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1.
Internal Medicine Journal ; 52(SUPPL 1):7, 2022.
Article in English | EMBASE | ID: covidwho-1916177

ABSTRACT

Background: Upper gastrointestinal bleeding (UGIB) is a common gastrointestinal emergency and carries a high morbidity and mortality. There are multiple risk factors for poorer outcomes, including malnutrition. Ascorbic acid is a water-soluble vitamin present in most plant foods. Dietary deficiency leads to scurvy, which may alter the natural history of UGIB through impaired tissue and mucosal integrity. Traditionally thought to be rare in developed countries, Vitamin C deficiency (VCD) is now well described in patients with pneumonia, sepsis and COVID-191, 2. There is a paucity of literature investigating the prevalence and clinical significance of VCD in UGIB;interim findings reported by our group suggested a prevalence of >30%. Aim: The aim of this study was to establish the prevalence of VCD in patients presenting with UGIB and its association with clinical outcomes. Methods: We conducted a prospective cohort study of adult patients presenting with UGIB to two metropolitan tertiary hospitals in Melbourne, Australia over a 12-month period (March 2020 to March 2021). Fasting Vitamin C levels were obtained on admission. Patients were risk stratified using the AIMS65 score and baseline demographic data and outcomes were recorded. The primary outcome was the prevalence of VCD (serum Vitamin C level <23mcmol/L) and severe VCD (<12mcmol/L). Secondary outcomes included a composite endpoint of adverse events (AE), comprising inpatient death, intensive care unit (ICU) admission, rebleeding, surgery, angioembolisation or massive transfusion (≥4 units of red cells). Multivariate logistic regression was used to determine the association between Vitamin C levels and the secondary endpoints. Subgroup analyses were performed in variceal and non-variceal UGIB and high- (AIMS65≥2) and low-risk (AIMS65 0-2) UGIB. Results: 227 patients were included. The mean age was 65±17 years, 145 (63.9%) were male and median AIMS65 score was 1 (IQR 1-2). The aetiology of UGIB was variceal bleeding in 20.3%, peptic ulcer disease (PUD) in 44.1% and other causes in 35.7%. The mean Vitamin C level was 40±26mcmol/L. In terms of patient outcomes, inpatient mortality was 4%, ICU admission occurred in 11.9% and mean length of stay (LOS) was 7.7±9.7 days. Red cell transfusion was required in 63.4% of patients with a mean requirement of 2.2±2.8 units. VCD was identified in 74 patients (32.6%) with severe deficiency in 32 (14.1%). VCD was associated with significantly higher in-hospital mortality (9.5% vs. 1.3%, p=0.01), prolonged LOS (10.8 vs. 6.2 days, p<0.01), rebleeding (17.6% vs. 7.88%, p=0.05) and a higher composite endpoint of AE (77% vs. 54.9%, p<0.01). At multivariate logistic regression, high-risk UGIB (OR 3.24, CI 1.42-7.42), VCD (OR 2.28, CI1.11-4.71) and chronic liver disease (OR 11.66, CI 2.92-46.64) were all independently associated with the composite endpoint of AE. At subgroup analysis, VCD was associated with a significantly increased composite endpoint of AE in patients with non-variceal (74% vs. 51%, p<0.01) and low-risk UGIB (66% vs. 44%, p=0.04). Conclusion: VCD is highly prevalent in patients with UGIB and associated with poorer outcomes, including higher mortality, rebleeding and LOS. Interventional studies are required to determine the impact of early Vitamin C supplementation on clinical outcomes.

3.
Front Microbiol ; 13: 878342, 2022.
Article in English | MEDLINE | ID: covidwho-1879462

ABSTRACT

COVID-19 emerged at varying intervals in different regions of the United States in 2020. This report details the epidemiologic and genetic evolution of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first year of the epidemic in the state of Nebraska using data collected from the Creighton Catholic Health Initiatives (CHI) health system. Statistical modelling identified age, gender, and previous history of diabetes and/or stroke as significant risk factors associated with mortality in COVID-19 patients. In parallel, the viral genomes of over 1,000 samples were sequenced. The overall rate of viral variation in the population was 0.07 mutations/day. Genetically, the first 9 months of the outbreak, which include the initial outbreak, a small surge in August and a major outbreak in November 2020 were primarily characterized by B.1. lineage viruses. In early 2021, the United Kingdom variant (B.1.1.7 or alpha) quickly became the dominant variant. Notably, surveillance of non-consensus variants detected B.1.1.7 defining mutations months earlier in Fall 2020. This work provides insights into the regional variance and evolution of SARS-CoV-2 in the Nebraska region during the first year of the pandemic.

4.
Front Cell Dev Biol ; 10: 855340, 2022.
Article in English | MEDLINE | ID: covidwho-1834354

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the Coronavirus disease 2019 (COVID-19), which has resulted in over 5.9 million deaths worldwide. While cells in the respiratory system are the initial target of SARS-CoV-2, there is mounting evidence that COVID-19 is a multi-organ disease. Still, the direct affinity of SARS-CoV-2 for cells in other organs such as the kidneys, which are often targeted in severe COVID-19, remains poorly understood. We employed a human induced pluripotent stem (iPS) cell-derived model to investigate the affinity of SARS-CoV-2 for kidney glomerular podocytes, and examined the expression of host factors for binding and processing of the virus. We studied cellular uptake of the live SARS-CoV-2 virus as well as a pseudotyped virus. Infection of podocytes with live SARS-CoV-2 or spike-pseudotyped lentiviral particles revealed cellular uptake even at low multiplicity of infection (MOI) of 0.01. We found that direct infection of human iPS cell-derived podocytes by SARS-CoV-2 virus can cause cell death and podocyte foot process retraction, a hallmark of podocytopathies and progressive glomerular diseases including collapsing glomerulopathy observed in patients with severe COVID-19 disease. We identified BSG/CD147 and ACE2 receptors as key mediators of spike binding activity in human iPS cell-derived podocytes. These results show that SARS-CoV-2 can infect kidney glomerular podocytes in vitro via multiple binding interactions and partners, which may underlie the high affinity of SARS-CoV-2 for kidney tissues. This stem cell-derived model is potentially useful for kidney-specific antiviral drug screening and mechanistic studies of COVID-19 organotropism.

5.
mBio ; 13(3): e0078422, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-1807327

ABSTRACT

The main protease, Mpro, of SARS-CoV-2 is required to cleave the viral polyprotein into precise functional units for virus replication and pathogenesis. Here, we report quantitative reporters for Mpro function in living cells in which protease inhibition by genetic or chemical methods results in robust signal readouts by fluorescence (enhanced green fluorescent protein [eGFP]) or bioluminescence (firefly luciferase). These gain-of-signal systems are scalable to high-throughput platforms for quantitative discrimination between Mpro mutants and/or inhibitor potencies as evidenced by validation of several reported inhibitors. Additional utility is shown by single Mpro amino acid variants and structural information combining to demonstrate that both inhibitor conformational dynamics and amino acid differences are able to influence inhibitor potency. We further show that a recent variant of concern (Omicron) has an unchanged response to a clinically approved drug, nirmatrelvir, whereas proteases from divergent coronavirus species show differential susceptibility. Together, we demonstrate that these gain-of-signal systems serve as robust, facile, and scalable assays for live cell quantification of Mpro inhibition, which will help expedite the development of next-generation antivirals and enable the rapid testing of emerging variants. IMPORTANCE The main protease, Mpro, of SARS-CoV-2 is an essential viral protein required for the earliest steps of infection. It is therefore an attractive target for antiviral drug development. Here, we report the development and implementation of two complementary cell-based systems for quantification of Mpro inhibition by genetic or chemical approaches. The first is fluorescence based (eGFP), and the second is luminescence based (firefly luciferase). Importantly, both systems rely upon gain-of-signal readouts such that stronger inhibitors yield higher fluorescent or luminescent signal. The high versatility and utility of these systems are demonstrated by characterizing Mpro mutants and natural variants, including Omicron, as well as a panel of existing inhibitors. These systems rapidly, safely, and sensitively identify Mpro variants with altered susceptibilities to inhibition, triage-nonspecific, or off-target molecules and validate bona fide inhibitors, with the most potent thus far being the first-in-class drug nirmatrelvir.


Subject(s)
Antiviral Agents , Coronavirus 3C Proteases , Protease Inhibitors , SARS-CoV-2 , Amino Acids , Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Luciferases, Firefly , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/genetics
6.
Clinical nutrition ESPEN ; 48:515-516, 2022.
Article in English | EuropePMC | ID: covidwho-1756124
7.
Non-conventional in English | International HTA Db, Grey literature | ID: grc-751140
9.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326588

ABSTRACT

Reports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet beta cells. This would require binding and entry of SARS-CoV-2 into host beta cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes. ACE2 and TMPRSS2 transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in alpha or beta cells from these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of significant ACE2 and TMPRSS2 co-expression in islet endocrine cells reduces the likelihood that SARS-CoV-2 directly infects pancreatic islet beta cells through these cell entry proteins.

10.
Gastroenterology ; 160(6):S-747, 2021.
Article in English | EMBASE | ID: covidwho-1594220

ABSTRACT

Background: Upper gastrointestinal bleeding (UGIB) remains the most common gastrointestinal emergency associated with high morbidity and mortality. Established risk factors for UGIB include Helicobacter pylori infection and non steroidal anti inflammatory use. While thought to be rare in developed countries, Vitamin C deficiency (VCD) is well described in patients with pneumonia, sepsis and more recently Coronavirus disease 2019. No previous studies have investigated the impact of VCD in UGIB. Aims: To investigate the prevalence of VCD in patients presenting with UGIB and the association between VCD and clinical outcomes. Methods: Patients presenting with UGIB to 2 Australian tertiary centers were prospectively recruited over a 10-month period. Fasting Vitamin C levels were obtained on admission. All patients were risk stratified using the AIMS65 score. The primary outcome was the prevalence of VCD (Vitamin C level <23mcmol/L) and severe deficiency (<11mcmol/L). Secondary outcomes included a composite endpoint of adverse events (AE), comprising inpatient death, intensive care unit (ICU) admission, rebleeding, surgery, angioembolization or massive transfusion ($4 units blood). Subgroup analyses were performed in variceal and non-variceal UGIB and outcomes stratified by AIMS65 score. Results: 157 patients were included. Median age was 64 years (IQR 53-77), 65% were male and median AIMS65 was 1 (IQR 1-2). Mean Vitamin C level was 39.5 ± 25mcmol/L. The etiology of UGIB was variceal bleeding (21.6%), peptic ulcer disease (45.2%) and other (33.1%). Inpatient mortality was 5.7% and mean length of stay (LOS) was 7.7 days. VCD was identified in 53 patients (33.8%) with severe deficiency in 21 (13.3%). VCD was associated with significantly higher mortality (13.2% vs. 1.9%, p<0.01) and AEs (composite endpoint 47.2% vs. 28.8%, p=0.02). Inpatient rebleeding was higher in the VCD group (13.2% vs. 7.7%, p=0.27);this did not reach significance, most likely due to Type 2 error. No differences in ICU admission, transfusion requirements, LOS or AIMS65 score were noted. In non-variceal UGIB (n=123), VCD was associated with higher mortality (5.6% vs. 0%, p=0.03) and AEs (composite endpoint 41.7% vs. 24.1%, p=0.05). VCD was most prevalent in patients with variceal UGIB (50% vs. 29%, p=0.02) and associated with a trend towards higher mortality (29.4% vs. 11.7%, p=0.21). In the low-risk UGIB cohort (AIMS65 score 0-2), VCD was associated with increased mortality (10% vs. 0%, p<0.01) and AEs (composite endpoint 36.7% vs. 17.1%, p=0.03);in the high-risk UGIB cohort (AIMS65 35), VCD was associated with a trend towards higher mortality (17.4% vs. 6.1%, p=0.18). Conclusion: VCD is prevalent in patients with UGIB and associated with significantly higher mortality and AEs. Further studies are required to determine the impact of early Vitamin C supplementation following UGIB.

11.
JAMIA Open ; 4(3): ooab077, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1584263

ABSTRACT

OBJECTIVE: We help identify subpopulations underrepresented in randomized clinical trials (RCTs) cohorts with respect to national, community-based or health system target populations by formulating population representativeness of RCTs as a machine learning (ML) fairness problem, deriving new representation metrics, and deploying them in easy-to-understand interactive visualization tools. MATERIALS AND METHODS: We represent RCT cohort enrollment as random binary classification fairness problems, and then show how ML fairness metrics based on enrollment fraction can be efficiently calculated using easily computed rates of subpopulations in RCT cohorts and target populations. We propose standardized versions of these metrics and deploy them in an interactive tool to analyze 3 RCTs with respect to type 2 diabetes and hypertension target populations in the National Health and Nutrition Examination Survey. RESULTS: We demonstrate how the proposed metrics and associated statistics enable users to rapidly examine representativeness of all subpopulations in the RCT defined by a set of categorical traits (eg, gender, race, ethnicity, smoking status, and blood pressure) with respect to target populations. DISCUSSION: The normalized metrics provide an intuitive standardized scale for evaluating representation across subgroups, which may have vastly different enrollment fractions and rates in RCT study cohorts. The metrics are beneficial complements to other approaches (eg, enrollment fractions) used to identify generalizability and health equity of RCTs. CONCLUSION: By quantifying the gaps between RCT and target populations, the proposed methods can support generalizability evaluation of existing RCT cohorts. The interactive visualization tool can be readily applied to identified underrepresented subgroups with respect to any desired source or target populations.

12.
Viruses ; 13(12)2021 11 23.
Article in English | MEDLINE | ID: covidwho-1542793

ABSTRACT

Evidence varies as to how far aerosols spread from individuals infected with SARS-CoV-2 in hospital rooms. We investigated the presence of aerosols containing SARS-CoV-2 inside of dedicated COVID-19 patient rooms. Three National Institute for Occupational Safety and Health BC 251 two-stage cyclone samplers were set up in each patient room for a six-hour sampling period. Samplers were place on tripods, which each held two samplers at various heights above the floor. Extracted samples underwent reverse transcription polymerase chain reaction for selected gene regions of the SARS-CoV-2 virus nucleocapsid. Patient medical data were compared between participants in rooms where virus-containing aerosols were detected and those where they were not. Of 576 aerosols samples collected from 19 different rooms across 32 participants, 3% (19) were positive for SARS-CoV-2, the majority from near the head and foot of the bed. Seven of the positive samples were collected inside a single patient room. No significant differences in participant clinical characteristics were found between patients in rooms with positive and negative aerosol samples. SARS-CoV-2 viral aerosols were detected from the patient rooms of nine participants (28%). These findings provide reassurance that personal protective equipment that was recommended for this virus is appropriate given its spread in hospital rooms.


Subject(s)
COVID-19/virology , Patients' Rooms , SARS-CoV-2/isolation & purification , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , Coronavirus Nucleocapsid Proteins/genetics , Hospitals , Humans , Middle Aged , Patients' Rooms/statistics & numerical data , Phosphoproteins/genetics , RNA, Viral/genetics , SARS-CoV-2/genetics
15.
Preprint in English | bioRxiv | ID: ppbiorxiv-468893

ABSTRACT

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the Coronavirus disease 2019 (COVID-19), which was declared a pandemic by the World Health Organization (WHO) in March 2020. The disease has caused more than 5.1 million deaths worldwide. While cells in the respiratory system are frequently the initial target for SARS-CoV-2, clinical studies suggest that COVID-19 can become a multi-organ disease in the most severe cases. Still, the direct affinity of SARS-CoV-2 for cells in other organs such as the kidneys, which are often affected in severe COVID-19, remains poorly understood. MethodIn this study, we employed a human induced pluripotent stem (iPS) cell-derived model to investigate the affinity of SARS-CoV-2 for kidney glomerular podocytes. We studied uptake of the live SARS-CoV-2 virus as well as pseudotyped viral particles by human iPS cell derived podocytes using qPCR, western blot, and immunofluorescence. Global gene expression and qPCR analyses revealed that human iPS cell-derived podocytes express many host factor genes (including ACE2, BSG/CD147, PLS3, ACTR3, DOCK7, TMPRSS2, CTSL CD209, and CD33) associated with SARS-CoV-2 binding and viral processing. ResultInfection of podocytes with live SARS-CoV-2 or spike-pseudotyped lentiviral particles revealed viral uptake by the cells at low Multiplicity of Infection (MOI of 0.01) as confirmed by RNA quantification and immunofluorescence studies. Our results also indicate that direct infection of human iPS cell-derived podocytes by SARS-CoV-2 virus can cause cell death and podocyte foot process retraction, a hallmark of podocytopathies and progressive glomerular diseases including collapsing glomerulopathy observed in patients with severe COVID-19 disease. Additionally, antibody blocking experiments identified BSG/CD147 and ACE2 receptors as key mediators of spike binding activity in human iPS cell-derived podocytes. ConclusionThese results show that SARS-CoV-2 can infect kidney glomerular podocytes in vitro. These results also show that the uptake of SARS-CoV-2 by kidney podocytes occurs via multiple binding interactions and partners, which may underlie the high affinity of SARS-CoV-2 for kidney tissues. This stem cell-derived model is potentially useful for kidney-specific antiviral drug screening and mechanistic studies of COVID-19 organotropism. Significant statementMany patients with COVID19 disease exhibit multiorgan complications, suggesting that SARS-CoV-2 infection can extend beyond the respiratory system. Acute kidney injury is a common COVID-19 complication contributing to increased morbidity and mortality. Still, SARS-Cov-2 affinity for specialized kidney cells remain less clear. By leveraging our protocol for stem cell differentiation, we show that SARS-CoV-2 can directly infect kidney glomerular podocytes by using multiple Spike-binding proteins including ACE2 and BSG/CD147. Our results also indicate that infection by SARS-CoV-2 virus can cause podocyte cell death and foot process effacement, a hallmark of podocytopathies including collapsing glomerulopathy observed in patients with severe COVID-19 disease. This stem cell-derived model is potentially useful for kidney-specific antiviral drug screening and mechanistic studies of COVID-19 organotropism.

16.
Journal of Gastroenterology and Hepatology ; 36(SUPPL 3):143, 2021.
Article in English | EMBASE | ID: covidwho-1467576

ABSTRACT

Background and Aim: Upper gastrointestinal bleeding (UGIB) is a common gastrointestinal emergency and carries high morbidity and mortality. There are multiple risk factors for poorer outcomes, including malnutrition. Ascorbic acid is a water-soluble vitamin present in most plant foods. Dietary deficiency leads to scurvy, which may alter the natural history of UGIB through impaired tissue and mucosal integrity. Traditionally thought to be rare in developed countries, vitamin C deficiency (VCD) is now well described in patients with pneumonia, sepsis, and coronavirus disease 2019. There is a paucity of literature investigating the prevalence and clinical significance of VCD in patients with UGIB;interim findings reported by our group suggested a prevalence of >30%. The aim of this study was to establish the prevalence of VCD in patients presenting with UGIB and its association with clinical outcomes. Methods: We conducted a prospective cohort study of adult patients presenting with UGIB to two metropolitan tertiary hospitals in Melbourne, Australia, over a 12-month period (March 2020 to March 2021). Fasting vitamin C levels were obtained on admission. Patients were risk-stratified using the AIMS65 score, and baseline demographic data and outcomes were recorded. The primary outcome was the prevalence of VCD (serum vitamin C level < 23 μmol/L) and severe VCD (<12 μmol/L). Secondary outcomes included a composite endpoint of adverse events (AE), comprising inpatient death, intensive care unit (ICU) admission, rebleeding, surgery, angioembolization, or massive transfusion (≥4 units of red cells). Multivariate logistic regression was used to determine the association between vitamin C levels and the secondary endpoints. Subgroup analyses were performed in variceal and non-variceal UGIB and high-risk (AIMS65, ≥2) and low-risk (AIMS65, 0-2) UGIB. Results: A total of 227 patients were included. The median age was 65 years (IQR, 54-78), 145 (63.9%) were male, and the median AIMS65 score was 1 (IQR, 1-2). The etiology of UGIB was variceal bleeding in 20.3%, peptic ulcer disease in 44.1%, and other causes in 35.7%. The mean vitamin C level was 40 ± 26 μmol/L. In terms of patient outcomes, inpatient mortality was 4%, ICU admission occurred for 11.9%, and mean length of stay (LOS) was 7.7 ± 9.7 days. Red cell transfusion was required in 63.4% of patients, with a mean requirement of 2.2 ± 2.8 units. VCD was identified in 74 patients (32.6%), with severe deficiency in 32 (14.1%). VCD was associated with significantly higher in-hospital mortality (9.5% vs 1.3%, P = 0.01), prolonged LOS (10.8 vs 6.2 days, P < 0.01), rebleeding (17.6% vs 7.88%, P = 0.05), and a higher composite endpoint of AE (77% vs 54.9%, P < 0.01). On multivariate logistic regression, high-risk UGIB (odds ratio [OR], 3.24;95% CI, 1.42-7.42), VCD (OR, 2.28;95% CI, 1.11-4.71), and chronic liver disease (OR, 11.66;95% CI, 2.92-46.64) were all independently associated with the composite endpoint of AE. In subgroup analysis, VCD was associated with a significantly increased composite endpoint of AE in patients with non-variceal (74% vs 51%, P < 0.01) and low-risk (66% vs 44%, P = 0.04) UGIB. Conclusion: VCD is highly prevalent in patients with UGIB and associated with poorer outcomes, including higher mortality, rebleeding, and LOS. Interventional studies are required to determine the impact of early vitamin C supplementation on clinical outcomes.

17.
Clin Infect Dis ; 73(7): e1790-e1794, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1455276

ABSTRACT

BACKGROUND: Previous research has shown that rooms of patients with coronavirus disease 2019 (COVID-19) present the potential for healthcare-associated transmission through aerosols containing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, data on the presence of these aerosols outside of patient rooms are limited. We investigated whether virus-containing aerosols were present in nursing stations and patient room hallways in a referral center with critically ill COVID-19 patients. METHODS: Eight National Institute for Occupational Safety and Health BC 251 2-stage cyclone samplers were set up throughout 6 units, including nursing stations and visitor corridors in intensive care units and general medical units, for 6 h each sampling period. Samplers were placed on tripods which held 2 samplers positioned 102 cm and 152 cm above the floor. Units were sampled for 3 days. Extracted samples underwent reverse transcription polymerase chain reaction for selected gene regions of the SARS-CoV-2 virus nucleocapsid and the housekeeping gene human RNase P as an internal control. RESULTS: The units sampled varied in the number of laboratory-confirmed COVID-19 patients present on the days of sampling. Some of the units included patient rooms under negative pressure, while most were maintained at a neutral pressure. Of 528 aerosol samples collected, none were positive for SARS-CoV-2 RNA by the estimated limit of detection of 8 viral copies/m3 of air. CONCLUSIONS: Aerosolized SARS-CoV-2 outside of patient rooms was undetectable. While healthcare personnel should avoid unmasked close contact with each other, these findings may provide reassurance for the use of alternatives to tight-fitting respirators in areas outside of patient rooms during the current pandemic.


Subject(s)
COVID-19 , SARS-CoV-2 , Critical Illness , Humans , RNA, Viral/genetics , Referral and Consultation , United States
18.
Preprint in English | bioRxiv | ID: ppbiorxiv-463234

ABSTRACT

Macrodomains are a class of conserved ADP-ribosylhydrolases expressed by viruses of pandemic concern, including coronaviruses and alphaviruses. Viral macrodomains are critical for replication and virus-induced pathogenesis; therefore, these enzymes are a promising target for antiviral therapy. However, no potent or selective viral macrodomain inhibitors currently exist, in part due to the lack of a high-throughput assay for this class of enzymes. Here, we developed a high-throughput ADP-ribosylhydrolase assay using the SARS-CoV-2 macrodomain Mac1. We performed a pilot screen which identified dasatinib and dihydralazine as ADP-ribosylhydrolase inhibitors. Importantly, dasatinib does not inhibit MacroD2, the closest Mac1 homolog in humans. Our study demonstrates the feasibility of identifying selective inhibitors based on ADP-ribosylhydrolase activity, paving the way for screening large compound libraries to identify improved macrodomain inhibitors and explore their potential as antiviral therapies for SARS-CoV-2 and future viral threats.

19.
Medicine and Science in Sports and Exercise ; 53(8):209-210, 2021.
Article in English | Web of Science | ID: covidwho-1436836
20.
Advances in Sociology Research. Volume 35 ; : 97-123, 2021.
Article in English | Scopus | ID: covidwho-1436835

ABSTRACT

As the global community awaits the distribution of the COVID-19 vaccine, the prevention etiquette of social distancing, also known as physical distancing, is being championed as a means of reducing the rate of infections. Social distancing measures offer valuable strategies to halt the spread of a virus and forms an integral part of a pandemic preparedness plan at both the national and international levels. The nationwide and restricted lockdowns implemented in many countries in a gradualist approach to limit and stop the spread;provide adequate care for the sick;limit the impact on social and economic life;inspire expansion of domestic capability and deepen self-reliance has brought to the fore, housings' significance in social development. These measures being in sync with the emergence and subsequent transmission of global pandemic (COVID-19) reveal the importance of access to decent housing as a strategic input in the economic, social, and civic development of every nation. With millions of people living in substandard housing units where the housing conditions and essential services do not support such a practice (social distancing), the adherence to social distancing and the practice of good hygiene (the necessary COVID-19 prevention protocols) has become an oxymoron for many of the global population. This chapter presents a synthesis of the evidence from literature on the implications of housing on social distancing effectiveness among people living in substandard housing units in Ghana. Specifically, it brings to the fore, new policy dimensions that the country have, is and should explore to support adherence to the directive (social distancing), especially among vulnerable populations like slum dwellers and the homeless. © 2021 Nova Science Publishers, Inc.

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