Clinical Characteristics of COVID-19 Reinfection: A Retrospective Study in China (preprint)

Purpose The number of patients with COVID-19 reinfection is gradually increasing.In this study, we aimed to investigate the clinical characteristics of individuals who experienced COVID-19 reinfection.Methods A retrospective data analysis was conducted involving patients diagnosed with COVID-19 between April 1, 2023, and June 20, 2023. The patients were categorized into two groups: the observation group, consisting of individuals with reinfection, and the control group, comprising those with primary infection.Results A Total 905(905/1025) patients were included in the study,with 407 in the observation group and 498 in the control group. The top three clinical symptoms in both groups were fever, cough with expectoration, and dizziness with fatigue (p < 0.001). The clinical classification of patients in the observation group primarily consisted of non-severe cases, (p<0.001). The proportion of hospitalized patients was lower in the observation group than in the control group (p < 0.001). The observation group exhibited a shorter clinical symptom recovery time than that of the control group (median, 5 d vs. 7 d,p < 0.001).Conclusion Patients experiencing COVID-19 reinfection were primarily classified as non-severe cases, with lower proportions of occurrence of severe and rare critical conditions. The severity was milder compared to that in patients with primary COVID-19 infections.

Lack of association between HLA and asymptomatic SARS-CoV-2 infection (preprint)

Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B*15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B*15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the US (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B*15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified. These findings suggest that memory T-cell immunity to seasonal coronaviruses does not strongly influence the outcome of SARS-CoV-2 infection in unvaccinated individuals.

The molecular reach of antibodies determines their SARS-CoV-2 neutralisation potency (preprint)

Antibodies play crucial roles in health and disease and are invaluable tools for diagnostics, research, and therapy. Although antibodies bind bivalently, we lack methods to analyse bivalent binding. Here, we introduce a particle-based model and use it to analyse bivalent binding of SARS-CoV-2 RBD-specific antibodies in surface plasmon resonance assays. The method reproduces the monovalent on/off-rates and enables measurements of new parameters, including the molecular reach, which is the maximum antigen separation that supports bivalent binding. We show that the molecular reach (22-46 nm) exceeds the physical size of an antibody (15 nm) and that the variation in reach across 45 patient-isolated antibodies is the best correlate of viral neutralisation. Using the complete set of fitted parameters, the model predicts an emergent antibody binding potency that equals the neutralisation potency. This novel analytical method should improve our understanding and exploitation of antibodies and other bivalent molecules.

Multicenter cohort study of the risk factors and mortality of Omicron variant SARS-CoV-2-infected patients with hematologic malignancies in hospitals (preprint)

Purpose Evaluating risk factors of mortality and characters in patients with hematologic malignancy (HM) after anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccination of China.Methods A total of 104 HMs were included with a median follow-up of 45 days.Results The overall mortality rate was 9.6%. In multivariable analyses, 1 or more comorbidities (P = 0.014), lactic dehydrogenase > 300 u/l (P = 0.014), albumin < 35 g/l (P = 0.017) and active malignancy (P = 0.009) were associated with severe and critical COVID-19. Conversely, patients who received 3 vaccinations had a lower possibility of severe infection (P = 0.022). Active malignancy and lactic dehydrogenase > 300 u/l were risk factors associated with higher mortality in multivariable analyses (P = 0.03; P = 0.038, respectively). We also found that the duration of a positive SARS-CoV-2 PCR test and the time to stable pneumonia by chest computed tomography scan in the severe and critical infection subgroups were significantly longer than those in the moderate infection group (P = 0.03 and P = 0.002, respectively).Conclusions These findings may contribute to guiding the management of HMs during the pandemic, and emphasizing the importance of starting treatment of aggressive HMs for earlier remission.

EGFR core fucosylation, induced by enveloped viruses, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses (preprint)

Aberrant N-glycosylation has been implicated in viral diseases. Alpha-(1,6)-fucosyltransferase (FUT8) is the sole enzyme responsible for core fucosylation of N-glycans during glycoprotein biosynthesis. Here we found that multiple viral envelope proteins (including HCV-E2, VSV-G, SARS-COV-2-Spike and HIV-gp120) enhanced FUT8 expression and core fucosylation. HCV-E2 manipulates host transcription factor SNAIL to induce FUT8 expression through EGFR-AKT-SNAIL activation and SNAIL nuclear translocation. These aberrant increased-FUT8 expression promotes TRIM40-mediated RIG-I K48-ubiquitination and suppresses the antiviral interferon (IFN)-I response through core fucosylated EGFR-JAK1-STAT3-RIG-I signaling. FUT8 inhibitor 2FF, N-glycosylation site-specific mutation (Q352AT) of EGFR, and tissue-targeted Fut8 silencing significantly increased antiviral IFN-I responses and suppressed RNA viral replication, suggesting that core fucosylation mediated by FUT8 is critical for antiviral innate immunity. These findings reveal an immune invasion mechanism in which virus-induced FUT8 suppresses endogenous RIG-I-mediated antiviral defenses by enhancing core fucosylated EGFR-mediated activation. FUT8 may be a promising target for RNA viral therapies.

Baricitinib treatment for hospitalized patients with severe COVID-19 on invasive mechanical ventilation：a propensity score-matched and retrospective analysis (preprint)

Introduction: Baricitinib is a selective inhibitor of Janus kinase (JAK)1 and JAK2, which is associated with clinical improvement in non-severe COVID-19 patients. But in severe COVID-19 patients, the efficacy of baricitinib is still controversial. Methods: A propensity score-matched and retrospective study was conducted to evaluate the efficacy of baricitinib in severe COVID-19 patients requiring invasive mechanical ventilation (IMV). Results: A total number of 46 patients treated with baricitinib were included, and 44 patients were assigned to control group by propensity score matching. The mean ages were high in both group (baricitinib group vs control group: 78.80±9.04 vs 82.57±9.27), and most were unvaccinated (65.2% vs 72.7%). Baricitinib group had a higher proportion of patients with hypertension (73.9% vs 45.5%). Control group had higher level of creatine kinase-myocardial band (247.50 vs 104.50). Patients in the baricitinib group were more likely to receive nirmatrelvir/ritonavir (41.3% vs 18.2%) and intravenous immunoglobin (15.2% vs 0). Both groups reported high all-cause 28-day mortality (73.9% vs 84.1%). The use of baricitinib didn’t reduce 28-days mortality. Conclusion: The present study revealed baricitinib didn’t reduce 28-days mortality in severe COVID-19 patients on IMV. The effectiveness of baricitinib in treating patients with severe COVID-19 on IMV needs to be further investigated through future studies.

Evaluation of the correlation between sleep quality and work engagement among nurses in Shanghai during the post-epidemic era.

AIM: To examine the status quo and influencing factors of sleep quality and work engagement of nurses participating in COVID-19 during the post-epidemic era and to study the relationship between them. DESIGN: We conducted a cross-sectional survey and correlational and predictive logic to determine the association between sleep quality and work engagement among nurses in Shanghai during the post-epidemic era. METHODS: This design involved 1060 frontline nurses in Shanghai. The Pittsburgh Sleep Quality Index questionnaire and the Utrecht Work Engagement Scale-9 scales were used for data collection. RESULTS: This study found that the sleep quality of frontline nurses was impaired and the nurses with poor sleep accounted for 48.20% during the post-epidemic era. The work engagement of frontline nurses was at the medium level. Factors affecting nurses' sleep quality were the number of nurse night shifts, family support and nurse health. The factors affecting the nurse work engagement were monthly income, profession title, family support and self-health status. There was a positive correlation between nurses' sleep quality and work engagement.

Effectiveness of different disinfectants and combinations against SARS-CoV-2 nucleic acid in COVID-19 quarantine wards (preprint)

Background To detect the contamination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the surroundings of coronavirus disease 2019 (COVID-19) patients and to evaluate the effectiveness of regular disinfectants and combinations against SARS-CoV-2 RNA.Methods We sampled the patients’ high contact surfaces in COVID-19 pediatric quarantine wards from April to June 2022. After conducting cleaning procedures using disinfectants, including trichloroisocyanuric acid (TCCA; 500, 1000, and 2000 mg/L), 5% hydrogen peroxide (H2O2), 0.5% povidone-iodine (PI), 75% ethanol (EA), 0.2% chlorhexidine gluconate (CHG), 0.2% quaternary ammonia compound (QAC), and five combinations, environmental samples in bathroom were collected at 0, 30 s, 10, 30, and 60 min. All samples were delivered to the medical laboratory for SARS-CoV-2 nucleic acid (ORF1ab and N) detection using real-time PCR.Results SARS-CoV-2 RNA was largely detected on surfaces in the COVID-19 quarantine ward and was highest in the floor, bathroom, and bed sheet. The ORF1ab and N genes remained detectable after 60 min of treatment with QAC, PI, EA, and CHG. H2O2 and TCCA2000 completely degraded SARS-CoV-2 RNA in 30 s, which was faster than TCCA1000 (10 min). Clearance of ORF1ab and N by TCCA500 required 10 and 60 min, respectively, whereas combination of TCCA500 with EA or PI destroyed ORF1ab and N faster at 30 s and 30 min, respectively.Conclusion The surroundings of patients with COVID-19 are contaminated by SARS-CoV-2 RNA. Effectiveness of disinfectants and combinations varies, N gene persists longer time than ORF1ab after some disinfection.

Characterization of viral shedding of Severe acute respiratory syndrome Coronavirus-2

Corona virus disease 2019 (COVID-19) is an emerging pandemic of highly contagious caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2). Understanding the infectivity of various clinical samples and its transmission routes have been the main focus of current researches since the causative pathogens was identified. In this comprehensive review, we discuss the viral shedding from different clinical samples and reveal that infectious virus may be mainly discharged through respiratory and digestive systems. Also, SARS-CoV-2 showed a potential tropism for eyes, kidney, testis, placenta and other extrapulmonary tissues and high viral loads correlated with severe conditions. A better understanding of viral shedding may help the studies on pathogenesis and transmission of SARS-CoV-2 and provide suggestions for the disease control.

Improved Neutralization of Omicron BA.4/5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with Bivalent BA.4/5 Vaccine (preprint)

The BNT162b2 bivalent BA.4/5 COVID-19 vaccine has been authorized to mitigate COVID-19 due to current Omicron and potentially future variants. New sublineages of SARS-CoV-2 Omicron continue to emerge and have acquired additional mutations, particularly in the spike protein, that may lead to improved viral fitness and immune evasion. The present study characterized neutralization activities against new Omicron sublineages BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 after a 4th dose (following three doses of BNT162b2) of either the original monovalent BNT162b2 or the bivalent BA.4/5 booster in individuals >55 years of age. For all participants, the 4th dose of monovalent BNT162b2 vaccine induced a 3.0, 2.9, 2.3, 2.1, 1.8, and 1.5 geometric mean neutralizing titer fold rise (GMFR) against USA/WA1-2020 (a strain isolated in January 2020), BA.4/5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1, respectively; the bivalent vaccine induced 5.8, 13.0, 11.1, 6.7, 8.7, and 4.8 GMFRs. For individuals without SARS-CoV-2 infection history, BNT162b2 monovalent induced 4.4, 3.0, 2.5, 2.0, 1.5, and 1.3 GMFRs, respectively; the bivalent vaccine induced 9.9, 26.4, 22.2, 8.4, 12.6, and 4.7 GMFRs. These data suggest the bivalent BA.4/5 vaccine is more immunogenic than the original BNT162b2 monovalent vaccine against circulating Omicron sublineages, including BQ.1.1 that is becoming prevalent globally.

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with critical COVID-19 (preprint)

Background We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and autoantibodies against type I IFN in another 15-20% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI:1.5-528.7, P=1.1x10-4), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2], P=2.1x10-4). Adding the recently reported TYK2 COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; P=3.4x10-3). When these 14 loci and TLR7 were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], P=4.7x10-7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], P=0.02). Finally, the patients 13 with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10-5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie lifethreatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Application of bioreactor technology for cell culture-based viral vaccine production: Present status and future prospects

Bioreactors are widely used in cell culture-based viral vaccine production, especially during the coronavirus disease 2019 (COVID-19) pandemic. In this context, the development and application of bioreactors can provide more efficient and cost-effective vaccine production to meet the global vaccine demand. The production of viral vaccines is inseparable from the development of upstream biological processes. In particular, exploration at the laboratory-scale is urgently required for further development. Therefore, it is necessary to evaluate the existing upstream biological processes, to enable the selection of pilot-scale conditions for academic and industrial scientists to maximize the yield and quality of vaccine development and production. Reviewing methods for optimizing the upstream process of virus vaccine production, this review discusses the bioreactor concepts, significant parameters and operational strategies related to large-scale amplification of virus. On this basis, a comprehensive analysis and evaluation of the various process optimization methods for the production of various viruses (SARS-CoV-2, Influenza virus, Tropical virus, Enterovirus, Rabies virus) in bioreactors is presented. Meanwhile, the types of viral vaccines are briefly introduced, and the established animal cell lines for vaccine production are described. In addition, it is emphasized that the co-development of bioreactor and computational biology is urgently needed to meet the challenges posed by the differences in upstream production scales between the laboratory and industry.

Investigation and analysis of the characteristics of a family cluster of coronavirus disease 2019 in Zibo. (Special Issue: Spatio-temporal dynamics analysis, risk assessment and emergency management for COVID-19 epidemic.) [Chinese]

Objective: To investigate a family cluster of coronavirus disease 2019(COVID-19)in Zibo, so as to analyze the characteristics of the epidemic.

Research progress of mRNA technology for viral infectious diseases

Messenger RNA (mRNA, mRNA) vaccines and antibodies are a new type of vaccine and antibody technology emerging in recent years. Compared with traditional vaccines, mRNA vaccines have the advantages of high safety, good balanced immunity, short development cycle, and low production costs. mRNA antibodies exert biological effects in vivo earlier and longer than other forms of delivered antibodies. With the rapid development of mRNA modification and delivery technology, mRNA technology is rapidly maturing, showing broad application prospects in tumor treatment, prevention and treatment of viral infectious diseases, etc. In particular, the new coronavirus mRNA vaccine has been completed at a record speed The development and successful application paves the way for the promotion of mRNA technology in the future. This paper reviews the important breakthroughs in the field of mRNA technology, focusing on the major progress of mRNA vaccines and antibodies in response to viral infectious diseases, and looks forward to the future research trends of this technology in the field of anti-viral infection.

The lending risk predicting of the folk informal financial organization from big data using the deep learning hybrid model

ABSTACT This article is first to predict and earlier warning folk lending risk used deep learning hybrid model, we find that the LSTM hybrid model has a higher predict accuracy on lending risk forecasting and earlier warning of the FIFO, with an obviously improvement of the average value of forecasting accuracy. The predict accuracy of LSTM-GRU and LSTM-CNN models on lending risk forecasting of the FIFO is higher than others during COVID-19 pandemic. Therefore, we believe that the LSTM hybrid model, especially the LSTM-GRU model can better predict and early warn lending risk of the FIFO on big data.

Effects of Online Psychological Crisis Intervention for Frontline Nurses in COVID-19 Pandemic

Objective The psychological problems of frontline nurses in COVID-19 prevention and control are very prominent, and targeted intervention is needed to alleviate them. This study was to assess the impact of online intervention programs on psychological crisis of anxiety, depression levels and physical symptoms among frontline nurses fighting the COVID-19 pandemic. Methods A three-stage online psychological crisis intervention program was established. The General Anxiety 7 (GAD-7) assessment, Patient Health Questionnaire-9 (PHQ-9), and the Self-rating Somatic Symptom Scale (SSS) were used to evaluate the effect of intervention on the day before entering isolation wards (Time 1), the first day after leaving the isolation ward (Time 2), and at the end of the intervention (Time 3). Results Sixty-two nurses completed the study, including 59 female (95.2%) and three male nurses (4.8%) with an age range of 23–49 (mean 33.37 ± 6.01). A significant (P < 0.01) difference existed in the scores of GAD-7, PHQ-9, and SSS at different intervention periods. The GAD-7 score was significantly (P < 0.001) lower at the end of quarantine period (time 3) than that before entering the isolation wards (time 1) or after leaving the isolation wards (time 2), the PHQ-9 score was significantly (P = 0.016) lower at the end of quarantine period (time 3) than that after leaving the isolation wards (time 2), and the SSS score was significantly (P < 0.001) lower at the end of quarantine period (time 3) than that before entering the isolation wards (time 1) or after leaving the isolation wards (time 2). Conclusion The three-stage online intervention program based on the psychological crisis can be effective in reducing negative emotions and somatic symptoms and improving the mental health of frontline nurses in prevention and control of the COVID-19 epidemic. It may provide an empirical basis for psychological crisis intervention of frontline medical staff when facing public health emergencies.

Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents (preprint)

SARS-CoV-2 Omicron sublineages have escaped most RBD-targeting therapeutic neutralizing antibodies (NAbs), which proves the previous NAb drug screening strategies deficient against the fast-evolving SARS-CoV-2. Better broad NAb drug candidate selection methods are needed. Here, we describe a rational approach for identifying RBD-targeting broad SARS-CoV-2 NAb cocktails. Based on high-throughput epitope determination, we propose that broad NAb drugs should target non-immunodominant RBD epitopes to avoid herd immunity-directed escape mutations. Also, their interacting antigen residues should focus on sarbecovirus conserved sites and associate with critical viral functions, making the antibody-escaping mutations less likely to appear. Following the criteria, a featured non-competing antibody cocktail, SA55+SA58, is identified from a large collection of broad sarbecovirus NAbs isolated from SARS convalescents. SA55+SA58 potently neutralizes ACE2-utilizing sarbecoviruses, including circulating Omicron variants, and could serve as broad SARS-CoV-2 prophylactics to offer long-term protection. Our screening strategy can also be further applied to identify broad-spectrum NAb drugs against other fast-evolving viruses.