Discovery of Isojacareubin as a covalent inhibitor of SARS-CoV-2 main protease using structural and experimental approaches.

The ongoing pandemic with the emergence of immune evasion potential and, particularly, the current omicron subvariants intensified the situation further. Although vaccines are available, the immune evasion capabilities of the recent variants demand further efficient therapeutic choices to control the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Hence, considering the necessity of the small molecule inhibitor, we target the main protease (3CLpro), which is an appealing target for the development of antiviral drugs against SARS-CoV-2. High-throughput molecular in silico screening of South African natural compounds database reported Isojacareubin and Glabranin as the potential inhibitors for the main protease. The calculated docking scores were reported to be -8.47 and -8.03 kcal/mol, respectively. Moreover, the structural dynamic assessment reported that Isojacareubin in complex with 3CLpro exhibit a more stable dynamic behavior than Glabranin. Inhibition assay indicated that Isojacareubin could inhibit SARS-CoV-2 3CLpro in a time- and dose-dependent manner, with half maximal inhibitory concentration values of 16.00 ± 1.35 µM (60 min incubation). Next, the covalent binding sites of Isojacareubin on SARS-CoV-2 3CLpro was identified by biomass spectrometry, which reported that Isojacareubin can covalently bind to thiols or Cysteine through Michael addition. To evaluate the inactivation potency of Isojacareubin, the inactivation kinetics was further investigated. The inactivation kinetic curves were plotted according to various concentrations with gradient-ascending incubation times. The KI value of Isojacareubin was determined as 30.71 µM, whereas the Kinact value was calculated as 0.054 min-1 . These results suggest that Isojacareubin is a covalent inhibitor of SARS-CoV-2 3CLpro .

Dual functionalisation of polyurethane foam for unprecedented flame retardancy and antibacterial properties using layer-by-layer assembly of MXene chitosan with antibacterial metal particles

Antibacterial surfaces in healthcare settings are an important tool for combating the increasing threat of antibacterial drug resistance, which the global Covid-19 pandemic has further exacerbated. Herein, we report a new method to achieve dual antibacterial and flame retardant functionalities in flexible polyurethane foam (PUF) by synthesising a multifunctional coating using a layer-by-layer assembly technique. The coating consists of Ti3C2 nanosheets and chitosan as the flame retardant and metal particles (copper or silver) for the antibacterial property. Results show that the multilayer Ti3C2/CH/Ag coating possesses excellent antibacterial performance with reductions of 99.97% in gram-negative bacteria (P. aeruginosa) and 88.9% in gram-positive bacteria (S. aureus) compared with the unmodified counterpart. Compared with the pristine PUF, the multifunctional coating yielded 66.3% reductions in the PHRR, and demonstrated outstanding smoke suppression performance with a PSPR reduction of 51.6% and a TSR decline of 65.5%. Moreover, Raman spectroscopy revealed an increased graphitisation level in the residual char of the coated foam, indicating the coating's remarkable charring performance. This exceptional multifunctional performance endows the coating technology with a great potential for eradicating the fire risks of antibacterial surfaces in healthcare settings and providing furniture, interior walls and building panels with antibacterial properties.

Re-emergence of Severe Acute Diarrhea Syndrome Coronavirus (SADS-CoV) in Guangxi, China, 2021 (preprint)

Severe acute diarrhea syndrome coronavirus (SADS-CoV) has had a major impact on the swine industry in China, but has not been detected since 2019. Using real-time qPCR and metagenomic surveillance we identified SADS-CoV in a pig farm experiencing diarrheal disease. Genomic analysis supported the undetected circulation of SADS-CoV since 2019.

Preparation of different fragments of SARS-co V-2 urine protein and its application in fluorescent layer system

Expression and purification of different fragments of the new coronavirus nucleocapsid (N) protein, establish a new coronavirus total antibody fluorescence immunochromatographic method and evaluate the influence of different protein fragments on the method. Using bioinformatics technology to analyze, synthesize, express and purify the N protein sequence, prepare different N protein fragments;use 1-ethyl-(3-dimethylaminopropyl) carbodiimide (1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) method of fluorescent microspheres coupled with antigen was established to establish a sandwich fluorescence chromatography antibody detection method, and the performance was evaluated respectively. In the prepared 4 N protein fragments, the full-length N protein (N419) is preferably coated, and N412 is labeled with 0.5mol/L NaCl as the optimal combination;the 91-120th amino acid (N412) of the N-terminus of the N antigen is deleted It can reduce 87.5% of non-specific interference;the linear range is 0.312-80U/L, the lowest detection limit is 0.165U/L, and the accuracy is above 95%. The fluorescence immunochromatographic detection method for total antibodies of the new coronavirus established by pairing the N protein fragments has a total coincidence rate of 98% compared with the Guangzhou Wanfu test strip. The improvement provides experimental basis and reference.

SARS-CoV-2 new variants: Characteristic features and impact on the efficacy of different vaccines.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its new variants reported in different countries have posed a serious threat to human health and social fabrics worldwide. In addition, these new variants hindered the efforts of vaccines and other therapeutic developments. In this review article, we explained the emergence of new variants of SARS-CoV-2, their transmission risk, mortality rate, and, more importantly, the impact of each new variant on the efficacy of the developed vaccines reported in different literature and findings. The literature reported that with the emergence of new variants, the efficacy of different vaccines is declined, hospitalization and the risk of reinfection is increased. The reports concluded that the emergence of a variant that entirely evades the immune response triggered by the vaccine is improbable. The emergence of new variants and reports of re-infections are creating a more distressing situation and therefore demands further investigation to formulate an effective therapeutic strategy.

Network of “drug-target-SARS-CoV-2 Related Genes” Through Integrated Analysis of Pharmacology and Geo Database (preprint)

BackgroundCoronavirus Disease 2019 (COVID-19) respiratory disease rapidly caused a global pandemic and social and economic disruption. The combination of Traditional Chinese medicine (TCM) and Conventional Western medicine (CWM) is more effective for COVID-19 treatment. Moreover, TCM and CWM are important data source for developing new drug targets and promote strategies treat SARS-CoV-2 infections. However, many studies have analyzed the therapeutic mechanism of CWM or TCM alone for COVID-19, it is still unclear the interaction mechanism between TCM and CWM on COVID-19.MethodsThis paper integrates network pharmacology and GEO database to mine and identify COVID-19 molecular therapeutic targets, providing potential targets and new ideas for COVID-19 gene therapy and new drug development. It includes: 1) using TCMSP, TTD, PubChem and CTD databases to analyze drug interactions and associated phenotypes for SARS-CoV-2, to correlate drug and disease interaction mechanisms to screen key drug targets; 2) using GEO database to correlate differential genes and drug targets to screen potential antiviral gene therapy targets, to construct regulatory network and key points of SARS-CoV-2 therapeutic drugs; 3) using computer simulation of molecular docking to screen virus-related proteins for new drugs. ResultsIntegrated analysis of network pharmacology discovered that baicalein, estrone and quercetin are the pivotal active ingredients in TCM and CWM. Combining drug target genes in pharmacology database and virus induced genes in GEO database, the result showed the core hub genes related to COVID-19: STAT1, IL1B, IL6, IL8, PTGS2 and NFKBIA, and these genes were significantly downregulated in A549 and NHBE cells by SARS-CoV-2 infection. Moreover, chemical interaction and molecular docking analysis of hub genes showed that folic acid might as be potential therapeutic drug for COVID-19 treatment, and SARS-CoV-2 nucleocapsid phosphoprotein was a potential drug target. The network of “drug-target-SARS-CoV-2 related genes” provide noval potential compounds and targets for further studies of SARS-CoV-2.ConclusionsIntegrated analysis of network pharmacology and big data mining provided noval potential compounds and targets for further studies of SARS-CoV-2. Our research implied folic acid and SARS-CoV-2 N as therapeutic target in TCM and CWM. Our research also suggests that targeting SARS-CoV-2 N protein is likely to be a common mechanism of TCM and CWM. On the one hand, the identification of pivotal genes provides a target for COVID-19 molecular therapy, on the other hand, it provides ideas for the analysis of interaction mechanism between virus and host.

Factors Associated with Disease Severity and Mortality among Patients with Coronavirus Disease 2019: A Systematic Review and Meta-Analysis (preprint)

Background: Understanding the factors associated with disease severity and mortality in Coronavirus disease (COVID19) is imperative to effectively triage patients. We performed a systematic review to determine the demographic, clinical, laboratory and radiological factors associated with severity and mortality in COVID-19. Methods: We searched PubMed, Embase and WHO database for English language articles from inception until May 8, 2020. We included Observational studies with direct comparison of clinical characteristics between a) patients who died and those who survived or b) patients with severe disease and those without severe disease. Data extraction and quality assessment were performed by two authors independently. Results: Among 15680 articles from the literature search, 109 articles were included in the analysis. The risk of mortality was higher in patients with increasing age, male gender (RR 1.45; 95%CI 1.23,1.71), dyspnea (RR 2.55; 95%CI 1.88,2.46), diabetes (RR 1.59; 95%CI 1.41,1.78), hypertension (RR 1.90; 95%CI 1.69,2.15). Congestive heart failure (OR 4.76; 95%CI 1.34,16.97), hilar lymphadenopathy (OR 8.34; 95%CI 2.57,27.08), bilateral lung involvement (OR 4.86; 95%CI 3.19,7.39) and reticular pattern (OR 5.54; 95%CI 1.24,24.67) were associated with severe disease. Clinically relevant cut-offs for leukocytosis(>10.0 x109/L), lymphopenia(< 1.1 x109/L), elevated C-reactive protein(>100mg/L), LDH(>250U/L) and D-dimer(>1mg/L) had higher odds of severe disease and greater risk of mortality. Conclusion: Knowledge of the factors associated of disease severity and mortality identified in our study may assist in clinical decision-making and critical-care resource allocation for patients with COVID-19.

Predictors of Severity and Mortality Among Patients with Coronavirus Disease 2019: A Systematic Review and Meta-Analysis (preprint)

Background: The COVID-19 pandemic has overwhelmed the global health systems, and it is imperative to understand how to effectively triage patients. Deeper understanding of predictors of disease severity and mortality is pivotal to effectively triage patients with COVID-19 to maximize the benefit of scarce intensive care unit resources, while minimizing the potential harm of outpatient management of ill patients. Methods: We performed a systematic review and meta-analysis of observational studies, assessing factors associated with severity and mortality among laboratory confirmed COVID-19 patients. We searched PubMed, Embase and WHO database for articles up to May 8, 2020. Randomized trials were excluded. Odds ratios (with 95% CI) and risk ratios (with 95% CI) were used to determine the association between the various demographic, clinical, laboratory and radiological factors and the development of severe disease or mortality. We performed meta-regression to determine the percentage change in the occurrence of the outcomes. Heterogeneity across studies were assessed using I2 and Tau2 statistics. Findings: Among 15680 articles obtained from the literature search, 109 articles were included in the analysis. Increasing age and male gender were associated with higher mortality rates and severe disease. The risk of mortality was higher in patients presenting with dyspnea (RR 2·55, 95% CI 1·88–2·46) and hemoptysis (RR 1·62, 95%CI 1·25–2·11). Co-morbidities such as diabetes (RR 1·59, 95%CI 1·41–1·78), hypertension (RR 1·90, 95%CI 1·69–2·15), cardiovascular diseases (RR 2·27, 95% CI 1·88–2·79) and chronic obstructive pulmonary disease (RR 2·29, 95% CI 1·90–2·75) were associated with a higher risk of death. In-hospital complications such as acute respiratory distress syndrome (ARDS), sepsis, shock and acute cardiac injury had adverse outcomes, with ARDS having the highest risk ratio (RR 20·19, 95% CI 10·87–37·52). Lung consolidation on computed tomography (CT) had significant association with death (RR 2·07, 95% CI 1·35–3·16). Congestive heart failure (OR 4·76, 95% CI 1·34–16·97) had greater odds of developing severe disease. Among the radiological features, hilar lymphadenopathy (OR 8·34, 95%CI 2·57–27·08), bilateral lung involvement (OR 4·86, 95%CI 3·19–7·39) and reticular pattern (OR 5·54, 95%CI 1·24–24·67) were more frequently seen in patients with severe disease. Patients with leukocytosis, lymphopenia, elevated C-reactive protein and D-dimer levels had higher odds of severe disease and greater risk of mortality. Interpretation: Our study identified several important predictors of disease severity and mortality among patients with COVID-19. Knowledge of these predictors might help in the prioritization and management of these patients. Funding: NoneDeclaration of Interests: The authors declare no competing interests.

Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan, China: Prevalence, Risk Factors, and Outcome

BACKGROUND: To investigate deep vein thrombosis (DVT) in hospitalized patients with coronavirus disease 2019 (COVID-19), we performed a single institutional study to evaluate its prevalence, risk factors, prognosis, and potential thromboprophylaxis strategies in a large referral and treatment center. METHODS: We studied a total of 143 patients with COVID-19 from January 29, 2020 to February 29, 2020. Demographic and clinical data, laboratory data, including ultrasound scans of the lower extremities, and outcome variables were obtained, and comparisons were made between groups with and without DVT. RESULTS: Of the 143 patients hospitalized with COVID-19 (age 63±14 years, 74 [51.7%] men), 66 patients developed lower extremity DVT (46.1%: 23 [34.8%] with proximal DVT and 43 [65.2%] with distal DVT). Compared with patients who did not have DVT, patients with DVT were older and had a lower oxygenation index, a higher rate of cardiac injury, and worse prognosis, including an increased proportion of deaths (23 [34.8%] versus 9 [11.7%];P=0.001) and a decreased proportion of patients discharged (32 [48.5%] versus 60 [77.9%];P<0.001). Multivariant analysis showed an association only between CURB-65 (confusion status, urea, respiratory rate, and blood pressure) score 3 to 5 (odds ratio, 6.122;P=0.031), Padua prediction score ≥4 (odds ratio, 4.016;P=0.04), D-dimer >1.0 µg/mL (odds ratio, 5.818;P<0.014), and DVT in this cohort, respectively. The combination of a CURB-65 score 3 to 5, a Padua prediction score ≥4, and D-dimer >1.0 µg/mL has a sensitivity of 88.52% and a specificity of 61.43% for screening for DVT. In the subgroup of patients with a Padua prediction score ≥4 and whose ultrasound scans were performed >72 hours after admission, DVT was present in 18 (34.0%) patients in the subgroup receiving venous thromboembolism prophylaxis versus 35 (66.0%) patients in the nonprophylaxis group (P=0.010). CONCLUSIONS: The prevalence of DVT is high and is associated with adverse outcomes in hospitalized patients with COVID-19. Prophylaxis for venous thromboembolism may be protective in patients with a Padua protection score ≥4 after admission. Our data seem to suggest that COVID-19 is probably an additional risk factor for DVT in hospitalized patients.

Factors Contributing to Healthcare Professional Burnout During the COVID-19 Pandemic: A Rapid Turnaround Global Survey (preprint)

Background: Healthcare professionals (HCPs) on the front lines against COVID-19 may face increased workload, and stress. Understanding HCPs risk for burnout is critical to supporting HCPs and maintaining the quality of healthcare during the pandemic. Methods: To assess exposure, perceptions, workload, and possible burnout of HCPs during the COVID-19 pandemic we conducted a cross-sectional survey. The main outcomes and measures were HCPs self-assessment of burnout and other experiences and attitudes associated with working during the COVID-19 pandemic. Findings: A total of 2,707 HCPs from 60 countries participated in this study. Fifty-one percent of HCPs reported burnout. Burnout was associated with work impacting household activities (RR=1.57, 95% CI=1.39-1.78, P<0.001), feeling pushed beyond training (RR=1.32, 95% CI=1.20-1.47, P<0.001), exposure to COVID-19 patients (RR=1.18, 95% CI=1.05-1.32, P=0.005), making life prioritizing decisions (RR=1.16, 95% CI=1.02-1.31, P=0.03). Adequate personal protective equipment (PPE) was protective against burnout (RR=0.88, 95% CI=0.79-0.97, P=0.01). Burnout was higher in high-income countries (HICs) compared to low- and middle-income countries (LMICs) (RR=1.18; 95% CI=1.02-1.36, P=0.018). Interpretation: Burnout is prevalent at higher than previously reported rates among HCPs working during the COVID-19 pandemic and is related to high workload, job stress, and time pressure, and limited organizational support. Current and future burnout among HCPs could be mitigated by actions from healthcare institutions and other governmental and non-governmental stakeholders aimed at potentially modifiable factors, including providing additional training, organizational support, support for family, PPE, and mental health resources. Funding: N/A