Pathologic immune hyperactivation is emerging as a key feature of critical illness in COVID-19, but the mechanisms involved remain poorly understood. We carried out proteomic profiling of plasma from cross-sectional and longitudinal cohorts of hospitalized patients with COVID-19 and analyzed clinical data from our health system database of more than 3300 patients. Using a machine learning algorithm, we identified a prominent signature of neutrophil activation, including resistin, lipocalin-2, hepatocyte growth factor, interleukin-8, and granulocyte colony-stimulating factor, which were the strongest predictors of critical illness. Evidence of neutrophil activation was present on the first day of hospitalization in patients who would only later require transfer to the intensive care unit, thus preceding the onset of critical illness and predicting increased mortality. In the health system database, early elevations in developing and mature neutrophil counts also predicted higher mortality rates. Altogether, these data suggest a central role for neutrophil activation in the pathogenesis of severe COVID-19 and identify molecular markers that distinguish patients at risk of future clinical decompensation.

Despite over 30 million infected and 800,000 deaths, the pathophysiological factors that determine the wide spectrum of clinical outcomes in COVID-19 remain inadequately defined. Importantly, patients with underlying cardiovascular disease have been found to have worse clinical outcomes (1), and autopsy findings of endotheliopathy in COVID-19 have accumulated (2). Nonetheless, circulating markers of endothelial or vascular injury associated with disease severity and mortality have not been reliably established. To address this limitation and better understand COVID-19 pathogenesis, we report plasma profiling of factors related to the vascular system from patients admitted to our Hospital with confirmed COVID-19 diagnosis, which revealed significant increases in markers of angiogenesis and endotheliopathy in hospitalized patients.

Highlights d Loss of METTL3 inhibits proliferation and differentiation of hematopoietic stem cells d Depletion of m 6 A results in aberrant dsRNA formation of long m 6 A-modified transcripts d Loss of METTL3 induces deleterious innate immune responses in hematopoiesis d Mavs and Rnasel depletion partially rescue defects in Vav-Cre + -Mettl3 fl/

Pathologic immune hyperactivation is emerging as a key feature of critical illness in COVID-19, but the mechanisms involved remain poorly understood. We carried out proteomic profiling of plasma from cross-sectional and longitudinal cohorts of hospitalized patients with COVID-19 and analyzed clinical data from our health system database of over 3,300 patients. Using a machine learning algorithm, we identified a prominent signature of neutrophil activation, including resistin, lipocalin-2, HGF, IL-8, and G-CSF, as the strongest predictors of critical illness. Neutrophil activation was present on the first day of hospitalization in patients who would only later require transfer to the intensive care unit, thus preceding the onset of critical illness and predicting increased mortality. In the health system database, early elevations in developing and mature neutrophil counts also predicted higher mortality rates. Altogether, we define an essential role for neutrophil activation in the pathogenesis of severe COVID-19 and identify molecular neutrophil markers that distinguish patients at risk of future clinical decompensation.

No abstract

The recent years have witnessed an increased activity in biocompatibility research aimed at limiting biomaterial-induced blood coagulation. From 2008 to 2016, a total of $36,946,764.00 USD was awarded in grants to 213 research proposals and as large as 50.4% ($18,627,854.00) of that award monies were distributed to 101 proposals over the fiscal years of FY14 to FY16 alone. However, the complexity in blood responses to biomaterials, variability in blood function between individuals and animal species, and differences in medical device application and test setting all continue to pose difficulties in making a breakthrough in this field. This review focuses on the remaining challenges in the context of biomaterial surface interaction with blood, biomaterial properties and their influence on coagulation, old and new surface anticoagulation methods, main test systems (complement and platelet function) for evaluating those methods, limitations of modification techniques, and the current state of systemic anticoagulation usage as adjunctive therapy for controlling blood coagulation on biomaterials. Finally, we propose ingredients necessary for advancing the field towards achieving totally local surface anticoagulation on blood contacting devices including standardization of in vitro and in-vivo test methods. Some highlights of recent forwardlooking work and articles on local anticoagulation are also presented.

Comprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current immunodeficient murine hosts. Here we report a MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient “MISTRG” mice that provides efficient and faithful disease representation across all MDS subtypes. MISTRG MDS patient-derived xenografts (PDX) reproduce patients’ dysplastic morphology with multi-lineage representation, including erythro- and megakaryopoiesis. MISTRG MDS-PDX replicate the original sample’s genetic complexity and can be propagated via serial transplantation. MISTRG MDS-PDX demonstrate the cytotoxic and differentiation potential of targeted therapeutics providing superior readouts of drug mechanism of action and therapeutic efficacy. Physiologic humanization of the hematopoietic stem cell niche proves critical to MDS stem cell propagation and function in vivo. The MISTRG MDS-PDX model opens novel avenues of research and long-awaited opportunities in MDS research.

Despite over 9.3 million infected and 479,000 deaths, the pathophysiological factors that determine the wide spectrum of clinical outcomes in COVID-19 remain inadequately defined. Importantly, patients with underlying cardiovascular disease have been found to have worse clinical outcomes,1 and autopsy findings of endotheliopathy as well as angiogenesis in COVID-19 have accumulated.2,3 Nonetheless, circulating vascular markers associated with disease severity and mortality have not been reliably established. To address this limitation and better understand COVID-19 pathogenesis, we report plasma profiling of factors related to the vascular system from a series of patients admitted to Yale-New Haven Hospital with confirmed diagnosis of COVID-19 via PCR, which demonstrate significant increase in markers of angiogenesis and endotheliopathy in patients hospitalized with COVID-19.