Endomembrane remodeling in SARS-CoV-2 infection.

During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the viral proteins intimately interact with host factors to remodel the endomembrane system at various steps of the viral lifecycle. The entry of SARS-CoV-2 can be mediated by endocytosis-mediated internalization. Virus-containing endosomes then fuse with lysosomes, in which the viral S protein is cleaved to trigger membrane fusion. Double-membrane vesicles generated from the ER serve as platforms for viral replication and transcription. Virions are assembled at the ER-Golgi intermediate compartment and released through the secretory pathway and/or lysosome-mediated exocytosis. In this review, we will focus on how SARS-CoV-2 viral proteins collaborate with host factors to remodel the endomembrane system for viral entry, replication, assembly and egress. We will also describe how viral proteins hijack the host cell surveillance system-the autophagic degradation pathway-to evade destruction and benefit virus production. Finally, potential antiviral therapies targeting the host cell endomembrane system will be discussed.

Does a Government Response to COVID-19 Hurt the Stock Price of an Energy Enterprise?

This research examines the shock of a government response to COVID-19 on the stock prices of 30 international energy enterprises spanning from January 1, 2020 to December 31, 2020. Overall, the empirical results denote that a government response stringency index, containment and health index, and economic support index all have a statistically significant negative impact on their stock prices. The negative impact from the containment and health index is especially the greatest, implying that a government's stringent responses have great negative effect on the stock prices of most energy enterprises.

What are the pandemic's shocks on carbon emission trading? The different management applications

Maintaining the stability of the carbon market is of great significance for China to meet its goal of "Double Carbon,” but at the beginning of 2020 the COVID-19 pandemic emerged and the economy was greatly affected. A natural question is whether it impacted domestic carbon markets. This paper thus presents the event research method on eight carbon emission trading markets in China, because it can timely exhibit the benefits investors gained during the COVID-19 pandemic and also can overcome the difficulty of separating those benefits from the overall performance of the carbon market via high-frequency data. The results herein confirm that China's carbon market has reacted negatively to the COVID-19 pandemic, which mainly relates to the mandatory blockade and isolation policy adopted by the central government. The production and operation activities of enterprises decreased along with the demand for carbon quotas. Because of the panic, investors also had a negative attitude towards the carbon market, influencing the supply and demand curve of carbon quotas and causing a decline in carbon prices. Under the effectiveness of government epidemic prevention and control policies, we further find that the negative impact was gradually eliminated. Overall, our findings offer some important information for the decision-making of governments, carbon market investors, and policymakers.

Autophagy in severe acute respiratory syndrome coronavirus 2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) orchestrates host factors to remodel endomembrane compartments for various steps of the infection cycle. SARS-CoV-2 also intimately intersects with the catabolic autophagy pathway during infection. In response to virus infection, autophagy acts as an innate defensive system by delivering viral components/particles to lysosomes for degradation. Autophagy also elicits antiviral immune responses. SARS-CoV-2, like other positive-stranded RNA viruses, has evolved various mechanisms to escape autophagic destruction and to hijack the autophagic machinery for its own benefit. In this review, we will focus on how the interplay between SARS-CoV-2 viral proteins and autophagy promotes viral replication and transmission. We will also discuss the pathogenic effects of SARS-CoV-2-elicited autophagy dysregulation and pharmacological interventions targeting autophagy for COVID-19 treatment.

Impact of the COVID-19 pandemic on cardiac implantable electronic device implantation in China: Insights from 2 years of changing pandemic conditions.

Background: A substantial reduction in the number of cardiac implantable electronic device (CIED) implantation was reported in the early stages of the COVID-19 pandemic. None of the studies have yet explored changes in CIED implantation during the following pandemic. Objective: To explore changes in CIED implantation during the COVID-19 pandemic from 2020 to 2021. Methods: From 2019 to 2021, 177,263 patients undergone CIED implantation from 1,227 hospitals in China were included in the analysis. Generalized linear models measured the differences in CIED implantation in different periods. The relationship between changes in CIED implantation and COVID-19 cases was assessed by simple linear regression models. Results: Compared with the pre-COVID-19 period, the monthly CIED implantation decreased by 17.67% (95% CI: 16.62-18.72%, p < 0.001) in 2020. In 2021, the monthly number of CIED implantation increased by 15.60% (95% CI: 14.34-16.85%, p < 0.001) compared with 2020. For every 10-fold increase in the number of COVID-19 cases, the monthly number of pacemaker implantation decreased by 429 in 2021, while it decreased by 676 in 2020. The proportion of CIED implantation in secondary medical centers increased from 52.84% in 2019 to 56.77% in 2021 (p < 0.001). For every 10-fold increase in regional accumulated COVID-19 cases, the proportion of CIED implantation in secondary centers increased by 6.43% (95% CI: 0.47-12.39%, p = 0.036). Conclusion: The impact of the COVID-19 pandemic on the number of CIED implantation is diminishing in China. Improving the ability of secondary medical centers to undertake more operations may be a critical way to relieve the strain on healthcare resources during the epidemic.

Impact of the COVID-19 pandemic on cardiac implantable electronic device implantation in China: Insights from 2 years of changing pandemic conditions

Background A substantial reduction in the number of cardiac implantable electronic device (CIED) implantation was reported in the early stages of the COVID-19 pandemic. None of the studies have yet explored changes in CIED implantation during the following pandemic. Objective To explore changes in CIED implantation during the COVID-19 pandemic from 2020 to 2021. Methods From 2019 to 2021, 177,263 patients undergone CIED implantation from 1,227 hospitals in China were included in the analysis. Generalized linear models measured the differences in CIED implantation in different periods. The relationship between changes in CIED implantation and COVID-19 cases was assessed by simple linear regression models. Results Compared with the pre-COVID-19 period, the monthly CIED implantation decreased by 17.67% (95% CI: 16.62–18.72%, p < 0.001) in 2020. In 2021, the monthly number of CIED implantation increased by 15.60% (95% CI: 14.34–16.85%, p < 0.001) compared with 2020. For every 10-fold increase in the number of COVID-19 cases, the monthly number of pacemaker implantation decreased by 429 in 2021, while it decreased by 676 in 2020. The proportion of CIED implantation in secondary medical centers increased from 52.84% in 2019 to 56.77% in 2021 (p < 0.001). For every 10-fold increase in regional accumulated COVID-19 cases, the proportion of CIED implantation in secondary centers increased by 6.43% (95% CI: 0.47–12.39%, p = 0.036). Conclusion The impact of the COVID-19 pandemic on the number of CIED implantation is diminishing in China. Improving the ability of secondary medical centers to undertake more operations may be a critical way to relieve the strain on healthcare resources during the epidemic.

Evaluating the Response and Safety of Inactivated COVID-19 Vaccines in Liver Transplant Recipients.

Purpose: To evaluate the response and safety of an inactivated vaccine (Sinovac Life Sciences Co., Ltd., Beijing, China) for coronavirus disease 2019 (COVID-19) in liver transplant (LTx) recipients from China. Patients and Methods: Thirty-five recipients post LTx from the First Affiliated Hospital of Zhejiang University School of Medicine who received inactivated vaccine from June to October 2021 were screened. Information regarding vaccine side effects and clinical data were collected. Results: Thirty-five LTx recipients were enrolled, with a mean age of 46 years, and most patients were male (30, 85.71%). All the participants had a negative history of COVID-19 infection. Predictors for negative response in the recipients were interleukin-2 receptor (IL-2R) induction during LTx, shorter time post LTx and application of a derivative from mycophenolate acid (MPA). No serious adverse events were observed during the progress of vaccination or after the vaccination. Conclusion: LTx recipients have a substantially partial immunological response to the inactivated vaccine for COVID-19. IL-2R induction during LTx, a shorter time post LTx and the application of a derivative from MPA seem to be predictors for a negative serological immunoglobulin G (IgG) antibody response in recipients. The findings require booster vaccination in these LTx recipients.

The SARS-CoV-2 B.1.351 Variant Can Transmit in Rats But Not in Mice.

Previous studies have shown that B.1.351 and other variants have extended the host range of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to mice. Sustained transmission is a prerequisite for viral maintenance in a population. However, no evidence of natural transmission of SARS-CoV-2 in wild mice has been documented to date. Here, we evaluated the replication and contact transmission of the B.1.351 variant in mice and rats. The B.1.351 variant could infect and replicate efficiently in the airways of mice and rats. Furthermore, the B.1.351 variant could not be transmitted in BALB/c or C57BL/6 mice but could be transmitted with moderate efficiency in rats by direct contact. Additionally, the B.1.351 variant did not transmit from inoculated Syrian hamsters to BALB/c mice. Moreover, the mouse-adapted SARS-CoV-2 strain C57MA14 did not transmit in mice. In summary, the risk of B.1.351 variant transmission in mice is extremely low, but the transmission risk in rats should not be neglected. We should pay more attention to the potential natural transmission of SARS-CoV-2 variants in rats and their possible spillback to humans.

ORF3a of SARS-CoV-2 promotes lysosomal exocytosis-mediated viral egress.

Viral entry and egress are important determinants of virus infectivity and pathogenicity. ß-coronaviruses, including the COVID-19 virus SARS-CoV-2 and mouse hepatitis virus (MHV), exploit the lysosomal exocytosis pathway for egress. Here, we show that SARS-CoV-2 ORF3a, but not SARS-CoV ORF3a, promotes lysosomal exocytosis. SARS-CoV-2 ORF3a facilitates lysosomal targeting of the BORC-ARL8b complex, which mediates trafficking of lysosomes to the vicinity of the plasma membrane, and exocytosis-related SNARE proteins. The Ca2+ channel TRPML3 is required for SARS-CoV-2 ORF3a-mediated lysosomal exocytosis. Expression of SARS-CoV-2 ORF3a greatly elevates extracellular viral release in cells infected with the coronavirus MHV-A59, which itself lacks ORF3a. In SARS-CoV-2 ORF3a, Ser171 and Trp193 are critical for promoting lysosomal exocytosis and blocking autophagy. When these residues are introduced into SARS-CoV ORF3a, it acquires the ability to promote lysosomal exocytosis and inhibit autophagy. Our results reveal a mechanism by which SARS-CoV-2 interacts with host factors to promote its extracellular egress.

What is the relationship between government response and COVID-19 pandemics? Global evidence of 118 countries.

Using daily data of novel coronavirus pneumonia (COVID-19) covering 118 countries from January 1 to April 13, 2021, this research examines the relationship between the government response stringency index (GRSI) and COVID-19 pandemic. The empirical results show that GRSI significantly negatively impacts confirmed cases, and the effects are especially larger around 14 to 21 days after the implementation of the government response. These results are robust through analysis with sub-samples of Asian countries and non-Asian countries, proving that public prevention policies of being isolated for 14 days and being observed for 7 days are effective. The Dumitrescu-Hurlin causality test uncovers a statistically significant bi-directional correlation between government response stringency and COVID-19 pandemic when analyzing the full samples. In terms of the sub-samples, a bi-directional relationship exists between government response stringency and confirmed cases, while one-way causality runs only from government response stringency to deaths in Asian countries. We offer a policy implication that countries all over the world should continue to carry out public prevention policies, and governments in non-Asian countries should be more concerned about confirmed cases.

The COVID-19 shocks on the stock markets of oil exploration and production enterprises

Using daily data from January 1, 2020 to March 31, 2021, this research explores COVID-19 shocks on the stock market of 15 representative oil exploration and production enterprises from 7 countries. We measure the COVID-19 epidemic from two levels, government response stringency index and number of confirmed cases, and employ stock prices and stock market returns to reflect the stock market. Our research results confirm that both the government response stringency index and the number of confirmed cases have a significantly negative influence on stock prices. We further find that the negative reaction of the stock market to the government response stringency index is greater than that from confirmed cases. Finally, we conclude that the government response stringency index have a significantly positive effect on stock market returns of oil exploration and production enterprises. Similar findings arise from analyzing specific enterprises. Overall, our conclusions provide some useful information for the decision-making of oil exploration and production enterprises’ investors and policy makers.

Oropharyngeal Probiotic ENT-K12 Prevents Respiratory Tract Infections Among Frontline Medical Staff Fighting Against COVID-19: A Pilot Study.

Healthcare workers at the frontline are facing a substantial risk of respiratory tract infection during the COVID-19 outbreak due to an extremely stressful work schedule and public health event. A well-established first-line defense on oropharyngeal microbiome could be a promising strategy to protect individuals from respiratory tract infections including COVID-19. The most thoroughly studied oropharyngeal probiotic product which creates a stable upper respiratory tract microbiota capable of preventing upper respiratory tract infections was chosen to evaluate the safety and efficacy on reducing episodes of upper respiratory tract infections for COVID-19 healthcare workers. To our knowledge to date, this is the very first study describing the beneficial effects of oropharyngeal probiotic been administered by healthcare workers during the COVID-19 pandemic. In this randomized controlled trial, we provided the probiotics to frontline medical staff who work in the hospitals in Wuhan and had been in close contact with hospitalized COVID-19 patients for prophylactic use on a daily basis. Our finding suggests that oropharyngeal probiotic administration significantly reduced the incidence of respiratory tract infections by 64.8%, reduced the time experiencing respiratory tract infections and oral ulcer symptoms by 78%, shortened the days absent from work by 95.5%, and reduced the time under medication where there is no record of antibiotic and anti-viral drug intake in the probiotic group. Furthermore, medical staff treated with Bactoblis experienced sustained protection from respiratory tract infections since the 10th day of oropharyngeal probiotic administration resulting in an extremely low incidence rate of respiratory tract infections.

Gastrointestinal Symptoms Onset in COVID-19 Patients in Wuhan, China.

BACKGROUND: Early detection is critical in limiting the spread of 2019 novel coronavirus (COVID-19). Although previous data revealed characteristics of GI symptoms in COVID-19, for patients with only GI symptoms onset, their diagnostic process and potential transmission risk are still unclear. METHODS: We retrospectively reviewed 205 COVID-19 cases from January 16 to March 30, 2020, in Renmin Hospital of Wuhan University. All patients were confirmed by virus nuclei acid tests. The clinical features and laboratory and chest tomographic (CT) data were recorded and analyzed. RESULTS: A total of 171 patients with classic symptoms (group A) and 34 patients with only GI symptoms (group B) were included. In patients with classical COVID-19 symptoms, GI symptoms occurred more frequently in severe cases compared to non-severe cases (20/43 vs. 91/128, respectively, p < 0.05). In group B, 91.2% (31/34) patients were non-severe, while 73.5% (25/34) patients had obvious infiltrates in their first CT scans. Compared to group A, group B patients had a prolonged time to clinic services (5.0 days vs. 2.6 days, p < 0.01) and a longer time to a positive viral swab normalized to the time of admission (6.9 days vs. 3.3 days, respectively, p < 0.01). Two patients in group B had family clusters of SARS-CoV-2 infection. CONCLUSION: Patients with only GI symptoms of COVID-19 may take a longer time to present to healthcare services and receive a confirmed diagnosis. In areas where infection is rampant, physicians must remain vigilant of patients presenting with acute gastrointestinal symptoms and should do appropriate personal protective equipment.

Proteomic characteristics of bronchoalveolar lavage fluid in critical COVID-19 patients.

Up to 10-20% of patients with coronavirus disease 2019 (COVID-19) develop a severe pulmonary disease due to immune dysfunction and cytokine dysregulation. However, the extracellular proteomic characteristics in respiratory tract of these critical COVID-19 patients still remain to be investigated. In the present study, we performed a quantitative proteomic analysis of the bronchoalveolar lavage fluid (BALF) from patients with critical COVID-19 and from non-COVID-19 controls. Our study identified 358 differentially expressed BALF proteins (P < 0.05), among which 41 were significantly changed after using the Benjamini-Hochberg correction (q < 0.05). The up-regulated signaling was found to be mainly involved in inflammatory signaling and response to oxidative stress. A series of increased extracellular factors including Tenascin-C (TNC), Mucin-1 (KL-6 or MUC1), Lipocalin-2 (LCN2), periostin (POSTN), Chitinase 3-like 1 (CHI3L1 or YKL40), and S100A12, and the antigens including lymphocyte antigen 6D/E48 antigen (LY6D), CD9 antigen, CD177 antigen, and prostate stem cell antigen (PSCA) were identified, among which the proinflammatory factors TNC and KL-6 were further validated in serum of another thirty-nine COVID-19 patients and healthy controls, showing high potentials of being biomarkers or therapeutic candidates for COVID-19. This BALF proteome associated with COVID-19 would also be a valuable resource for researches on anti-inflammatory medication and understanding the molecular mechanisms of host response. DATABASE: Proteomic raw data are available in ProteomeXchange (http://proteomecentral.proteomexchange.org) under the accession number PXD022085, and in iProX (www.iprox.org) under the accession number IPX0002429000.

Bromhexine Hydrochloride Tablets for the Treatment of Moderate COVID-19: An Open-Label Randomized Controlled Pilot Study.

This open-label randomized controlled pilot study aimed to test the study feasibility of bromhexine hydrochloride (BRH) tablets for the treatment of mild or moderate coronavirus disease 2019 (COVID-19) and to explore its clinical efficacy and safety. Patients with mild or moderate COVID-19 were randomly divided into the BRH group or the control group at a 2:1 ratio. Routine treatment according to China's Novel Coronavirus Pneumonia Diagnosis and Treatment Plan was performed in both groups, whereas patients in the BRH group were additionally given oral BRH (32 mg t.i.d.) for 14 consecutive days. The efficacy and safety of BRH were evaluated. A total of 18 patients with moderate COVID-19 were randomized into the BRH group (n = 12) or the control group (n = 6). There were suggestions of BRH advantage over placebo in improved chest computed tomography, need for oxygen therapy, and discharge rate within 20 days. However, none of these findings were statistically significant. BRH tablets may potentially have a beneficial effect in patients with COVID-19, especially for those with lung or hepatic injury. A further definitive large-scale clinical trial is feasible and necessary.

Lessons learned from early compassionate use of convalescent plasma on critically ill patients with Covid-19.

BACKGROUND: The management of critically ill patients with coronavirus disease 2019 (COVID-19), caused by a new human virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is challenging. Recently, there have been several reports with inconsistent results after treatment with convalescent plasma (CP) on critically ill patients with COVID-19, which was produced with a neutralizing antibody titer and tested in a P3 or P4 laboratory. However, due to the limitation of the conditions on mass production of plasma, most producers hardly had the capability to isolate the neutralizing antibody. Here, we report the clinical courses of three critically ill patients with COVID-19 receiving CP treatments by total immunoglobulin G (IgG) titer collection. METHODS: Three patients with COVID-19 in this study were laboratory confirmed to be positive for SARS-CoV-2, with radiographic and clinical features of pneumonia. CP was collected by total IgG titer of 160 (range, 200-225 mL), and patients were transfused between 20 and 30 days after disease onset at the critical illness stage as a trial in addition to standard care. The clinical courses of these patients, including laboratory results and pulmonary functional and image studies after receiving convalescent plasma infusions, were reviewed. RESULTS: No therapeutic effect of CP was observed in any of the patients; instead, all three patients deteriorated and required extracorporeal membrane oxygenation treatment. A potential cytokine storm 4 hours after infusion of CP in Patient 2 was observed. No more patients were put on the trial of CP transfusion. CONCLUSIONS: We recommend extreme caution in using CP in critically ill patients more than 2 weeks after the onset of COVID-19 pneumonia.

Expert consensus on protocol of rehabilitation for COVID-19 patients using framework and approaches of WHO International Family Classifications.

Coronavirus disease 2019 (COVID-19) has widely spread all over the world and the numbers of patients and deaths are increasing. According to the epidemiology, virology, and clinical practice, there are varying degrees of changes in patients, involving the human body structure and function and the activity and participation. Based on the World Health Organization (WHO) International Classification of Functioning, Disability and Health (ICF) and its biopsychosocial model of functioning, we use the WHO Family of International Classifications (WHO-FICs) framework to form an expert consensus on the COVID-19 rehabilitation program, focusing on the diagnosis and evaluation of disease and functioning, and service delivery of rehabilitation, and to establish a standard rehabilitation framework, terminology system, and evaluation and intervention systems based the WHO-FICs.