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SARS-CoV-2 proteins

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    Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

    Authors: Adam Pickard; Ben C Calverley; Joan Chang; Richa Garva; Yinhui Lu; Karl E Kadler

    doi:10.1101/2021.01.31.428851 Date: 2021-02-01 Source: bioRxiv

    Background: The SARS-CoV-2 virus that was first identified in Wuhan, China has caused the death of over 2 million people worldwide during the COVID-19 pandemic MESHD. Whilst effective vaccines have been developed and vaccination schedules are being rolled out, the identification of safe and inexpensive drugs to slow the replication of SARS-CoV-2 could help thousands of people worldwide whilst awaiting vaccination. Methods: Using SARS-CoV-2 tagged with nano-luciferase (SARS-CoV-2-{Delta} Orf7a PROTEIN-NLuc) we screened a variety of cells under optimised cell culture conditions for their ability to be infected by, and support the replication of, SARS-CoV-2. Electron microscopy was used to demonstrate generation of infectious virus particles. We assessed a library of 1971 FDA-approved drugs for their ability to inhibit or enhance viral replication in Vero (simian kidney cells) but also in the human hepatocyte cell, HUH7 HGNC. Initial hits were further tested to identify compounds that could suppress viral replication, post-viral infection. Dose response curves were obtained for a shortlist of 9 compounds of interest ( COI HGNC). Findings: Our SARS-CoV-2-{Delta} Orf7a PROTEIN-NLuc virus was as effective as wild-type SARS-CoV-2 in inducing CPE and replicating in Vero cells. Conventional electron microscopy showed the NLuc-tagged virus to be structurally indistinguishable from the wild-type virus, and both could be identified within the endosomal system of infected cells. SARS-CoV-2-{Delta} Orf7a PROTEIN-NLuc was used in experiments to robustly quantitate virus infection MESHD and replication. A wide variety of human cells including lung fibroblasts and epithelial cells were susceptible to infection but were not effective in supporting SARS-CoV-2-{Delta} Orf7a PROTEIN-NLuc replication. In contrast, human kidney epithelial cells and human hepatic cells were particularly susceptible and supported SARS-CoV-2-replication, which is in-line with reported proteinuria MESHD and liver damage MESHD in patients with COVID-19 MESHD. Our screening of FDA approved compounds identified 35 COI HGNC that inhibited virus infection MESHD and replication in either Vero or human cell lines. Nine of these also inhibited SARS-CoV-2 replication when treatment commenced after virus infection MESHD. Therapeutics approved for treatment of cancer MESHD, malaria MESHD, hypertension MESHD and viral infection MESHD were identified with atovaquone, manidipine, vitamin D3 and ebastine being well tolerated with minimal side effects. Only two COI HGNC were consistently found to enhance SARS-CoV-2 replication, aliskiren and lithocholic acid. Interpretation: Re-purposing of safe, well-tolerated FDA-approved drugs that inhibit SARS-CoV-2 replication is an attractive strategy to reduce the risk of COVID-19 MESHD infection prior to receiving an effective vaccine. The COI HGNC identified here hold potential to contain COVID-19 MESHD whilst wide-scale vaccination proceeds. The identification of FDA-approved drugs that enhance SARS-CoV-2 replication in human cells suggests that entry routes into cells can be made more accessible to the virus by certain medications. The information provided in this research paper is for information only and is not meant to be a substitute for advice provided by a doctor or other qualified health care professional.

    COVID-19 MESHD and the kidney: A retrospective analysis of 37 critically ill patients using machine learning

    Authors: Anna Laura Herzog; Holger K. Jouanne-Diedrich; Christoph Wanner; Dirk Weismann; Tobias Schlesinger; Patrick Meybohm; Jan Stumpner

    doi:10.21203/rs.3.rs-155976/v1 Date: 2021-01-26 Source: ResearchSquare

    Introduction There is evidence that SARS-CoV2 has a particular affinity for kidney tissue and is often associated with kidney failure MESHD.Methods We assessed whether proteinuria MESHD can be predictive of kidney failure MESHD, the development of chronic kidney disease MESHD, and mortality in 37 critically ill COVID-19 MESHD patients. We used machine learning (ML) methods as decision trees and cut-off points created by the OneR package to add new aspects, even in smaller cohorts.Results Among a total of 37 patients, 24 suffered higher-grade renal failure MESHD, 20 of whom required kidney replacement therapy. More than 40% of patients remained on hemodialysis after intensive care unit discharge or died (27%). Due to frequent anuria proteinuria MESHD measured in two-thirds of the patients, it was not predictive for the investigated endpoints; albuminuria MESHD was higher in patients with AKI 3, but the difference was not significant. ML found cut-off points of > 31.4 kg/m2 for BMI and > 69 years for age, constructed decision trees with great accuracy, and identified highly predictive variables for outcome and remaining chronic kidney disease MESHD.Conclusions Different ML methods and their clinical application, especially decision trees, can provide valuable support for clinical decisions. Presence of proteinuria MESHD was not predictive of CKD or AKI and should be confirmed in a larger cohort.

    Predictors of Mortality in COVID-19 MESHD Patients at Kinshasa Medical Center and A Survival Analysis: A Retrospective Cohort Study

    Authors: Yannick MAYAMBA NLANDU; Danny Mafuta; Junior Sakaji; Melinda Brecknell; Yannick Engole; Jessy Abatha; Jean-Robert Nkumu; Aliocha Nkodila; Marie-France Mboliassa; Olivier Tuyinama; Dauphin Bena; Yves Mboloko; Patrick Kobo; Patrick Boloko; Joseph Tshangu; Philippe Azika; Jean-Pierre Kanku; Pally Mafuta; Magloire Atantama; Jean-Michel Mavungu; Rosita Kitenge; Asma Sehli; Karel Van Eckout; Cathy Mukuku; Léo Bergeret; David Benchetritt; Golan Kalifa; Ahmed Rodolphe; Justine Bukabau

    doi:10.21203/rs.3.rs-153818/v1 Date: 2021-01-23 Source: ResearchSquare

    BackgroundDespite it being a global pandemic, there is little research examining the clinical features of severe COVID-19 MESHD in sub-Saharan Africa. This study aims to identify predictors of mortality in COVID-19 MESHD patients in an African setting.MethodsIn this retrospective, observational, cohort study carried out at the Kinshasa Medical Centre (KMC) between March 10 HGNC, 2020 and July 10, 2020, we included all adult inpatients (≥18 years old) with a laboratory diagnosis by PCR of COVID-19 MESHD. The end point of the study was survival to discharge (time-to-death).The study population was dichotomized into survivors and non-survivors group. Kaplan-Meier plot was used for survival analyses. The Log-Rank test was employed to compare the survival curves. Predictors of mortality were identified by Cox regression models. The significance level of P value was set at 0.05.Results106 patients (mean age 55.6±13.2 years old, 80.2% were male), were included in this study, of whom 34 (32 %) died during their hospitalisation. The main Complications of the patients included ARDS in 59/66 (89.4%) patients, coagulopathy MESHD in 35/93 (37.6%) patients, acute cardiac injury MESHD in 24/98 (24.5%) patients, AKI in 15/74 (20.3%) patients and secondary infection MESHD in 12/81 (14.8%) patients. The independent predictors of mortality were found to be age ≥ 65 years [aHR 2.49; 95% CI: 1.53-5.69], AKI stage 3 [aHR 2.51; 95% CI: 1.33-6.80], proteinuria MESHD [aHR 2.60; 95% CI: 1.40-6.42], CRP HGNC >150 mg/L [aHR 2.75; 95% CI: 1.29-3.68] and procalcitonin (PCT) > 0.5 ng/ml [aHR 3.20; 95% CI: 1.70-7.49].The median survival time of the entire group was 12 days. The cumulative survival rate of COVID-19 MESHD patients was 86.9%, 65.0% and 19.9% respectively at 5, 10 and 20 days. Levels of creatinine (p= 0.012), were clearly elevated in non-survivors compared with survivors throughout the clinical course and increased deterioration.ConclusionThe results from this study demonstrated that an advanced age, proteinuria MESHD, AKI and raised CRP HGNC and PCT offered a worse prognosis in COVID-19 MESHD patients. In addition, serum levels of creatinine significantly rose during admission in the non-survivor group compared with those who survived to discharge.

    Altered kidney function and acute kidney damage markers predict survival outcomes of COVID-19 MESHD patients: A prospective pilot study.

    Authors: Mustafa Zafer Temiz; Ibrahim Hacibey; Ramazan Omer Yazar; Mehmet Salih Sevdi; Suat Hayri Kucuk; Gizem Alkurt; Levent Doganay; Gizem Dinler-Doganay; Muhammed Murat Dincer; Emrah Yuruk; Kerem Erkalp; Ahmet Yaser Muslumanoglu

    doi:10.1101/2021.01.10.20249079 Date: 2021-01-12 Source: medRxiv

    Background: The central role in the pathogenesis of severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), called as coronavirus disease 2019 MESHD ( COVID-19 MESHD), infection is attributed to angiotensin-converting enzyme 2 (ACE-2). ACE-2 expressing respiratory system involvement is the main clinical manifestation of the infection. However, literature about the association between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection MESHD and higher ACE-2 expressing kidney is very limited. In this study, we primarily aimed to investigate whether there is a kidney injury MESHD during the course of SARS-CoV-2 infection MESHD. The predictive value of kidney injury MESHD for survival was also determined. Methods: A total of 47 participants who met the inclusion criteria were included in the study. The participants were classified as COVID-19 MESHD patients before treatment, COVID-19 MESHD patients after treatment, COVID-19 MESHD patients under treatment in ICU and controls. The parameters comorbidity, serum creatinine and cystatin C HGNC levels, CKD-EPI eGFR HGNC levels, KIM-1 HGNC and NGAL HGNC levels, urine KIM-1 HGNC/creatinine and NGAL HGNC/creatinine ratios were statistically compared between the groups. The associations between covariates including kidney disease MESHD indicators and death from COVID-19 MESHD were examined using Cox proportional hazard regression analysis. Results: Serum creatinine and cystatin C HGNC levels, urine KIM-1 HGNC/creatinine levels, and CKD-EPI, CKD-EPI cystatin C HGNC and CKD-EPI creatinine- cystatin C HGNC eGFR HGNC levels exhibited significant difference in the groups. The causes of the difference were more altered kidney function and increased acute kidney damage MESHD in COVID-19 MESHD patients before treatment and under treatment in ICU. Additionally, incidences of comorbidity and proteinuria MESHD in the urine analysis were higher in the COVID-19 MESHD patients under treatment in ICU group. Urine KIM-1 HGNC/creatinine ratio and proteinuria MESHD were associated with COVID-19 MESHD specific death. Conclusions: We found that COVID-19 MESHD patients under treatment in ICU exhibited extremely higher levels of serum cystatin C HGNC, and urine KIM-1 HGNC/creatinine and urine NGAL HGNC/creatinine ratios. These results clearly described the acute kidney damage MESHD by COVID-19 MESHD using molecular kidney damage markers for the first time in the literature. Lowered CKD-EPI, CKD-EPI cystatin C HGNC and CKD-EPI creatinine-cystatin C eGFR levels were determined in them, as well. Urine KIM-1 HGNC/creatinine ratio and proteinuria MESHD were associated with COVID-19 MESHD specific death. In this regard, considering kidney function and kidney damage MESHD markers must not be ignored in the COVID-19 MESHD patients, and serial monitoring of them should be considered.

    Systemic Lupus Erythematosus triggered by SARS-CoV-2 Infection MESHD: A Systematic Review Based on a Case Report

    Authors: Abraham Edgar Gracia-Ramos; Miguel Angel Saavedra-Salinas

    doi:10.21203/rs.3.rs-105222/v1 Date: 2020-11-09 Source: ResearchSquare

    Systemic lupus erythematosus MESHD ( SLE MESHD) is an autoimmune and multisystemic chronic inflammatory disease MESHD that can affect various organs, including skin, joints, kidneys, lungs and the nervous system. Infectious agents have long been implicated in the pathogenesis of SLE MESHD. The new viral infection MESHD caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) has shown that, in genetically predisposed patients, could trigger the presentation or exacerbation of autoimmune disease MESHD. We herein report a case of a 45-year-old man who presented respiratory symptoms MESHD, bilateral pleural effusion MESHD, ascites MESHD, splenomegaly MESHD, severe thrombocytopenia MESHD and renal failure MESHD with proteinuria MESHD and hematuria MESHD. SARS-CoV-2 PCR confirmed the COVID-19 MESHD diagnosis. We diagnosed the patient with SLE MESHD based on the clinical manifestations and positive immunological markers (2019 European League Against Rheumatism MESHD/American College of Rheumatology score of 18). Glucocorticoid pulses were administered to the patient with improvement in renal function. However, thrombocytopenia MESHD was also refractory to IV immunoglobulin and rituximab, so the patient underwent splenectomy. Through a systematic search of the medical literature, we retrieved 2 cases with SLE MESHD new onset and 5 cases with previous SLE MESHD diagnosis that shown activity of disease due SARS-CoV-2 infection MESHD. We herein present a systemic review of these cases and discuss the clinical manifestations that could help to the diagnosis of this clinical condition.

    Acute Kidney Injuries of otherwise normal kidneys have different characteristics in different stages of COVID-19 MESHD

    Authors: Ahmet Murt; Mevlut Tamer Dincer; Cebrail Karaca; Sinan Trabulus; Ridvan Karaali; Ilker Inanc Balkan; Nurhan Seyahi; Mehmet Riza Altiparmak

    doi:10.21203/rs.3.rs-105205/v3 Date: 2020-11-09 Source: ResearchSquare

    BackgroundKidney involvement in COVID-19 MESHD may manifest as acute kidney injury MESHD ( AKI MESHD). This study aimed to analyze and compare AKIs in different stages of COVID-19 MESHD.Methods1056 hospitalized COVID-19 MESHD patients were retrospectively evaluated and 383 of them met the inclusion criteria. Eighty-nine patients who developed AKI MESHD, but didn’t have prior kidney diseases MESHD were involved in the final analysis. Patients were classified into three groups, those who had AKI MESHD on admission, those who developed AKI MESHD in the first week and those who developed AKI MESHD starting from the 7th day. Electrolytes, acid-base status and changes in the inflammatory markers were compared. ResultsPatients who developed AKI MESHD after the 7th day had higher peak CRP HGNC and D-dimer levels and lower nadir lymphocyte counts (p=0.000, 0.004 and 0.003 respectively). AKI MESHD that developed later was more related to immunologic response and had significantly higher mortality, reaching as high as 44% for those who developed AKI MESHD after 7th day. Patients who died had lower serum albumin levels than those who survived (p=0,000). Hematuria MESHD and proteinuria MESHD (p=0.001; OR: 2.4; 95% CI: 1.4 – 3.8 and p=0.015; OR: 4.34; 95% CI: 1.3 – 14.3 respectively) were more common in patients who died. Hypernatremia MESHD (p=0.000, OR: 6.5; 95% CI:3.0 – 13.9) and hyperchloremia (p=0,002, OR:3,8; 95%CI: 1,7 – 8,4) were also observed more often in patients who died.ConclusionsAKI in COVID-19 MESHD is not of one kind. When developed, AKI MESHD should be evaluated in conjunction with the disease stage and possible etiologies. AKI MESHD that develops later has a worse prognosis and is more related to electrolyte abnormalities.

    Proteinuria in COVID-19 MESHD: prevalence, characterization and prognostic role

    Authors: Justine Huart; Antoine Bouquegneau; Laurence Lutteri; Pauline Erpicum; Stéphanie Grosch; Guillaume Résimont; Patricia Wiesen; Christophe Bovy; Jean-Marie Krzesinski; Marie Thys; Bernard Lambermont; Benoit Misset; Hans Pottel; Christophe Mariat; Etienne Cavalier; Stéphane Burtey; François Jouret; Pierre Delanaye

    doi:10.21203/rs.3.rs-57181/v1 Date: 2020-08-11 Source: ResearchSquare

    Background: Proteinuria MESHD has been commonly reported in patients with COVID-19 MESHD, suggesting a renal involvement in this infection. However, only dipstick tests have been used thus far. Here, the quantification and characterization of proteinuria MESHD and hematuria MESHD are investigated. Their potential association with mortality was assessed. Methods: This retrospective, observational and monocentric study includes 153 patients hospitalized with COVID-19 MESHD between March 28th and April 30th 2020, in whom total proteinuria MESHD and urine α1-microglobulin (a marker of tubular injury MESHD) have been measured. Association with mortality was evaluated with a follow-up until May 7th 2020. Results: According to the Kidney Disease MESHD Improving Global Outcomes staging, 14% (n=21) had stage 1 proteinuria MESHD (<150 mg/g of urine creatinine), 42% (n=64) had stage 2 (between 150 and 500 mg/g) and 44% (n=68) had stage 3 (over 500 mg/g). Urine α1-microglobulin concentration was higher than 10 or 15 mg/g in 94% and 89% of patients, respectively. After a median follow-up of 27 [14;30] days, the mortality rate reached 18%. Total proteinuria MESHD and urine α1-microglobulin (as continuous and/or categorical variables) were associated with mortality in unadjusted and adjusted models. This association was even stronger in subgroups of patients with normal renal function or without urinary catheter. Conclusions: Proteinuria MESHD is frequent in patients with COVID-19 MESHD. Its characterization suggests a tubular origin with increased urine α1-microglobulin. Tubular proteinuria MESHD seems associated with mortality in COVID-19 MESHD.

    Incidence, risk factors and mortality outcome in patients with acute kidney injury in COVID-19 MESHD: a single-center observational study

    Authors: Gaetano Alfano; Annachiara Ferrari; Francesco Fontana; Giacomo Mori; Riccardo Magistroni; Meschiari Marianna; Franceschini Erica; Marianna Menozzi; Gianluca Cuomo; Gabriella Orlando; Antonella Santoro; Margherita Di Gaetano; Cinzia Puzzolante; Federica Carli; Andrea Bedini; Jovana Milic; Paolo Raggi; Massimo Girardis; Cristina Mussini; Gianni Cappelli; Giovanni Guaraldi

    doi:10.1101/2020.06.24.20138230 Date: 2020-06-24 Source: medRxiv

    Background Acute kidney injury MESHD ( AKI MESHD) is a recently recognized complication of coronavirus disease-2019 ( COVID-19 MESHD). This study aims to evaluate the incidence, risk factors and case-fatality rate of AKI MESHD in patients with documented COVID-19 MESHD. Methods We reviewed the health medical records of 307 consecutive patients hospitalized for symptoms of COVID-19 MESHD at the University Hospital of Modena, Italy. Results AKI MESHD was diagnosed in 69 out of 307 (22.4%) patients. The stages of AKI MESHD were stage 1 in 57.9%, stage 2 in 24.6% and stage 3 in 17.3%. Hemodialysis was performed in 7.2% of the subjects. AKI MESHD patients had a mean age of 74.7 {+/-} 9.9 years and higher serum levels of the main marker of inflammation MESHD and organ involvement (lung, liver, hearth and liver) than non- AKI MESHD patients. AKI MESHD events were more frequent in subjects with severe lung comprise. Two peaks of AKI MESHD events coincided with in-hospital admission and death of the patients. Kidney injury MESHD was associate with a higher rate of urinary abnormalities MESHD including proteinuria MESHD (0.448{+/-} 0.85 vs 0.18 {+/-} 0.29; P=<0.0001) and hematuria MESHD (P=0.032) compared to non- AKI MESHD patients. At the end of follow-up, 65.2% of the patients did not recover their renal function after AKI MESHD. Risk factors for kidney injury MESHD were age, male sex, CKD and non-renal SOFA. Adjusted Cox regression analysis revealed that AKI MESHD was independently associated with in-hospital death (hazard ratio [HR]=3.74; CI 95%, 1.34-10.46) compared to non- AKI MESHD patients. Groups of patients with AKI MESHD stage 2-3 and failure to recover kidney function were associated with the highest risk of in-hospital mortality. Lastly, long-hospitalization was positively associated with a decrease of serum creatinine, likely due to muscle depletion occurred with prolonged bed rest. Conclusions AKI MESHD was a dire consequence of patients with COVID-19 MESHD. Identification of patients at high-risk for AKI MESHD and prevention of kidney injury MESHD by avoiding dehydration MESHD and nephrotoxic MESHD agents is imperative in this vulnerable cohort of patients.

    Clinical and pathological findings of SARS-CoV-2 infection MESHD and concurrent IgA nephropathy: A case report

    Authors: Liu Liu

    doi:10.21203/rs.3.rs-35388/v1 Date: 2020-06-14 Source: ResearchSquare

    Background: Since the Coronavirus Disease 2019 MESHD ( COVID-19 MESHD) outbreak, there is limited data on the clinical characteristics, treatment strategies and prognosis of COVID-19 MESHD in patients with concurrent renal disease MESHD. The kidney is believed to have a predisposition for COVID-19 MESHD due to its abundant angiotensin-converting enzyme 2 (ACE2) expression, which acts as a cell entry receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent postmortem investigations reveal renal involvement in COVID-19 MESHD, and case reports describe collapsing glomerulopathy MESHD in African American patients with COVID-19 MESHD. However, there is limited data regarding IgA nephropathy MESHD in the setting of COVID-19 MESHD.Case presentation: In the present case, we report a 65-year old Chinese woman who presented with macroscopic hematuria MESHD, worsening proteinuria MESHD and decreased renal function MESHD after COVID-19 MESHD infection. She received a renal biopsy during COVID-19 MESHD infection. The renal biopsy revealed IgA nephropathy MESHD without any evidence for SARS-Cov-2. The findings suggest that the renal abnormalities MESHD were a consequence of exacerbation of this patient’s underlying glomerular disease MESHD after COVID-19 MESHD infection. After a regimen of 3-day course of glucocorticoid and angiotensin II receptor blocker therapy, the patient recovered and remained stable upon follow-up. Conclusions: It is important to consider the underlying glomerular disease MESHD exacerbation rather than virus induced injury MESHD when dealing with renal abnormalities MESHD in patients with COVID-19 MESHD.

    Incidence and risk factors of kidney impairment on patients with COVID-19 MESHD: a systematic review and meta-analysis

    Authors: Qixin Yang; Xiyao Yang

    doi:10.1101/2020.05.28.20116400 Date: 2020-06-03 Source: medRxiv

    Background: The novel coronavirus is pandemic around the world. Several researchers have given the evidence of impacts of COVID-19 MESHD on the respiratory, cardiovascular and gastrointestinal system MESHD. Studies still have debated on kidney injury MESHD of COVID-19 MESHD patients. The purpose of the meta-analysis was to evaluate the association of kidney impairment MESHD with the development of COVID-19 MESHD. Methods: The PubMed, Embase and MedRxiv databases were searched until April 1, 2020. We extracted data from eligible studies to summarize the clinical manifestations and laboratory indexes of kidney injury MESHD on COVID-19 MESHD infection patients and further compared the prevalence of acute kidney injury MESHD ( AKI MESHD) and the mean differences of three biomarkers between in ICU/severe and non-ICU/non-severe cases. Heterogeneity was evaluated using the I2 method. Results: In the sum of 19 studies with 4375 patients were included in this analysis. The pooled prevalence of AKI MESHD, increased serum creatinine (Scr), increased blood urea nitrogen (BUN), increased D-dimer, proteinuria MESHD and hematuria MESHD in patients with COVID-19 MESHD were 7.7%, 6.6%, 6.2%, 49.8%, 42% and 30.3% respectively. Moreover, the means of Scr, BUN and D-dimer were shown 6-folds, 1.8-folds and 0.68-folds, respectively, higher in ICU/severe cases than in corresponding non-ICU/non-severe patients. The prevalence of AKI MESHD was about 17 folds higher in ICU/severe patients compared with the non-ICU/non-severe cases. Conclusions: Overall, we assessed the incidences of the clinic and laboratory features of kidney injury MESHD in COVID-19 MESHD patients. And kidney dysfunction MESHD may be a risk factor for COVID-19 MESHD patients developing into the severe condition. In reverse, COVID-19 MESHD can also cause damage to the kidney.

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