COVID-19 and changes in activity and treatment of ST elevation MI from a UK cardiac centre.

Background: The international healthcare response to COVID-19 has been driven by epidemiological data related to case numbers and case fatality rate. Second order effects have been less well studied. This study aimed to characterise the changes in emergency activity of a high-volume cardiac catheterisation centre and to cautiously model any excess indirect morbidity and mortality. Method: Retrospective cohort study of patients admitted with acute coronary syndrome fulfilling criteria for the heart attack centre (HAC) pathway at St. Bartholomew's hospital, UK. Electronic data were collected for the study period March 16th - May 16th 2020 inclusive and stored on a dedicated research server. Standard governance procedures were observed in line with the British Cardiovascular Intervention Society audit. Results: There was a 28% fall in the number of primary percutaneous coronary interventions (PCIs) for ST elevation myocardial infarction (STEMI) during the study period (111 vs. 154) and 36% fewer activations of the HAC pathway (312 vs. 485), compared to the same time period averaged across three preceding years. In the context of 'missing STEMIs', the excess harm attributable to COVID-19 could result in an absolute increase of 1.3% in mortality, 1.9% in nonfatal MI and 4.5% in recurrent ischemia. Conclusions: The emergency activity of a high-volume PCI centre was significantly reduced for STEMI during the peak of the first wave of COVID-19. Our data can be used as an exemplar to help future modelling within cardiovascular workstreams to refine aggregate estimates of the impact of COVID-19 and inform targeted policy action

DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation

Hematopoietic stem cells give rise to all blood cells in a differentiation process that involves widespread epigenome remodeling. Here we present genome-wide reference maps of the associated DNA methylation dynamics. We used a meta-epigenomic approach that combines DNA methylation profiles across many small pools of cells and performed single-cell methylome sequencing to assess cell-to-cell heterogeneity. The resulting dataset identified characteristic differences between HSCs derived from fetal liver, cord blood, bone marrow, and peripheral blood. We also observed lineage-specific DNA methylation between myeloid and lymphoid progenitors, characterized immature multi-lymphoid progenitors, and detected progressive DNA methylation differences in maturing megakaryocytes. We linked these patterns to gene expression, histone modifications, and chromatin accessibility, and we used machine learning to derive a model of human hematopoietic differentiation directly from DNA methylation data. Our results contribute to a better understanding of human hematopoietic stem cell differentiation and provide a framework for studying blood-linked diseases.This work was funded by the BLUEPRINT project (European Union’s Seventh Framework Programme grant 282510), the NIHR Cambridge Biomedical Research Centre, and the Austrian Academy of Sciences. F.A.C. is supported by a Medical Research Council Clinical Training Fellowship (grant MR/K024043/1). F.H. is supported by a postdoctoral fellowship of the German Research Council (DFG; grant HA 7723/1-1). J.K. is supported by a DOC Fellowship of the Austrian Academy of Sciences. W.H.O. is supported by the NIHR, BHF (grants PG-0310-1002 and RG/09/12/28096), and NHS Blood and Transplant. E.L. is supported by a Wellcome Trust Sir Henry Dale Fellowship (grant 107630/Z/15/Z) and core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. M. Frontini is supported by the BHF Cambridge Centre of Excellence (grant RE/13/6/30180). C.B. is supported by a New Frontiers Group award of the Austrian Academy of Sciences and by a European Research Council (ERC) Starting Grant (European Union’s Horizon 2020 research and innovation program; grant 679146)

A randomized double-blind control study of early intra-coronary autologous bone marrow cell infusion in acute myocardial infarction: the REGENERATE-AMI clinical trial

Clinical trials suggest that intracoronary delivery of autologous bone marrow-derived cells (BMCs) 1–7 days post-acute myocardial infarction (AMI) may improve left ventricular (LV) function. Earlier time points have not been evaluated. We sought to determine the effect of intracoronary autologous BMC on LV function when delivered within 24 h of successful reperfusion therapy. Methods and results A multi-centre phase II randomized, double-blind, and placebo-controlled trial. One hundred patients with anterior AMI and significant regional wall motion abnormality were randomized to receive either intracoronary infusion of BMC or placebo (1:1) within 24 h of successful primary percutaneous intervention (PPCI). The primary endpoint was the change in left ventricular ejection fraction (LVEF) between baseline and 1 year as determined by advanced cardiac imaging. At 1 year, although LVEF increased compared with baseline in both groups, the between-group difference favouring BMC was small (2.2%; 95% confidence interval, CI: −0.5 to 5.0; P = 0.10). However, there was a significantly greater myocardial salvage index in the BMC-treated group compared with placebo (0.1%; 95% CI: 0.0–0.20; P = 0.048). Major adverse events were rare in both treatment groups. Conclusion The early infusion of intracoronary BMC following PPCI for patients with AMI and regional wall motion abnormality leads to a small non-significant improvement in LVEF when compared with placebo; however, it may play an important role in infarct remodelling and myocardial salvage.UK Stem Cells Foundation, the Heart Cells Foundation, and Barts and the London Charity. Funding to pay the Open Access publication charges for this article was provided by the Barts Cardiovascular Biomedical Research Unit (CVBRU)

Transcriptional characterization of human megakaryocyte polyploidization and lineage commitment

BACKGROUND: Megakaryocytes (MKs) originate from cells immuno-phenotypically indistinguishable from hematopoietic stem cells (HSCs), bypassing intermediate progenitors. They mature within the adult bone marrow and release platelets into the circulation. Until now, there have been no transcriptional studies of primary human bone marrow MKs. OBJECTIVES: To characterize MKs and HSCs from human bone marrow using single-cell RNA sequencing, to investigate MK lineage commitment, maturation steps, and thrombopoiesis. RESULTS: We show that MKs at different levels of polyploidization exhibit distinct transcriptional states. Although high levels of platelet-specific gene expression occur in the lower ploidy classes, as polyploidization increases, gene expression is redirected toward translation and posttranslational processing transcriptional programs, in preparation for thrombopoiesis. Our findings are in keeping with studies of MK ultrastructure and supersede evidence generated using in vitro cultured MKs. Additionally, by analyzing transcriptional signatures of a single HSC, we identify two MK-biased HSC subpopulations exhibiting unique differentiation kinetics. We show that human bone marrow MKs originate from these HSC subpopulations, supporting the notion that they display priming for MK differentiation. Finally, to investigate transcriptional changes in MKs associated with stress thrombopoiesis, we analyzed bone marrow MKs from individuals with recent myocardial infarction and found a specific gene expression signature. Our data support the modulation of MK differentiation in this thrombotic state. CONCLUSIONS: Here, we use single-cell sequencing for the first time to characterize the human bone marrow MK transcriptome at different levels of polyploidization and investigate their differentiation from the HSC

Randomised trial of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with non-ischaemic dilated cardiomyopathy - the regenerate-dcm randomized phase II

The REGENERATE-DCM trial is the first phase II randomized, placebo-controlled trial aiming to assess if granulocyte colony-stimulating factor (G-CSF) administration with or without adjunctive intracoronary (IC) delivery of autologous bone marrow-derived cells (BMCs) improves global left ventricular (LV) function in patients with dilated cardiomyopathy (DCM) and significant cardiac dysfunction. Methods and results Sixty patients with DCM and left ventricular ejection fraction (LVEF) at referral of ≤45%, New York Heart Association (NYHA) classification ≥2 and no secondary cause for the cardiomyopathy were randomized equally into four groups: peripheral placebo (saline), peripheral G-CSF, peripheral G-CSF and IC serum, and peripheral G-CSF and IC BMC. All patients, except the peripheral placebo group, received 5 days of G-CSF. In the IC groups, this was followed by bone marrow harvest and IC infusion of cells or serum on Day 6. The primary endpoint was LVEF change from baseline to 3 months, determined by advanced cardiac imaging. At 3 months, peripheral G-CSF combined with IC BMC therapy was associated with a 5.37% point increase in LVEF (38.30%+12.97 from 32.93%+16.46 P ¼ 0.0138), which was maintained to 1 year. This was associated with a decrease in NYHA classification, reduced NT-pro BNP, and improved exercise capacity and quality of life. No significant change in LVEF was seen in the remaining treatment groups. Conclusion This is the first randomized, placebo-controlled trial with a novel combination of G-CSF and IC cell therapy that demonstrates an improvement in cardiac function, symptoms, and biochemical parameters in patients with DCM.The trial was supported by unrestricted grants from the Heart Cells Foundation and Barts and the London Charity. Chugai Pharmaceutical donated supplies of G-CSF and pharmaceutical costs. Funding to pay the Open Access publication charges for this article was provided by the Barts Cardiovascular Biomedical Research Unit (CVBRU)

Collective Quadrupole Behavior in \u3csup\u3e106\u3c/sup\u3ePd

Excited states in 106Pd were studied with the (n,n′γ) reaction, and comprehensive information for excitations with spin ≤6ℏ was obtained. The data include level lifetimes in the femtosecond regime, spins and parities, transition multipolarities, and multipole mixing ratios, which allow the determination of reduced transition probabilities. The E2 decay strength to the low-lying states is mapped up to ≈2.4 MeV in excitation energy. The structures associated with quadrupole collectivity are elucidated and organized into bands