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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (4)

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ORF1a (1)

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    Within-country age-based prioritisation, global allocation, and public health impact of a vaccine against SARS-CoV-2: a mathematical modelling analysis

    Authors: Alexandra B Hogan; Peter Winskill; Oliver J Watson; Patrick G T Walker; Charles Whittaker; Marc Baguelin; Nicholas F Brazeau; Giovanni D Charles; Katy A M Gaythorpe; Arran Hamlet; Edward Knock; Daniel J Laydon; John A Lees; Alessandra Løchen; Robert Verity; Lilith K Whittles; Farzana Muhib; Katharina Hauck; Neil M Ferguson; Azra C Ghani

    doi:10.1101/2021.03.19.21253960 Date: 2021-03-20 Source: medRxiv

    The worldwide endeavour to develop safe and effective COVID-19 MESHD vaccines has been extraordinary, and vaccination is now underway in many countries. However, the doses available in 2021 are likely to be limited. We extended a mathematical model of SARS-CoV-2 transmission across different country settings to evaluate the public health impact of potential vaccines using WHO-developed target product profiles. We identified optimal vaccine allocation strategies within- and between-countries to maximise averted deaths under constraints on dose supply. We found that the health impact of SARS-CoV-2 vaccination depends on the cumulative population-level infection incidence when vaccination begins, the duration of natural immunity, the trajectory of the epidemic prior to vaccination, and the level of healthcare available to effectively treat those with disease. Within a country we find that for a limited supply (doses for <20% of the population) the optimal strategy is to target the elderly. However, with a larger supply, if vaccination can occur while other interventions are maintained, the optimal strategy switches to targeting key transmitters to indirectly protect the vulnerable. As supply increases, vaccines that reduce or block infection MESHD have a greater impact than those that prevent disease alone due to the indirect protection provided to high-risk groups. Given a 2 billion global dose supply in 2021, we find that a strategy in which doses are allocated to countries proportional to population size is close to optimal in averting deaths and aligns with the ethical principles agreed in pandemic preparedness planning.

    Functional Antibodies in COVID-19 MESHD Convalescent Plasma

    Authors: Jonathan D Herman; Chuangqi Wang; Carolin Loos; Hyun ah Yoon; Johanna Rivera; M. Eugenia Dieterle; Denise Haslwanter; Rohit K Jangra; Robert Bortz; Katharine Bar; Boris Julg; Kartik Chandran; Liise-anne Pirofski; Douglas Lauffenburger; Galit Alter

    doi:10.1101/2021.03.08.21253157 Date: 2021-03-11 Source: medRxiv

    In the absence of an effective vaccine or monoclonal therapeutic, transfer of convalescent plasma (CCP) was proposed early in the SARS-CoV-2 pandemic as an easily accessible therapy. However, despite the global excitement around this historically valuable therapeutic approach, results from CCP trials have been mixed and highly debated. Unlike other therapeutic interventions, CCP represents a heterogeneous drug. Each CCP unit is unique and collected from an individual recovered COVID-19 MESHD patient, making the interpretation of therapeutic benefit more complicated. While the prevailing view in the field would suggest that it is administration of neutralizing antibodies via CCP that centrally provides therapeutic benefit to newly infected COVID-19 MESHD patients, many hospitalized COVID-19 MESHD patients already possess neutralizing antibodies. Importantly, the therapeutic benefit of antibodies can extend far beyond their simple ability to bind and block infection MESHD, especially related to their ability to interact with the innate immune system. In our work we deeply profiled the SARS-CoV-2-specific Fc-response in CCP donors, along with the recipients prior to and after CCP transfer, revealing striking SARS-CoV-2 specific Fc-heterogeneity across CCP units and their recipients. However, CCP units possessed more functional antibodies than acute COVID-19 MESHD patients, that shaped the evolution of COVID-19 MESHD patient humoral profiles via distinct immunomodulatory effects that varied by pre-existing SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN (S)-specific IgG titers in the patients. Our analysis identified surprising influence of both S and Nucleocapsid (N PROTEIN) specific antibody functions not only in direct antiviral activity but also in anti-inflammatory effects. These findings offer insights for more comprehensive interpretation of correlates of immunity in ongoing large scale CCP trials and for the design of next generation therapeutic design.

    IMMUNO-COV™ v2.0: Development and Validation of a High-Throughput Clinical Assay for Measuring SARS-CoV-2-Neutralizing Antibody Titers MESHD

    Authors: Rianna Vandergaast; Timothy Carey; Samantha Reiter; Chase Lathrum; Patrycja Lech; Clement Gnanadurai; Michelle Haselton; Jason Buehler; Riya Narjari; Luke Schnebeck; Anne Roesler; Kara Sevola; Lukkana Suksanpaisan; Alice Bexon; Shruthi Naik; Bethany Brunton; Scott C. Weaver; Grace Rafael; Sheryl Tran; Alina Baum; Christos A. Kyratsous; Kah-Whye Peng; Stephen J. Russell

    doi:10.1101/2021.02.16.21251653 Date: 2021-02-19 Source: medRxiv

    Neutralizing antibodies are key determinants of protection from future infection, yet well-validated high-throughput assays for measuring titers of SARS-CoV-2-neutralizing antibodies are not generally available. Here we describe the development and validation of IMMUNO-COV v2.0 a scalable surrogate virus assay, which titrates antibodies that block infection MESHD of Vero-ACE2 cells by a luciferase-encoding vesicular stomatitis MESHD virus displaying SARS-CoV-2 spike PROTEIN glycoproteins (VSV-SARS2-Fluc). Antibody titers, calculated using a standard curve consisting of stepped concentrations of SARS-CoV-2 spike PROTEIN monoclonal antibody, correlated closely (p < 0.0001) with titers obtained from a gold-standard PRNT50% assay performed using a clinical isolate of SARS-CoV-2. IMMUNO-COV v2.0 was comprehensively validated using data acquired from 242 assay runs performed over seven days by five analysts, utilizing two separate virus lots, and 176 blood samples. Assay performance was acceptable for clinical use in human serum and plasma based on parameters including linearity, dynamic range, limit of blank and limit of detection, dilutional linearity and parallelism, precision, clinical agreement, matrix equivalence, clinical specificity and sensitivity, and robustness. Sufficient VSV-SARS2-Fluc virus MESHD reagent has been banked to test 5 million clinical samples. Notably, a significant drop in IMMUNO-COV v2.0 neutralizing antibody titers was observed over a six-month period in people recovered from SARS-CoV-2 infection MESHD. Together, our results demonstrate the feasibility and utility of IMMUNO-COV v2.0 for measuring SARS-CoV-2-neutralizing antibodies in vaccinated individuals and those recovering from natural infections. Such monitoring can be used to better understand what levels of neutralizing antibodies are required for protection from SARS-CoV-2, and what booster dosing schedules are needed to sustain vaccine-induced immunity.

    12-lead Electrocardiogram in Hospitalized COVID 19 Patients

    Authors: Mohamed Shokr; Omar Chehab; Mustafa Ajam; Manmohan Singh; Said Ashraf; John Dawdy; Mohit Pahuja; Vivek Reddy; Ahmed Subahi; M. Chadi Alraies; Luis Afonso; Randy Lieberman

    doi:10.1101/2021.01.29.21250407 Date: 2021-02-01 Source: medRxiv

    COVID-19 pandemic MESHD resulted in considerable morbidity and mortality. We analyzed 345 Electrocardiograms of 100 COVID-19 MESHD patients admitted to our tertiary care center in Detroit, during the initial month of Covid-19 MESHD. Findings were correlated with mortality, cardiac injury MESHD and inflammatory markers. Our cohort included 61% males and 77% African Americans. The median age and BMI were 66 years (57-74) and 31 kg/m2 (26.1-39), respectively. We observed atrial arrhythmias MESHD in 29% of the patients (17% new onset), First degree heart block MESHD in 12%, ST-T segment changes in 17%, S1Q3T3 pattern in 19%, premature ventricular complexes in 23%, premature atrial complexes in 13%, Q waves in 27%, T wave inversion in 42% of the cases. While presence of premature atrial complexes or left atrial abnormality MESHD correlated with mortality (P = 0.02 & 0.03, respectively), other findings did not show significant correlation in this small cohort of patients.

    Intranasal administration of SARS-CoV-2 neutralizing human antibody prevents infection in mice

    Authors: Ankit K. Pathak; Saman Fatihi; Tahseen Abbas; Bharathram Uppili; Gyan Prakash Mishra; Arup Ghosh; Sofia Banu; Rahul C. Bhoyar; Abhinav Jain; Mohit Kumar Divakar; Mohamed Imran; Mohammed Faruq; Divya Tej Sowpati; Sunil K. Raghav; Lipi Thukral; Mitali Mukerji; James A Triccas

    doi:10.1101/2020.12.08.416677 Date: 2020-12-09 Source: bioRxiv

    Prevention of SARS-CoV-2 infection MESHD at the point of nasal entry is a novel strategy that has the potential to help contain the ongoing pandemic. Using our proprietary technologies, we have engineered a human antibody that recognizes SARS-CoV-2 S1 spike protein PROTEIN with an enhanced affinity for mucin to improve the antibodys retention in respiratory mucosa. The modified antibody, when administered into mouse nostrils, was shown to block infection MESHD in mice that were exposed to high titer SARS-CoV-2 pseudovirus 10 hours after the initial antibody treatment. Our data show that the protection against SARS-CoV-2 infection MESHD is effective in both nasal and lung areas 7 days after viral exposure. The modified antibody is stable in a nasal spray formulation and maintains its SARS-CoV-2 neutralizing activity. Nasal spray of the modified antibody can be developed as an affordable and effective prophylactic product to protect people from infection by exposure to SARS-CoV-2 virus in the air. One-sentence summaryA Fc-modified human antibody prevents SARS-CoV-2 viral infection via nasal administration

    Postoperative Analgesic Efficiency of Quadratus Lumborum Block Iii Versus Peritubal Local Infiltration in Patients Undergoing Percutaneous Nephrolithotomy Operation: A Randomized Comparative Trial

    Authors: Simon Halim Armanious; Peter M. Youssef; Manal Kamal; Galal El Kady; Tamer N. Abdelrahman

    doi:10.21203/rs.3.rs-78028/v2 Date: 2020-09-15 Source: ResearchSquare

    Background: The postoperative pain MESHD after percutaneous nephrolithotomy (PCNL) can be managed by many peripheral blocks techniques (e.g., paravertebral and quadrates lumborum block), and local anesthesia infiltration. Therefore, this prospective study was conducted to evaluate the effect of quadratus lumborum type III versus peritubal local infiltrating on postoperative analgesia for patients undergoing PCNL under general anesthesia.Methods: Eligible subjects after exclusion of COVID-19 MESHD patients, with renal stones MESHD less than 2 cm undergoing PCNL surgery under general anesthesia. Exclusion criteria were: 21 60 years of age; bleeding disorders MESHD; allergies MESHD to local anesthetics; psychiatric MESHD patients; and American Society of Anesthesia (ASA) physical status III and IV. Eighty patients were randomly allocated to 2 equal groups. In the Quadratus group, participant received 20 mL of bupivacaine 0.25% in the fascial plane between the quadratus lumborum and Psoas muscle; and in the peritubal group, patients received 10 mL of bupivacaine 0.25% around the nephrostomy tube MESHD at 6 and 12 o’clock positions (total 20 mL). The quadratus lumborum block MESHD and peritubal infiltration were performed by the primary investigator and the urologist, respectively. All patients received standard postoperative analgesia (paracetamol, ketorolac, and morphine via patient-controlled analgesia. Both patients and Data collecting staff were blinded to study group. Primary outcome was the visual analogue score at rest and on coughing or movement at 2, 4, 6, 12, and 24 hours. Secondary outcomes were 24 hours total morphine consumption, 1st use of morphine pump, incidence of side effects (pruritis and nausea and vomiting) and patient satisfaction.Results: Data were analyzed from 78 patients (39 patients in each group). The mean resting VAS score in quadratus group at 6 and 12 hours was (3), while the mean VAS in peritubal group was (5) and (6) at 6 and 12 hours, respectively. Dynamic VAS score in peritubal group at 6 hours was (mean 6) with p<0.0001 when compared to resting value. The 24 hours’ morphine consumption was 8.5-11mg and 16-19 mg, in quadratus and peritubal group, respectively (the difference in mean of 9 at the 95% confidence interval; p<0.0001). patients start to use morphine pump after 121.4 min and 180.2 min in group peritubal and quadratus, respectively. Patients in group quadratus were statistically more satisfied, in both groups incidence of complication was low.Conclusion: Quadratus Lumborum block was more effective than Peritubal LA infiltration regarding postoperative VAS score both at rest and during movement with lower postoperative morphine consumption and more satisfaction in patients undergoing PCNL surgery.

    SARS-CoV-2 uses clathrin-mediated endocytosis to gain access into cells

    Authors: Armin Bayati; Rahul Kumar; Vincent Francis; Peter S McPherson

    doi:10.1101/2020.07.13.201509 Date: 2020-07-14 Source: bioRxiv

    With more than 13 million cases and 570,000 deaths, and with the resulting social upheaval, the COVID-19 pandemic MESHD COVID-19 pandemic MESHD presents one of the greatest challenges ever to the scientific community. It is thus vital to fully understand the biology of SARS-CoV-2, the causative agent of COVID-19 MESHD. SARS-CoV-2 uses the spike PROTEIN glycoprotein to interact with the cell surface and to drive fusion of the viral membrane with cellular membranes, thus allowing transfer of viral RNA to the cytosol. Here we use purified spike glycoprotein PROTEIN protein and lentivirus pseudotyped with spike glycoprotein PROTEIN to determine that SARS-CoV-2 undergoes rapid endocytosis following binding to the plasma membrane. Using chemical inhibitors and loss of function approaches, we demonstrate that this cellular entry is through clathrin-mediated endocytosis. Thus, it appears that SARS-CoV-2 first engages the plasma membrane, then rapidly enters the lumen of the endosomal system, strongly suggesting that fusion of the viral membrane occurs with the lumenal membrane of endosomes. This discovery has important implications for the development of chemical probes to reduce or block infection MESHD.

    Evidence That Quinine Exhibits Antiviral Activity against SARS-CoV-2 Infection MESHD In Vitro

    Authors: Maximilian Große; Natalia Ruetalo; Ramona Businger; Sascha Rheber; Christian Setz; Pia Rauch; Janina Auth; Ekkehard Brysch; Michael Schindler; Ulrich Schubert

    id:202007.0102/v1 Date: 2020-07-06 Source: Preprints.org

    Since there is no vaccine or regulatory approved therapy available for treatment of SARS-CoV-2 infection MESHD, the medical need to prevent the transition of a mild into the severe COVID-19 MESHD stage of infection is of outmost importance. Among several drug candidates, Chloroquine (CQN) and Hydroxy-Chloroquine (H-CQN) have been tested most intensively. However, the therapeutic effect of H-CQN MESHD and CQN has been discussed controversially in the light of severe side effects. Originally, H-CQN descended from the natural substance Quinine, a medicinal product used since the Middle Ages and is now regulatory approved for various indications. We hypothesized that Quinine also exerts anti-SARS-CoV-2 activity. First, virus production in Vero B4 cells was analyzed by Western blot, showing that Quinine exerts antiviral activity against SARS-CoV-2 that at 10 µM was even stronger than that of H-CQN MESHD or CQN. Second, fluorescence end-point and time lapse analysis of SARS-CoV-2-mNeonGreen-infected Caco-2 cells could confirm a similar antiviral effect of Quinine in a human-derived cell line. Thereby, our in vitro studies revealed, that the antiviral effect appears to be specific, since in Vero cells Quinine impacted cell viability at approximately 50-fold higher concentration, while the therapeutic window of H-CQN MESHD and CQN was approximately 10-fold lower. In Caco-2 cells no toxic effect was observed while complete block of infection MESHD occurred between 50 and 100 µM at high MOIs. In conclusion, our data indicate that Quinine would have the potential of a well tolerable and widely used treatment option for SARS-CoV-2 infections MESHD, with a predictable and significantly better toxicological profile when compared to H-CQN MESHD or CQN.

    Think Different with RNA Therapy: Can Antisense Oligonucleotides Be Used to Inhibit Replication and Transcription of SARS-Cov-2?

    Authors: Eric Barrey; Veronica Burzio; Sophie Dhorne-Pollet; Jean-François Eléouët; Bernard Delmas

    id:10.20944/preprints202004.0412.v1 Date: 2020-04-23 Source: Preprints.org

    The severity of the global COVID-19 MESHD COVID-19 MESHD pandemic, with a high transmission rate, 2.6-4.7% lethality and a huge economic impact, poses an urgent need for efficient medical treatments and vaccines. Currently, there are only non-specific treatments to assist the patients in acute respiratory distress during the inflammatory step following the preliminary infection by SARS-CoV-2. Clinical trials of drug repurposing were quickly launched at the international level. Specific treatments such as the transfusion of plasma from patients who have recovered into infected MESHD patients or the use of specific inhibitors of the viral RNA-polymerase complex are promising strategies to block infection MESHD. To complete the therapeutic arsenal, we believe that the opportunity of targeting the SARS-CoV-2 genome by RNA therapy should be deeply investigated. In the present paper, we propose to design specific antisense oligonucleotides targeting transcripts encoding viral proteins associated to replication and transcription of SARS-CoV-2, aiming to block infection MESHD. We designed antisense oligonucleotides targeting the genomic 5’ untranslated region (5’-UTR), open reading frames 1a PROTEIN and 1b ( ORF1a PROTEIN and ORF1b) governing expression of the replicase/transcriptase complex, and the gene N PROTEIN encoding the nucleoprotein PROTEIN that is genome-associated. To maximize the probability of efficiency, we predicted the antisense oligonucleotides by using two design methods: i) conventional antisense oligonucleotides with 100% phosphorothioate modifications (ASO); ii) antisense locked nucleic acids GapmeR. After binding the viral RNA target, the hetero-duplexes antisense oligonucleotide-RNA are cleaved by RNAse H1 HGNC. Nine potent ASO candidates were found and we selected five of them targeting ORF1a PROTEIN (3), ORF1b (1) and N (1). Nine GapmeR candidates were predicted with excellent properties and we retained four of them targeting 5’-UTR (1), ORF1a PROTEIN (3), ORF1b (1) and N (1). The most potent GapmeR candidate targets the 5’-UTR, a key genomic domain with multiple functions in the viral cycle. By this open publication, we are pleased to share these in silico results with the scientific community in hopes of stimulating innovation in translational research in order to fight the unprecedented COVID-19 pandemic MESHD. These antisense oligonucleotide candidates should be now experimentally evaluated.

    Structural Basis for Potent Neutralization of Betacoronaviruses by Single-domain Camelid Antibodies

    Authors: Daniel Wrapp; Dorien De Vlieger; Kizzmekia S Corbett; Gretel M Torres; Wander Van Breedam; Kenny Roose; Loes van Schie; - VIB-CMB COVID-19 Response Team; Markus Hoffmann; Stefan Pöhlmann; Barney S Graham; Nico Callewaert; Bert Schepens; Xavier Saelens; Jason S McLellan

    doi:10.1101/2020.03.26.010165 Date: 2020-03-28 Source: bioRxiv

    The pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV) MESHD, severe acute respiratory syndrome coronavirus (SARS-CoV-1) MESHD and COVID-19 MESHD coronavirus (SARS-CoV-2) have all emerged into the human population with devastating consequences. These viruses make use of a large envelope protein PROTEIN called spike (S) to engage host cell receptors and catalyze membrane fusion. Because of the vital role that these S proteins PROTEIN play, they represent a vulnerable target for the development of therapeutics to combat these highly pathogenic coronaviruses. Here, we describe the isolation and characterization of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs are capable of potently neutralizing MERS-CoV MESHD or SARS-CoV-1 S pseudotyped viruses. The crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs block MESHD receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S MESHD, and demonstrate that this cross-reactive VHH is capable of neutralizing SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion. These data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that these molecules may serve as useful therapeutics during coronavirus outbreaks.

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