Corpus overview


Overview

MeSH Disease

Human Phenotype

Transmission

Seroprevalence
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    Design and rationale of a randomized, double-blind, placebo-controlled, Phase 2/3 study to evaluate the safety and efficacy of dociparstat sodium (DSTAT) in adults TRANS with acute lung injury MESHD associated with severe COVID-19

    Authors: Joseph A. Lasky; Jyotsna Fuloria; Marion E. Morrison; Randall Lanier; Odin Naderer; Tom Brundage; Allen Melemed

    doi:10.21203/rs.3.rs-52289/v1 Date: 2020-08-01 Source: ResearchSquare

    Background: The COVID-19 Global Pandemic caused by the novel coronavirus, SARS-CoV-2, and the consequent morbidity and mortality attributable to progressive hypoxemia HP and subsequent respiratory failure HP, threaten to overrun hospital critical care units globally. New agents that can address the hyperinflammatory “cytokine storm” and hypercoagulable pathology seen in these patients may be a promising approach to treat patients, minimize hospital stays, and ensure hospital wards and critical care units are able to operate effectively.  Dociparstat sodium (DSTAT) is a glycosaminoglycan derivative of heparin with robust anti-inflammatory properties, including the potential to address underlying causes of coagulation disorders with substantially reduced risk of bleeding complications compared to commercially available forms of heparin. Methods: This study is a randomized, double-blind, placebo-controlled, Phase 2/3 trial to determine the safety and efficacy of DSTAT added to standard of care versus placebo, in adults TRANS with COVID-19 who require hospitalization and supplemental oxygen therapy. The Phase 2 portion will enroll 12 participants in each of two dose escalating cohorts, to confirm the safety of DSTAT in this population. Following a data monitoring committee review of the data, an additional 50 participants will be enrolled. Contingent upon positive results, the Phase 3 portion of the study will enroll approximately 450 participants randomized 1:1 to DSTAT or placebo. The primary endpoint, agreed on by the US FDA, is the proportion of participants who survive and do not require mechanical ventilation through day 28. Discussion: Advances in standard of care regimens and the recent emergency MESHD use authorization of remdesivir and positive data with dexamethasone, has likely contributed to an increasing proportion of patients who are surviving without the need for mechanical ventilation. Therefore, examining the time to improvement of NIAID score will be essential to provide a more continuous measure of drug effect on recovery. Additional analysis of other endpoints, including supportive biomarkers (e.g., IL-6, HMGB1, soluble RAGE, D-dimer) will be performed at the conclusion of Phase 2 to further define the effect of DSTAT in patients hospitalized with COVID-19 infection MESHD. Trial Registration: ClinicalTrials.gov identifier NCT04389840, Registered 13 May 2020, https://clinicaltrials.gov/ct2/keydates/NCT04389840

    ACE2 Expression is elevated in Airway Epithelial Cells from aged TRANS and male TRANS donors but reduced in asthma MESHD asthma HP

    Authors: Peter Wark; Prabuddha Pathinyake; Gerard Kaiko; Kristy Nichol; Ayesha Ali; Ling Chen; Erika Suntanto; Luke Garrat; Sukhwinder S Sohal; Wenying Lu; Matthew Eapen; Christopher Oldmeadow; Nathan Bartlett; Andrew Reid; Punnam Veerati; Alan Hsu; Thomas Iosifides; Stephen Stick; Philip M Hansbro; Anthony Kicic

    doi:10.1101/2020.07.26.20162248 Date: 2020-07-29 Source: medRxiv

    Rationale: COVID-19 is complicated by acute lung injury MESHD, and death MESHD in some individuals. It is caused by SARS-CoV-2 that requires the ACE2 receptor and serine proteases to enter airway epithelial cells (AECs). Objective: To determine what factors are associated with ACE2 expression particularly in patients with asthma MESHD asthma HP and chronic obstructive pulmonary disease MESHD chronic obstructive pulmonary disease HP (COPD). Methods: We obtained upper and lower AECs from 145 people from two independent cohorts, aged TRANS 2-89, Newcastle (n=115), and from Perth (n= 30) Australia. The Newcastle cohort was enriched with people with asthma MESHD asthma HP (n=37) and COPD (n=38). Gene expression for ACE2 and other genes potentially associated with SARS-CoV-2 cell entry were assessed by quantitative PCR, protein expression was confirmed with immunohistochemistry on endobronchial biopsies and cultured AECs. Results: Increased gene expression of ACE2 was associated with older age TRANS (p=0.02) and male TRANS sex (p=0.03), but not pack-years smoked. When we compared gene expression between adults TRANS with asthma MESHD asthma HP, COPD and healthy controls, mean ACE2 expression was lower in asthma MESHD asthma HP (p=0.01). Gene expression of furin, a protease that facilitates viral endocytosis, was also lower in asthma MESHD asthma HP (p=0.02), while ADAM-17, a disintegrin that cleaves ACE2 from the surface was increased (p=0.02). ACE2 protein levels were lower in endobronchial biopsies from asthma MESHD asthma HP patients. Conclusions: Increased ACE2 expression occurs in older people and males TRANS. Asthma MESHD Asthma HP patients have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism and may in part explain susceptibility factors and why asthma MESHD asthma HP patients are not over-represented in those with COVID-19 complications.

    Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage. An autopsy study with clinical correlation and review of the literature.

    Authors: Mariel F. Valdivia-Mazeyra; Clara Salas; Jesús M. Nieves-Alonso; Luz Martín-Fragueiro; Carmen Bárcena; Patricia Muñoz-Hernández; Karen Villar-Zarra; Javier Martín-López; Fernando Ramasco-Rueda; Javier Fraga; José A. Jiménez-Heffernan

    doi:10.21203/rs.3.rs-49093/v1 Date: 2020-07-25 Source: ResearchSquare

    Megakaryocytes are normally present in the lung where they play a role in platelet homeostasis. The latter are well known to participate in the pathogenesis of lung damage, particularly in acute lung injury MESHD. Although megakaryocytes are usually not mentioned as a characteristic histopathologic finding associated to acute pulmonary injury, a few studies point out that their number is increased in the lungs of patients with diffuse alveolar damage. In this autopsy study we have observed a relevant number of pulmonary megakaryocytes in COVID-19 patients dying with acute respiratory distress HP syndrome MESHD. We have studied pulmonary tissue samples of 18 patients most of which died after prolonged disease MESHD and use of mechanical ventilation. Most samples showed fibroproliferative or fibrotic diffuse alveolar damage and an increased number of megakaryocytes. In six, thrombi of the pulmonary microcirculation were seen. We compare our findings with previous published autopsy reports, mainly focusing on the description of megakaryocytes. Our patients showed abnormal coagulation parameters with high levels of fibrinogen, D-dimers and variable thrombocytopenia MESHD thrombocytopenia HP. Since the lung is considered an active site of megakariopoiesis, a prothrombotic status leading to platelet activation, aggregation and consumption may trigger a compensatory pulmonary response. An increased number of pulmonary megakaryocytes suggests and supports a relation with the thrombotic events so often seen in COVID-19. Regardless of its etiology, future studies of patients dying with acute pulmonary injury should include pulmonary megakaryocytes as a histologic variable of interest.

    Can Adenosine Fight COVID-19 Acute Respiratory Distress HP Syndrome MESHD?

    Authors: Carmela Falcone; Massimo Caracciolo; Pierpaolo Correale; Sebastiano Macheda; Eugenio Giuseppe Vadalà; Stefano La Scala; Marco Tescione; Roberta Danieli; Anna Ferrarelli; Maria Grazia Tarsitano; Lorenzo Romano; Antonino De Lorenzo

    id:10.20944/preprints202007.0426.v1 Date: 2020-07-19 Source: Preprints.org

    Some COVID-19 patients develop interstitial pneumonia MESHD pneumonia HP that can evolve into Acute Respiratory Distress HP Syndrome MESHD (ARDS). This is accompanied by an inflammatory cytokine storm. SarS-CoV has proteins capable of promoting cytokine storm, especially in patients with comorbidities, including obesity MESHD obesity HP. Since there is currently no resolutive therapy for ARDS and given the scientific literature regarding the use of adenosine, its application has been hypothesized. Adenosine through its receptors is able to inhibit the acute inflammatory process, increase the protection capacity of the epithelial barrier and reduce the damage due to an overactivation of the immune system, such as in cytokine storms. These features are known in ischemia MESHD / reperfusion models and could also be exploited in acute lung injury MESHD, with hypoxia MESHD. In light of these hypotheses, for compassionate use, a COVID-19 patient, with unresponsive respiratory failure HP, was treated with adenosine. The results showed a rapid and clear improvement in clinical conditions, with the negative effect of detection of SarS-CoV2.

    COVID-19: Role of the Inflammasome

    Authors: Claudio G. Gallo; Sirio Fiorino; Giovanni Posabella; Donato Antonacci; Antonio Tropeano; Emanuele Pausini; Carlotta Pausini; Tommaso Guarniero; Marco Zancanaro

    id:202007.0246/v1 Date: 2020-07-12 Source: Preprints.org

    Covid-19 disease MESHD is caused by SARS Cov-2 virus. Despite its high transmissibility TRANS, the CFR (Case Fatality Rate) of COVID-19 seems to be lower than the SARS (9,5%) and MERS (34,4%) ones93 , but higher than the influenza one (0-1%)94,95 . The disease is asymptomatic MESHD asymptomatic TRANS or paucisymptomatic in most of the patients, although in few cases it can be characterized by serious complications. The main causes of hospitalization in intensive care are represented by ALI ( Acute Lung Injury MESHD), ARDS (Acute Respiratory Distress HP Syndrome MESHD), cardiovascular problems and coagulopathies (diffuse thrombosis MESHD, microthrombosis, embolisms MESHD, myocarditis MESHD myocarditis HP, arrhytmias, heart failure MESHD, stroke MESHD stroke HP)96-98, acute nephropathy99,100 and encephalopathies101. The virus presence in the vascular wall can cause endotheliitis, which triggers the process of diffuse coagulation that can lead to a worsening of the systemic inflammation MESHD. The exaggerated inflammatory response seems to be connected with the development of ARDS, MOF ( Multiple Organ Failure MESHD) and coagulopathies102-107.

    Cerium oxide nanoparticles conjugated to anti-inflammatory microRNA-146a prevent bleomycin-induced acute lung injury MESHD

    Authors: Stephen Niemiec; Sarah Hilton; Alison Wallbank; Mark Azeltine-Bannerman; Amanda Louiselle; Hanan Elajaili; Ayed Allawzi; Junwang Xu; Courtney Mattson; Lindel Dewberry; Junyi Hu; Sushant Singh; Tamil Sakthivel; Eva Nozik-Grayck; Bradford Smith; Sudipta Seal; Carlos Zgheib; Kenneth Liechty

    doi:10.21203/rs.3.rs-40082/v1 Date: 2020-07-03 Source: ResearchSquare

    Acute respiratory distress HP syndrome MESHD (ARDS) is a devastating pulmonary disease MESHD with significant inhospital mortality and is the leading cause of death MESHD in COVID-19 patients. Potential therapies remain limited despite advancements in understanding ARDS pathophysiology. Excessive leukocyte recruitment, unregulated inflammation MESHD, and resultant fibrosis MESHD contribute to poor ARDS outcomes. In this study, we evaluated the potential of the radical scavenging cerium oxide nanoparticle (CNP) conjugated to the anti-inflammatory microRNA-146a (CNP-miR146a) to prevent acute lung injury MESHD (ALI) following exposure to bleomycin. We have found that CNP-miR146a can prevent ALI by altering leukocyte recruitment, reducing inflammation MESHD, and decreasing collagen deposition, ultimately improving pulmonary biomechanics.

    A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury MESHD during the COVID-19 pandemic

    Authors: Maria Malimova; Abhigyan Satyam; Michelle Melanson; Brian T. Chamberlain; Seth L. Alper; Jean Santos; Juan Gutierrez; Ayshwarya Subramanian; Elizabeth Grinkevich; Estefania Reyes Bricio; Abbe Clark; Rebecca Thompson; Jamie Marshall; Juan Lorenzo Pablo; Julie Roignot; Maheswarareddy Emani; Matthew Racette; Valeria Padovano; Stephen P. McAdoo; Frederick W.K. Tam; Lucienne Ronco; Florence Wagner; George C. Tsokos; Jillian L. Shaw

    doi:10.1101/2020.06.30.180380 Date: 2020-06-30 Source: bioRxiv

    Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease MESHD arising from SARS-CoV-2 infection MESHD. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury MESHD (ALI) and respiratory distress HP syndrome MESHD (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia MESHD thrombocytopenia HP, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury MESHD.

    Pulmonary toxicity and inflammatory response of e-cigarettes containing medium-chain triglyceride oil and vitamin E acetate: Implications in the pathogenesis of EVALI but independent of SARS-COV-2 COVID-19 related proteins

    Authors: Thivanka Muthumalage; Joseph Lucas; Qixin Wang; Thomas Lamb; Mathew McGraw; Irfan Rahman

    doi:10.1101/2020.06.14.151381 Date: 2020-06-15 Source: bioRxiv

    Recently, there has been an outbreak associated with the use of e-cigarette or vaping products, associated lung injury MESHD (EVALI). The primary components of vaping products, vitamin E acetate (VEA) and medium-chain triglycerides (MCT) may be responsible for acute lung toxicity. Currently, little information is available on the physiological and biological effects of exposure to these products. We hypothesized that these e-cig cartridges and their constituents (VEA and MCT) induce pulmonary toxicity, mediated by oxidative damage and inflammatory responses, leading to acute lung injury MESHD. We studied the potential mechanisms of cartridge aerosol induced inflammatory response by evaluating the generation of reactive oxygen species by MCT, VEA, and cartridges, and their effects on the inflammatory state of pulmonary epithelium and immune cells both in vitro and in vivo. Cells exposed to these aerosols generated reactive oxygen species, caused cytotoxicity, induced epithelial barrier dysfunction, and elicited an inflammatory response. Using a murine model, the parameters of acute toxicity to aerosol inhalation were assessed. Infiltration of neutrophils and lymphocytes was accompanied by significant increases in IL-6, eotaxin, and G-CSF in the bronchoalveolar lavage fluid (BALF). In mouse plasma SERO, eicosanoid inflammatory mediators, leukotrienes, were significantly increased. Plasma SERO from e-cig users also showed increased levels of hydroxyeicosatetraenoic acid (HETEs) and various eicosanoids. Exposure to e-cig cartridge aerosols showed the most significant effects and toxicity compared to MCT and VEA. In addition, we determined at SARS-COV-2 related proteins and found no impact associated with aerosol exposures from these tested cartridges. Overall, this study demonstrates acute exposure to specific e-cig cartridges induces in vitro cytotoxicity, barrier dysfunction, and inflammation MESHD and in vivo mouse exposure induces acute inflammation MESHD with elevated pro-inflammatory markers in the pathogenesis of EVALI.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    Pulmonary toxicity and inflammatory response of e-cigarettes containing medium-chain triglyceride oil and vitamin E acetate: Implications in the pathogenesis of EVALI but independent of SARS-COV-2 COVID-19 related proteins

    Authors: Thivanka Muthumalage; Joseph H. Lucas; Qixin Wang; Thomas Lamb; Matthew D. McGraw; Irfan Rahman

    doi:10.21203/rs.3.rs-35770/v1 Date: 2020-06-15 Source: ResearchSquare

    Recently, there has been an outbreak associated with the use of e-cigarette or vaping products, associated lung injury MESHD (EVALI). The primary components of vaping products, vitamin E acetate (VEA) and medium-chain triglycerides (MCT) may be responsible for acute lung toxicity. Currently, little information is available on the physiological and biological effects of exposure to these products. We hypothesized that these e-cig cartridges and their constituents (VEA and MCT) induce pulmonary toxicity, mediated by oxidative damage and inflammatory responses, leading to acute lung injury MESHD. We studied the potential mechanisms of cartridge aerosol induced inflammatory response by evaluating the generation of reactive oxygen species by MCT, VEA, and cartridges, and their effects on the inflammatory state of pulmonary epithelium and immune cells both in vitro and in vivo. Cells exposed to these aerosols generated reactive oxygen species, caused cytotoxicity, induced epithelial barrier dysfunction, and elicited an inflammatory response. Using a murine model, the parameters of acute toxicity to aerosol inhalation were assessed. Infiltration of neutrophils and lymphocytes was accompanied by significant increases in IL-6, eotaxin, and G-CSF in the bronchoalveolar lavage fluid (BALF). In mouse plasma SERO, eicosanoid inflammatory mediators, leukotrienes, were significantly increased. Plasma SERO from e-cig users also showed increased levels of hydroxyeicosatetraenoic acid (HETEs) and various eicosanoids. Exposure to e-cig cartridge aerosols showed the most significant effects and toxicity compared to MCT and VEA. In addition, we determined at SARS-COV-2 related proteins and found no impact associated with aerosol exposures from these tested cartridges. Overall, this study demonstrates acute exposure to specific e-cig cartridges induces in vitro cytotoxicity, barrier dysfunction, and inflammation MESHD and in vivo mouse exposure induces acute inflammation MESHD with elevated pro-inflammatory markers in the pathogenesis of EVALI.

    Genotypic and antigenic study of SARS-CoV-2 from an Indian isolate.

    Authors: Ruby Dhar; Akhauri Yash Sinha; Ashikh A Seethy; Sri Anusha Matta; Karthikeyan Pethusamy; Trymbak Srivastava; Sunil Singh; Indrani Mukherjee; Sajib Sarkar; Rashmi Minocha; Kakali Purkayastha; Jai Bhagwan Sharma; Suman Paine; Subhradip Karmakar

    doi:10.1101/2020.06.10.140657 Date: 2020-06-14 Source: bioRxiv

    Coronaviruses (CoVs) are one of the largest groups of positive-sense RNA virus families within the Nidovirales order, which are further classified into four genera: alpha, beta, gamma, and delta. Coronaviruses have an extensive range of natural hosts and are known to be responsible for a broad spectrum of diseases MESHD in multiple species. Severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease MESHD 2019 (COVID-19) that has unleashed a global threat to public health and the economy. Coronaviruses are extensively present in birds and mammals, with horseshoe bats (Rhinolophus affinis), being the reservoir for the ongoing SARS-CoV-2 that seems to have resulted from a zoonotic spillover to the human host, causing respiratory infections MESHD, lung injury and Acute MESHD Respiratory Distress HP Syndrome MESHD(ARDS). About six coronavirus serotypes are linked with the disease MESHD in humans, namely HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, SARS-CoV-2, and MERS-CoV. SARS-CoV-2 is the seventh CoV to infect humans. We analyzed the genome sequence of CoV-2 from isolates derived from China as well from India and encountered minute variations in their sequence. A cladogram analysis revealed the predominant strain circulating in India belongs to the A2a clad. We took one such strain (MT012098) and performed a rigorous in-silico genotypic and antigenic analysis to identify its relatedness to other strains. Further, we also performed a detailed prediction for B and T cell epitopes using BepiPred 2.0 server and NetCTL 1.2 server (DTU Bioinformatics), respectively. We hope this information may assist in an effective vaccine designing program against SARS-CoV-2.

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MeSH Disease
Human Phenotype
Transmission
Seroprevalence


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