Pathological Effects of SARS-CoV-19 Associated With Hematological Abnormalities (preprint)

The SARS coronavirus 2 (SARS-CoV-2) is the causative agent of the 2019 coronavirus disease (COVID-19) pandemic that has executed 6.9 million people and infected over 765 million. It’s become a major worldwide health alarm and is also known to cause abnormalities in various systems, including the hematologic system. COVID-19 infection primarily affects the lower res-piratory tract and can lead to a cascade of events, including a cytokine storm, intravascular thrombosis, and subsequent complications such as arterial and venous thromboses. COVID-19 can cause thrombocytopenia, lymphopenia, and neutrophilia, which are associated with worse out-comes. Prophylactic anticoagulation is essential to prevent complication and death rate associated with the virus's effect on the coagulation system. It is crucial to recognize these complications early and promptly start therapeutic anticoagulation to improve patient outcomes. While rare, COVID-19-induced disseminated intravascular coagulation exhibits some similarities to DIC induced by sepsis. LDH, D-dimer, ferritin, and CRP biomarker are often increase in serious COVID-19 cases and poor prognosis. Understanding the pathophysiology of the disease and identifying risk factors for adverse outcomes is critical for effective management of COVID-19.

The Explanatory Models for Anxiety among Pregnant Women Infected with COVID-19 in China: A Thematic Analysis of 336 Postings from Infected Individuals (preprint)

Background: Infection with COVID-19 aggravates the anxiety of pregnant women. Our study aimed to establish explanatory models to investigate the causes of anxiety in pregnant women infected with COVID-19. Methods: To achieve this, we captured 336 postings of infected pregnant women on Sina Weibo from 7 November 17, 2022, to January 16, 2023, during which the number of infected people continued to rise after China lifted control of the epidemic. We used Python to filter the postings and NVivo12 for thematic analysis. Results: Our analysis revealed four central themes and thirteen sub-themes: Theme 1: Neglecting Maternity Care, including Discomfort Without Special Treatment, Special Care Absence, and Exploitation of Healthcare Resources; Theme 2: High-risk Pregnancy Process, including Collapse of Safe Space, Risk of Mother-to-Child Transmission, Unknown Drug Risk Impact, and Emergence of Childbirth Risk; Theme 3: The Pressure of Motherhood Expectations, including Motherhood Negligence and Lost Opportunities to Become Mothers; Theme 4: Insufficient Social Support, including Delayed Policy Support, Lack of Instrumental Support, Negative Informational Support, and Weak Inter-individual Support. Conclusions: For pregnant women with COVID-19, it is crucial to have mental health interventions, eHealth programs, social media content moderation, and flexible hospital policies.

Tongue and pulse features of 668 asymptomatic patients infected with the severe acute respiratory syndrome coronavirus 2 omicron variant in Shanghai.

OBJECTIVE: To characterize the tongue and pulse manifestations in asymptomatic coronavirus disease 2019 (COVID-19) cases in Shanghai. METHODS: We conducted a clinical study of 668 patients with asymptomatic infections in which we analyzed the tongue and pulse features in the Shanghai New International Expo Center mobile cabin hospital. The medical records of the patients, including tongue color, tongue coating, and pulse manifestations, were reviewed by healthcare workers. RESULTS: In total, 668 COVID-19 cases were included in the study. Patient age ranged from 5 to 96 years, with a median of 44.0 (IQR 33.0-53.0) years. Among the patients, 6.14% had comorbidities. The most common comorbid condition was diabetes (1.65%), followed by hypertension (0.89%), coronary heart disease (0.89%), thrombotic diseases (0.89%), congestive heart failure (0.60%), and stroke (0.45%). Pink-red (75.4%) was the most common tongue color, followed by red (23.4%) and pale red (1.2%). Tongue coating color and thickness were classified as white fur (9.28%), thin and yellow fur (48.65%), white greasy fur (8.98%), yellow greasy fur (24.70%), and less coating (8.39%). In addition, a large number of patients ( 300, 44.91%) presented superficial and rapid pulses, and 250 patients (37.4%) exhibited a slippery pulse. CONCLUSION: Our preliminary results showed that wind, heat, and dampness were the main etiologies of the severe acute respiratory syndrome coronavirus 2 Omicron (B.1.1.529) variant infection in traditional Chinese medicine. Furthermore, the main symptoms of the disease may be wind-heat invading the lung syndrome or damp-heat with the exuberance of virulence syndrome, which is of most significance in COVID-19 treatment.

Preventive measures significantly reduced the risk of nosocomial infection in elderly inpatients during the COVID-19 pandemic

In December 2019, there was an outbreak of pneumonia of unknown causes in Wuhan, China. The etiological pathogen was identified to be a novel coronavirus, named severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). The number of infected patients has markedly increased since the 2019 outbreak and COVID-19 has also proven to be highly contagious. In particular, the elderly are among the group of patients who are the most susceptible to succumbing to COVID-19 within the general population. Cross-infection in the hospital is one important route of SARS-CoV-2 transmission, where elderly patients are more susceptible to nosocomial infections due to reduced immunity. Therefore, the present study was conducted to search for ways to improve the medical management workflow in geriatric departments to ultimately reduce the risk of nosocomial infection in elderly inpatients. The present observational retrospective cohort study analysed elderly patients who were hospitalised in the Geriatric Department of the First Affiliated Hospital with Nanjing Medical University (Nanjing, China). A total of 4,066 elderly patients, who were admitted between January and March in 2019 and 2020 and then hospitalised for >48 h were selected. Among them, 3,073 (75.58%) patients hospitalised from January 2019 to March 2019 were allocated into the non-intervention group, whereas the remaining 933 (24.42%) patients hospitalised from January 2020 to March 2020 after the COVID-19 outbreak were allocated into the intervention group. Following multivariate logistic regression analysis, the risk of nosocomial infections was found to be lower in the intervention group compared with that in the non-intervention group. After age stratification and adjustment for sex, chronic disease, presence of malignant tumour and trauma, both inverse probability treatment weighting and standardised mortality ratio revealed a lower risk of nosocomial infections in the intervention group compared with that in the non-intervention group. To rule out interference caused by changes in the community floating population and social environment during this 1-year study, 93 long-stay patients in stable condition were selected as a subgroup based on 4,066 patients. The so-called floating population refers to patients who have been in hospital for <2 years. Patients aged ≥65 years were included in the geriatrics program. The incidence of nosocomial infections during the epidemic prevention and control period (24 January 2020 to 24 March 2020) and the previous period of hospitalisation (24 January 2019 to 24 March 2019) was also analysed. In the subgroup analysis, a multivariate analysis was also performed on 93 elderly patients who experienced long-term hospitalisation. The risk of nosocomial and pulmonary infections was found to be lower in the intervention group compared with that in the non-intervention group. During the pandemic, the geriatric department took active preventative measures. However, whether these measures can be normalised to reduce the risk of nosocomial infections among elderly inpatients remain unclear. In addition, the present study found that the use of an indwelling gastric tube is an independent risk factor of nosocomial pulmonary infection in elderly inpatients. However, nutritional interventions are indispensable for the long-term wellbeing of patients, especially for those with dysphagia in whom an indwelling gastric tube is the most viable method of providing enteral nutrition. To conclude, the present retrospective analysis of the selected cases showed that enacting preventative and control measures resulted in the effective control of the incidence of nosocomial infections.

Pre-Clinical Development of a Potent Neutralizing Antibody MW3321 With Extensive SARS-CoV-2 Variants Coverage

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, several variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged and have consistently replaced the previous dominant variant. Therapeutics against variants of SARS-CoV-2 are urgently needed. Ideal SARS-CoV-2 therapeutic antibodies would have high potency in viral neutralization against several emerging variants. Neutralization antibodies targeting SARS-CoV-2 could provide immediate protection after SARS-CoV-2 infection, especially for the most vulnerable populations. In this work, we comprehensively characterize the breadth and efficacy of SARS-CoV-2 RBD-targeting fully human monoclonal antibody (mAb) MW3321. MW3321 retains full neutralization activity to all tested 12 variants that have arisen in the human population, which are assigned as VOC (Variants of Concern) and VOI (Variants of Interest) due to their impacts on public health. Escape mutation experiments using replicating SARS-CoV-2 pseudovirus show that escape mutants were not generated until passage 6 for MW3321, which is much more resistant to escape mutation compared with another clinical staged SARS-CoV-2 neutralizing mAb MW3311. MW3321 could effectively reduce viral burden in hACE2-transgenic mice challenged with either wild-type or Delta SARS-CoV-2 strains through viral neutralization and Fc-mediated effector functions. Moreover, MW3321 exhibits a typical hIgG1 pharmacokinetic and safety profile in cynomolgus monkeys. These data support the development of MW3321 as a monotherapy or cocktail against SARS-CoV-2-related diseases.

Virtually Enhancing Public Engagement During the Pandemic: Measuring the Impact of Virtual Reality Powered Immersive Videos on Corporate Social Responsibility Communication

Many companies have applied virtual reality (VR), a new and popular technology, to their corporate social responsibility (CSR) activities. This study examines how 360-degree VR-powered videos might further enhance consumers? engagement in CSR activities and facilitate business outcomes during a crisis setting. The researchers conducted an online survey study, during the coronavirus (COVID-19) pandemic, with 1422 representative U.S. residents and applied the structural equation modeling for data analysis. Results indicated that the four categories of gratifications-sought (i.e., being there, enhancement, interaction, and fun) on 360-degree VR-powered videos could all positively influence CSR engagement;in contrast, CSR skepticism would reduce such engagement online. Corporate social responsibility engagement further improved the organization-public relationships (OPRs) and ultimately influenced consumers? word-of-mouth toward the company. Theoretical and practical implications of these findings were discussed.

Development and application of an uncapped mRNA platform (preprint)

A novel uncapped mRNA platform was developed. Five lipid nanoparticle (LNP)-encapsulated mRNA constructs were made to evaluate several aspects of our platform, including transfection efficiency and durability in vitro and in vivo and the activation of humoral and cellular immunity in several animal models. The constructs were eGFP-mRNA-LNP (for enhanced green fluorescence mRNA), Fluc-mRNA-LNP (for firefly luciferase mRNA), S{delta}T-mRNA-LNP (for Delta strain SARS-CoV-2 spike protein trimer mRNA), gDED-mRNA-LNP (for truncated glycoprotein D mRNA coding ectodomain from herpes simplex virus type 2 (HSV2)) and gDFR-mRNA-LNP (for truncated HSV2 glycoprotein D mRNA coding amino acids 1~400). Quantifiable target protein expression was achieved in vitro and in vivo with eGFP- and Fluc-mRNA-LNP. S{delta}T-mRNA-LNP, gDED-mRNA-LNP and gDFR-mRNA-LNP induced both humoral and cellular immune responses comparable to those obtained by previously reported capped mRNA-LNP constructs. Notably, 25, 50 and 100 g of S{delta}T-mRNA-LNP all elicited neutralizing antibodies in hamsters against the Omicron and Delta strains. Additionally, gDED-mRNA-LNP and gDFR-mRNA-LNP induced potent neutralizing antibodies in rabbits and mice. The mRNA constructs with uridine triphosphate (UTP) outperformed those with N1-methylpseudouridine triphosphate (N1m{psi}TP) in the in vivo expression of luciferase and the induction of antibodies via S{delta}T-mRNA-LNP. Our uncapped, process-simplified, and economical mRNA platform may have broad utility in vaccines and protein replacement drugs.

Trends in secondary inorganic aerosol pollution in China and its responses to emission controls of precursors in wintertime

The Chinese government recently proposed ammonia (NH3) emission reductions (but without a specific national target) as a strategic option to mitigate fine particulate matter (PM2.5) pollution. We combined a meta-analysis of nationwide measurements and air quality modeling to identify efficiency gains by striking a balance between controlling NH3 and acid gas (SO2 and NOx) emissions. We found that PM2.5 concentrations decreased from 2000 to 2019, but annual mean PM2.5 concentrations still exceeded 35 µg m-3 at 74 % of 1498 monitoring sites during 2015–2019. The concentration of PM2.5 and its components were significantly higher (16 %–195 %) on hazy days than on non-hazy days. Compared with mean values of other components, this difference was more significant for the secondary inorganic ions SO42-, NO3-, and NH4+ (average increase 98 %). While sulfate concentrations significantly decreased over this period, no significant change was observed for nitrate and ammonium concentrations. Model simulations indicate that the effectiveness of a 50 % NH3 emission reduction for controlling secondary inorganic aerosol (SIA) concentrations decreased from 2010 to 2017 in four megacity clusters of eastern China, simulated for the month of January under fixed meteorological conditions (2010). Although the effectiveness further declined in 2020 for simulations including the natural experiment of substantial reductions in acid gas emissions during the COVID-19 pandemic, the resulting reductions in SIA concentrations were on average 20.8 % lower than those in 2017. In addition, the reduction in SIA concentrations in 2017 was greater for 50 % acid gas reductions than for the 50 % NH3 emission reductions. Our findings indicate that persistent secondary inorganic aerosol pollution in China is limited by emissions of acid gases, while an additional control of NH3 emissions would become more important as reductions of SO2 and NOx emissions progress.

Birds carry a diversity of significant viruses in their virome (preprint)

Birds can carry and transmit viruses to humans and other animals. Thus, understanding the viral community hosted by birds could help us predict future outbreaks of human disease. A recent metagenomics study took a broad look at the viruses found in the gut of wild and captive birds. The dataset included samples from over 3,000 birds that represented over 87 species and 10 different phylogenetic orders and the researchers characterized genomes from numerous viral families including astroviruses, coronaviruses, parvoviruses, and adenoviruses. Examining trends, they found that wild birds had higher viral diversity than captive birds. There was also evidence of potential cross-species transmission between wild birds and domestic poultry. Further analysis of the viral genomic sequences revealed differences in virus distribution patterns between wild and captive birds. Different phylogenetic orders of birds and geographic sites also had distinct distribution patterns. Interestingly, there were no significant differences in virus distribution patterns between migratory and resident birds. While further studies are needed to explore the diversity and potential pathogenicity of these viruses in more detail, this study expanded our understanding of viral diversity in birds.

Sudden shock and stock market network structure characteristics: A comparison of past crisis events

Studying the correlation structure of the stock market is crucial for systemic risk and portfolio optimization. We construct the price volatility network of the Shanghai and Shenzhen 300 index components in China's stock market in the period 2007–2020. We select three representative major emergencies: the global financial crisis in 2008, the stock disaster in 2015, and the COVID-19 epidemic in 2020. First, we find that when the stock market is impacted by the major events, the network shows a cluster phenomenon. The cluster effect of the financial crisis events is smallest, while that of the epidemic events occurs most rapidly. Second, the key nodes in the stock market network have greater risk transmission ability. The manufacturing plays a crucial role during the later stages of events, while the financial industry plays an important role during the epidemic's recovery period. Third, the network structure of the stock market has an indicator effect on the systemic risk contributions. Generally, the greater a stock's eigenvector centrality, the greater its systemic risk contribution, while its closeness centrality and clustering coefficient have opposite effects. The study has important enlightenment significance for market regulators to prevent risk diffusion and reduce portfolio risk for market participants.

Investigation of Anti-Epithelial-Mesenchymal Transition and Anti-Inflammation effects of Qing Fei Hua Xian Decotion on Pulmonary Fibrosis via Network Pharmacology and Experimental Verification (preprint)

Background Pulmonary fibrosis (PF) is a common interstitial pneumonia disease, also occurred in post-COVID-19 survivors. The mechanism underlying the anti-PF effect of Qing Fei Hua Xian Decotion (QFHXD), a traditional Chinese medicine formula applied for treating PF in COVID-19 survivors, is unclear. This study aimed to uncover the mechanisms related to the anti-PF effect of QFHXD through analysis of network pharmacology and experimental verification.Methods The candidate chemical compounds of QFHXD and its putative targets for treating PF were achieved from public databases, thereby we established the corresponding “herb- compound -target” network of QFHXD. Moreover, The protein–protein interaction (PPI) network of potential targets was also constructed to screen the core targets. Furthermore, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to predict targets, and pathways, then validated by in vivo experiments.Results A total of 188 active compounds in QFHXD and 50 target genes were identified from databases. The key therapeutic targets of QFHXD, such as PI3K/Akt, IL-6, TNF, IL-1β, STAT3, MMP-9, and TGF-β1 were identified by KEGG and GO analysis. Anti-PF effects of QFHXD (in a dose-dependent manner) and prednisone were confirmed by HE, Masson staining, and Sirius red staining as well as in vivo Micro-CT and immunohistochemical analysis in a rat model of bleomycin-induced PF. Besides, QFXHD remarkably inhibits the activity of PI3K/Akt/NF-κB and TGF‑β1/Smad2/3.Conclusion QFXHD significantly attenuated bleomycin-induced PF via inhibiting inflammation and EMT. PI3K/Akt/NF-κB and TGF‑β1/Smad2/3 pathways might be the potential therapeutic effects of QFHXD for treating PF.

BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection (preprint)

Recent emergence of SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.2. The new variants' receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we showed that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1; while BA.4/BA.5 shows the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization escape from the plasma of 3-dose vaccinees and, most strikingly, from vaccinated BA.1 convalescents. To delineate the underlying evasion mechanism, we determined the escaping mutation profiles, epitope distribution and Omicron sublineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype (WT) induced humoral memory and elicits antibodies that neutralize both WT and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes; and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure of Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to WT SARS-CoV-2, due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths. As for therapeutic NAbs, LY-CoV1404 (Bebtelovimab) and COV2-2130 (Cilgavimab) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum protection.

BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron BA.1 infection (preprint)

Recent emergence of SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.2. The new variants’ receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we showed that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1; while BA.4/BA.5 shows the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization escape from the plasma of 3-dose vaccinees and, most strikingly, from vaccinated BA.1 convalescents. To delineate the underlying evasion mechanism, we determined the escaping mutation profiles, epitope distribution and Omicron sub-lineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype-induced humoral memory and elicits antibodies that neutralize both wild-type and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes; and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure of Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to wild-type SARS-CoV-2, due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths. As for therapeutic NAbs, LY-CoV1404 (Bamlanivimab) and COV2-2130 (Cilgavimab) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum protection.

Evaluation on potential detriments from lockdown-related isolation to mental health among school-aged youth in central China (preprint)

Background: Home isolation is a generally effective strategy for coronavirus disease control during lockdown periods. This study is to determine the potential adverse consequences of home isolation to mental health among school-aged youth after lifting of major lockdown measures in central China. Methods: This cohort study assessed the mental health of school-aged children and adolescents enrolled in Wuhan city and nearby areas in Hubei province, China, from July 1 to August 31, 2020. Post-lockdown responses to anxiety, depression, sleep disturbances and post-traumatic stress symptoms were assessed in online questionnaire-based surveys. Participants’ scores for the Zung self-rated anxiety scale, the Patient Health Questionnaire-9, the self-rating scale of sleep and the post-traumatic stress disorder self-rating scale (PTSS) were analyzed. Results: Questionnaire responses of 730 school children were collected. Among the participants, 6.25% of them had scores above thresholds for PTSS, 5.81% had anxiety, and 48.84% had depression. All subjects reported that they experienced sleep disturbances. Subjects who had anxiety might have a high risk for developing depression [OR: 16.07, p =0.008, 95%CI (2.08-123.94)] and PTSS [OR: 12.97, p <0.001, 95%CI (5.41-31.11)]. Both depression [OR: 17.35, p =0.006, 95%CI (2.28-131.87)] and PTSS [OR: 14.18, p <0.001, 95%CI (6.00-33.47)] were risk factors for developing anxiety among participants. Interestingly, higher educational levels of primary caregivers were a risk factor for developing depression [OR: 1.62, p =0.005, 95%CI (1.16-2.28)] in the participants, but a protective factor against PTSS [OR: 0.47, p =0.048, 95%CI (0.23-0.99)].Conclusions: The local youth had less than expected degree of increases in their self-reported PTSS and anxiety, after exiting lockdown-related isolation. As a result of a combination of compensatory mechanisms including internet-based home-schooling and increased intra-familial interactions, home isolation did not affect the mental health of local school-aged youth to an extent as great as expected.Trial registration: The Registration number of this trial is ChiCTR2000033054.

Comprehensive Epitope Mapping of Broad Sarbecovirus Neutralizing Antibodies (preprint)

Constantly emerging SARS-CoV-2 variants, such as Omicron BA.1, BA.1.1 and BA.2, pose a severe challenge to COVID-19 control. Broad-spectrum antibody therapeutics and vaccines are needed for defending against future SARS-CoV-2 variants and sarbecovirus pandemics; however, we have yet to gain a comprehensive understanding of the epitopes capable of inducing broad sarbecovirus neutralization. Here, we report the identification of 241 anti-RBD broad sarbecovirus neutralizing antibodies isolated from 44 SARS-CoV-2 vaccinated SARS convalescents. Neutralizing efficacy of these antibodies against D614G, SARS-CoV-1, Omicron variants (BA.1, BA.1.1, BA.2), RATG13 and Pangolin-GD is tested, and their binding capability to 21 sarbecovirus RBDs is measured. High-throughput yeast-display mutational screening was further applied to determine each antibody's RBD escaping mutation profile, and unsupervised epitope clustering based on escaping mutation hotspots was performed. A total of 6 clusters of broad sarbecovirus neutralizing antibodies with diverse breadth and epitopes were identified, namely Group E1 (S309, BD55-3152 site), E3 (S2H97 site), F1 (CR3022, S304 site), F2 (DH1047, BD55-3500 site), F3 (ADG-2, BD55-3372 site) and B' (S2K146 site). Members of E1, F2 and F3 demonstrate the highest neutralization potency; yet, Omicron, especially BA.2, has evolved multiple mutations (G339D, N440K, T376A, D405N, R408S) to escape antibodies of these groups. Nevertheless, broad sarbecovirus neutralizing antibodies that survived Omicron would serve as favorable therapeutic candidates. Furthermore, structural analyses of selected drug candidates propose two non-competing antibody pairing strategies, E1-F2 and E1-F3, as broad-spectrum antibody cocktails. Together, our work provides a comprehensive epitope map of broad sarbecovirus neutralizing antibodies and offers critical instructions for designing broad-spectrum vaccines.

Lung Ultrasound in COVID-19 Patients: Characteristics and Factors Affecting its Diagnostic Accuracy (preprint)

Background: Although chest computed tomography (CT) is the gold standard for diagnosing the majority of lung conditions, its use in screening patients for coronavirus disease 2019(COVID-19) pneumonia is not recommended. Lung ultrasound (LUS) is an alternative modality. To investigate the characteristics and diagnostic accuracy (DA) of bedside ultrasound for lung lesions in patients with COVID-19 and to determine the factors influencing the DA of lung ultrasound (LUS). Methods: A total of 330 patients with COVID-19 admitted to the hospital between February and March 2020 were retrospectively recruited. The imaging characteristics of LUS and computed tomography (CT) scans were analysed and summarized. DA was calculated using a chest CT scan as the reference standard. Furthermore, a binary logistic regression analysis was conducted to investigate the factors influencing the DA of LUS for interstitial syndrome. Results: The ultrasound findings of COVID-19 patients presented mainly as B lines (195/330, 59.1%), unsmooth or interrupted pleural lines (118/330, 35.8%), consolidation lesions (74/330, 22.4%), and pleural effusion (11/330, 3.33%). Compared with the chest CT scan, the DA of LUS for interstitial syndrome, consolidation, pleural effusion, and pleural thickening were 0.821, 0.927, 0.988, and 0.863, respectively. The diagnostic coincidence rate of LUS and chest CT in the mild, common, severe, and critical groups were 93%, 68.6%, 100%, and 100%, respectively. According to the results of the binary logistic regression, sex, disease duration, experience of the doctor, and involved lobes were independent predictors of the DA for interstitial syndrome. Conclusions: LUS had good diagnostic performance for diagnosing COVID-19 pneumonia, and showed a relatively low DA for interstitial syndrome. Female sex, doctors with less experience, long disease duration, and lesions limited to the upper or lower lobes may decrease the DA.

Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein.

An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant KD) of 0.0947 µM and anti-virus IC50 of 85.75 µM.

Phase 1 safety and pharmacokinetics studies of BRII-196 and BRII-198, SARS-CoV-2 spike-targeting monoclonal antibodies (preprint)

Background. BRII-196 and BRII-198 are two anti-SARS-CoV-2 monoclonal neutralizing antibodies with modified Fc region that extends half-life and are being developed as cocktail therapy for the treatment of COVID-19. Safety, tolerability, pharmacokinetics, and immunogenicity of BRII-196 and BRII-198 were investigated in healthy adults. Methods. Single ascending doses of BRII-196 and BRII-198 were evaluated in parallel in the first-in-human, placebo-controlled phase 1 studies. A total of 32 healthy adults were randomized and received a single intravenous infusion of 750, 1500, and 3000 mg of BRII-196 (n=12), BRII-198 (n=12), or placebo (n=8) and were followed for 180 days. Results. All infusions were well tolerated at infusion rates between 0.5 mL/min to 4 mL/min with no dose-limiting adverse events, deaths, serious adverse events, or any systemic or local infusion reactions. Most treatment-emergent adverse events were isolated asymptomatic laboratory abnormalities of Grade 1-2 in severity. Each mAb displayed pharmacokinetics expected of Fc-engineered human IgG1 with mean terminal half-lives of approximately 46 days and 76 days, respectively, with no evidence of significant anti-drug antibody development. Conclusions. BRII-196 and BRII-198 were well-tolerated. Clinical results support further development as therapeutic or prophylactic options for SARS-CoV-2 infection.

Factors Influencing Nurses' Work Interruption in Wuhan Isolation Wards During the COVID-19 Pandemic.

BACKGROUND Through January 2021, the novel coronavirus (COVID-19) continued to create significant pressure on medical staff who have worked to treat patients with the disease and control its spread. This study aimed to increase understanding of the situation and influencing factors of nurses' work interruption in Wuhan's isolation ward during the COVID-19 pandemic. MATERIAL AND METHODS A self-designed general situation questionnaire and work interruption questionnaire were used to survey 160 nurses from Beijing, Chongqing, and Jilin who worked during the COVID-19 pandemic in Wuhan in March 2020. The questionnaire could only be answered once by each nurse via a WeChat account. The submitted answers were verified by 2 researchers. RESULTS The results showed that the rate of interruption of work among nurses in the isolation ward was 25%, and the rate of nurses experiencing a negative experience was 96.9%. The results of univariate analysis showed that the following factors were related to the work interruption of the nurses in the isolation ward (all P<0.05): emergency public incident training; emergency public incident treatment experience; knowledge of COVID-19 pneumonia; hours worked per shift in the quarantine area; and negative physiologic experience. Logistic regression analysis showed that negative experience, hours worked per shift, and emergency public incident training were the independent factors influencing work interruption among nurses in the isolation wards. CONCLUSIONS The incidence of interruption of work among nurses in the isolation ward was 25%. Negative experiences, long working hours per shift, and lack of emergency public incident training made the nurses more prone to work interruption.