scholarly journals COVID-19-Associated Hyper-Fibrinolysis: Mechanism and Implementations

2020 ◽  
Vol 11 ◽  
Author(s):  
Giris Jacob ◽  
Anat Aharon ◽  
Benjamin Brenner
Keyword(s):  
Endothelial Cell ◽  
Host Cell ◽  
Concomitant Administration ◽  
Morbidity And Mortality ◽  
Activated Macrophages ◽  
Poor Outcome ◽  
Novel Coronavirus ◽  
D Dimer ◽  
Hemostatic Disorder ◽  
High Infectivity

The emerging novel coronavirus disease (COVID-19), which is caused by the SARS-CoV-2 presents with high infectivity, morbidity and mortality. It presenting a need for immediate understanding of its pathogenicity. Inflammation and coagulation systems are over-activated in COVID-19. SARS-CoV-2 damages endothelial cell and pneumocyte, resulting in hemostatic disorder and ARDS. An influential biomarkers of poor outcome in COVID-19 are high circulating cytokines and D-dimer level. This latter is due to hyper-fibrinolysis and hyper-coagulation. Plasmin is a key player in fibrinolysis and is involved in the cleavage of many viruses envelop proteins, including SARS-CoV. This function is similar to that of TMPRSS2, which underpins the entry of viruses into the host cell. In addition, plasmin is involved in the pathophysiology of ARDS in SARS and promotes secretion of cytokine, such as IL-6 and TNF, from activated macrophages. Here, we suggest an out-of-the-box treatment for alleviating fibrinolysis and the ARDS of COVID-19 patients. This proposed treatment is concomitant administration of an anti-fibrinolytic drug and the anticoagulant.

scholarly journals Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 821
Author(s):  
Rohitash Yadav ◽  
Jitendra Kumar Chaudhary ◽  
Neeraj Jain ◽  
Pankaj Kumar Chaudhary ◽  
Supriya Khanra ◽  
...  
Keyword(s):  
Host Cell ◽  
Protein S ◽  
Structural Similarity ◽  
Cell Receptor ◽  
Molecular Assembly ◽  
The Body ◽  
Spike Protein ◽  
Structural Proteins ◽  
Structural Protein ◽  
Novel Coronavirus

Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10–20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5′ end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.

scholarly journals COVID-19 & OBESITY: BEYOND BMI

2020 ◽  
Vol 26 (8) ◽  
pp. 923-925
Author(s):  
Karl Z. Nadolsky ◽  
Daniel L. Hurley ◽  
W. Timothy Garvey
Keyword(s):  
Insulin Resistance ◽  
Chronic Disease ◽  
Patient Characteristics ◽  
Morbidity And Mortality ◽  
International Crisis ◽  
Obstructive Sleep ◽  
Patient Health ◽  
Poor Outcomes ◽  
Novel Coronavirus ◽  
End Stage

The pandemic of novel coronavirus disease 2019 (COVID-19) has triggered an international crisis resulting in excess morbidity and mortality with adverse societal, economic, and geopolitical consequences. Like other disease states, there are patient characteristics that impact clinical risk and determine the spectrum of severity. Obesity, or adiposity-based chronic disease, has emerged as an important risk factor for morbidity and mortality due to COVID-19. It is imperative to further stratify risk in patients with obesity to determine optimal mitigation and perhaps therapeutic preparedness strategies. We suspect that insulin resistance is an important pathophysiologic cause of poor outcomes in patients with obesity and COVID-19 independent of body mass index. This explains the association of type 2 diabetes mellitus (T2DM), hypertension (HTN), and cardiovascular disease with poor outcomes since insulin resistance is the main driver of both dysglycemia-based chronic disease and cardiometabolic-based chronic disease towards end-stage disease manifestations. Staging the severity of adiposity-related disease in a “complication-centric” manner (HTN, dyslipidemia, metabolic syndrome, T2DM, obstructive sleep apnea, etc.) among different ethnic groups in patients with COVID-19 should help predict the adverse risk of adiposity on patient health in a pragmatic and actionable manner during this pandemic.

scholarly journals Timing of Antiretroviral Therapy for HIV in the Setting of TB Treatment

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Damani A. Piggott ◽  
Petros C. Karakousis
Keyword(s):  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Concomitant Administration ◽  
Morbidity And Mortality ◽  
Therapeutic Modality ◽  
Optimal Timing ◽  
Highly Active ◽  
Tb Treatment ◽  
Immunodeficiency Virus ◽  
Inflammatory Syndrome

The convergent human immunodeficiency virus (HIV) and tuberculosis (TB) pandemics continue to collectively exact significant morbidity and mortality worldwide. Highly active antiretroviral therapy (HAART) has been a critical component in combating the scourge of these two conditions as both a preemptive and therapeutic modality. However, concomitant administration of antiretroviral and antituberculous therapies poses significant challenges, including cumulative drug toxicities, drug-drug interactions, high pill burden, and the immune reconstitution inflammatory syndrome (IRIS), thus complicating the management of coinfected individuals. This paper will review data from recent studies regarding the optimal timing of HAART initiation relative to TB treatment, with the ultimate goal of improving coinfection-related morbidity and mortality while mitigating toxicity resulting from concurrent treatment of both infections.

D-Dimer as a prognostic marker of morbidity and mortality among HIV patients: a call for attention

2016 ◽  
Vol 48 (11-12) ◽  
pp. 860-861 ◽  
Author(s):  
Federico Aranda ◽  
Silvia Perés Wingeyer ◽  
Gabriela de Larrañaga
Keyword(s):  
Prognostic Marker ◽  
Morbidity And Mortality ◽  
Hiv Patients ◽  
D Dimer

scholarly journals Microbes, Clinical trials, Drug Discovery, and Vaccine Development: The Current Perspectives

2021 ◽  
Vol 4 (4) ◽  
pp. 311-323
Author(s):  
Venkataramana Kandi ◽  
Tarun Kumar Suvvari ◽  
Sabitha Vadakedath ◽  
Vikram Godishala
Keyword(s):  
Drug Discovery ◽  
Genetic Variants ◽  
Vaccine Development ◽  
Treatment Options ◽  
Morbidity And Mortality ◽  
Therapeutic Interventions ◽  
Multi Drug Resistance ◽  
The Novel ◽  
Normal Human ◽  
Novel Coronavirus

Because of the frequent emergence of novel microbial species and the re-emergence of genetic variants of hitherto known microbes, the global healthcare system, and human health has been thrown into jeopardy. Also, certain microbes that possess the ability to develop multi-drug resistance (MDR) have limited the treatment options in cases of serious infections, and increased hospital and treatment costs, and associated morbidity and mortality. The recent discovery of the novel Coronavirus (n-CoV), the Severe Acute Respiratory Syndrome CoV-2 (SARS-CoV-2) that is causing the CoV Disease-19 (COVID-19) has resulted in severe morbidity and mortality throughout the world affecting normal human lives. The major concern with the current pandemic is the non-availability of specific drugs and an incomplete understanding of the pathobiology of the virus. It is therefore important for pharmaceutical establishments to envisage the discovery of therapeutic interventions and potential vaccines against the novel and MDR microbes. Therefore, this review is attempted to update and explore the current perspectives in microbes, clinical research, drug discovery, and vaccine development to effectively combat the emerging novel and re-emerging genetic variants of microbes.

scholarly journals Gene Expression Network Analysis Provides Potential Targets Against SARS-CoV-2

2020 ◽  
Author(s):  
Ana I. Hernández Cordero ◽  
Xuan Li ◽  
Chen Xi Yang ◽  
Stephen Milne ◽  
Yohan Bossé ◽  
...  
Keyword(s):  
Gene Expression ◽  
Network Analysis ◽  
Host Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Tissue Samples ◽  
Drug Compounds ◽  
Bioinformatics Databases ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease

ABSTRACTBACKGROUNDCell entry of SARS-CoV-2, the novel coronavirus causing COVID-19, is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We aimed to identify and characterize genes that are co-expressed with ACE2 and TMPRSS2, and to further explore their biological functions and potential as druggable targets.METHODSUsing the gene expression profiles of 1,038 lung tissue samples, we performed a weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. We explored the biology of co-expressed genes using bioinformatics databases, and identified known drug-gene interactions.RESULTSACE2 was in a module of 681 co-expressed genes; 12 genes with moderate-high correlation with ACE2 (r>0.3, FDR<0.05) had known interactions with existing drug compounds. TMPRSS2 was in a module of 1,086 co-expressed genes; 15 of these genes were enriched in the gene ontology biologic process ‘Entry into host cell’, and 53 TMPRSS2-correlated genes had known interactions with drug compounds.CONCLUSIONDozens of genes are co-expressed with ACE2 and TMPRSS2, many of which have plausible links to COVID-19 pathophysiology. Many of the co-expressed genes are potentially targetable with existing drugs, which may help to fast-track the development of COVID-19 therapeutics.

scholarly journals “SARS-CoV-2 infection of endothelial cell, clinical laboratory and autopsy findings, and outcomes suggest role of hypoxia-inducible factor-1 in COVID-19”

2021 ◽  
Author(s):  
Vivek Ambade
Keyword(s):  
Endothelial Cell ◽  
Severe Acute Respiratory Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Clinical Laboratory ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Novel Coronavirus

Researchers around the world have experienced the dual nature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ‘tragically lethal in some persons and surprisingly benign in others’. They have congregated to study novel coronavirus disease (COVID-19), a disease that mainly attacks the lungs, but also has mystifying effects on the heart, kidneys and brain. Researchers are also gathering information to determine what actually kills COVID-19 patients, whether respiratory disorder or coagulation disorder or multi organ failure. Various laboratory parameters like lactate, ferritin, hypoalbuminemia have been established as risk factor or associated with poor outcomes, but yet could not be substantiated with the scientific biochemical rationale.  SARS-CoV-2 affects the alveolar type II epithelial cells, that significantly disturbs its surfactant homeostasis, deprive Na,K-ATPase of  ATP, thereby  disturbing the alveolar lining fluid which then gradually decreases the alveolar gaseous exchange  initiating intracellular hypoxic conditions. This activates AMP-activated kinase, which further inhibits Na,K-ATPase, that  can  progressively cause  respiratory distress syndrome. The virus may infect endothelial cell (EC), which being low energetic, cannot withstand the huge energy requirement towards viral replication,  and therefore glycolysis,  the prime energy generating pathway,  has to mandatorily be upregulated, which can be achieved by Hypoxia-inducible factor 1 (HIF-1). However, HIF-1 activates transcription of von Willebrand factor, plasminogen activator inhibitor-1, and suppresses the release of thrombomodulin, thereby setting off the coagulation cascade that leads to in-situ pulmonary thrombosis and micro clots. The proposed HIF-1 hypothesis can rationalize various features, clinical laboratory as well as autopsy findings such as respiratory distress syndrome, increased  blood ferritin and lactate levels, endothelial invasion, in-situ pulmonary thrombosis and micro clots,  and multiorgan failure in COVID -19 Keywords: novel coronavirus, COVID-19, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, hypoxia-inducible factor-1

scholarly journals Outcome Following Hemorrhage From Cranial Dural Arteriovenous Fistulae

Stroke ◽  
2021 ◽  
Vol 52 (10) ◽  
Author(s):  
Matthew J. Koch ◽  
Christopher J. Stapleton ◽  
Ridhima Guniganti ◽  
Giuseppe Lanzino ◽  
Jason Sheehan ◽  
...  
Keyword(s):  
Arteriovenous Fistula ◽  
Odds Ratio ◽  
Dural Arteriovenous Fistula ◽  
Multivariable Analysis ◽  
Patient Characteristics ◽  
Morbidity And Mortality ◽  
Cerebrovascular Lesions ◽  
Arteriovenous Fistulae ◽  
Poor Outcome

Background and Purpose: Dural arteriovenous fistulae can present with hemorrhage, but there remains a paucity of data regarding subsequent outcomes. We sought to use the CONDOR (Consortium for Dural Arteriovenous Fistula Outcomes Research), a multi-institutional registry, to characterize the morbidity and mortality of dural arteriovenous fistula–related hemorrhage. Methods: A retrospective review of patients in CONDOR who presented with dural arteriovenous fistula–related hemorrhage was performed. Patient characteristics, clinical follow-up, and radiographic details were analyzed for associations with poor outcome (defined as modified Rankin Scale score ≥3). Results: The CONDOR dataset yielded 262 patients with incident hemorrhage, with median follow-up of 1.4 years. Poor outcome was observed in 17.0% (95% CI, 12.3%–21.7%) at follow-up, including a 3.6% (95% CI, 1.3%–6.0%) mortality. Age and anticoagulant use were associated with poor outcome on multivariable analysis (odds ratio, 1.04, odds ratio, 5.1 respectively). Subtype of hemorrhage and venous shunting pattern of the lesion did not affect outcome significantly. Conclusions: Within the CONDOR registry, dural arteriovenous fistula–related hemorrhage was associated with a relatively lower morbidity and mortality than published outcomes from other arterialized cerebrovascular lesions but still at clinically consequential rates.

scholarly journals Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients

2020 ◽  
Author(s):  
Yingxia Liu ◽  
Fengming Huang ◽  
Jun Xu ◽  
Penghui Yang ◽  
Yuhao Qin ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Meta Analysis ◽  
Severe Disease ◽  
Morbidity And Mortality ◽  
Angiotensin Ii Receptor Blocker ◽  
Angiotensin Ii Receptor ◽  
Elderly Age ◽  
Positive Effects ◽  
Angiotensin I Converting Enzyme ◽  
Novel Coronavirus

SummaryBackgroundThe novel coronavirus (CoV) severe acute respiratory syndrome (SARS)-CoV-2 outbreak started at the end of 2019 in Wuhan, China, and spread over 100 countries. SARS-CoV-2 uses the membrane protein Angiotensin I converting enzyme 2(ACE2) as a cell entry receptor. Indeed, it was reported that the balance of Renin-Angiotensin System (RAS), regulated by both ACE and ACE2, was altered in COVID-19 patients. It is controversial, however, whether commonly used anti-hypertensive drugs Angiotensin I converting enzyme inhibitor (ACEI) and Angiotensin II receptor blocker (ARB) shall be continued in the confirmed COVID-19 patients. This study was designed to investigate any difference in disease severity between COVID-19 patients with hypertension comorbidity. The included COVID-19 patients used ACEI, ARB, calcium channel blockers (CCB), beta blockers (BB), or thiazide to treat preexisting hypertension prior to the hospital were compared to patients who did not take any of those drugs.MethodsIn this multicentre retrospective study, clinical data of 511 COVID-19 patients were analyzed. Patients were categorized into six sub-groups of hypertension comorbidity based on treatment using one of anti-hypertension drugs (ACEI, ARB, CCB, BB, thiazide), or none. A meta-analysis was performed to evaluate the use of ACEI and ARB associated with pneumonia using published studies.FindingsAmong the elderly (age>65) COVID-19 patients with hypertension comorbidity, the risk of COVID-19-S (severe disease) was significantly decreased in patients who took ARB drugs prior to hospitalization compared to patients who took no drugs (OR=0·343, 95% CI 0·128-0·916, p=0·025). The meta-analysis showed that ARB use has positive effects associated with morbidity and mortality of pneumonia.InterpretationElderly (age>65) COVID-19 patients with hypertension comorbidity who are taking ARB anti-hypertension drugs may be less likely to develop severe lung disease compared to patients who take no anti-hypertension drugs.FundingNational Natural Science Foundation of China, Chinese Academy of Medical SciencesResearch in contextEvidence before this studyWe searched PubMed for articles published up to March 15, 2020 using keywords “2019-nCoV”, “SARS-CoV-2”, “novel coronavirus”, and COVID-19 AND “ARB”, and “angiotensin II receptor blocker” for papers published in both English and Chinese. We found three papers: one from our group, published in Science China Life Science that demonstrated an elevated Angiotensin II level in blood samples from COVID-19 patients; another a perspective article in Chinese recommending ACEI and ARBs as potential remedies for SARS-CoV-2 infections; the third a retrospective study in Chinese identifying no significant difference between ACEI/ARB associated with outcomes in 112 COVID-19 patients with CVD comorbidity. The International society of Hypertension stated on March 16th, 2020: “there are no clinical data in human to show that ACE-inhibitors or ARBs either improve or worsen susceptibility to COVID-19 infection nor do they affect the outcomes of those infected”.Added value of this studyWe retrospectively reviewed different types of anti-hypertensive drugs taken by COVID-19 patients with hypertension comorbidity prior to entering the hospital. We discovered that ARB hypertensive drugs were associated with a decreased risk of severe disease in elderly (age>65) COVID-19 patients (OR=0·343, 95% CI 0·128-0·916, p=0·025), the first evidence of ARBs association to COVID-19 infections in human. We conducted a meta-analysis in the literature and found that ARB has positive effects associated with morbidity and mortality of pneumonia.Implications of all the available evidenceARB drugs are widely used in the population with hypertension. Treatments with ACEI and ARBs should be continuous according to medical guidelines. RCT trials of ARB associated with morbidity and mortality of SARS-CoV-2 infection are recommended in the future.

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