Beneficial effects of Chinese patent medicine ZhengQi tablet on treating the mild COVID-19 (preprint)

Objectives: This study aimed to assess the effectiveness of a Chinese patent medicine called ZhengQi tablet in the treatment of mild COVID-19 patients. Methods: A prospective cohort trial was carried out in the mobile cabin hospital of City Footprint Hall in Shanghai (ChiCTR2200058693). A total of 800 mild COVID-19 patients were enrolled in this clinical trial and assigned to receive 7 days of treatment with ZhengQi tablet (ZQT group) or TCM placebo (control group) by oral administration per day. The nucleic acid conversion rate of SARS-CoV-2 was the percentage of subjects who got two negative results of Nucleic Acid Amplification Tests (NAATs) at a 24-hour interval out of the total number. The primary clinical indicators included the nucleic acid conversion rate of SARS-CoV-2 and the incidence rate of common COVID-19. The secondary ones, including the time of negative conversion of SARS-CoV-2 RNA and the hospitalization duration were evaluated. Results: A total of 850 mild COVID-19 patients were recruited, and 800 patients were qualified to undergo the clinical trial, with 423 patients assigned for ZQT and 377 patients for TCM placebo. Finally, 390 patients in the ZQT group and 368 patients in the control group completed the follow-up assessments. The nucleic acid conversion rates in ZQT group at 2-day, 3-day and 4-day post-treatment were higher than that in the control group (27.9%vs.9.2%, P<0.001; 38.2%vs.16.6%, P<0.001; 45.4%vs.36.1%, P=0.010). There were no patients who developed into a severe disease. The median time of negative conversion in ZQT group was higher than that in the control group (4[2-6]vs.5[4-6]days, P=0.001). The median hospitalization durations were not different between ZQT group and the control group (5[3-7]vs.6[5-6]days , P=0.065). In terms of the improvement of clinical symptoms, the difference in diarrhea between two groups was statistically significant (100.0%vs.83.3%, P=0.026). There was no significant difference in the improvement of other clinical symptoms. No serious adverse events were reported in both groups. Conclusions: ZhengQi tablet showed beneficial effectiveness in treating patients with mild COVID-19 viaimproving the nucleic acid conversion rate of SARS-CoV-2 and shortening the time of negative conversion.

Navigating nursing curriculum change during COVID-19 pandemic: A systematic review and meta-synthesis.

AIM: To consolidate the evidence around the experiences of nursing undergraduates and faculty members navigating through remote and online education during the COVID-19 pandemic. BACKGROUND: The Coronavirus disease 2019 caused by the SARS-CoV-2 Virus (COVID-19) has placed massive pressure on healthcare, economic and education systems globally. Restrictive social distancing policies and public health measures necessitated educational institutions to switch from face-to-face to remote and online education to sustain the learning process. These changes have created an uncertain path and undue stress for healthcare learners and faculty, especially for professional roles that traditionally require more hands-on and access to clinical practice particularly pre-licensure nursing students. As such, there is an urgent need to consolidate evidence on the experiences of nursing undergraduates and faculty members as they navigate the rapid transition from face-to-face to remote and online education to ensure continuity of learning in achieving optimal learning outcomes and to support them during current and future public health crises. DESIGN: A systematic review and meta-synthesis of the qualitative literature was undertaken using Sandelowski and Barroso's approach. METHODS: Six electronic databases, CINAHL, Embase, ERIC, PsycINFO, PubMed and Scopus, were searched systematically using the eligibility criteria from December 2019 to September 2022. The Critical Appraisal Skills Program checklist for qualitative studies was used to conduct the critical appraisal of the selected articles. RESULTS: Forty-seven studies were included in this review, which encapsulates the experiences of 3052 undergraduates and 241 faculty members. An overarching meta-theme 'Remote and online education: a rollercoaster ride', emerged along with three main meta-themes: (1) Transition to remote and online education: A turbulent road, (2) Acceptance of the untravelled road, (3) Hopes and recommendations for the road ahead. CONCLUSION: To improve nursing undergraduates' and faculty member's navigation of remote and online education, more institutions should move towards establishing hybrid education as the new 'normal' and exercise prudence in the organisation and delivery of curriculum, teaching, well-being and clinical attachment contingencies of their healthcare courses.

SARS-CoV-2 Variant Identification Using a Genome Tiling Array and Genotyping Probes (preprint)

With over three million deaths worldwide attributed to the respiratory disease COVID-19 caused by the novel coronavirus SARS-CoV-2, it is essential that continued efforts be made to track the evolution and spread of the virus globally. We previously presented a rapid and cost-effective method to sequence the entire SARS-CoV-2 genome with 95% coverage and 99.9% accuracy. This method is advantageous for identifying and tracking variants in the SARS-CoV-2 genome when compared to traditional short read sequencing methods which can be time consuming and costly. Herein we present the addition of genotyping probes to our DNA chip which target known SARS-CoV-2 variants. The incorporation of the genotyping probe sets along with the advent of a moving average filter have improved our sequencing coverage and accuracy of the SARS-CoV-2 genome.

Clinical characteristics and therapeutic procedure for a critical case of novel coronavirus pneumonia treated with glucocorticoids and non-invasive ventilator treatment

The novel coronavirus pneumonia (NCP) outbreak occurred in Wuhan, China at the end of 2019. Here, we report the clinical characteristics and therapeutic procedure for a case of severe NCP. The patient was started on glucocorticoids and non-invasive ventilator treatment. After treatment, the patient's symptoms improved, and the status was confirmed as NCP negative. Our results may provide clues for the treatment of NCP.

Modeling the Opening SARS-CoV-2 Spike: an Investigation of its Dynamic Electro-Geometric Properties (preprint)

The recent COVID-19 pandemic has brought about a surge of crowd-sourced initiatives aimed at simulating the proteins of the SARS-CoV-2 virus. A bottleneck currently exists in translating these simulations into tangible predictions that can be leveraged for pharmacological studies. Here we report on extensive electrostatic calculations done on an exascale simulation of the opening of the SARS-CoV-2 spike protein, performed by the Folding@home initiative. We compute the electric potential as the solution of the non-linear Poisson-Boltzmann equation using a parallel sharp numerical solver. The inherent multiple length scales present in the geometry and solution are reproduced using highly adaptive Octree grids. We analyze our results focusing on the electro-geometric properties of the receptor-binding domain and its vicinity. This work paves the way for a new class of hybrid computational and data-enabled approaches, where molecular dynamics simulations are combined with continuum modeling to produce high-fidelity computational measurements serving as a basis for protein bio-mechanism investigations.

Large-scale single-cell analysis reveals critical immune characteristics of COVID-19 patients (preprint)

Dysfunctional immune response in the COVID-19 patients is a recurrent theme impacting symptoms and mortality, yet the detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 205 COVID-19 patients and controls to create a comprehensive immune landscape. Lymphopenia and active T and B cell responses were found to coexist and associated with age, sex and their interactions with COVID-19. Diverse epithelial and immune cell types were observed to be virus-positive and showed dramatic transcriptomic changes. Elevation of ANXA1 and S100A9 in virus-positive squamous epithelial cells may enable the initiation of neutrophil and macrophage responses via the ANXA1-FPR1 and S100A8/9-TLR4 axes. Systemic up-regulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis and designing effective therapeutic strategies for COVID-19.

Characteristics of Peripheral Blood Cells in COVID-19 Patients Revealed by a Retrospective Cohort Study (preprint)

Background Peripheral hematological changes in severe COVID-19 patients may reflect the immune reaction during SARS-CoV-2 infection. Characteristics of peripheral blood cells as early signals were needed to be investigated for clarifying its associations with the fatal outcomes in COVID-19 patients. Methods A retrospective cohort study was performed and the hospitalized COVID-19 patients were recruited in wards of Tongji Hospital (Wuhan, China). Characteristics of peripheral blood cells in survivors and non-survivors were analyzed. Also the comparison among patients with different level of eosinophils was performed. Results198 patients were included in this study, of whom 185 were discharged and 13 died in hospital. Compared to the survivors, counts of lymphocytes, monocytes, eosinophils and basophils were significantly decreased in non-survivors. According to the level of eosinophils, patients were divided into low EOS group (< 0.02×109/L) and normal EOS group (≥ 0.02×109/L). Patients in the low EOS group showed a significantly higher fever compared to normal EOS group. The proportion of patients in low EOS group who used glucocorticoids increased significantly than the other group. Death rate in the low EOS group was higher and no patient death in normal EOS group. Moreover, positive correlation was found between the counts of lymphocytes and eosinophils in patients with glucocorticoids use but not in patients without the treatment. Conclusions Hematological changes differed between survivors and non-survivors with COVID-19. Lymphopenia and eosinopenia could serve to predict the poor prognosis of COVID-19 patients. Initial counts of eosinophils may guide us in usage of glucocorticoids for COVID-19 treatment. 

Analysis SARS-CoV-2 Genomes of G20 Areas on Phylogeny Tree, t-SNE based on Machine Learning (preprint)

The new coronavirus disease (COVID-19) broke out earlier in Wuhan, and the plague spread rapidly from multiple resources of different countries. COVID-19 has caused millions of diagnosed people worldwide, causing many deaths and posing a severe threat to public health in countries around the world. Facing this urgent situation, in-depth research on the emerging SARS-CoV-2 to understand the related pathogenic mechanism and epidemiological characteristics is urgent. This type of activity would be useful to determine its origin to formulate effective prevention and treatment strategies for affected patients.This paper adopts t-SNE based on machine learning to draw a phylogenetic tree from collected genomic sequences to analyze G20 countries’ samples. The phylogenetic tree of the generating mechanism was described, and intermediate results were illustrated. The results of this research showed that viruses in many countries have similar or similar relationships among the gene sequences.

The Effect of Neutropenia and Filgrastim (G-CSF) in Cancer Patients With COVID-19 Infection (preprint)

BackgroundNeutropenia is commonly encountered in cancer patients, and recombinant human granulocyte colony-stimulating factor (G-CSF, filgrastim) is widely given to oncology patients to counteract neutropenia and prevent infection. G-CSF is both a growth factor and cytokine that initiates proliferation and differentiation of mature granulocytes. However, the clinical impact of neutropenia and G-CSF use in cancer patients, who are also afflicted with coronavirus disease 2019 (COVID-19), remains unknown. MethodsAn observational cohort of 304 hospitalized patients with COVID-19 at Memorial Sloan Kettering Cancer Center was assembled to investigate links between concurrent neutropenia (N=55) and G-CSF administration (N=16) on COVID-19-associated respiratory failure and death. These factors were assessed as time-dependent predictors using an extended Cox model, controlling for age and underlying cancer diagnosis. To determine whether the degree of granulocyte response to G-CSF affected outcomes, a similar model was constructed with patients that received G-CSF, categorized into "high"- and "low"- response, based on the level of absolute neutrophil count (ANC) rise 24 hours after growth factor administration. ResultsNeutropenia (ANC < 1 K/mcL) during COVID-19 course was not independently associated with severe respiratory failure or death (HR: 0.71, 95% Cl: 0.34-1.50, P value: 0.367) in hospitalized COVID-19 patients. When controlling for neutropenia, G-CSF administration was associated with increased need for high oxygen supplementation and death (HR: 2.97, 95% CI: 1.06-8.28, P value: 0.038). This effect was predominantly seen in patients that exhibited a "high" response to G-CSF based on their ANC increase post-G-CSF administration (HR: 5.18, 95% CI: 1.61-16.64, P value: 0.006). ConclusionPossible risks versus benefits of G-CSF administration should be weighed in neutropenic cancer patients with COVID-19 infection, as G-CSF may lead to worsening clinical and respiratory status in this setting.

Ultrafast Preliminary Screening of COVID-19 by Machine Learning Analysis of Exhaled NO (preprint)

Background A new coronavirus, SARS-CoV-2, has caused the coronavirus disease-2019 (COVID-19) epidemic. Current diagnostic methods mainly include nucleic acid detection, antibody detection, antigen detection, and chest computed tomography (CT) imaging. Although these methods are crucial for the diagnosis of COVID-19, there is a lack of a rapid and economical method for preliminary screening COVID-19.Methods We measured the FeNO concentrations of 103 subjects without COVID-19 and 46 patients with COVID-19. Using machine learning (ML) method, we build a ML model based on fractional exhaled nitric oxide (FeNO) concentration and features of age, and body size for rapid preliminary screening COVID-19 suspects with low-cost.Findings The statistical analysis t-test show that there is a significant difference between the FeNO of healthy people and patients with COVID-19. The ML model can screen out the patients with COVID-19 or other diseases, which show abnormal FeNO distributions. An area under the curve of 0.982 and a sensitivity 0.917 have been achieved for preliminary screening COVID-19 suspects. This non-invasive detection method which takes in two minutes and costs less than a dollar could provide a direction for the control of the rapid spread COVID-19.Interpretation During the COVID-19 pandemic, large numbers and extensive testing of COVID-19 patients remains a problem. Public healthy efforts to limit SARS-CoV-2 spread need to find a more economical and faster screening method.

A dynamic regulatory interface on SARS-CoV-2 RNA polymerase (preprint)

The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is the core machinery responsible for the viral genome replication and transcription and also a major antiviral target. Here we report the cryo-electron microscopy structure of a post-translocated SARS-CoV-2 RdRp core complex, comprising one nsp12, one separate nsp8(I) monomer, one nsp7-nsp8(II) subcomplex and a replicating RNA substrate. Compared with the recently reported SARS-CoV-2 RdRp complexes, the nsp8(I)/nsp7 interface in this RdRp complex shifts away from the nsp12 polymerase. Further functional characterizations suggest that specific interactions between the nsp8(I) and nsp7, together with the rearrangement of nsp8(I)/nsp7 interface, ensure the efficient and processive RNA synthesis by the RdRp complex. Our findings provide a mechanistic insight into how nsp7 and nsp8 cofactors regulate the polymerase activity of nsp12 and suggest a potential new intervention interface, in addition to the canonical polymerase active center, in RdRp for antiviral design. Author summarySince it was first discovered and reported in late 2019, the coronavirus disease 2019 (COVID-19) pandemic caused by highly contagious SARS-CoV-2 virus is wreaking havoc around the world. Currently, no highly effective and specific antiviral drug is available for clinical treatment. Therefore, the threat of COVID-19 transmission necessitates the discovery of more effective antiviral strategies. Viral RNA-dependent RNA polymerase (RdRp) is an important antiviral drug target. Here, our cryo-EM structure of a SARS-CoV-2 RdRp/RNA replicating complex reveals a previously uncharacterized overall shift of the cofactor nsp8(I)/nsp7 interface, leading to its rearrangement. Through in vitro functional test, we found that the specific interactions on the interface are important to the efficient RNA polymerase activity of SARS-CoV-2 RdRp. These observations let us to suggest this interface as a potential new drug intervention site, outside of the canonical polymerase active center, in RdRp for antiviral design. Our findings would provide new insights into regulatory mechanism of this novel SARS-CoV-2 RdRp, contribute to the design of antiviral drugs against SARS-CoV-2, and benefit the global public health.

Prevalence and Prognostic Value of Elevated Troponins in Patients Hospitalised for Coronavirus Disease 2019: A Systematic Review and Meta-Analysis (preprint)

Background: The clinical significance of cardiac troponin measurement in patients hospitalised for coronavirus disease-2019 (covid-19) is uncertain. We investigated the prevalence of elevated troponins in these patients and its prognostic value for predicting mortality. Methods: : Studies were identified by searching electronic databases and preprint servers. We included studies of hospitalised covid-19 patients that reported the frequency of troponin elevations above the upper reference limit and/or the association between troponins and mortality. Meta-analyses were performed using random-effects models. Results: : Forty-four studies were included. Elevated troponins were found in 21.3% (95% confidence interval [CI] 18.0-24.9 %) of patients who received troponin test on hospital admission. Elevated troponins on admission were associated with a higher risk of subsequent death (risk ratio 2.81, 95% CI 2.01-3.93) after adjusting for confounders in multivariable analysis. The pooled sensitivity of elevated admission troponins for predicting death was 0.64 (95% CI 0.58-0.70), and the specificity was 0.88 (0.82-0.92). The post-test probability of death was about 50% for patients with elevated admission troponins, and was about 7% for those with non-elevated troponins on admission. There were significant heterogeneity and publication bias in the analyses, and many included studies were at risk of selection bias due to the lack of systematic troponin measurement and inadequate follow-up. Conclusion: Elevated troponins were relatively common in patients hospitalised for covid-19. Troponin measurement on admission might help in risk stratification, especially in identifying patients at high risk of death when troponin levels are elevated. High-quality prospective studies are needed to validate these findings. Systematic Review Registration: PROSPERO (CRD42020176747).

Single-cell RNA-seq and V(D)J profiling of immune cells in COVID-19 patients (preprint)

Coronavirus disease 2019 (COVID-19) has caused over 220,000 deaths so far and is still an ongoing global health problem. However, the immunopathological changes of key types of immune cells during and after virus infection remain unclear. Here, we enriched CD3+ and CD19+ lymphocytes from peripheral blood mononuclear cells of COVID-19 patients (severe patients and recovered patients at early or late stages) and healthy people (SARS-CoV-2 negative) and revealed transcriptional profiles and changes in these lymphocytes by comprehensive single-cell transcriptome and V(D)J recombination analyses. We found that although the T lymphocytes were decreased in the blood of patients with virus infection, the remaining T cells still highly expressed inflammatory genes and persisted for a while after recovery in patients. We also observed the potential transition from effector CD8 T cells to central memory T cells in recovered patients at the late stage. Among B lymphocytes, we analyzed the expansion trajectory of a subtype of plasma cells in severe COVID-19 patients and traced the source as atypical memory B cells (AMBCs). Additional BCR and TCR analyses revealed a high level of clonal expansion in patients with severe COVID-19, especially of B lymphocytes, and the clonally expanded B cells highly expressed genes related to inflammatory responses and lymphocyte activation. V-J gene usage and clonal types of higher frequency in COVID-19 patients were also summarized. Taken together, our results provide crucial insights into the immune response against patients with severe COVID-19 and recovered patients and valuable information for the development of vaccines and therapeutic strategies.

Characteristics of patients with COVID-19 during epidemic ongoing outbreak in Wuhan, China (preprint)

BackgroundSince Dec 2019, SARS-CoV-2 has caused about fifty thousand patients and over two thousand deaths in Wuhan, China. We reported characteristics of patients with COVID-19 during epidemic ongoing outbreak in Wuhan. MethodsData of COVID-19 patients with clinical outcome in a designated hospital in Wuhan, were retrospectively collected from electronic medical records. Characteristics were compared between patients who died or recovered, and between patients with different disease severity. ResultsBy Feb 25, 2020, 403 patients were enrolled, 100 died and 303 recovered. Most of non-survivors tended to be males, old aged, or with chronic diseases. Duration from illness onset to admission was 9 (7-12) days. Patients with severe or critical illness had more days from onset to admission compared to those with ordinary illness. Lymphopenia, anemia, hypoproteinemia, and abnormal serum sodium were presented in 52.6%, 54.6%, 69.8%, and 21.8% cases, respectively. Patients who died or with severe/critical illness showed increased white blood cell and neutrophil count, serum total bilirubin, creatinine, hypersensitive troponin I, D-dimer, procalcitonin, and C-reactive protein, and decreased red blood cell, lymphocyte, platelet count, and serum albumin on admission compared to those who recovered or with ordinary illness. Complications of acute organ injury and secondary infection were common in patients with COVID-19, especially in non-survivors. ConclusionsMultiple homeostasis disturbances were common in patients with severe or critical illness at admission. Early support should be provided, especially for old men with chronic disease, which is vital to control disease progression and reduce mortality of COVID-19 during epidemic ongoing outbreak.

Prognostic value of C-reactive protein in patients with COVID-19 (preprint)

BackgroundElevated serum C-reactive protein (CRP) level was observed in most patients with COVID-19. MethodsData of COVID-19 patients with clinical outcome in a designated hospital in Wuhan, China, were retrospectively collected and analyzed from Jan 30 to Feb 20, 2020. The prognostic value of admission CRP was evaluated in patients with COVID-19. ResultsOut of 298 patients enrolled, 84 died and 214 recovered. Most non-survivors tended to be males, old aged, or with chronic diseases. Compared to survivors, non-survivors showed significantly elevated white blood cell and neutrophil count, neutrophil to lymphocyte ratio (NLR), systemic immune-inflammation index (SII, defined by platelet count multiply by NLR), CRP, procalcitonin, and D-dimer, and decreased red blood cell, lymphocyte, and platelet count. Age, neutrophil count, platelet count, and CRP were identified as independent predictors of adverse outcome. The area under the receiver operating characteristic (ROC) curve (AUC) of CRP (0.896) was significantly higher than that of age (0.833), neutrophil count (0.820), and platelet count (0.678) in outcome prediction (all p<0.05). With a cut-off value of 41.4, CRP exhibited sensitivity 90.5%, specificity 77.6%, positive predictive value 61.3%, and negative predictive value 95.4%. Subgroup analysis revealed that CRP remained robust accuracy in adverse outcome prediction in patients with different disease severity (AUC 0.832, z=10.23, p<0.001; AUC 0.989, z=44.04, p<0.001). CRP was also an independent discriminator of severe/critical illness on admission (AUC 0.783, z=10.69, p<0.001). ConclusionsIn patients with COVID-19, admission CRP correlated with disease severity and tended to be a good predictor of adverse outcome.