Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19.

The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.

Adenovirus-mediated Over-Expression of FcγRIIB Attenuates Pulmonary Inflammation and Fibrosis.

Progressive fibrosing interstitial lung diseases (PF-ILDs) result in high mortality and lack effective therapies. The pathogenesis of PF-ILDs involves macrophages driving inflammation and irreversible fibrosis. Fc-gamma receptors (FcγRs) regulate macrophages and inflammation, but their roles in PF-ILDs remain unclear. We characterized the expression of FcγRs and found up-regulated FcγRIIB in human and mouse lungs following exposure to silica. FcγRIIB deficiency aggravated lung dysfunction, inflammation and fibrosis in silica-exposed mice. Using single-cell transcriptomics and in vitro experiments, FcγRIIB was found in alveolar macrophages, where it regulated the expression of fibrosis-related genes Spp1 and Ctss. In mice with macrophage-specific over-expression of FcγRIIB, and in mice treated with adenovirus by intra-tracheal instillation to up-regulate FcγRIIB, silica-induced functional and histological changes were ameliorated. Our data from three genetic models and a therapeutic model suggest that FcγRIIB plays a protective role that can be enhanced by adenoviral over-expression, representing a potential therapeutic strategy for PF-ILDs.

Supply of basic necessities to vulnerable populations during the COVID-19 pandemic: Empirical evidence from Shanghai, China.

Background: In spite of initial widespread skepticism, city lockdown has been proved to be an effective short-term tool in containing and delaying the spread of a viral epidemic. The measures to ensure the supply of the basic necessities adequately and equitably, especially for those vulnerable ones has become a major challenge faced by all countries taking a city lockdown measure during the epidemic. Methods: Data was collected through relevant government documents, work records, policy reports, media reports and the online-work information platform designed by the research group. Based on these references, the study analyzed the mainly technical difficulties and the countermeasures of the supply process, and summarized the key characteristics of basic necessities supply strategy for vulnerable groups in Shanghai. Results: The supply strategy for vulnerable groups in Shanghai covers 16 districts, 232 streets and 6,028 neighborhood communities, which has already been in test running in April in some districts. The practical experience in Shanghai solved three key materials supply problems (lack of purchase channels, insufficient material reserves, insufficient transportation capacity) faced by government during the city lockdown, and showed three essential characteristics (overall coordination, community-centered intervention, technical support). Conclusions: The findings in this study may provide some suggestions to other countries about how to better manage the preparation, dispatch and transportation of basic necessities in shortage for those vulnerable ones during the city lockdown.

A Four-Channel Surface Plasmon Resonance Sensor Functionalized Online for Simultaneous Detections of Anti-SARS-CoV-2 Antibody, Free Viral Particles, and Neutralized Viral Particles.

Current tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detect either the constituent nucleic acids/proteins of the viral particles or antibodies specific to the virus, but cannot provide information about viral neutralization by an antibody and the efficacy of an antibody. Such information is important about individuals' vulnerability to severe symptoms or their likelihood of showing no symptoms. We immobilized online SARS-CoV-2 spike (S1) protein and angiotensin-converting enzyme 2 (ACE2) into separate surface plasmon resonance (SPR) channels of a tris-nitrilotriacetic acid (tris-NTA) chip to simultaneously detect the anti-S1 antibody and viral particles in serum samples. In addition, with a high-molecular-weight-cutoff filter, we separated the neutralized viral particles from the free antibody molecules and used a sensing channel immobilized with Protein G to determine antibody-neutralized viral particles. The optimal density of probe molecules in each fluidic channel can be precisely controlled through the closure and opening of the specific ports. By utilizing the high surface density of ACE2, multiple assays can be carried out without regenerations. These three species can be determined with a short analysis time (<12 min per assay) and excellent sensor-to-sensor/cycle-to-cycle reproducibility (RSD < 5%). When coupled with an autosampler, continuous assays can be performed in an unattended manner at a single chip for up to 6 days. Such a sensor capable of assaying serum samples containing the three species at different levels provides additional insights into the disease status and immunity of persons being tested, which should be helpful for containing the SARS-CoV-2 spread during the era of incessant viral mutations.

Regenerable and high-throughput surface plasmon resonance assay for rapid screening of anti-SARS-CoV-2 antibody in serum samples.

Current serological antibody tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) require enzyme or fluorescent labels, and the titer well plates cannot be reused. By immobilizing histidine (His)-tagged SARS-CoV-2 spike (S1) protein onto tris‒nitrilotriacetic acid (tris-NTA) sensor and using the early association phase for mass-transfer-controlled concentration determination, we developed a rapid and regenerable surface plasmon resonance (SPR) method for quantifying anti-SARS-CoV-2 antibody. On a five-channel SPR instrument and with optimized S1 protein immobilization density, each of the four analytical channels is sequentially used for multiple measurements, and all four channels can be simultaneously regenerated once they have reached a threshold value. Coupled with a programmable autosampler, each sensor can be regenerated at least 20 times, enabling uninterrupted assays of more than 800 serum samples. The accuracy and speed of our method compare well with those of the enzyme-linked immunosorbent assay (ELISA), and the detection limit (0.057 µg mL-1) can easily meet the requirement for screening low antibody levels such as those in convalescent patients. In addition, our method exhibits excellent channel-to-channel (RSD = 1.9%) and sensor-to-sensor (RSD = 2.1%) reproducibility. Obviation of an enzyme label drastically reduced the assay cost, rending our method (<60 cents) much more cost effective than those of commercial ELISA kits ($4.4-11.4). Therefore, our method offers a cost-effective and high-throughput alternative to the existing methods for serological measurements of anti-SARS-CoV-2 antibody levels, holding great promise for rapid screening of clinical samples without elaborate sample pretreatments and special reagents.

Human carboxylesterase 1A plays a predominant role in the hydrolytic activation of remdesivir in humans.

Remdesivir, an intravenous nucleotide prodrug, has been approved for treating COVID-19 in hospitalized adults and pediatric patients. Upon administration, remdesivir can be readily hydrolyzed to form its active form GS-441524, while the cleavage of the carboxylic ester into GS-704277 is the first step for remdesivir activation. This study aims to assign the key enzymes responsible for remdesivir hydrolysis in humans, as well as to investigate the kinetics of remdesivir hydrolysis in various enzyme sources. The results showed that remdesivir could be hydrolyzed to form GS-704277 in human plasma and the microsomes from human liver (HLMs), lung (HLuMs) and kidney (HKMs), while the hydrolytic rate of remdesivir in HLMs was the fastest. Chemical inhibition and reaction phenotyping assays suggested that human carboxylesterase 1 (hCES1A) played a predominant role in remdesivir hydrolysis, while cathepsin A (CTSA), acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) contributed to a lesser extent. Enzymatic kinetic analyses demonstrated that remdesivir hydrolysis in hCES1A (SHUTCM) and HLMs showed similar kinetic plots and much closed Km values to each other. Meanwhile, GS-704277 formation rates were strongly correlated with the CES1A activities in HLM samples from different individual donors. Further investigation revealed that simvastatin (a therapeutic agent for adjuvant treating COVID-19) strongly inhibited remdesivir hydrolysis in both recombinant hCES1A and HLMs. Collectively, our findings reveal that hCES1A plays a predominant role in remdesivir hydrolysis in humans, which are very helpful for predicting inter-individual variability in response to remdesivir and for guiding the rational use of this anti-COVID-19 agent in clinical settings.

Initial Public-Health Emergency Response to SARS and COVID-19 Pandemics in Mainland China: A Retrospective Comparative Study.

BACKGROUND: Severe acute respiratory syndrome (SARS) was reported first in China in 2003. The world is currently coping with coronavirus disease-2019 (COVID-19). We conducted a retrospective study to compare the initial public-health emergency response (PHER) to SARS and COVID-19 in mainland China. METHODS: A qualitative comparative study was conducted to compare the PHER timelines to SARS and COVID-19 by selecting six crucial time points. Besides, we explored the speed of spread, peak time and plateau period of SARS and COVID-19, respectively, by comparing the confirmed cases in the same time interval. RESULTS: The government of the People's Republic of China (PRC) accomplished the entire initial PHER to SARS in 127 days and for COVID-19 in 44 days. The speed of PHER for COVID-19 was 83 days faster. The peak time of SARS arose ~80 days later than that of COVID-19. Though the peak number of confirmed daily cases for COVID-19 was fivefold more than that of SARS, the onset of the stabilization period for COVID-19 was >2 months earlier than that of SARS. CONCLUSION: Overall, the speed of the initial PHER to COVID-19 pandemic was faster than that for SARS. Compared with the speed of hospital reporting and government policymaking, the speed of pathogen identification improved the most. The COVID-19 pandemic curve entered a plateau period earlier than the SARS pandemic curve, which suggests that the pandemic was controlled more effectively because of a timely PHER. The PRC government should emphasize improving the ability of hospitals to restrain infectious diseases by enhancing the direct reporting system and cultivating crisis management to empower relevant individuals to make timely scientific decisions.

Early Surveillance and Public Health Emergency Responses Between Novel Coronavirus Disease 2019 and Avian Influenza in China: A Case-Comparison Study.

Background: Since the novel coronavirus disease (COVID-19) has been a worldwide pandemic, the early surveillance and public health emergency disposal are considered crucial to curb this emerging infectious disease. However, studies of COVID-19 on this topic in China are relatively few. Methods: A case-comparison study was conducted using a set of six key time nodes to form a reference framework for evaluating early surveillance and public health emergency disposal between H7N9 avian influenza (2013) in Shanghai and COVID-19 in Wuhan, China. Findings: A report to the local Center for Disease Control and Prevention, China, for the first hospitalized patient was sent after 6 and 20 days for H7N9 avian influenza and COVID-19, respectively. In contrast, the pathogen was identified faster in the case of COVID-19 than in the case of H7N9 avian influenza (12 vs. 31 days). The government response to COVID-19 was 10 days later than that to avian influenza. The entire process of early surveillance and public health emergency disposal lasted 5 days longer in COVID-19 than in H7N9 avian influenza (46 vs. 41 days). Conclusions: The identification of the unknown pathogen improved in China between the outbreaks of avian influenza and COVID-19. The longer emergency disposal period in the case of COVID-19 could be attributed to the government's slower response to the epidemic. Improving public health emergency management could lessen the adverse social effects of emerging infectious diseases and public health crisis in the future.

Achieving Universal Wearing of Face Masks During the COVID-19 Pandemic: A Practical Solution from Shanghai, China.

BACKGROUND: Face masks are basic protective equipment for preventing respiratory infectious diseases. The measures to properly dispose of and allocate face masks during the early stage of an epidemic caused by respiratory infectious diseases deserve worldwide attention. METHODS: A qualitative research approach was used to document the practice of a citywide face mask-wearing strategy of the Shanghai Municipal Government (called the "Shanghai solution" in this article). Based on data from government work documents, an online face mask-allocation and sales system was built to offer real-time updates of face-mask appointments and sales information in all designated pharmacies and neighborhood committees in Shanghai. RESULTS: In the Shanghai solution, a total of 24.8 million residents in 6,031 committees were covered, in order to achieve universal wearing of face masks during the COVID-19 crisis. Up to 110 million face masks were dispensed to residents in six rounds of face-mask allocation during February to April. This practical experience in Shanghai solved two key problems (insufficient face-mask capacity, protection of vulnerable population) with the supply of face masks by addressing four essential characteristics: overall coordination, on-demand distribution, efficient distribution, and technical support. CONCLUSION: The practice of the citywide face mask-supply strategy of Shanghai could provide several pointers for management of a shortage of emergency materials, dispatch, and transport to other countries during the pandemic.

Prolonging the flush-lock interval of totally implantable venous access ports in patients with cancer: A systematic review and meta-analysis.

BACKGROUND: Recently, some studies have shown that prolonging flush interval is safe and feasible for patients who complete chemotherapy. However, there is no consensus about the optimal flush interval for those patients. OBJECTIVE: The purpose of this review was to evaluate whether the flush interval could be prolonged based on monthly interval for regular maintenance and to explore the optimal flush interval. DATA SOURCES: We searched the following databases for articles published between 1 January 1982 and 21 February 2020: PubMed, Cochrane Library, Web of Science, EMBASE, CINAHL, and Ovid. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials, retrospective and prospective cohort studies of flush interval less than 4 weeks versus longer than 4 weeks for patients who completed chemotherapy, were included. RESULTS: Two reviewers extracted information and assessed the quality of the articles independently. In total, 389 articles were retrieved, and 4 studies including 862 cases fulfilled the inclusion criteria. There was no statistical heterogeneity (I2 = 0, p > 0.05) among the included studies. Hence, the fixed-effects model was used for the meta-analysis. The meta-analysis showed that the total complication rate associated with longer than 4-week interval was higher than that associated with less than 4-week interval. Nevertheless, there was no significant difference between the two groups (7.2% vs 7.6%, p = 0.83). Moreover, the meta-analysis showed that the total complication and catheter occlusion rates associated with the 4-week interval were higher than those associated with the 8-week interval. However, there was no significant difference between the two groups (total complications: 11.4% vs 9.5%, p = 0.68; catheter occlusions: 4.9% vs 4.1%, p = 0.89). LIMITATIONS: Only four non-randomized controlled studies were included, and the outcomes of the included studies were reported incompletely. CONCLUSION: Extending the flush interval to longer than 4 weeks is safe and feasible. Based on previous studies, extending the flush interval to 8 weeks might not increase the incidence of total complications and catheter occlusions. However, there is no conclusion on whether the flush interval could be extended to 3 months or longer.

Characteristics of and Public Health Emergency Responses to COVID-19 and H1N1 Outbreaks: A Case-Comparison Study.

BACKGROUND: Recently, the novel coronavirus disease (COVID-19) has already spread rapidly as a global pandemic, just like the H1N1 swine influenza in 2009. Evidences have indicated that the efficiency of emergency response was considered crucial to curb the spread of the emerging infectious disease. However, studies of COVID-19 on this topic are relatively few. METHODS: A qualitative comparative study was conducted to compare the timeline of emergency responses to H1N1 (2009) and COVID-19, by using a set of six key time nodes selected from international literature. Besides, we also explored the spread speed and peak time of COVID-19 and H1N1 swine influenza by comparing the confirmed cases in the same time interval. RESULTS: The government's entire emergency responses to the epidemic, H1N1 swine influenza (2009) completed in 28 days, and COVID-19 (2019) completed in 46 days. Emergency responses speed for H1N1 was 18 days faster. As for the epidemic spread speed, the peak time of H1N1 came about 4 weeks later than that of COVID-19, and the H1N1 curve in America was flatter than COVID-19 in China within the first four months after the disease emerged. CONCLUSIONS: The speed of the emergency responses to H1N1 was faster than COVID-19, which might be an important influential factor for slowing down the arrival of the peak time at the beginning of the epidemic. Although COVID-19 in China is coming to an end, the government should improve the public health emergency system, in order to control the spread of the epidemic and lessen the adverse social effects in possible future outbreaks.