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A 55-year-old woman with a recent history of surgically and radioiodine treated thyroid cancer experienced a run of polymorphic ventricular tachycardia with hemodynamic perturbation during anaesthetic induction with propofol, fentanyl and rocuronium for elective surgical excision of right hip metastasis. Electrocardiography showed new T-wave inversion and QT prolongation that subsequently resolved. Cardiac enzymes were elevated but invasive coronary angiography showed unobstructed epicardial coronary arteries. Cardiovascular magnetic resonance showed not only normal biventricular size and systolic function but also a striking pattern of patchy myocardial oedema involving the basal-to-mid anterior, septal and inferior walls and some associated hypertrophy in the anteroseptum (representing focal myocardial swelling from the oedema) but no focal or diffuse myocardial fibrosis. All these abnormalities resolved on subsequent convalescent imaging. A diagnosis of multifactorial acquired long QT syndrome secondary to atypical variant stress-induced cardiomyopathy was made with the likely provoking factors in this case having been the female sex, understandable pre-operative anxiety, anaesthetic drugs, supraglottic airway placement and thyroid dysfunction. An implantable loop recorder during follow-up detected no further significant arrhythmias and she remains well and asymptomatic to date on a low dose of beta-blocker.

Background To assess the feasibility of biventricular SAPPHIRE T 1 mapping in vivo across field strengths using diastolic, systolic and dark-blood (DB) approaches. Methods 10 healthy volunteers underwent same-day non-contrast cardiovascular magnetic resonance at 1.5 Tesla (T) and 3 T. Left and right ventricular (LV, RV) T 1 mapping was performed in the basal, mid and apical short axis using 4-variants of SAPPHIRE: diastolic, systolic, 0th and 2nd order motion-sensitized DB and conventional modified Look-Locker inversion recovery (MOLLI). Results LV global myocardial T 1 times (1.5 T then 3 T results) were significantly longer by diastolic SAPPHIRE (1283 ± 11|1600 ± 17 ms) than any of the other SAPPHIRE variants: systolic (1239 ± 9|1595 ± 13 ms), 0th order DB (1241 ± 10|1596 ± 12) and 2nd order DB (1251 ± 11|1560 ± 20 ms, all p  < 0.05). In the mid septum MOLLI and diastolic SAPPHIRE exhibited significant T 1 signal contamination (longer T 1 ) at the blood-myocardial interface not seen with the other 3 SAPPHIRE variants (all p  < 0.025). Additionally, systolic, 0th order and 2nd order DB SAPPHIRE showed narrower dispersion of myocardial T 1 times across the mid septum when compared to diastolic SAPPHIRE (interquartile ranges respectively: 25 ms, 71 ms, 73 ms vs 143 ms, all p  < 0.05). RV T 1 mapping was achievable using systolic, 0th and 2nd order DB SAPPHIRE but not with MOLLI or diastolic SAPPHIRE. All 4 SAPPHIRE variants showed excellent re-read reproducibility (intraclass correlation coefficients 0.953 to 0.996). Conclusion These small-scale preliminary healthy volunteer data suggest that DB SAPPHIRE has the potential to reduce partial volume effects at the blood-myocardial interface, and that systolic SAPPHIRE could be a feasible solution for right ventricular T 1 mapping. Further work is needed to understand the robustness of these sequences and their potential clinical utility.

Background : Most biomedical research has focused on sampling COVID-19 patients presenting to hospital with advanced disease, with less focus on the asymptomatic or paucisymptomatic. We established a bioresource with serial sampling of health care workers (HCWs) designed to obtain samples before and during mainly mild disease, with follow-up sampling to evaluate the quality and duration of immune memory. Methods : We conducted a prospective study on HCWs from three hospital sites in London, initially at a single centre (recruited just prior to first peak community transmission in London), but then extended to multiple sites 3 weeks later (recruitment still ongoing, target n=1,000). Asymptomatic participants attending work complete a health questionnaire, and provide a nasal swab (for SARS-CoV-2 RNA by RT-PCR tests) and blood samples (mononuclear cells, serum, plasma, RNA and DNA are biobanked) at 16 weekly study visits, and at 6 and 12 months. Results : Preliminary baseline results for the first 731 HCWs (400 single-centre, 331 multicentre extension) are presented. Mean age was 38±11 years; 67% are female, 31% nurses, 20% doctors, and 19% work in intensive care units. COVID-19-associated risk factors were: 37% black, Asian or minority ethnicities; 18% smokers; 13% obesity; 11% asthma; 7% hypertension and 2% diabetes mellitus. At baseline, 41% reported symptoms in the preceding 2 weeks. Preliminary test results from the initial cohort (n=400) are available: PCR at baseline for SARS-CoV-2 was positive in 28 of 396 (7.1%, 95% CI 4.9-10.0%) and 15 of 385 (3.9%, 2.4-6.3%) had circulating IgG antibodies. Conclusions : This COVID-19 bioresource established just before the peak of infections in the UK will provide longitudinal assessments of incident infection and immune responses in HCWs through the natural time course of disease and convalescence. The samples and data from this bioresource are available to academic collaborators by application  https://covid-consortium.com/application-for-samples/ .

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 infections 1 – 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 . Seronegative healthcare workers with an innate signature of infection preferentially expand pre-existing T cells targeting the conserved replication transcription complex of SARS-CoV-2 in abortive infection.

BackgroundLamins A/C (encoded by the LMNA gene) can lead to dilated cardiomyopathy (DCM). LMNA DCM to be ranked clinically as one of the most dreaded forms of DCM because of its high propensity for sudden cardiac death and advanced heart failure. However, lamin heart disease (LHD) remains to be poorly understood. Thus, this study sought to undertake proteomic analysis of myocardial tissue to explore the postgenomic phenotype of end-stage lamin heart disease.MethodsThis prospective clinical trial (NCT03860454) enrolled consecutive patients with end-stage LHD (LMNA-group, n=7) and ischaemic DCM (ICM-group, n=7) who were undergoing heart transplantation. For comparison, samples from healthy unused control donor hearts (CTRL, n=6) collected from the University of Sydney Heart Bank were also included. Samples were obtained from left atrium (LA), left ventricle (LV), right atrium (RA), right ventricle (RV) and interventricular septum (IVS). Liquid chromatography combined with mass-spectrometry (MS) was used to quantify protein concentrations. We compared protein concentrations in cardiac samples between LMNA and ICM groups. Proteins were considered differentially abundant if two simultaneous criteria were met: (1) there was a 1.5-fold increase/decrease, and (2) the p-value passed the correction for multiple testing at a false discovery rate of 0.01 (i.e., q-value<0.05). Given the slight differences in MS methodologies, only qualitative comparisons were made with the CTRL group. Gene ontology (GO) enrichment analysis explored the related biological processes. Biological processes, cellular components and molecular function GO categories with >2 members were considered.ResultsParticipant characteristics are presented in Table 1. 4,247 proteins were identified in LMNA and ICM samples, of which 633 were differentially abundant in LA, 39 in LV, 181 in RA, 52 in RV, and 85 in IVS (Table 2). The top 25 differentially abundant proteins ranked by q-value are presented using volcano plots in Figure 1. Abundance of lamin A/C was reduced but lamin B (LMNB) increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV, with lamin B being absent in CTRL septal samples. Across all tissue samples, ECM proteins levels were differently abundant with pro-fibrotic fibrillar proteins being found at higher levels. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM while sarcomeric proteins such as titin and cardiac myosin heavy chain were generally reduced in RA/LA of LMNA. In RV/LV, glycolysis enzymes and sarcoendoplasmic reticulum calcium-binding proteins appeared to be decreased. Protein expression profiling and GO enrichment analysis revealed sarcopenia, extracellular matrix (ECM) remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. For LV, box plots comparing the intensities of the top 25 differentially abundant proteins between LMNA and ICM based on q-value, and the top 20 enriched biological processes are presented in Figure 2.ConclusionLHD is a biventricular and biatrial disease, characterized by sarcopenia, aberrant metabolism, and ECM remodeling. LMNB and transthyretin were unexpectedly abundant in the atria and ventricles respectively of patients with end-stage lamin heart disease potentially hinting to the possibility of compensatory responses.Abstract 125 Table 1Participant characteristics LMNA (n=7) ICM (n=7) p-value* Demographics Age, years42 (39.0, 43.4)52 (48.0, 60.5)0.306Sex, Males4 (57.1%)6 (85.7%)0.554Body Mass Index (kg/m2)28.5 (26.0, 29.3)26.1 (24.5, 28.7)0.699Ethnicity, White5 (71.4%)4 (57.1%)0.503 Co-morbidities High cholesterol, yes1 (14.3%)3 (42.9%)0.306Diabetes, yes1 (14.3%)2 (28.6%)1.00Atrial Fibrillation, yes5 (71.4%)1 (14.3%)0.105 Echocardiography LVIDd, mm60 (57.0, 62.0)58.0 (51.0, 62.0)0.807IVSd thickness, mm8.4 (7.9, 8.5)8.1 (8.0, 8.3)0.807Ejection Fraction (%)24.3 (14.5, 32.3)24.0 (20.3, 25.6)0.876LV mass (grams)173.2 (161.1, 205.2)209.0 (143.9, 209.9)1.00Medial E/e’15.8 (11.6, 24.5)15.0 (12.0, 18.1)0.659TAPSE, cm1.7 (1.2, 1.8)1.5 (1.4, 1.7)0.679*Reported p values were derived using Mann Whitney U-test, χ2 or Fisher’s exact test as appropriate.d, diastolic; IVS, interventricular septum; LV, left ventricle; LVID, LV internal diameter; TAPSE, tricuspid annular plane systolic excursion. Abstract 125 Table 2Contingency table showing number of differentially abundant proteins between heart regions (RA, RV, LA, LV, IVS) and between groups (LMNA, ICM) LA_ICM LA_LMNA LV_ICM LV_LMNA RA_ICM RA_LMNA RV_ICM RV_LMNA IVS_ICM IVS_LMNA LA_ICM N/A 633 156185307443194224318242 LA_LMNA N/A721723177838489481053952 LV_ICM N/A 39 530779396413277 LV_LMNA N/A484769592816633 RA_ICM N/A 181 639715838685 RA_LMNA N/A9099481077944 RV_ICM N/A 52 6747 RV_LMNA N/A11610 IVS_ICM N/A 85 IVS_LMNA N/AAbstract 125 Figure 1Volcano plots of differentially expressed proteins.Proteins in the (A) right atrium, (B) left atrium, (C) right ventricle, (D) left ventricle and (E) interventricular septum differentially abundant between LMNA and ICM samples. Only the top 25 differentially expressed proteins ranked by q-value are annotated in red in these volcano plots.ICM, ischaemic dilated cardiomyopathy; IVS, interventricular septum; LA, left atrium; LMNA, lamin; log, logarithm; LV, left ventricle; RA, right atrium; RV, right ventricle.Abstract 125 Figure 2Left ventricular myocardial proteins and their gene ontology.A. Box plots comparing intensities of the top 25 LV proteins between LMNA and ICM based on q-value. Genes coding for the proteins rather than the proteins themselves are named.B. The top 20 enriched biological processes across the 39 proteins differentially abundant in the LV myocardium of LMNA and ICM, are presented in the rightmost panel. The raw (red), Benjamini-Hochberg corrected (green) and Bonferroni corrected enrichment p-values are displayed in the leftmost panel. Fold enrichment is shown in the middle panel.Abbreviations as in Figure 2.Conflict of InterestNone

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).

Background : Most biomedical research has focused on sampling COVID-19 patients presenting to hospital with advanced disease, with less focus on the asymptomatic or paucisymptomatic. We established a bioresource with serial sampling of health care workers (HCWs) designed to obtain samples before and during mainly mild disease, with follow-up sampling to evaluate the quality and duration of immune memory. Methods : We conducted a prospective observational study on HCWs from three hospital sites in London, initially at a single centre (recruited just prior to first peak community transmission in London), but then extended to multiple sites 3 weeks later (recruitment still ongoing, target n=1,000). Asymptomatic participants attending work complete a health questionnaire, and provide a nasal swab (for SARS-CoV-2 RNA by RT-PCR tests) and blood samples (mononuclear cells, serum, plasma, RNA and DNA are biobanked) at 16 weekly study visits, and at 6 and 12 months. Results : Preliminary baseline results for the first 731 HCWs (400 single-centre, 331 multicentre extension) are presented. Mean age was 38±11 years; 67% are female, 31% nurses, 20% doctors, and 19% work in intensive care units. COVID-19-associated risk factors were: 37% black, Asian or minority ethnicities; 18% smokers; 13% obesity; 11% asthma; 7% hypertension and 2% diabetes mellitus. At baseline, 41% reported symptoms in the preceding 2 weeks. Preliminary test results from the initial cohort (n=400) are available: PCR at baseline for SARS-CoV-2 was positive in 28 of 396 (7.1%, 95% CI 4.9-10.0%) and 15 of 385 (3.9%, 2.4-6.3%) had circulating IgG antibodies. Conclusions : This COVID-19 bioresource established just before the peak of infections in the UK will provide longitudinal assessments of incident infection and immune responses in HCWs through the natural time course of disease and convalescence. The samples and data from this bioresource are available to academic collaborators by application  https://covid-consortium.com/application-for-samples/ .