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    Acute Lung injury MESHD evolution in Covid-19

    Authors: Claudio Doglioni; Claudia Ravaglia; Giulio Rossi; Alessandra Dubini; Federica Pedica; Sara Piciucchi; Antonio Vizzuso; Lorenza Pecciarini; Franco Stella; Stefano Maitan; Vanni Agnoletti; Emiliano Gamberini; Emanuele Russo; Silvia Puglisi; Antonella Arcadu; Luca Donati; Simona Di Cesare; Carmela Grosso; Giovanni Poletti; Vittorio Sambri; Elisabetta Fabbri; Giovanni Pizzolo; Stefano Ugel; Vincenzo Bronte; Athol U Wells; Marco Chilosi; Venerino Poletti; Tobias Boettler; Bertram Bengsch; Robert Thimme; Maike Hofmann; Christoph Neumann-Haefelin

    doi:10.1101/2020.08.09.20170910 Date: 2020-08-13 Source: medRxiv

    BACKGROUND Pathogenesis of Coronavirus disease MESHD 2019 (Covid-19) is poorly understood. Most histologic studies come from post-mortem analysis, with existing data indicating that histologic features of acute respiratory distress syndrome MESHD respiratory distress HP syndrome are typically present in fatal cases. However, this observation may be misleading, due to confounding factors in pre-terminal disease, including injury resulting from prolonged mechanical ventilation. Ante-mortem lung biopsy may provide major pathogenetic insights, potentially providing a basis for novel treatment approaches. AIM This comparative, multicenter, prospective, observational study was planned to identify ante-mortem histological profile and immunohistochemical features of lung tissue in patients with Covid-19 in early and late phases of the disease, including markers of inflammatory cells and major pathways involved in the cytokine storm triggering. METHODS Enrolled patients underwent lung biopsy, according to the study protocol approved by local Ethical Committee, either within 15 days of the first symptoms appearing (early phase) or after > 15 days (more advanced disease). Key exclusion criteria were excessive or uncorrectable bleeding MESHD risk and cardiovascular disease MESHD with heart failure MESHD. Lung samples were obtained by conventional trans-bronchialbiopsy, trans-bronchial lung cryobiopsy or surgical lung biopsy. RESULTS 23 patients were enrolled: 12 patients underwent lung biopsy within 15 days and 11 patients more than 15 days after the onset of symptoms TRANS. Early biopsies were characterized by spots of patchy acute lung injury MESHD ( ALI MESHD) with alveolar type II MESHD cells hyperplasia MESHD and significant vascular abnormalities MESHD (disordered angiogenesis with alveolar capillary hyperplasia, luminal enlargement MESHD and thickened walls of pulmonary venules, perivascularCD4-T-cell infiltration), with no hyaline membranes. In the later stages, the alveolar architecture MESHD appeared disrupted, with areas of organizing ALI MESHD, venular congestion and capillary thromboembolic microangiopathy MESHD. Striking phenotypic features were demonstrated in hyper plastic pneumocytes MESHD and endothelial cells, including the expression of phospho-STAT3 and molecules involved in immunoinhibitory signals (PD-L1 and IDO1). Alveolar MESHD macrophages exhibited macrophage-related markers (CD68, CD11c, CD14) together with unusual markers, such as DC-Lamp/CD208, CD206, CD123/IL3AR. CONCLUSION A morphologically distinct Covid pattern was identified in the earlier stages of the disease, with prominent epithelial and endothelial cell abnormalities, that may be potentially reversible, differing strikingly from findings in classical diffuse alveolar damage MESHD. These observations may have major therapeutic implications, justifying studies of early interventions aimed at mitigating inflammatory organ injury.

    The global impact of the first Coronavirus Disease MESHD 2019 (COVID-19) pandemic wave on vascular services

    Authors: - Vascular and Endovascular Research Network; Ruth A Benson; Sandip Nandhra

    doi:10.1101/2020.07.16.20153593 Date: 2020-07-17 Source: medRxiv

    Background: The Coronavirus Disease MESHD 2019 (COVID-19) pandemic is having an unprecedented impact on healthcare delivery. This international qualitative study captured the global impact on vascular patient care during the first pandemic wave. Methods: An online structured survey was used to collect regular unit-level data regarding the modification to a wide range of vascular services and treatment pathways on a global scale. Results: The survey commenced on 23rd March 2020 worldwide. Over six weeks, 249 vascular units took part in 53 countries (465 individual responses). Overall, 65% of units stopped carotid surgery for anyone except patients with crescendo symptoms or offered surgery on a case-by-case basis, 25% only intervened for symptomatic aortic aneurysms HP aortic aneurysms MESHD cancelling all elective repairs. For patients with symptomatic peripheral arterial disease MESHD 60% of units moved to an endovascular-first strategy. For patients who had previously undergone endovascular aortic aneurysm MESHD aortic aneurysm HP repair, 31.8% of units stopped all postoperative surveillance. Of those units regularly engaging in multidisciplinary team meetings, 59.5% of units stopped regular meetings and 39.1% had not replaced them. Further, 20% of units did not have formal personal protective equipment (PPE) guidelines in place and 25% reported insufficient PPE availability. Conclusions: The COVID-19 pandemic has had a major impact on vascular services worldwide. There will be a significant vascular disease MESHD burden awaiting screening and intervention after the pandemic.

    Systemic analysis of putative SARS-CoV-2 entry and processing genes in cardiovascular tissues identifies a positive correlation of BSG with age TRANS in endothelial cells

    Authors: Blerina Ahmetaj-Shala; Ricky-Kumar Vaja; Santosh S Atanur; Peter M George; Nicholas S Kirkby; Jane A. Mitchell

    doi:10.1101/2020.06.23.165324 Date: 2020-06-23 Source: bioRxiv

    COVID-19, caused by severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2) has rapidly spread throughout the world with unprecedented global healthcare and socio-economic consequences. There is now an established secondary syndrome of COVID-19 characterised by thrombosis MESHD, vascular dysfunction MESHD and hypertension HP hypertension MESHD, seen in those most severely affected. Advancing age TRANS in adults TRANS is the single most significant risk factor for hospitalisation and death with COVID-19. In light of the cardiovascular/ thrombotic sequalae MESHD associated with severe COVID-19 disease and the overwhelming risk that increased age TRANS carries, in this study, our aim was to obtain mechanistic insight by interrogating gene expression profiles in cardiovascular tissues and cells. Our focus was on the two putative receptors for SARS-CoV-2, ACE2 and BSG along with a selected range of genes thought to be involved in virus binding/processing. In this study we have made four important observations: (i)Cardiovascular tissues and/or endothelial cells express the required genes for SARS-CoV-2 infection MESHD, (ii) SASR-CoV-2 receptor pathways, ACE2/TMPRSS2 and BSG/PPIB(A) polarise to lung/epithelium and vessel/endothelium respectively, (iii) expression of SARS-CoV-2 host genes are, on the whole, relatively stable with age TRANS and (iv) notable exceptions were ACE2 which decreases with age TRANS in some tissues and BSG which increases with age TRANS in endothelial cells. Our data support the idea that that BSG is the dominate pathway utilised by SARS-CoV-2 in endothelial cells and are the first to demonstrate a positive correlation with age TRANS. We suggest BSG expression in the vasculature is a critical driver which explains the heightened risk of severe disease and death MESHD observed in those >40 years of age TRANS. Since BSG is utilised by other pathogens our findings have implications beyond the current pandemic. Finally, because BSG is functions in a range of cardiovascular diseases MESHD and fibrosis MESHD, our observations may have relevance to our understanding of the diseases associated with aging.

    Androgen regulates SARS-CoV-2 receptor levels and is associated with severe COVID-19 symptoms in men

    Authors: Zaniar Ghazizadeh; Homa Majd; Mikayla Richter; Ryan Samuel; Seyedeh Maryam Zekavat; Hosseinali Asgharian; Sina Farahvashi; Ali Kalantari; Jonathan Ramirez; Hongyu Zhao; Pradeep Natarajan; Hani Goodarzi; Faranak Fattahi

    doi:10.1101/2020.05.12.091082 Date: 2020-05-12 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection MESHD has led to a global health crisis, and yet our understanding of the disease pathophysiology and potential treatment options remains limited. SARS-CoV-2 infection MESHD occurs through binding and internalization of the viral spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane. Lethal complications are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with the 5 alpha reductase inhibitor dutasteride reduced ACE2 levels and internalization of recombinant spike receptor binding domain (Spike-RBD) in hESC-derived cardiac cells and human alveolar epithelial MESHD cells. Finally, clinical data on coronavirus disease 2019 (COVID-19) patients demonstrated that abnormal androgen states are significantly associated with severe disease complications MESHD and cardiac injury MESHD as measured by blood SERO troponin T levels. These findings provide important insights on the mechanism of increased disease susceptibility in male TRANS COVID-19 patients and identify androgen receptor inhibition as a potential therapeutic strategy.

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