Infection with SARS-CoV-2 is causing a deadly and pandemic disease called coronavirus disease–19 (COVID-19). While SARS-CoV-2–triggered hyperinflammatory tissue-damaging and immunothrombotic responses are thought to be major causes of respiratory failure and death, how they relate to lung immunopathological changes remains unclear. Neutrophil extracellular traps (NETs) can contribute to inflammation-associated lung damage, thrombosis, and fibrosis. However, whether NETs infiltrate particular compartments in severe COVID-19 lungs remains to be clarified. Here we analyzed postmortem lung specimens from four patients who succumbed to COVID-19 and four patients who died from a COVID-19–unrelated cause. We report the presence of NETs in the lungs of each COVID-19 patient. NETs were found in the airway compartment and neutrophil-rich inflammatory areas of the interstitium, while NET-prone primed neutrophils were present in arteriolar microthrombi. Our results support the hypothesis that NETs may represent drivers of severe pulmonary complications of COVID-19 and suggest that NET-targeting approaches could be considered for the treatment of uncontrolled tissue-damaging and thrombotic responses in COVID-19.

Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are characterised by aberrant immunological responses leading to chronic inflammation without tissue regeneration. These two diseases are considered distinct entities, and there is some evidence that neutrophil behaviour, above all other aspects of immunity, clearly separate them. Neutrophils are the first immune cells recruited to the site of inflammation, and their action is crucial to limit invasion by microorganisms. Furthermore, they play an essential role in proper resolution of inflammation. When these processes are not tightly regulated, they can trigger positive feedback amplification loops that promote neutrophil activation, leading to significant tissue damage and evolution toward chronic disease. Defective chemotaxis, as observed in Crohn’s disease, can also contribute to the disease through impaired microbe elimination. In addition, through NET production, neutrophils may be involved in thrombo-embolic events frequently observed in IBD patients. While the role of neutrophils has been studied in different animal models of IBD for many years, their contribution to the pathogenesis of IBD remains poorly understood, and no molecules targeting neutrophils are used and validated for the treatment of these pathologies. Therefore, it is crucial to improve our understanding of their mode of action in these particular conditions in order to provide new therapeutic avenues for IBD.

To obtain the normal ranges for 2D echocardiographic (2DE) indices of myocardial work (MW) from a large group of healthy volunteers over a wide range of ages and gender. A total of 226 (85 men, mean age: 45 ± 13 years) healthy subjects were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. Global work index (GWI), global constructive work (GCW), global work waste (GWW), and global work efficiency (GWE) were estimated from left ventricle (LV) pressure-strain loops. Peak LV systolic pressure was non-invasively derived from brachial artery cuff pressure. The lowest values of MW indices in men and women were 1270 mmHg% and 1310 mmHg% for GWI, 1650 mmHg% and 1544 mmHg% for GCW, and 90% and 91% for GWE, respectively. The highest value for GWW was 238 mmHg% in men and 239 mmHg% in women. Men had significant lower values of GWE and higher values of GWW. GWI and GCW significantly increased with age in women. The NORRE study provides useful 2DE reference ranges for novel indices of non-invasive MW.

In the western world, calcific aortic stenosis (AS), the most common valvular heart disease, represents a major public health burden.¹ Currently, there is no pharmacological treatment that prevents or slows the progression of AS.² Surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) are the only therapies to significantly improve both survival and symptoms^3,4 and are recommended in symptomatic patients with severe AS.^5,6 Quiz Ref ID The management of patients with asymptomatic severe AS, particularly the choice between early intervention vs watchful waiting, continues to be a matter of debate.^7,8 Current guidelines advocate delaying AVR until symptoms or left ventricular (LV) systolic dysfunction develop.^5,6 However, observational studies in 2010⁹ and 2015¹⁰ have suggested that early elective AVR might improve outcomes in patients with severe asymptomatic AS. This approach has been reinforced by continued advances in surgical techniques and aortic valve prostheses, the advent of TAVR, and the low perioperative mortality and morbidity rates achieved in valve centers of reference.^11,12 However, preemptive surgery before onset of symptoms or LV systolic dysfunction is considered in only a selected group of patients after careful risk stratification. This is at least in part because the evidence for intervention in asymptomatic severe AS is derived from small, heterogeneous, retrospective, single-center studies, which have generally included the need for AVR (not always motivated by the development of symptoms or LV dysfunction) in the composite study end point.^13-20 Moreover, decision making for AVR remains particularly difficult in older patients in whom it is sometimes unclear if the benefits of intervention outweigh the risk.^5,6

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

TEL is a novel member of the ETS family of transcriptional regulators which is frequently involved in human leukemias as the result of specific chromosomal translocations. We show here by co‐immunoprecipitation and GST chromatography analyses that TEL and TEL‐derived fusion proteins form homotypic oligomers in vitro and in vivo . Deletion mutagenesis identifies the TEL oligomerization domain as a 65 amino acid region which is conserved in a subset of the ETS proteins including ETS‐1, ETS‐2, FLI‐1, ERG‐2 and GABPα in vertebrates and PNTP2, YAN and ELG in Drosophila . TEL‐induced oligomerization is shown to be essential for the constitutive activation of the protein kinase activity and mitogenic properties of TEL–platelet derived growth factor receptor β (PDGFRβ), a fusion oncoprotein characteristic of the leukemic cells of chronic myelomonocytic leukemia harboring a t(5;12) chromosomal translocation. Swapping experiments in which the TEL oligomerization domain was exchanged by the homologous domains of representative vertebrate ETS proteins including ETS‐1, ERG‐2 and GABPα show that oligomerization is a specific property of the TEL amino‐terminal conserved domain. These results indicate that the amino‐terminal domain conserved in a subset of the ETS proteins has evolved to generate a specialized protein–protein interaction interface which is likely to be an important determinant of their specificity as transcriptional regulators.