Abstract Considering the immense pace of developments in deep learning (DL), its applications in medicine are relatively limited. One main issue that hinders the utilization of DL in the medical practice workflow is its reliability. A radiologist interpreting an image can easily say “I don9t know”, while a DL model is forced to output a result. Evidential deep learning (EDL) is one of the methods for uncertainty quantification (UQ). In this work, we aimed to use EDL to express model uncertainty in detecting COVID-19. We used SIIM-FISABIO-RSNA COVID-19 chest x-ray dataset and trained a model to diagnose typical COVID-19 pneumonia. When applied to a separate test set, it yielded an accuracy of 88% with median uncertainty scores of 0.25 and 0.07 for normal and typical COVID-19 images, respectively. Moreover, the model labeled unseen indeterminate and atypical COVID-19 x-rays with median uncertainties of 0.32 and 0.35, respectively. Our model9s performance was superior to the exact model trained with conventional approach of DL (i.e., using the cross-entropy loss), which is not able to express the uncertainty level. Overall, this study demonstrates applicability of UQ in disease detection that could facilitate the use of DL in practice by increasing its reliability.
Multiple clinical phenotypes have been proposed for COVID-19, but few have stemmed from data-driven methods. We aimed to identify distinct phenotypes in patients admitted with COVID-19 using cluster analysis, and compare their respective characteristics and clinical outcomes. We analyzed the data from 547 patients hospitalized with COVID-19 in a Canadian academic hospital from January 1, 2020, to January 30, 2021. We compared four clustering algorithms: K-means, PAM (partition around medoids), divisive and agglomerative hierarchical clustering. We used imaging data and 34 clinical variables collected within the first 24 hours of admission to train our algorithm. We then conducted survival analysis to compare clinical outcomes across phenotypes and trained a classification and regression tree (CART) to facilitate phenotype interpretation and phenotype assignment. We identified three clinical phenotypes, with 61 patients (17%) in Cluster 1, 221 patients (40%) in Cluster 2 and 235 (43%) in Cluster 3. Cluster 2 and Cluster 3 were both characterized by a low-risk respiratory and inflammatory profile, but differed in terms of demographics. Compared with Cluster 3, Cluster 2 comprised older patients with more comorbidities. Cluster 1 represented the group with the most severe clinical presentation, as inferred by the highest rate of hypoxemia and the highest radiological burden. Mortality, mechanical ventilation and ICU admission risk were all significantly different across phenotypes. We conducted a phenotypic analysis of adult inpatients with COVID-19 and identified three distinct phenotypes associated with different clinical outcomes. Further research is needed to determine how to properly incorporate those phenotypes in the management of patients with COVID-19.
Objective: COVID-19 pandemic was anticipated to exacerbate burnout among healthcare professionals. This study aims to compare the level of burnout syndrome in medical residents before and during the COVID-19 pandemic and identify potential risk factors. Methods: This cross-sectional study was conducted on medical residents from three different university hospitals in Turkey in March 2021, one year after the pandemic hit Turkey. Burnout is measured by the Maslach Burnout Inventory which assesses three dimensions of it: emotional exhaustion, depersonalization, and personal accomplishment. Collected data were combined and compared with the data of a previous study which was held in the same hospitals in December 2019, three months before the pandemic. Results: A total of 412 medical residents from three universities participated in this study. The mean age was 27.8±2.4 and half of them were female. Compared to pre- pandemic levels, residents have a significantly decreased feeling of personal accomplishment one year after (from 20.8±5.1 to 10.9±5, p<0.001). No significant differences in emotional exhaustion (pre: 19.0±7.6 post: 18.8±7.8) and depersonalization (pre: 7.3±4.3 post: 7.2±4.4) scores were observed. Emotional exhaustion is higher in residents who are female, have more night shifts, live with someone at the risk of severe COVID-19 and experience personal problems during COVID-19. Depersonalization increases as the age, residency year, and the number of night shifts increases and it is higher in married residents. Residents of the state university hospital feel less personal accomplishment than those of foundational universities. Conclusion: Already high pre-pandemic levels of burnout and a relative decrease in demand due to social restrictions may explain not increasing emotional exhaustion and depersonalization. However, the substantial decrease in the feeling of personal accomplishment among residents is concerning. Without immediate action, it may lead to serious consequences on human resources and the quality of health care in the short to middle term.
Background: Little is known regarding the effectiveness of tixagevimab/cilgavimab in preventing SARS-CoV-2 infection in this population, particularly after the emergence of the Omicron variant. Objective: To determine the effectiveness of tixagevimab/cilgavimab for prevention of SARS-CoV-2 infection and severe disease among immunocompromised patients. Design: Retrospective cohort study with propensity matching and difference-in-difference analyses. Setting: U.S. Department of Veterans Affairs (VA) healthcare system. Participants: Veterans age ≥18 years as of January 1, 2022, receiving VA healthcare. We compared a cohort of 1,848 patients treated with at least one dose of intramuscular tixagevimab/cilgavimab to matched controls selected from 251,756 patients who were on immunocompromised or otherwise at high risk for COVID-19. Patients were followed through April 30, 2022, or until death, whichever occurred earlier. Main Outcomes: Composite of SARS-CoV-2 infection, COVID-19-related hospitalization, and all-cause mortality. We used cox proportional hazards modelling to estimate the hazard ratios (HR) and 95% CI for the association between receipt of tixagevimab/cilgavimab and outcomes. Results: Most (69%) tixagevimab/cilgavimab recipients were ≥65 years old, 92% were identified as immunocompromised in electronic data, and 73% had ≥3 mRNA vaccine doses or two doses of Ad26.COV2. Compared to propensity-matched controls, tixagevimab/cilgavimab-treated patients had a lower incidence of the composite COVID-19 outcome (17/1733 [1.0%] vs 206/6354 [3.2%]; HR 0.31; 95%CI, 0.18-0.53), and individually SARS-CoV-2 infection (HR 0.34; 95%CI, 0.13-0.87), COVID-19 hospitalization (HR 0.13; 95%CI, 0.02-0.99), and all-cause mortality (HR 0.36; 95%CI, 0.18-0.73). Limitations: Confounding by indication and immortal time bias. Conclusions: Using national real-world data from predominantly vaccinated, immunocompromised Veterans, administration of tixagevimab/cilgavimab was associated with lower rates of SARS-CoV-2 infection, COVID-19 hospitalization, and all-cause mortality during the Omicron surge.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are characterized by differences in transmissibility and response to therapeutics. Therefore, discriminating among them is vital for surveillance, infection prevention, and patient care. While whole viral genome sequencing (WGS) is the “gold standard” for variant identification, molecular variant panels have become increasingly available. Most, however, are based on limited targets and have not undergone comprehensive evaluation. We assessed the diagnostic performance of the highly multiplexed Agena MassARRAY® SARS-CoV-2 Variant Panel v3 to identify variants in a diverse set of 391 SARS-CoV-2 clinical RNA specimens collected across our health systems in New York City, USA as well as in Bogota, Colombia (September 2, 2020 - March 2, 2022). We demonstrate almost perfect levels of interrater agreement between this assay and WGS for 9 of 11 variant calls (κ ≥ 0.856) and 25 of 30 targets (κ ≥ 0.820) tested on the panel. The assay had a high diagnostic sensitivity (≥93.67%) for contemporary variants (e.g., Iota, Alpha, Delta, Omicron [BA.1 sublineage]) and a high diagnostic specificity for all 11 variants (≥96.15%) and all 30 targets (≥94.34%) tested. Moreover, we highlight distinct target patterns that can be utilized to identify variants not yet defined on the panel including the Omicron BA.2 and other sublineages. These findings exemplify the power of highly multiplexed diagnostic panels to accurately call variants and the potential for target result signatures to elucidate new ones.
This study investigates that how the number of COVID-19 vaccines secured correlates with the vaccination coverage (full and booster) depending on whether there is trust in national government or not across 47 countries. The data are based on global figures as of Nov. 2021 and Feb. 2022 while measures for confidence in government is according to Gallup World Poll, Oct. 2021. The model includes an interaction term of the two key variables, also controls for a range of socio-economic factors and country specific variables. The results indicate a non-linear and mixed relationship between the number secured, the public trust, and the vaccination rate. In Feb. 2022, with confidence in government, securing number of vaccines to cover 200% of the population (or more) increased the full vaccination rate by 12.26% (95% CI: 11.70 - 12.81); where number secured was 300% (or more), the coverage increased by 7.46% (95% CI: 6.95 - 7.97). Under similar scenarios, rate of booster shots increased by 13.16% (95% CI: 12.62 - 13.70; p < 0.01) and 14.36% (95% CI: 13.86 - 14.85; p < 0.01), respectively. Where the number secured fell below 200%, confidence in government had a revers relationship with the rate of full vaccination (-2.65; 95% CI: -3.32 - -1.99), yet positive with the rate of booster shots (1.65; 95% CI: 1.18 - 2.12). These results indicate that better success can be achieved by a combination of factors including securing sufficient number of vaccines and also ensuring the public trust. Vaccine abundance, however, cannot be translated into greater success in vaccination coverage. This study highlights the importance of efficiency in acquiring vaccine resources and need for improvement in public belief in immunization programmes rather than stock piling.
Background: Observational research provides a unique opportunity to learn causal effects when randomized trials are not available, but obtaining the correct estimates hinges on a multitude of design and analysis choices. We illustrate the advantages of modern causal inference methods and compare to standard research practice to estimate the effect of corticosteroids on mortality in hospitalized COVID-19 patients in an observational dataset. We use several large RCTs to benchmark our results. Methods: Our retrospective data source consists of 3,293 COVID-19 patients hospitalized at New York Presbyterian March 1-May 15, 2020. We design our study using the Target Trial Emulation framework. We estimate the effect of an intervention consisting of 6 days of corticosteroids administered at the time of severe hypoxia and contrast with an intervention consisting of no corticosteroids administration. The dataset includes dozens of time-varying confounders. We estimate the causal effects using a doubly robust estimator where the probabilities of treatment, outcome, and censoring are estimated using flexible regressions via super learning. We compare these analyses to standard practice in clinical research, consisting of two main methods: (i) Cox models for an exposure of corticosteroids receipt within various time windows of hypoxia, and (ii) a Cox time-varying model where the exposure is daily administration of corticosteroids starting at the time of hospitalization. Results: The effect in our target trial emulation is qualitatively identical to an RCT benchmark, estimated to reduce 28-day mortality from 32% (95% confidence interval: 31-34) to 23% (21-24). The estimated effect from meta-analyses of RCTs for corticosteroids is an odds ratio of 0.66 (0.53-0.82)(1). Hazard ratios from the Cox models range in size and direction from 0.50 (0.41-0.62) to 1.08 (0.80-1.47) and all study designs suffer from various forms of bias. Conclusion: We demonstrate in a case study that clinical research based on observational data can unveil true causal relations. However, the correctness of these effect estimates requires designing and analyzing the data based on principles which are different from the current standard in clinical research. The widespread communication and adoption of these design and analytical techniques is of high importance for the improvement of clinical research based on observational data.
Purpose: The effect of vasopressors on mortality of critically ill patients with COVID-19 has not been studied extensively. Methods: A systematic search of PubMed, Scopus, and clinicaltrials.gov was conducted for relevant articles until January 2022. Eligibility criteria were randomized controlled and non-randomized trials. The primary outcome was all-cause mortality at 28 days or 30 days. The quality of studies was assessed using the MINORS tool. Paired meta- analysis was used to estimate the pooled risk ratios along with their 95% Confidence Interval. Results: In total, 33 studies were included. Twenty-one studies with a total population of 7900 individuals provided data on mortality. Patients who received vasopressors were statistically significantly more likely to die compared to those who did not receive vasopressor therapy [RR (95%CI): 4.26 (3.15, 5.76); p<0.001]. This result remained statistically significant regardless of the in-hospital setting. In-hospital and 30-day mortality were statistically significantly higher in patients who received vasopressors [RR (95%CI): 4.60 (2.47, 8.55); p<0.001 and RR (95%CI): 2.97 (1.72, 5.14); p<0.001, respectively]. Four studies provided data on specific vasopressors; the highest mortality rate was observed in patients treated with vasopressin or epinephrine, while patients receiving angiotensin-II as a sole or second-line vasopressor agent had the lowest mortality rate. Also, analysis of 10 studies with a total population of 3519 individuals revealed that patients who received vasopressors were statistically significantly more likely to experience acute kidney injury [RR (95%CI): 3.17 (2.21, 4.54); p<0.001]. Conclusion: Vasopressors have detrimental effect on survival of critically ill patients with COVID-19.
Objective: To assess myocarditis and pericarditis reporting rate as adverse drug reactions (ADRs) for the messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccines authorized in Europe. Methods: Data on myocarditis and pericarditis related to mRNA COVID-19 vaccines (period: January 1, 2021 - February 11, 2022) were collected from the EudraVigilance database and combined with the European Centre for Disease Prevention and Control9s (ECDC) vaccination tracker database. The reporting rate was expressed as 1 million individual vaccinated-days with a corresponding 95% confidence interval (CI), and an observed-to-expected (OE) analysis was performed to check if there was an excess risk for myocarditis or pericarditis following mRNA COVID-19 vaccination. Results: The reporting rate of myocarditis per 1 million individual vaccinated-days in the study period was 17.27 (95% CI, 16.34-18.26) for the CX-024414 vaccine and 8.44 (95% CI, 8.18-8.70) for TOZINAMERAN vaccine. The reporting rate for pericarditis per 1 million individual vaccinated-days in the study period was 9.76 (95% CI, 9.06-10.51) for the CX-024414 vaccine and 5.79 (95% CI, 5.56-6.01) for TOZINAMERAN vaccine. The OE analysis showed that both vaccines produced a myocarditis standardized morbidity ratio (SMR) greater than 1, with the CX-024414 vaccine having a greater SMR than TOZINAMERAN. The SMR for pericarditis was greater than 1 when considering the lowest background incidence, but smaller than 1 when considering the highest background incidence. Conclusions: Our results suggest an excess risk of myocarditis following the first dose of mRNA COVID-19 vaccine, but the relationship between pericarditis and mRNA COVID-19 vaccine remains unclear.
We assessed the association between self-reported mask use during non-household interactions and COVID-19 infection during three pandemic periods. Odds of infection for those who did not always compared to those who always wore a mask was 66% higher during pre-Delta, 53% higher during Delta, declining to 16% higher during Omicron.
It has been previously reported that chronic infection with human cytomegalovirus (CMV) may contribute to poor vaccine responses against de novo antigens in older adults. We assessed effects of CMV serostatus on antibody quantity and quality, as well as cellular memory responses, after 2 and 3 SARS-CoV-2 mRNA vaccine doses, in older adults in congregate living facilities. CMV serostatus did not affect anti-Spike and anti-RBD IgG antibody levels, nor neutralization capacity against wildtype or beta variants of SARS-CoV-2. CMV seropositivity altered T cell expression of senescence-associated markers and increased TEMRA cell numbers, as has been previously reported; however, this did not impact the Spike-specific CD4+ T cell memory responses. CMV seropositive individuals did not have a higher incidence of COVID-19, though prior infection influenced humoral immunity. Therefore, CMV seropositivity may alter T cell composition but does not impede humoral or cellular memory responses after SARS-CoV-2 mRNA vaccination in older adults.
Background. Variant-adaptated vaccines against coronavirus disease 2019 (COVID-19) as boosters are needed to increase a broader protection against SARS CoV-2 variants. New adjuvanted recombinant protein vaccines as heterologous boosters could maximize the response. Methods. In this randomized, single-blinded, multicenter trial, adults who had received two doses of Pfizer-BioNTech mRNA vaccine (BNT162b2) 3 to7 months before were randomly assigned to receive a boost of BNT162b2, Sanofi/GSK SARS-CoV-2 adjuvanted recombinant protein MV D614 (monovalent parental formulation) or SARS-CoV-2 adjuvanted recombinant protein MV B.1.351 vaccine (monovalent Beta formulation). The primary endpoint was the percentage of subjects with a ≥ 10-fold increase in neutralizing antibody titers for the Wuhan (D614) and B.1.351 (Beta) SARS-CoV-2 viral strains between day 0 and day 15. Findings. The percentages of participants whose neutralizing antibody titers against the Wuhan (D614) SARS-CoV-2 strain increased by a factor ≥10 between day 0 and day 15 was 55.3% (95% CI 43.4-66.7) in MV D614 group (n=76), 76.1% (64.5-85.4) in MV B.1.351 (Beta) group (n=71) and 63.2% (51.3-73.9) in BNT162b2 group (n=76). These percentages were 44.7% (33.3-56.6), 84.5% (74.0-92.0) and 51.3% (39.6-63.0) for the B.1.351 (Beta) viral strain, respectively. Higher neutralizing antibodies rates against Delta and Omicron BA.1 variants were also elicited after Sanofi/GSK MV Beta vaccine compared to the other vaccines. Comparable reactogenicity profile was observed with the three vaccines. Interpretation. Heterologous boosting with the Sanofi/GSK Beta formulation vaccine resulted in a higher neutralizing antibody response against Beta variant but also the original strain and Delta and Omicron BA.1 variants, compared with mRNA BNT162b2 vaccine or the Sanofi/GSK MVD614 formulation. New vaccines containing Beta spike protein may represent an interesting strategy for broader protection against SARS CoV-2 variants.
A Safety and Efficacy Study of Hymecromone Tablets for the Treatment of Patients With COVID-19. - Condition: COVID-19
Interventions: Drug: Hymecromone tablets; Other: Placebo
Sponsor: Shanghai Zhongshan Hospital
Recruiting
Study on Sequential Immunization of Omicron Inactivated COVID-19 Vaccine and Prototype Inactivated COVID-19 Vaccine in Population Aged 18 Years Old and Above - Condition: COVID-19
Interventions: Biological: Omicron COVID-19 Vaccine (Vero Cell), Inactivated; Biological: COVID-19 Vaccine (Vero Cell), Inactivated
Sponsors:
China National Biotec Group Company Limited; Beijing Institute of Biological Products Co Ltd.; Hunan Provincial Center for Disease Control and Prevention
Recruiting
A Phase Ia, Dose-finding Study to Assess the Safety and Immunogenicity of a COVID-19 Vaccine Booster in Healthy Adults - Condition: COVID-19
Intervention: Biological: Prime-2-CoV_Beta
Sponsors:
University Hospital Tuebingen; FGK Clinical Research GmbH; VisMederi srl; Staburo GmbH; Viedoc Technologies AB
Not yet recruiting
A Study to Learn About the Study Medicine (Called Nirmatrelvir/Ritonavir) in Pregnant Women With Mild or Moderate COVID-19. - Condition: COVID-19
Interventions: Drug: nirmatrelvir; Drug: ritonavir
Sponsor: Pfizer
Not yet recruiting
Evaluation of COVID-19 Vaccines Given as a Booster in Healthy Adults in Indonesia (MIACoV Indonesia) - Condition: COVID-19
Interventions: Biological: Pfizer-BioNTech Standard dose; Biological: AstraZeneca Standard dose; Biological: Pfizer-BioNTech Fractional dose; Biological: AstraZeneca Fractional dose; Biological: Moderna Standard dose; Biological: Moderna Fractional dose
Sponsors: Murdoch Childrens Research Institute; Universitas Padjadjaran (UNPAD); Universitas Indonesia (UI); Health Development Policy Agency, Ministry of Health Republic of Indonesia; Coalition for Epidemic Preparedness Innovations; The Peter Doherty Institute for Infection and Immunity
Not yet recruiting
A Study to Evaluate the Efficacy and Safety of DXP604 in Patients With Mild to Moderate COVID-19 - Condition: COVID-19
Intervention: Biological: DXP604
Sponsor:
Wuhan Institute of Biological Products Co., Ltd
Not yet recruiting
Sequential Immunization of Two Doses of Inactivated COVID-19 Vaccine (Omicron) in Vaccinated Population Aged 18 Years and Above - Condition: COVID-19
Interventions: Biological: BIBP Omicron Inactivated COVID-19 vaccine (Vero Cell); Biological: WIBP Omicron Inactivated COVID-19 vaccine (Vero Cell); Biological: COVID-19 Vaccine (Vero Cell), Inactivated
Sponsors: China National Biotec Group Company Limited; Beijing Institute of Biological Products Co Ltd.; Wuhan Institute of Biological Products Co., Ltd; The University of Hong Kong
Not yet recruiting
Immunogenicity and Safety of Booster Immunization of COVID-19 Vaccine (Vero Cell), Inactivated (Omicron Variant) in Healthy People Aged 18 Years and Above - Condition: COVID-19
Interventions: Biological: COVID-19 Vaccine (Vero cell), Inactivated (Omicron variant); Biological: COVID-19 Vaccine (Vero cell), Inactivated (CZ strain)
Sponsor:
Sinovac Research and Development Co., Ltd.
Not yet recruiting
A Randomized, Open-label, Dose-ranging Study in Adults and Pediatric Individuals ≥ 12 Years of Age to Assess the Safety, Immunogenicity, Pharmacokinetics, and Pharmacodynamics of AZD7442, for Pre-exposure Prophylaxis of COVID-19 - Condition: Coronavirus Disease 2019 (COVID-19)
Intervention: Biological: AZD7442 (tixagevimab [AZD8895] + cilgavimab [AZD1061])
Sponsor: AstraZeneca
Not yet recruiting
Inhaled Interferon α2b Treatment in Mild-to-moderate COVID-19 Infected Children - Conditions: COVID-19; Children
Interventions: Drug: Inhaled Interferon α2b; Other: Standard of Care
Sponsors: Children’s Hospital of Fudan University; RenJi Hospital; Shanghai Children’s Hospital; Shanghai Children’s Medical Center Affiliated to Shanghai Jiaotong University School of Medicine
Recruiting
INTEGrating Ag-RDTs for COVID in MNCH,HIV and TB Services in Cameroon and Kenya:A Cluster Randomized Trial of Two Models - Condition: COVID-19
Intervention: Diagnostic Test: Test all
Sponsors:
Elizabeth Glaser Pediatric AIDS Foundation; UNITAID; Kenya Ministry of Health; Ministry of Public Health, Cameroon
Not yet recruiting
Pulmonary Rehabilitation Program With Pulsed Electromagnetic Field Therapy in Patients With Post-covid Sequelae. - Condition: COVID-19
Interventions: Device: Pulsed ectromagnetid field therapy; Other: Pulmonary rehabilitation program (PRP)
Sponsor: University of Malaga
Not yet recruiting
Paxlovid in the Treatment of COVID-19 Patients With Uremia - Conditions: COVID-19; Uremia
Interventions: Drug: Paxlovid; Drug: standard-of-care
Sponsor: Ruijin Hospital
Not yet recruiting
Telemedically Assisted Sampling of COVID-19 Patients - Is the Sampling Quality Sufficient - Conditions: Telemedicine; Pharynx; COVID-19
Intervention: Diagnostic Test: telemedically guided oropharyngeal + nasal (OP+N) self-sampling (GSS) and nasopharyngeal (NP) or OP+N sampling performed by health care professionals (HCP)
Sponsor: Teststation Praxis Dr. med Bielecki
Active, not recruiting
Improving Pediatric COVID-19 Vaccine Uptake Using an mHealth Tool - Conditions: COVID-19 Vaccines; Telemedicine; Vaccine Hesitancy; Pediatric ALL
Interventions: Behavioral: COVID-19 Vaccine Uptake App; Other: General Health App
Sponsors:
University of Arkansas; National Institutes of Health (NIH); University of Nebraska; University of Montana
Not yet recruiting
Retraction: Jiang, H.; Mei, Y.-F. SARS-CoV-2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro. Viruses 2021, 13, 2056 - The published article […].
Palmitoylethanolamide (PEA) Inhibits SARS-CoV-2 Entry by Interacting with S Protein and ACE-2 Receptor - Lipids play a crucial role in the entry and egress of viruses, regardless of whether they are naked or enveloped. Recent evidence shows that lipid involvement in viral infection goes much further. During replication, many viruses rearrange internal lipid membranes to create niches where they replicate and assemble. Because of the close connection between lipids and inflammation, the derangement of lipid metabolism also results in the production of inflammatory stimuli. Due to its pivotal…
Infectious Bronchitis Virus Nsp14 Degrades JAK1 to Inhibit the JAK-STAT Signaling Pathway in HD11 Cells - Coronaviruses (CoVs) are RNA viruses that can infect a wide range of animals, including humans, and cause severe respiratory and gastrointestinal disease. The Gammacoronavirus avian infectious bronchitis virus (IBV) causes acute and contagious diseases in chickens, leading to severe economic losses. Nonstructural protein 14 (Nsp14) is a nonstructural protein encoded by the CoV genome. This protein has a regulatory role in viral virulence and replication. However, the function and mechanism of…
SARS-CoV-2 Envelope (E) Protein Binds and Activates TLR2 Pathway: A Novel Molecular Target for COVID-19 Interventions - This paper presents a molecular characterization of the interaction between the SARS-CoV-2 envelope (E) protein and TLR2. We demonstrated that the E protein, both as a recombinant soluble protein and as a native membrane protein associated with SARS-CoV-2 viral particles, interacts physically with the TLR2 receptor in a specific and dose-dependent manner. Furthermore, we showed that the specific interaction with the TLR2 pathway activates the NF-κB transcription factor and stimulates the…
A Unique Robust Dual-Promoter-Driven and Dual-Reporter-Expressing SARS-CoV-2 Replicon: Construction and Characterization - The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, SARS2) remains a great global health threat and demands identification of more effective and SARS2-targeted antiviral drugs, even with successful development of anti-SARS2 vaccines. Viral replicons have proven to be a rapid, safe, and readily scalable platform for high-throughput screening, identification, and evaluation of antiviral drugs against positive-stranded RNA viruses. In the study, we report a unique robust HIV long…
Comparison of Six Serological Immunoassays for the Detection of SARS-CoV-2 Neutralizing Antibody Levels in the Vaccinated Population - Neutralizing antibody (NAb) detection is critical for evaluating herd immunity and monitoring the efficacy of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, quantitative SARS-CoV-2 antibody levels after vaccination were measured by chemiluminescent immunoassays, enzyme immunoassays, and surrogate virus neutralization tests (sVNTs), as well as plaque reduction neutralization tests (PRNT). Sequential blood samples were collected before and 1 and 3…
A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses - New strategies to rapidly develop broad-spectrum antiviral therapies are urgently required for emerging and re-emerging viruses. Host-targeting antivirals (HTAs) that target the universal host factors necessary for viral replication are the most promising approach, with broad-spectrum, foresighted function, and low resistance. We and others recently identified that host dihydroorotate dehydrogenase (DHODH) is one of the universal host factors essential for the replication of many…
Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication - RNA viruses like SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) are dependent on host genes for replication. We investigated if probenecid, an FDA-approved and safe urate-lowering drug that inhibits organic anion transporters (OATs) has prophylactic or therapeutic efficacy to inhibit RSV replication in three epithelial cell lines used in RSV studies, i.e., Vero E6 cells, HEp-2 cells, and in primary normal human bronchoepithelial (NHBE) cells, and in BALB/c mice. The studies…
Targeting of Silver Cations, Silver-Cystine Complexes, Ag Nanoclusters, and Nanoparticles towards SARS-CoV-2 RNA and Recombinant Virion Proteins - Background: Nanosilver possesses antiviral, antibacterial, anti-inflammatory, anti-angiogenesis, antiplatelet, and anticancer properties. The development of disinfectants, inactivated vaccines, and combined etiotropic and immunomodulation therapy against respiratory viral infections, including COVID-19, remains urgent. Aim: Our goal was to determine the SARS-CoV-2 molecular targets (genomic RNA and the structural virion proteins S and N) for silver- containing nanomaterials. Methods: SARS-CoV-2…
Montelukast Inhibits HCoV-OC43 Infection as a Viral Inactivator - Coronaviruses (CoVs) consist of a large group of RNA viruses causing various diseases in humans and in lots of animals. Human coronavirus (HCoV) OC43, the prototype of beta-coronavirus discovered in the 1960s, has been circulating in humans for long time, and infection with other emerging strains of beta-coronavirus (SARS-CoV, SARS-CoV-2, and MERS-CoV) can lead to severe illness and death. In this study, we found that montelukast, a leukotriene receptor antagonist, potently inhibited the…
Antimicrobial Biomaterial on Sutures, Bandages and Face Masks with Potential for Infection Control - Antimicrobial resistance (AMR) is a challenge for the survival of the human race. The steady rise of resistant microorganisms against the common antimicrobials results in increased morbidity and mortality rates. Iodine and a plethora of plant secondary metabolites inhibit microbial proliferation. Antiseptic iodophors and many phytochemicals are unaffected by AMR. Surgical site and wound infections can be prevented or treated by utilizing such compounds on sutures and bandages. Coating surgical…
Inclusion of a Phytomedicinal Flavonoid in Biocompatible Surface-Modified Chylomicron Mimic Nanovesicles with Improved Oral Bioavailability and Virucidal Activity: Molecular Modeling and Pharmacodynamic Studies - Morin hydrate (MH) is a widely-used Asian phytomedicinal flavonoid with a wide range of reported therapeutic activities. However, MH has limited oral bioavailability due to its low aqueous solubility and intestinal permeability, which in turn hinders its potential antiviral activity. The study reported herein was designed to encapsulate MH in polyethyleneglycolated (PEGylated) chylomicrons (PCMs) and to boost its antiviral activity and biological availability for oral administration using a rat…
Methylene Blue Is a Nonspecific Protein-Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19 - We have previously identified methylene blue, a tricyclic phenothiazine dye approved for clinical use for the treatment of methemoglobinemia and for other medical applications as a small-molecule inhibitor of the protein-protein interaction (PPI) between the spike protein of the SARS-CoV-2 coronavirus and ACE2, the first critical step of the attachment and entry of this coronavirus responsible for the COVID-19 pandemic. Here, we show that methylene blue concentration dependently inhibits this…
Inhibition of Human Respiratory Influenza A Virus and Human Betacoronavirus-1 by the Blend of Double-Standardized Extracts of Aronia melanocarpa (Michx.) Elliot and Sambucus nigra L - Viral and bacterial diseases are among the greatest concerns of humankind since ancient times. Despite tremendous pharmacological progress, there is still a need to search for new drugs that could treat or support the healing processes. A rich source of bioactive compounds with antiviral potency include plants such as black chokeberry and elderberry. The aim of this study was to assess the in vitro antiviral ability of an originally designed double- standardized blend of extracts from Aronia…
Integrin/TGF-β1 Inhibitor GLPG-0187 Blocks SARS-CoV-2 Delta and Omicron Pseudovirus Infection of Airway Epithelial Cells In Vitro, Which Could Attenuate Disease Severity - As COVID-19 continues to pose major risk for vulnerable populations, including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins, either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate the blockade of SARS- CoV-2 pseudovirus infection of…