Spatial Heterogeneity of the Recovery of Road Traffic Volume from the Impact of COVID-19: Evidence from China

The impact of COVID-19 on traffic volume makes it essential to study the spatial heterogeneity and impact mechanisms of the recovery of road traffic volume to promote the sustainability of related industries. As the research method, this study used a principal component analysis to evaluate the recovery of road traffic volume in China quantitatively, and further conducted an empirical study using a spatial autocorrelation index and a dynamic spatial panel model. The results show that income has a negative impact on the recovery of road traffic volume, while climate suitability has a positive impact. Economic development and COVID-19 can play moderating and mediating effects, respectively. From the aspect of spatial heterogeneity, the recovery of road traffic volume has a positive spatial spillover effect on the surrounding provinces, while the spread of COVID-19 has a negative short-term indirect spatial spillover effect. Corresponding practical insights are provided for the stakeholders based on the above findings. The results of this study will contribute to the development of effective policies to facilitate the recovery of road traffic volume from the impact of COVID-19 and the revitalization of the transportation industry.

Systems Pharmacology Dissection of Pharmacological Mechanisms of Xiaochaihu Decoction against human coronavirus (preprint)

Background Coronavirus disease 2019 (COVID-19) pandemic is still raging worldwide, while the treatment of human coronaviruses (HCoVs) infections remains limited. Qingfeipaidu decoction (QFPDD), formulated by four classical prescriptions, was the most widely used prescription for COVID-19 containment and exhibited positive effects in China. As one critical prescription in QFPDD, Xiaochaihu decoction (XCHD) could relieve the symptoms of fever, fatigue, anorexia, sore throat in TCM theory. To explore the role and mechanisms of XCHD against HCoVs, we presented an integrated systems pharmacology framework in this study.Methods We constructed a global herb-compound-target network of XCHD against HCoVs. Subsequently, multi-level systems pharmacology analyses highlighted the key regulatory proteins of XCHD, and revealed that XCHD may affect multiple biological functions related to HCoVs. We further applied network-based prediction, drug-likeness analysis, combined with literature investigation to uncover the key ani-HCoV constituents in XCHD, while in vitro HCoV-229E virus-induced cytopathic effect assay was carried out to verify our prediction. Finally, we proposed molecular mechanism hypothesis for these compounds against HCoVs via subnetwork analysis.Results Based on the systems pharmacology framework, we identified 163 XCHD constituents connecting to 37 HCoV-associated genes. And an integrated pathway comprising TLR signaling pathway, RIG-1-like receptor signaling pathway, cytoplasmic DNA sensing pathway, and IL-6/STAT3 pro-inflammatory signal transduction axis was further proposed, revealing the mechanism of action of XCHD against HCoVs. Through in vitro assay, several constituents (e.g. betulinic acid, chrysin, isoliquiritigenin, schisandrin B, and (20R)-Ginsenoside Rh1) in XCHD exerted good inhibitory activity against HCoV-229E virus.Conclusion Our work presented a comprehensive systems pharmacology approach to explore the molecular mechanism and effective substances of XCHD against HCoVs.

The Alleviation of LPS-Induced Murine Acute Lung Injury by GSH-Mediated PEGylated Artesunate Prodrugs

Acute lung injury (ALI) or its aggravated stage acute respiratory distress syndrome (ARDS) is a common severe clinical syndrome in intensive care unit, may lead to a life-threatening form of respiratory failure, resulting in high mortality up to 30–40% in most studies. Nanotechnology-mediated anti-inflammatory therapy is an emerging novel strategy for the treatment of ALI, has been demonstrated with unique advantages in solving the dilemma of ALI drug therapy. Artesunate (ART), a derivative of artemisinin, has been reported to have anti-inflammatory effects. Therefore, in the present study, we designed and synthesized PEGylated ART prodrugs and assessed whether ART prodrugs could attenuate lipopolysaccharide (LPS) induced ALI in vitro and in vivo. All treatment groups were conditioned with ART prodrugs 1 h before challenge with LPS. Significant increased inflammatory cytokines production and decreased GSH levels were observed in the LPS stimulated mouse macrophage cell line RAW264.7. Lung histopathological changes, lung W/D ratio, MPO activity and total neutrophil counts were increased in the LPS-induced murine model of ALI via nasal administration. However, these results can be reversed to some extent by treatment of ART prodrugs. The effectiveness of mPEG2k-SS-ART in inhibition of ALI induced by LPS was confirmed. In conclusion, our results demonstrated that the ART prodrugs could attenuate LPS-induced ALI effectively, and mPEG2k-SS-ART may serve as a novel strategy for treatment of inflammation induced lung injury.

NLRP3 Inflammasome: Mechanism of Action, Role, and Therapeutics in Liver Diseases (preprint)

Liver inflammation is a universal characteristic of chronic liver diseases. NLRP3 is an intracellular sensor that recognizes various endogenous danger signals and environmental irritants, contributing to the formation and activation of the NLRP3 inflammasome. NLRP3 inflammasome is closely related to the progression of various liver diseases and is strongly associated with replicating COVID-19, which is still spreading globally. The assembly and activation of NLRP3 inflammasome in the liver diseases aggravate inflammation and subsequent fibrosis, and this effect is abolished by genetic or pharmacologic deletion of NLRP3 inflammasome. Here, we summarized the latest advances in the critical regulatory role of NLRP3 inflammasome in a variety of liver diseases, including COVID-19 induced liver diseases, NAFLD, ALD, and ischemia-reperfusion (I/R) injury. Additionally, we also discuss small-molecule inhibitors identifying the NLRP3 inflammasome signaling are novel therapeutic targets in treating liver diseases. Our review provides novel insights into the underlying mechanisms of NLRP3 inflammasome in liver diseases and may offer a potential therapeutic strategy for treating liver diseases by targeting NLRP3 inflammasome.

Ligand/Receptor-mediated Cell Communication Alteration Causes the Lung Inflammation Microenvironment and the Redistribution of Inter-tissue Immune Cells in COVID-19 Patients (preprint)

How SARS-CoV-2 causes disturbances of the lung microenvironment and systemic immune response remains a mystery. Here, we first analyze detailedly paired single-cell transcriptome data of the lungs, blood and bone marrow of two patients who died of COVID-19. Second, our results demonstrate that SARS-CoV-2 infection significantly increases the cellular communication frequency between AT1/AT2 cells and highly inflammatory myeloid cells, and induces the pulmonary inflammation microenvironment, and drives the disorder of fibroblasts, club and ciliated cells, thereby causing the increase of pulmonary fibrosis and mucus accumulation. Third, our works reveal that the increase of the lung T cell infiltration is mainly recruited by myeloid cells through certain ligands/receptors (ANXA1/FPR1, C5AR1/RPS19 and CCL5/CCR1), rather than AT1/AT2. Fourth, we find that some ligands and receptors such as ANXA1/FPR1, CD74/COPA, CXCLs/CXCRs, ALOX5/ALOX5AP, CCL5/CCR1, are significantly activated and shared among patients’ lungs, blood and bone marrow, implying that dysregulated ligands and receptors may cause the migration, redistribution and the inflammatory storm of immune cells in different tissues. Overall, our study reveals a latent mechanism by which the disorders of ligands and receptors caused by SARS-CoV-2 infection drive cell communication alteration, the pulmonary inflammatory microenvironment and systemic immune responses across tissues in COVID-19 patients.

Dynamic Zero-Covid strategy curtails mutagenesis and emergence of new variants of the SARS-CoV-2 (preprint)

Within the local outbreak period of SARS-CoV-2 Delta variant in Nanjing and Yangzhou, China, we analyzed the mutation process of the Delta variants in 520 cases, as well as the production, spread and elimination of new mutant strains under the non-pharmaceutical interventions (NPI) strategy. The investigation on distribution of COVID-19 cases and phylogenetic analysis of SARS-CoV-2 genome sequences attributed to tracking the transmission chains, transmission chains were terminated by the isolation of the COVID-19 patients and quarantine of close-contracts, suggesting the importance of NPI in prompting some mutations to disappear and stopping the transmission of new variants. Dynamic zero-Covid strategy has been implemented successfully to against the second-largest local epidemic caused by an imported COVID-19 case in China.

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial

Objective: To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19). Design: Multicentre, open label, randomised controlled trial. Setting 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020. Participants: 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone). Interventions Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively). Main outcome measure: Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone.

Inflammasome activation in infected macrophages drives COVID-19 pathology (preprint)

Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA, and sustained interferon (IFN) response all of which are recapitulated and required for pathology in the SARS-CoV-2 infected MISTRG6-hACE2 humanized mouse model of COVID-19 with a human immune system 1-20 . Blocking either viral replication with Remdesivir 21-23 or the downstream IFN stimulated cascade with anti-IFNAR2 in vivo in the chronic stages of disease attenuated the overactive immune-inflammatory response, especially inflammatory macrophages. Here, we show SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release IL-1 and IL-18 and undergo pyroptosis thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and its accompanying inflammatory response is necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Remarkably, this same blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 by production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.

Impact of the COVID-19 Pandemic on Career Intention Among Undergraduate Medical Students: A Single-center Cross-Sectional Study in Hubei Province (preprint)

Background: ：Undergraduate medical (UM) students faced the realities of the difficulties inherent in medical careers due to the coronavirus 2019 (COVID-19) outbreak. Thus imperative containment measures could affect UM students’ career intentions. There is limited information regarding the factors potentially associated with these students’ career change intentions.Methods：we conducted a cross-sectional survey to investigate the impact of the COVID-19 pandemic on career intention and the associated factors in UM students in August 2020. Univariate analyses and logistic regression analysis were used to identify the factors that contributed to any change of career intention. Results: A total of 2,040 medical students were contained from Hubei University of Medicine. The change of career intention was related to grade, attitude towards being a health worker and the impact of the COVID-19 pandemic. Conclusions: Changes in career intentions were particularly influenced by grade, attitude towards being a health worker, and the degree of COVID-19’s impact on the participants’ lives. Treating large-scale public health emergencies in rational way, setting up correct views of occupation choice and building reasonable career planning may reduce the loss of medical talents.

Heterogeneous nuclear ribonucleoprotein A2B1, a novel drug target for hepatitis B virus infection (preprint)

HBV infection is a major global health burden that needs novel immunotherapeutic approaches. Herein, we show that heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is a novel drug target for HBV infection. We reveal the new target with highly selective probes of PAC5, a natural sesquiterpene derivative. PAC5 show potent anti-HBV activity in vivo and in vitro. Further studies on its mode of action indicate that PAC5 binds to the residue Asp49 and a deep groove in the RNA recognition motif1 (RRM1) region of hnRNPA2B1. PAC5-bound hnRNPA2B1 is activated, dimerized, and translocated to the cytoplasm where it activates the TBK1-IRF3 pathway, leading to the production of type I interferons (IFNs). Furthermore, PAC5 also suppresses other viral replications, such as SARS-CoV-2 and vesicular stomatitis virus (VSV). Our results indicate that PAC5 is the first small molecule agonist of hnRNPA2B1, a drug target potentially valid for broad-spectrum viral infections, providing a novel strategy for viral immunotherapy.

A humanized mouse model of chronic COVID-19 to evaluate disease mechanisms and treatment options (preprint)

Coronavirus-associated acute respiratory disease, called coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). More than 90 million people have been infected with SARS-CoV-2 and more than 2 million people have died of complications due to COVID-19 worldwide. COVID-19, in its severe form, presents with an uncontrolled, hyperactive immune response and severe immunological injury or organ damage that accounts for morbidity and mortality. Even in the absence of complications, COVID-19 can last for several months with lingering effects of an overactive immune system. Dysregulated myeloid and lymphocyte compartments have been implicated in lung immunopathology. Currently, there are limited clinically-tested treatments of COVID-19 with disparities in the apparent efficacy in patients. Accurate model systems are essential to rapidly evaluate promising discoveries but most currently available in mice, ferrets and hamsters do not recapitulate sustained immunopathology described in COVID19 patients. Here, we present a comprehensively humanized mouse COVID-19 model that faithfully recapitulates the innate and adaptive human immune responses during infection with SARS-CoV-2 by adapting recombinant adeno-associated virus (AAV)-driven gene therapy to deliver human ACE2 to the lungs1 of MISTRG6 mice. Our unique model allows for the first time the study of chronic disease due to infection with SARS-CoV-2 in the context of patient-derived antibodies to characterize in real time the potential culprits of the observed human driving immunopathology; most importantly this model provides a live view into the aberrant macrophage response that is thought to be the effector of disease morbidity and ARDS in patients. Application of therapeutics such as patient-derived antibodies and steroids to our model allowed separation of the two aspects of the immune response, infectious viral clearance and immunopathology. Inflammatory cells seeded early in infection drove immune-patholgy later, but this very same early anti-viral response was also crucial to contain infection.

Targeting CTP Synthetase 1 to Restore Interferon Induction and Impede Nucleotide Synthesis in SARS-CoV-2 Infection (preprint)

The newly emerged SARS-CoV-2 caused a global pandemic with astonishing mortality and morbidity. The mechanisms underpinning its highly infectious nature remain poorly understood. We report here that SARS-CoV-2 exploits cellular CTP synthetase 1 (CTPS1) to promote CTP synthesis and suppress interferon (IFN) induction. Screening a SARS-CoV-2 expression library identified ORF7b and ORF8 that suppressed IFN induction via inducing the deamidation of interferon regulatory factor 3 (IRF3). Deamidated IRF3 fails to bind the promoters of classic IRF3-responsible genes, thus muting IFN induction. Conversely, a shRNA-mediated screen focused on cellular glutamine amidotransferases corroborated that CTPS1 deamidates IRF3 to inhibit IFN induction. Functionally, ORF7b and ORF8 activate CTPS1 to promote de novo CTP synthesis while shutting down IFN induction. De novo synthesis of small-molecule inhibitors of CTPS1 enabled CTP depletion and IFN induction in SARS-CoV-2 infection, thus impeding SARS-CoV-2 replication. Our work uncovers a strategy that a viral pathogen couples immune evasion to metabolic activation to fuel viral replication. Inhibition of the cellular CTPS1 offers an attractive means for developing antiviral therapy that would be resistant to SARS-CoV-2 mutation.

Aspergillus But Not Candida: Fatal Fungus Infection in COVID-19 Critical Patients (preprint)

Objectives: Earlier researches suggested patients should be routinely screened for bacteria and fungi infection after COVID-19 being confirmed. Here, we enrolled 236 patients with COVID-19 to analyze the clinical characteristics, fungal strains, mortality, and laboratory data of different groups.Design: Single center retrospective studyPatients: A total of 236 COVID-19 patients from Huoshenshan Hospital were included in this study, consisting of 14(6%) died cases, 222(94%) discharged cases.Results: The result revealed that 5 mortality in positive group were all related to aspergillus infection while candida infection rarely caused death. Aspergillus was most common in non-survivors while candida was most common in survivors. In terms of interleukin-6 (IL6), viral loads, nucleic acid clearance time, etc, fungal serologically positive group had a higher level than negative group.Conclusions: Non-survivors of Covid-19 with fungal infection were almost associated with aspergillus infection. Aspergillus infection, instead of candida infection might be fatal for critical ill patients with COVID-19. There is great significance to carry out routine screening for fungal infection especially for critical patients to enable early treatment to be implemented.Funding Statement: This study was financially supported by grants Key Foundation of Wuhan Huoshenshan Hospital (2020[18]), Key Research& Development Program of Jiangsu Province (BE2018713), Medical Innovation Project of Logistics Service (18JS005).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: This study was approved by the Medical Ethical Committee of Wuhan Huoshenshan Hospital (No. HSSLL011). Written informed consent was obtained from each patient.

Diabetes Patients of COVID-19 Infection Treated with Convalescent Plasma Transfusion in Wuhan, China (preprint)

Background: The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 had spread all over the world, causing public health emergency. Although the diagnosis for COVID-19 such as nucleic acid test and antibody detection have been well defined, there is still a big gap of knowledge regarding for COVID-19 patients receiving convalescent plasma transfusion (CPT) therapy, especially patients with comorbidity of diabetes. Method: In this study, out of 3059 COVID-19 patients admitted in Wuhan Huoshenshan Hospital of China, we described the characteristics of 39 diabetes patients receiving the transfusion of ABO-compatible convalescent plasma, and compared the baseline information and clinical outcome with that of 328 diabetes patients receiving traditional treatment. Results: It was found that the intervention of CPT therapy was effective and beneficial for COVID-19 patients, including severe or critical patients with comorbidity of diabetes, without obvious adverse effects observing during the treatments. The CPT therapy significantly improved the clinical outcome of diabetes patients with COVID-19 infection, especially the duration based on six categories compared to the patients with traditional therapy. Conclusions: This study not only provided a better understanding of COVID-19 in diabetes people receiving CPT, but also highlighted the CPT therapy was helpful for COVID-19 patients with comorbidity of diabetes.

Quarantine Fatigue: first-ever decrease in social distancing measures after the COVID-19 outbreak before reopening United States (preprint)

By the emergence of the novel coronavirus disease (COVID-19) in Wuhan, China, and its rapid outbreak worldwide, the infectious illness has changed our everyday travel patterns. In this research, our team investigated the changes in the daily mobility pattern of people during the pandemic by utilizing an integrated data panel. To incorporate various aspects of human mobility, the team focused on the Social Distancing Index (SDI) which was calculated based on five basic mobility measures. The SDI patterns showed a plateau stage in the beginning of April that lasted for about two weeks. This phenomenon then followed by a universal decline of SDI, increased number of trips and reduction in percentage of people staying at home. We called the observation Quarantine Fatigue. The Rate of Change (ROC) method was employed to trace back the start date of quarantine fatigue which was indicated to be April 15th. Our analysis showed that despite the existence of state-to-state variations, most states started experiencing a quarantine fatigue phenomenon during the same period. This observation became more important by knowing that none of the states had officially announced the reopening until late April showing that people decided to loosen up their social distancing practices before the official reopening announcement. Moreover, our analysis indicated that official reopening led to a rapid decline in SDI, raising the concern of a second wave of outbreak. The synchronized trend among states also emphasizes the importance of a more nationwide decision-making attitude for the future as the condition of each state depends on the nationwide behavior.

Olfactory and Gustatory Dysfunction as An Early Identifier of COVID-19 in Adults and Children: An International Multicenter Study (preprint)

Abstract Objective: Evaluate the prevalence and characteristics of olfactory or gustatory dysfunction in COVID-19 patients Study Design: Multicenter Case Series Setting: 5 tertiary care hospitals (3 in China, 1 in France, 1 in Germany) Subjects and Methods: 394 PCR confirmed COVID-19 positive patients were screened, and those with olfactory or gustatory dysfunction were included. Data including demographics, COVID-19 severity, patient outcome, and the incidence and degree of olfactory and/or gustatory dysfunction were collected and analyzed. The Questionnaire of Olfactory Disorders (QOD) and Visual Analogue Scale (VAS) were used to quantify olfactory and gustatory dysfunction respectively. All subjects at one hospital (Shanghai) without subjective olfactory complaints underwent objective testing. Results: Of 394 screened subjects, 161 (41%) reported olfactory and/or gustatory dysfunction and were included. Incidence of olfactory and/or gustatory disorders in Chinese (n=239), German (n=39) and French (n=116) cohorts were 32%, 69%, and 49% 138 respectively. The median age of included subjects was 39 years old, 92/161 (57%) were male, and 10/161 (6%) were children. Of included subjects, 10% had only olfactory or gustatory symptoms, and 19% had olfactory and/or gustatory complaints prior to any other COVID-19 symptom. Of subjects with objective olfactory testing, 10/90 demonstrated abnormal chemosensory function despite reporting normal subjective olfaction. 43% (44/102) of subjects with follow-up showed symptomatic improvement in olfaction or gustation. Conclusions: Olfactory and/or gustatory disorders may represent early or isolated symptoms of SARS-CoV-2 infection. They may serve as a useful additional screening criterion, particularly for the identification of patients in the early stages of infection.

No evidence of Re-infection or Human-to-Human Transmission in Cured COVID-19 Patients, a Retrospective Cohort Study (preprint)

Objective: To clarify the clinical features of cured patients with coronavirus disease (COVID-19) and the relevance of IgM and IgG testing.Methods: A total of 187 cured COVID-19 patients with antibody test were followed up every two weeks at Guangzhou Eighth People's hospital. Assessment for general condition, symptoms, epidemiological contact history, polymerase chain reaction (PCR) assay, and antibody tests were performed and recorded. Information from Guangzhou CDC was also screened.Results: There were 154 (82.4%) patients with positive results for IgG and 35 (18.7%) patients with positive results for IgM. PCR assay was positive in 10 (5.3%) patients. Neither IgG nor IgM results showed a relationship with PCR test results (all P > 0.05). No re-infection was found in the cured patients. Among people who were in close contact with the cured patients, no one was diagnosed with COVID-19 as reported both by the cured patients and the Guangzhou CDC. Factors associated with appearance of IgG comprised hospitalization days (OR: 1.07, 95%CI: 1.02-1.13, P = 0.004) and antibiotics treatment (OR: 2.78, 95%CI: 1.10-7.01, P = 0.031) .Conclusion: In our study, neither re-infection nor human-to-human transmission was found in cured patients with COVID-19. Additionally, neither IgG nor IgM can be used to replace the PCR test in cured patients.

Human Mobility Trends during the COVID-19 Pandemic in the United States (preprint)

In March of this year, COVID-19 was declared a pandemic and it continues to threaten public health. This global health crisis imposes limitations on daily movements, which have deteriorated every sector in our society. Understanding public reactions to the virus and the non-pharmaceutical interventions should be of great help to fight COVID-19 in a strategic way. We aim to provide tangible evidence of the human mobility trends by comparing the day-by-day variations across the U.S. Large-scale public mobility at an aggregated level is observed by leveraging mobile device location data and the measures related to social distancing. Our study captures spatial and temporal heterogeneity as well as the sociodemographic variations regarding the pandemic propagation and the non-pharmaceutical interventions. All mobility metrics adapted capture decreased public movements after the national emergency declaration. The population staying home has increased in all states and becomes more stable after the stay-at-home order with a smaller range of fluctuation. There exists overall mobility heterogeneity between the income or population density groups. The public had been taking active responses, voluntarily staying home more, to the in-state confirmed cases while the stay-at-home orders stabilize the variations. The study suggests that the public mobility trends conform with the government message urging to stay home. We anticipate our data-driven analysis offers integrated perspectives and serves as evidence to raise public awareness and, consequently, reinforce the importance of social distancing while assisting policymakers.