmia data. MAD defined as a separation ≥2 mm between left ventricular myocardium and mitral annulus. Presence and pattern of late gadolinium enhancement (LGE) were analyzed. LGE in the papillary muscles and adjacent to MAD were identified as MAD related. Ventricular arrhythmias (VA) were grouped into non-sustained ventricular arrhythmias (NSVA) or sustained. Cardiovascular death assessed. STATISTICAL TESTS: Differences between baseline characteristics were compared. Univariate regression was used to investigate possible associations between ventricular arrhythmia and cardiovascular death with characteristics associated with the severity of MAD. A multivariable logistic regression included significant variables from the univariate analysis and was performed for MAD-related and global LGE. RESULTS: MAD extent 5.0 ± 2.6 mm. MV annulus expanded during systole for MAD ≥6 mm. Systolic expansion associated with prolapse, billowing, and curling. LGE present in 82 patients (36.9%). Twenty-three patients (10.4%) showed MAD-related LGE by three different observers. No association of LGE with MAD extent (P = 0.545) noted. Follow-up 4.1 ± 2.4 years. No sustained VA observed. In univariable analysis, NSVA was more prevalent in patients with MAD ≥6 mm (33.3% vs. 9.9%), but this was attenuated on multivariate analysis (P = 0.054). The presence of NSVA was associated with global LGE but not MAD-related LGE in isolation (P = 0.750). Three patients died of cardiovascular causes (1.4%) and none had MAD-related LGE. None died of sudden cardiac arrest. CONCLUSION: In patients referred for cardiac MRI, mitral valve dysfunction was associated with MAD severity. Scar was not related to the extent of MAD, but associated with NSVA. The risk of sustained arrhythmias and cardiovascular death was low in this population. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Technical development and feasibility of a reusable vest to integrate cardiovascular magnetic resonance with electrocardiographic imaging.

BACKGROUND: Electrocardiographic imaging (ECGI) generates electrophysiological (EP) biomarkers while cardiovascular magnetic resonance (CMR) imaging provides data about myocardial structure, function and tissue substrate. Combining this information in one examination is desirable but requires an affordable, reusable, and high-throughput solution. We therefore developed the CMR-ECGI vest and carried out this technical development study to assess its feasibility and repeatability in vivo. METHODS: CMR was prospectively performed at 3T on participants after collecting surface potentials using the locally designed and fabricated 256-lead ECGI vest. Epicardial maps were reconstructed to generate local EP parameters such as activation time (AT), repolarization time (RT) and activation recovery intervals (ARI). 20 intra- and inter-observer and 8 scan re-scan repeatability tests. RESULTS: 77 participants were recruited: 27 young healthy volunteers (HV, 38.9 ± 8.5 years, 35% male) and 50 older persons (77.0 ± 0.1 years, 52% male). CMR-ECGI was achieved in all participants using the same reusable, washable vest without complications. Intra- and inter-observer variability was low (correlation coefficients [rs] across unipolar electrograms = 0.99 and 0.98 respectively) and scan re-scan repeatability was high (rs between 0.81 and 0.93). Compared to young HV, older persons had significantly longer RT (296.8 vs 289.3 ms, p = 0.002), ARI (249.8 vs 235.1 ms, p = 0.002) and local gradients of AT, RT and ARI (0.40 vs 0.34 ms/mm, p = 0,01; 0.92 vs 0.77 ms/mm, p = 0.03; and 1.12 vs 0.92 ms/mm, p = 0.01 respectively). CONCLUSION: Our high-throughput CMR-ECGI solution is feasible and shows good reproducibility in younger and older participants. This new technology is now scalable for high throughput research to provide novel insights into arrhythmogenesis and potentially pave the way for more personalised risk stratification. CLINICAL TRIAL REGISTRATION: Title: Multimorbidity Life-Course Approach to Myocardial Health-A Cardiac Sub-Study of the MRC National Survey of Health and Development (NSHD) (MyoFit46). National Clinical Trials (NCT) number: NCT05455125. URL: https://clinicaltrials.gov/ct2/show/NCT05455125?term=MyoFit&draw=2&rank=1.

HLA-DR polymorphism in SARS-CoV-2 infection and susceptibility to symptomatic COVID-19.

SARS-CoV-2 infection results in different outcomes ranging from asymptomatic infection to mild or severe disease and death. Reasons for this diversity of outcome include differences in challenge dose, age, gender, comorbidity and host genomic variation. Human leukocyte antigen (HLA) polymorphisms may influence immune response and disease outcome. We investigated the association of HLAII alleles with case definition symptomatic COVID-19, virus-specific antibody and T-cell immunity. A total of 1364 UK healthcare workers (HCWs) were recruited during the first UK SARS-CoV-2 wave and analysed longitudinally, encompassing regular PCR screening for infection, symptom reporting, imputation of HLAII genotype and analysis for antibody and T-cell responses to nucleoprotein (N) and spike (S). Of 272 (20%) HCW who seroconverted, the presence of HLA-DRB1*13:02 was associated with a 6·7-fold increased risk of case definition symptomatic COVID-19. In terms of immune responsiveness, HLA-DRB1*15:02 was associated with lower nucleocapsid T-cell responses. There was no association between DRB1 alleles and anti-spike antibody titres after two COVID vaccine doses. However, HLA DRB1*15:01 was associated with increased spike T-cell responses following both first and second dose vaccination. Trial registration: NCT04318314 and ISRCTN15677965.

Study protocol: MyoFit46-the cardiac sub-study of the MRC National Survey of Health and Development.

BACKGROUND: The life course accumulation of overt and subclinical myocardial dysfunction contributes to older age mortality, frailty, disability and loss of independence. The Medical Research Council National Survey of Health and Development (NSHD) is the world's longest running continued surveillance birth cohort providing a unique opportunity to understand life course determinants of myocardial dysfunction as part of MyoFit46-the cardiac sub-study of the NSHD. METHODS: We aim to recruit 550 NSHD participants of approximately 75 years+ to undertake high-density surface electrocardiographic imaging (ECGI) and stress perfusion cardiovascular magnetic resonance (CMR). Through comprehensive myocardial tissue characterization and 4-dimensional flow we hope to better understand the burden of clinical and subclinical cardiovascular disease. Supercomputers will be used to combine the multi-scale ECGI and CMR datasets per participant. Rarely available, prospectively collected whole-of-life data on exposures, traditional risk factors and multimorbidity will be studied to identify risk trajectories, critical change periods, mediators and cumulative impacts on the myocardium. DISCUSSION: By combining well curated, prospectively acquired longitudinal data of the NSHD with novel CMR-ECGI data and sharing these results and associated pipelines with the CMR community, MyoFit46 seeks to transform our understanding of how early, mid and later-life risk factor trajectories interact to determine the state of cardiovascular health in older age. TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov with trial ID: 19/LO/1774 Multimorbidity Life-Course Approach to Myocardial Health- A Cardiac Sub-Study of the MCRC National Survey of Health and Development (NSHD).

A Hybrid Architecture (CO-CONNECT) to Facilitate Rapid Discovery and Access to Data Across the United Kingdom in Response to the COVID-19 Pandemic: Development Study.

BACKGROUND: COVID-19 data have been generated across the United Kingdom as a by-product of clinical care and public health provision, as well as numerous bespoke and repurposed research endeavors. Analysis of these data has underpinned the United Kingdom's response to the pandemic, and informed public health policies and clinical guidelines. However, these data are held by different organizations, and this fragmented landscape has presented challenges for public health agencies and researchers as they struggle to find relevant data to access and interrogate the data they need to inform the pandemic response at pace. OBJECTIVE: We aimed to transform UK COVID-19 diagnostic data sets to be findable, accessible, interoperable, and reusable (FAIR). METHODS: A federated infrastructure model (COVID - Curated and Open Analysis and Research Platform [CO-CONNECT]) was rapidly built to enable the automated and reproducible mapping of health data partners' pseudonymized data to the Observational Medical Outcomes Partnership Common Data Model without the need for any data to leave the data controllers' secure environments, and to support federated cohort discovery queries and meta-analysis. RESULTS: A total of 56 data sets from 19 organizations are being connected to the federated network. The data include research cohorts and COVID-19 data collected through routine health care provision linked to longitudinal health care records and demographics. The infrastructure is live, supporting aggregate-level querying of data across the United Kingdom. CONCLUSIONS: CO-CONNECT was developed by a multidisciplinary team. It enables rapid COVID-19 data discovery and instantaneous meta-analysis across data sources, and it is researching streamlined data extraction for use in a Trusted Research Environment for research and public health analysis. CO-CONNECT has the potential to make UK health data more interconnected and better able to answer national-level research questions while maintaining patient confidentiality and local governance procedures.

Use of quantitative cardiovascular magnetic resonance myocardial perfusion mapping for characterization of ischemia in patients with left internal mammary coronary artery bypass grafts.

BACKGROUND: Quantitative myocardial perfusion mapping using cardiovascular magnetic resonance (CMR) is validated for myocardial blood flow (MBF) estimation in native vessel coronary artery disease (CAD). Following coronary artery bypass graft (CABG) surgery, perfusion defects are often detected in territories supplied by the left internal mammary artery (LIMA) graft, but their interpretation and subsequent clinical management is variable. METHODS: We assessed myocardial perfusion using quantitative CMR perfusion mapping in 38 patients with prior CABG surgery, all with angiographically-proven patent LIMA grafts to the left anterior descending coronary artery (LAD) and no prior infarction in the LAD territory. Factors potentially determining MBF in the LIMA-LAD myocardial territory, including the impact of delayed contrast arrival through the LIMA graft were evaluated. RESULTS: Perfusion defects were reported on blinded visual analysis in the LIMA-LAD territory in 27 (71%) cases, despite LIMA graft patency and no LAD infarction. Native LAD chronic total occlusion (CTO) was a strong independent predictor of stress MBF (B = - 0.41, p = 0.014) and myocardial perfusion reserve (MPR) (B = - 0.56, p = 0.005), and was associated with reduced stress MBF in the basal (1.47 vs 2.07 ml/g/min; p = 0.002) but not the apical myocardial segments (1.52 vs 1.87 ml/g/min; p = 0.057). Extending the maximum arterial time delay incorporated in the quantitative perfusion algorithm, resulted only in a small increase (3.4%) of estimated stress MBF. CONCLUSIONS: Perfusion defects are frequently detected in LIMA-LAD subtended territories post CABG despite LIMA patency. Although delayed contrast arrival through LIMA grafts causes a small underestimation of MBF, perfusion defects are likely to reflect true reductions in myocardial blood flow, largely due to proximal native LAD disease.

Hearts and Minds: Real-Life Cardiotoxicity With Clozapine in Psychosis.

BACKGROUND: Schizophrenia has a 1% prevalence in the population; 30% of these patients are treatment refractory. Clozapine is the only drug licensed to treat treatment refractory psychosis, but concerns about potential adverse effects result in only a proportion of eligible patients being treated. Although a well-documented neutropenia risk is mitigated by routine blood testing, cardiac toxicity is a commonly cited reason to discontinue clozapine treatment. However, there is little data on the real-life cardiac outcomes in those receiving clozapine treatment. METHODS: Retrospective review of electrocardiogram, echocardiogram, and clinical outcomes in 39 inpatients with treatment-refractory schizophrenia, treated with clozapine and other antipsychotic medication, referred for cardiology opinion. RESULTS: Commonest reasons for referral were development of left ventricular (LV) impairment or sinus tachycardia with normal LV function. Patients were reviewed by a range of cardiologists, receiving varied interventions.Median LV ejection fraction in the clozapine group was normal (52%). Serial echocardiograms demonstrated that clozapine-treated patients with LV impairment had no change in LV ejection fraction over a 4-month follow-up. Left ventricular ejection fraction did not differ between patients treated with clozapine and other antipsychotics. However, over an 11-year follow-up period, 48% of patients had discontinued clozapine treatment. CONCLUSIONS: This naturalistic study demonstrates that clozapine is not associated with significant cardiac mortality or morbidity. There is a real need for multidisciplinary working between specialist cardiologists and psychiatrists caring for these complex patients to facilitate optimal long-term physical and mental health outcomes.

Middle East Nurses Turnover Intention and its Correlates Amid the COVID-19 Pandemic: A Systematic Review.

Global nursing scarcity was more evident during COVID-19. This study investigated the rates and contributing factors of turnover intention in the middle east through meta-analysis. Medline EMCARE, Cochrane, CINAHL, EMBASE, Ovid, Psych Info, PubMed, Science Direct, Scopus, and Web of Science databases searched, Protocol PROSPERO Registration Number was CRD42022337686. The turnover intention rate was 42.3% [CI: 40%, 44.6%]. Working environment, stress, deployment to COVID, fear of infection, long working hours, shift duties, and lack of social support were the major contributing factors.