DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner.

Identifying host genes essential for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has the potential to reveal novel drug targets and further our understanding of Coronavirus Disease 2019 (COVID-19). We previously performed a genome-wide CRISPR/Cas9 screen to identify proviral host factors for highly pathogenic human coronaviruses. Few host factors were required by diverse coronaviruses across multiple cell types, but DYRK1A was one such exception. Although its role in coronavirus infection was previously undescribed, DYRK1A encodes Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A and is known to regulate cell proliferation and neuronal development. Here, we demonstrate that DYRK1A regulates ACE2 and DPP4 transcription independent of its catalytic kinase function to support SARS-CoV, SARS-CoV-2, and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) entry. We show that DYRK1A promotes DNA accessibility at the ACE2 promoter and a putative distal enhancer, facilitating transcription and gene expression. Finally, we validate that the proviral activity of DYRK1A is conserved across species using cells of nonhuman primate and human origin. In summary, we report that DYRK1A is a novel regulator of ACE2 and DPP4 expression that may dictate susceptibility to multiple highly pathogenic human coronaviruses.

CD73: Friend or Foe in Lung Injury.

Ecto-5'-nucleotidase (CD73) plays a strategic role in calibrating the magnitude and chemical nature of purinergic signals that are delivered to immune cells. Its primary function is to convert extracellular ATP to adenosine in concert with ectonucleoside triphosphate diphosphohydrolase-1 (CD39) in normal tissues to limit an excessive immune response in many pathophysiological events, such as lung injury induced by a variety of contributing factors. Multiple lines of evidence suggest that the location of CD73, in proximity to adenosine receptor subtypes, indirectly determines its positive or negative effect in a variety of organs and tissues and that its action is affected by the transfer of nucleoside to subtype-specific adenosine receptors. Nonetheless, the bidirectional nature of CD73 as an emerging immune checkpoint in the pathogenesis of lung injury is still unknown. In this review, we explore the relationship between CD73 and the onset and progression of lung injury, highlighting the potential value of this molecule as a drug target for the treatment of pulmonary disease.

Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection.

Identification of host determinants of coronavirus infection informs mechanisms of viral pathogenesis and can provide new drug targets. Here we demonstrate that mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) chromatin remodeling complexes, specifically canonical BRG1/BRM-associated factor (cBAF) complexes, promote severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and represent host-directed therapeutic targets. The catalytic activity of SMARCA4 is required for mSWI/SNF-driven chromatin accessibility at the ACE2 locus, ACE2 expression and virus susceptibility. The transcription factors HNF1A/B interact with and recruit mSWI/SNF complexes to ACE2 enhancers, which contain high HNF1A motif density. Notably, small-molecule mSWI/SNF ATPase inhibitors or degraders abrogate angiotensin-converting enzyme 2 (ACE2) expression and confer resistance to SARS-CoV-2 variants and a remdesivir-resistant virus in three cell lines and three primary human cell types, including airway epithelial cells, by up to 5 logs. These data highlight the role of mSWI/SNF complex activities in conferring SARS-CoV-2 susceptibility and identify a potential class of broad-acting antivirals to combat emerging coronaviruses and drug-resistant variants.

Prolonged viral shedding in feces of children with COVID-19: a systematic review and synthesis of data.

During the coronavirus disease 2019 (COVID-19) epidemic, many reports have indicated that children shed the virus longer than adults in stool, and that most of the children had mild or even asymptomatic infections, which increased the potential risk for feces to be a source of contamination and may play an important role in the spread of the virus. In this review, we collected relevant literature to summarize the duration of fecal viral shedding in children with COVID-19. We found that in about 60% of the cases, the fecal shedding time was between 28 and 42 days, which was much longer than that of adults. We further explored the possible reason for prolonged shedding and its the potential impact. The poor hand hygiene practices of children, their tendency to swallow sputum and/or saliva, the significant difference in expression of angiotensin-converting enzyme 2 (ACE2) in intestine between children and adults, and the variance in immune status and intestinal microbiome could be considered as potential casual agents of longer fecal viral shedding duration of children.   Conclusion: Children with COVID-19 show prolonged fecal shedding compared to adults. Several mechanisms may be involved in the longer fecal viral shedding. Viral shedding in the stool could be contributing to a possible route of transmission. Therefore, we think that further preventive measures in children should be taken to reduce the spread of the disease. What is Known: • Children with COVID-19 are more likely to have asymptomatic infections and to experience mild symptoms. • Some patients continue to shed the virus in feces, despite respiratory samples testing negative. What is New: • Children with COVID-19 carried a longer-term fecal viral shedding than adults. • The poor hand hygiene practices of children, their tendency to swallow sputum and/or saliva, the difference in expression of ACE2 in intestine between children and adults, and the variance in immune status and intestinal microbiome could be considered as potential casual agents of longer fecal viral shedding duration of children.

A Multi-Center Study on the Negative Psychological Impact and Associated Factors in Chinese Healthcare Workers 1 Year After the COVID-19 Initial Outbreak.

Objectives: The study aimed at analyzing the prevalence of five psychological outcomes (depression, anxiety, stress, post-traumatic stress disorder (PTSD), and suicidal ideation) among Chinese healthcare workers (HCWs), and measured the total possible negative psychological impact 1 year after the COVID-19 initial outbreak. Methods: A cross-sectional nationwide multi-center study was performed between November 2020 and March 2021 in China. A self-report questionnaire was applied, and three psychological scales were used. Binary logistic regression was performed to analyze the risk factors associated with each psychological outcome. Results: The findings demonstrated that the COVID-19 pandemic had a negative psychological impact on HCWs, which was still evident 1 year after the initial outbreak. Nurses showed higher depression and anxiety than other HCWs. Female gender, passive coping, long working hours, having a chronic disease, and experiencing violence, among other factors, were all risk factors for psychological impairment. Conclusion: Developing and promoting programs to improve mental health among HCWs, and identifying those who might need psychological support is still relevant 1 year after the initial outbreak.

Acceptance of the COVID-19 vaccine based on the health belief model: a multicenter national survey among medical care workers in China.

Vaccine uptake rate is crucial for herd immunity. Medical care workers (MCWs) can serve as ambassadors of COVID-19 vaccine acceptance. This study aimed to assess MCWs' willingness to receive the COVID-19 vaccine, and to explore the factors affecting COVID-19 vaccination acceptance. A multicenter study among medical care workers was conducted in seven selected hospitals from seven geographical territories of China, and data were collected on sociodemographic characteristics, vaccine hesitancy, and health beliefs on COVID-19 vaccination among participants. Univariate and multivariate logistic regression models were performed to explore the correlations between individual factors and the acceptance of the COVID-19 vaccine. Among the 2681 subjects, 82.5% of the participants were willing to accept the COVID-19 vaccination. Multivariate regression analyses revealed that individuals with more cues to action about the vaccination, higher level of confidence about the vaccine, and higher level of trust in the recommendations of COVID-19 vaccine from the government and the healthcare system were more likely to get the COVID-19 vaccine. In contrast, subjects with higher level of perceived barriers and complacency were less likely to accept the COVID-19 vaccine. Overall, MCWs in China showed a high willingness to get the COVID-19 vaccine. The governmental recommendation is an important driver and lead of vaccination. Relevant institutions could increase MCWs' willingness to COVID-19 vaccines by increasing MCWs' perception of confidence about COVID-19 vaccines and cues to action through various strategies and channels. Meanwhile, it can also provide evidence in similar circumstances in the future to develop vaccine promotion strategies.

Feasibility of COVID-19 control from a pandemic to endemic (preprint)

Evaluations of the pandemic to endemic phase are a great concern, especially in Zero-COVID-19 countries. Herein, we developed a mathematical model to simulate future scenarios for the variants of concern (VOCs) in the condition of several immune barriers and controlling measures. The results demonstrated that the Omicron variant would lead to 592.0 (mean ± standard deviation (SD): 433.9–750.0) million symptomatic, 24.3 (mean ± SD: 17.4–312.8) million hospital admission, 9.6 (mean ± SD:7.0–12.3) million ICU admission, and 5.4 (mean ± SD:3.7–7.5) million death cases after simulation with 1,000 days. At the endemic phase, there were nearly 500 death cases per day attributed to reinfection (66% [range: 62–70%]), infection from birth (18% [range: 16–21%]), and infection from migration (16% [range: 14–17%]). Actively treating more than 80% of cases could effectively reduce disease severity and death rates. It is feasible to transmit pandemic to endemic with Omicron variant and other milder VOCs. We recommend that the successful transition strategy is to improve medical resource allocation and enhance the prevention and control capabilities of health agencies.

Emergency Department Crowding is Harder to Solve: The Impact of COVID-19 of Longer Length of Stay (preprint)

Objectives: To determine the impact of the Coronavirus disease-2019 (COVID-19) pandemic on the length of stay (LOS) and prognosis of patients in the emergency department (ED). Methods A retrospective review of case data of patients in the ED during the early stages of the COVID-19 pandemic in the First Affiliated Hospital of Soochow University (January 15, 2020– January 14, 2021) was performed and compared with that during the pre-COVID-19 period (January 15, 2019 – January 14, 2020). Patient information including age, sex, length of stay, and death was collected. Wilcoxon Rank sum test was utilized to compare the difference in LOS between the two cohorts. Chi-Squared test was utilized to analyze the prognosis of patients. The LOS and prognosis in different departments (emergency internal medicine, emergency surgery, emergency neurology, and other departments) were further analyzed. Results Of the total 8278 patients, 4159 (50.24%) were ordered in the COVID-19 pandemic group and 4119 (49.76%) were ordered in the pre-COVID-19 group. The length of stay prolongs significantly in the COVID-19 group compared with that in the pre-COVID-19 group(13h vs 9.8h; p < 0.001). There was no significant difference in mortality between the two cohorts (4.8% VS 5.3%; p=0.341). Conclusion The COVID-19 pandemic was associated with a significant increase in the length of stay, which may lead to emergency department crowding. And the influence of the COVID-19 pandemic on patients in different emergency departments is different. There is no significant impact on the LOS of emergency neuropathy. Across departments, COVID-19 didn’t have a significant impact on the prognosis of ED patients.

Nomogram for prediction of fatal outcome in patients with severe COVID-19: a multicenter study.

BACKGROUND: To develop an effective model of predicting fatal outcomes in the severe coronavirus disease 2019 (COVID-19) patients. METHODS: Between February 20, 2020 and April 4, 2020, consecutive confirmed 2541 COVID-19 patients from three designated hospitals were enrolled in this study. All patients received chest computed tomography (CT) and serological examinations at admission. Laboratory tests included routine blood tests, liver function, renal function, coagulation profile, C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), and arterial blood gas. The SaO2 was measured using pulse oxygen saturation in room air at resting status. Independent high-risk factors associated with death were analyzed using Cox proportional hazard model. A prognostic nomogram was constructed to predict the survival of severe COVID-19 patients. RESULTS: There were 124 severe patients in the training cohort, and there were 71 and 76 severe patients in the two independent validation cohorts, respectively. Multivariate Cox analysis indicated that age ≥ 70 years (HR = 1.184, 95% CI 1.061-1.321), panting (breathing rate ≥ 30/min) (HR = 3.300, 95% CI 2.509-6.286), lymphocyte count < 1.0 × 109/L (HR = 2.283, 95% CI 1.779-3.267), and interleukin-6 (IL-6) >  10 pg/ml (HR = 3.029, 95% CI 1.567-7.116) were independent high-risk factors associated with fatal outcome. We developed the nomogram for identifying survival of severe COVID-19 patients in the training cohort (AUC = 0.900, 95% CI 0.841-0.960, sensitivity 95.5%, specificity 77.5%); in validation cohort 1 (AUC = 0.811, 95% CI 0.763-0.961, sensitivity 77.3%, specificity 73.5%); in validation cohort 2 (AUC = 0.862, 95% CI 0.698-0.924, sensitivity 92.9%, specificity 64.5%). The calibration curve for probability of death indicated a good consistence between prediction by the nomogram and the actual observation. The prognosis of severe COVID-19 patients with high levels of IL-6 receiving tocilizumab were better than that of those patients without tocilizumab both in the training and validation cohorts, but without difference (P = 0.105 for training cohort, P = 0.133 for validation cohort 1, and P = 0.210 for validation cohort 2). CONCLUSIONS: This nomogram could help clinicians to identify severe patients who have high risk of death, and to develop more appropriate treatment strategies to reduce the mortality of severe patients. Tocilizumab may improve the prognosis of severe COVID-19 patients with high levels of IL-6.

Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection.

Identification of host genes essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may reveal novel therapeutic targets and inform our understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here we performed genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, Middle East respiratory syndrome CoV (MERS-CoV), bat CoV HKU5 expressing the SARS-CoV-1 spike, and vesicular stomatitis virus (VSV) expressing the SARS-CoV-2 spike. We identified known SARS-CoV-2 host factors, including the receptor ACE2 and protease Cathepsin L. We additionally discovered pro-viral genes and pathways, including HMGB1 and the SWI/SNF chromatin remodeling complex, that are SARS lineage and pan-coronavirus specific, respectively. We show that HMGB1 regulates ACE2 expression and is critical for entry of SARS-CoV-2, SARS-CoV-1, and NL63. We also show that small-molecule antagonists of identified gene products inhibited SARS-CoV-2 infection in monkey and human cells, demonstrating the conserved role of these genetic hits across species. This identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS lineage-specific and pan-CoV host factors that regulate susceptibility to highly pathogenic CoVs.

WBC-Net: A white blood cell segmentation network based on UNet++ and ResNet

The counting and identification of white blood cells (WBCs, i.e., leukocytes) in blood smear images play a crucial role in the diagnosis of certain diseases, including leukemia, infections, and COVID-19 (corona virus disease 2019). WBC image segmentation lays a firm foundation for automatic WBC counting and identification. However, automated WBC image segmentation is challenging due to factors such as background complexity and variations in appearance caused by histological staining conditions. To improve WBC image segmentation accuracy, we propose a deep learning network called WBC-Net, which is based on UNet++ and ResNet. Specifically, WBC-Net designs a context-aware feature encoder with residual blocks to extract multi-scale features, and introduces mixed skip pathways on dense convolutional blocks to obtain and fuse image features at different scales. Moreover, WBC-Net uses a decoder incorporating convolution and deconvolution to refine the WBC segmentation mask. Furthermore, WBC-Net defines a loss function based on cross-entropy and the Tversky index to train the network. Experiments on four image datasets show that the proposed WBC-Net achieves better WBC segmentation performance than several state-of-the-art methods.

Clinical Features of COVID-19 Patients in Xiaogan City.

On February 6, 2020, Xiaogan City became the second most seriously affected city with coronavirus disease 2019 (COVID-19), outside Wuhan district, Hubei Province, China. The objectives are to study the clinical features of COVID-19 patients and assess the relationship between the severity of COVID-19, age, and C-reactive protein (CRP) levels. The retrospective data of 134 COVID-19 patients hospitalized in 3 hospitals of Xiaogan City, between February 1 and March 1, 2020, was collected. This study documented COVID-19 patients. Clinical data in terms of body temperature, history of travel, and direct contact with COVID-19 patients, and incubation period was collected. Out of the 134 patients, only 5 required intensive care. Moreover, 2 patients succumbed during this period. The median age of patients was 45 (33-56) years. The most common symptoms at the onset of disease were fever (66.4%), cough (33, 6%), and sore throat (14.7%). Amongst the medicines used, antiviral agents (92.3%) followed by the traditional Chinese medicine (89.5%) were most commonly used. In both the crude and adjusted (I to III) models, odds ratio and its 95% confidence interval for both age and CRP levels were > 1. Moreover, the smooth curve fitting graph reflected that the severity of COVID-19 was positively correlated with both age and CRP levels (all P value < 0.05). The signs and symptoms of COVID-19 patients were fairly moderate. The health care professionals treating the COVID-19 patients should be aware of the increased likelihood of progression to severe COVID-19 in elderly patients and those with high CRP levels.

Clinical characteristics and survival analysis in critical and non-critical patients with COVID-19 in Wuhan, China: a single-center retrospective case control study (preprint)

Since the outbreak of COVID-19 in China at the end of 2019, the world has experienced a large-scale epidemic caused by the SARS-CoV-2. Epidemiological and clinical course of COVID-19 patients have been reported, but there have been few analyses about the characteristics, predictive risk factors and outcomes of critical patients. In this single-center retrospective case-control study, 90 adult inpatients hospitalized at Tongji Hospital (Wuhan, China) were included. Demographic, clinical, laboratory test and treatment data were obtained and compared between critical and non-critical patients. We found that compared with non-critical patients, the critical patients had higher SOFA score and qSOFA scores. Critical patients had lower lymphocyte and platelet count, elevated D-dimer, decreased fibrinogen, and elevated high-sensitivity C-reactive protein (hsCRP) and interleukin-6(IL-6). More critical patients received treatment including antibiotics, anticoagulation, corticosteroid and oxygen therapy than non-critical ones. Multivariable regression showed higher qSOFA score and elevation of IL-6 were related to critical patients. Antibiotic usage and anticoagulation were associated with decreased in-hospital mortality. And critical grouping contributed greatly to in-hospital death. Critical COVID-19 patients have a more severe clinical cours. qSOFA score and elevation of IL-6 are risk factors for critical condition. Non-critical grouping, positive antibiotic application and anticoagulation may be beneficial for patient survival.

COVID-19 and Liver Dysfunction: Current Insights and Emergent Therapeutic Strategies.

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has attracted increasing worldwide attention. Cases of liver damage or dysfunction (mainly characterized by moderately elevated serum aspartate aminotransferase levels) have been reported among patients with COVID-19. However, it is currently uncertain whether the COVID-19-related liver damage/dysfunction is due mainly to the viral infection per se or other coexisting conditions, such as the use of potentially hepatotoxic drugs and the coexistence of systemic inflammatory response, respiratory distress syndrome-induced hypoxia, and multiple organ dysfunction. Based on the current evidence from case reports and case series, this review article focuses on the demographic and clinical characteristics, potential mechanisms, and treatment options for COVID-19-related liver dysfunction. This review also describes the geographical and demographic distribution of COVID-19-related liver dysfunction, as well as possible underlying mechanisms linking COVID-19 to liver dysfunction, in order to facilitate future drug development, prevention, and control measures for COVID-19.

The differential diagnosis of pulmonary infiltrates in cancer patients during the outbreak of the 2019 novel coronavirus disease / 中华肿瘤杂志

Objective@#To investigate the principles of differential diagnosis of pulmonary infiltrates in cancer patients during the outbreak of novel coronavirus (2019-nCoV) by analyzing one case of lymphoma who presented pulmonary ground-glass opacities (GGO) after courses of chemotherapy.@*Methods@#Baseline demographics and clinicopathological data of eligible patients were retrieved from medical records. Information of clinical manifestations, history of epidemiology, lab tests and chest CT scan images of visiting patients from February 13 to February 28 were collected. Literatures about pulmonary infiltrates in cancer patients were searched from databases including PUBMED, EMBASE and CNKI.@*Results@#Among the 139 cancer patients underwent chest CT scans before chemotherapy, pulmonary infiltrates were identified in eight patients (5.8%), five of whom were characterized as GGOs in lungs. 2019-nCoV nuclear acid testing was performed in three patients and the results were negative. One case was a 66-year-old man diagnosed as non-Hodgkin lymphoma and underwent CHOP chemotherapy regimen. His chest CT scan image displayed multiple GGOs in lungs and the complete blood count showed decreased lymphocytes. This patient denied any contact with confirmed/suspected cases of 2019-nCoV infection and without fever and other respiratory symptoms. Considering the negative result of nuclear acid testing, this patient was presumptively diagnosed as viral pneumonia and an experiential anti-infection treatment had been prescribed for him.@*Conclusions@#The 2019 novel coronavirus disease (COVID-19) complicates the clinical scenario of pulmonary infiltrates in cancer patients. The epidemic history, clinical manifestation, CT scan image and lab test should be combined consideration. The 2019-nCoV nuclear acid testing might be applicated in more selected patients. Active anti-infection treatment and surveillance of patient condition should be initiated if infectious disease is considered.