SARS-CoV-2 Omicron (B.1.1.529) infection in rhesus macaques, hamsters, and BALB/c mice with severe lung histopathological damage.

Since the first SARS-CoV-2 outbreak in late 2019, the SARS-CoV-2 genome has harbored multiple mutations, especially spike protein mutations. The currently fast-spreading Omicron variant that manifests without symptoms or with upper respiratory diseases has been recognized as a serious global public health problem. However, its pathological mechanism is largely unknown. In this work, rhesus macaques, hamsters, and BALB/C mice were employed as animal models to explore the pathogenesis of Omicron (B.1.1.529). Notably, Omicron (B.1.1.529) infected the nasal turbinates, tracheae, bronchi, and lungs of hamsters and BALB/C mice with higher viral loads than in those of rhesus macaques. Severe histopathological damage and inflammatory responses were observed in the lungs of Omicron (B.1.1.529)-infected animals. In addition, viral replication was found in multiple extrapulmonary organs. Results indicated that hamsters and BALB/c mice are potential animal models for studies on the development of drugs/vaccines and therapies for Omicron (B.1.1.529).

Aggravated pneumonia and diabetes in SARS-CoV-2 infected diabetic mice.

Multiple clinical and epidemiological studies have shown an interconnection between coronavirus disease 2019 (COVID-19) and diabetes, but experimental evidence is still lacking. Understanding the interplay between them is important because of the global health burden of COVID-19 and diabetes. We found that C57BL/6J mice were susceptible to the alpha strain of SARS-CoV-2. Moreover, diabetic C57BL/6J mice with leptin receptor gene deficiency (db/db mice) showed a higher viral load in the throat and lung and slower virus clearance in the throat after infection than C57BL/6J mice. Histological and multifactor analysis revealed more advanced pulmonary injury and serum inflammation in SARS-CoV-2 infected diabetic mice. Moreover, SARS-CoV-2 infected diabetic mice exhibited more severe insulin resistance and islet cell loss than uninfected diabetic mice. By RNA sequencing analysis, we found that diabetes may reduce the collagen level, suppress the immune response and aggravate inflammation in the lung after infection, which may account for the greater susceptibility of diabetic mice and their more severe lung damage after infection. In summary, we successfully established a SARS-CoV-2 infected diabetic mice model and demonstrated that diabetes and COVID-19 were risk factors for one another.

A network analysis of anxiety and depression symptoms among Chinese nurses in the late stage of the COVID-19 pandemic.

Background: Nurses are at high risk for depression and anxiety symptoms after the outbreak of the COVID-19 pandemic. We aimed to assess the network structure of anxiety and depression symptoms among Chinese nurses in the late stage of this pandemic. Method: A total of 6,183 nurses were recruited across China from Oct 2020 to Apr 2021 through snowball sampling. We used Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder scale-7 (GAD-7) to assess depression and anxiety, respectively. We used the Ising model to estimate the network. The index "expected influence" and "bridge expected influence" were applied to determine the central symptoms and bridge symptoms of the anxiety-depression network. We tested the stability and accuracy of the network via the case-dropping procedure and non-parametric bootstrapping procedure. Result: The network had excellent stability and accuracy. Central symptoms included "restlessness", "trouble relaxing", "sad mood", and "uncontrollable worry". "Restlessness", "nervous", and "suicidal thoughts" served as bridge symptoms. Conclusion: Restlessness emerged as the strongest central and bridge symptom in the anxiety-depression network of nurses. Intervention on depression and anxiety symptoms in nurses should prioritize this symptom.

The prevalence and risk factors of mental problems in medical students during COVID-19 pandemic: A systematic review and meta-analysis.

BACKGROUND: This meta-analysis and systematic review aimed to evaluate the global prevalence and risk factors of mental problems (i.e., depression, anxiety, stress, sleep disorder, posttraumatic stress disorder (PTSD), burnout, psychological distress, and suicidal ideation) among medical students during the COVID-19 pandemic. METHOD: We searched PubMed, Embase, Web of Science, psycARTICLES, PsycINFO, CNKI, and Wan Fang for studies on the prevalence of mental problems among medical students from January 1, 2020, to April 1, 2022. The pooled prevalence was calculated by random-effect models. We performed a narrative review to identify the risk factors. RESULTS: The meta-analysis included 201 studies (N = 198,000). The prevalence of depression (41 %, 95 % CI, 37-45 %,), anxiety (38 %,95 % CI, 34 %-42 %), stress (34 %, 95 % CI, 27 %-42 %), sleep disorder (52 %, 95 % CI, 44 %-60 %), psychological distress (58 %, 95 % CI, 51 %-65 %), PTSD (34 %, 95 % CI, 22 %-46 %), suicidal ideation (15 %, 95 % CI, 11 %-18 %) and burnout (38 %, 95 % CI, 25 %-50 %) was high. The major risk factors were being female, being junior or preclinical students, exposure to COVID-19, academic stress, psychiatric or physical disorders history, economic trouble, fear of education impairment, online learning trouble, fear of infection, loneliness, low physical activity, low social support, problematic internet or smartphone use, and young age. LIMITATIONS: Most studies were cross-sectional. Few studies provided a reasonable response rate, suggesting potential selection bias. CONCLUSIONS: The study demonstrated a high prevalence and risk factors for mental problems during COVID-19, calling for mental health services. Our findings are valuable for college and health authorities to identify high-risk students and provide targeted intervention.

A self-assembled trimeric protein vaccine induces protective immunity against Omicron variant.

The recently emerged Omicron (B.1.1.529) variant has rapidly surpassed Delta to become the predominant circulating SARS-CoV-2 variant, given the higher transmissibility rate and immune escape ability, resulting in breakthrough infections in vaccinated individuals. A new generation of SARS-CoV-2 vaccines targeting the Omicron variant are urgently needed. Here, we developed a subunit vaccine named RBD-HR/trimer by directly linking the sequence of RBD derived from the Delta variant (containing L452R and T478K) and HR1 and HR2 in SARS-CoV-2 S2 subunit in a tandem manner, which can self-assemble into a trimer. In multiple animal models, vaccination of RBD-HR/trimer formulated with MF59-like oil-in-water adjuvant elicited sustained humoral immune response with high levels of broad-spectrum neutralizing antibodies against Omicron variants, also inducing a strong T cell immune response in vivo. In addition, our RBD-HR/trimer vaccine showed a strong boosting effect against Omicron variants after two doses of mRNA vaccines, featuring its capacity to be used in a prime-boost regimen. In mice and non-human primates, RBD-HR/trimer vaccination could confer a complete protection against live virus challenge of Omicron and Delta variants. The results qualified RBD-HR/trimer vaccine as a promising next-generation vaccine candidate for prevention of SARS-CoV-2, which deserved further evaluation in clinical trials.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells.

Neutrophil extracellular traps (NETs) can capture and kill viruses, such as influenza viruses, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV), thus contributing to host defense. Contrary to our expectation, we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2, as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model. The histone H3 or H4 selectively binds to subunit 2 of the spike (S) protein, as shown by a biochemical binding assay, surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids. Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein. Moreover, histones enhance cell-cell fusion. Finally, treatment with an inhibitor of NETosis, histone H3 or H4, or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model. These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

Protective prototype-Beta and Delta-Omicron chimeric RBD-dimer vaccines against SARS-CoV-2.

Breakthrough infections by SARS-CoV-2 variants become the global challenge for pandemic control. Previously, we developed the protein subunit vaccine ZF2001 based on the dimeric receptor-binding domain (RBD) of prototype SARS-CoV-2. Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2 variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine elicited broader sera neutralization of variants and conferred better protection in mice. The protection of the chimeric vaccine was further verified in macaques. This approach was generalized to develop Delta-Omicron chimeric RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine elicited broader sera neutralization of SARS-CoV-2 variants and conferred better protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The chimeric approach is applicable for rapid updating of immunogens, and our data supported the use of variant-adapted multivalent vaccine against circulating and emerging variants.

Characteristic analysis of Omicron‐included SARS‐CoV‐2 variants of concern

In view of the rapid development of the COVID‐19 pandemic and SARS‐CoV‐2 mutation, we characterized the emerging SARS‐CoV‐2 variants of concern (VOCs) by both bioinformatics methods and experiments. The representative genomic sequences of SARS‐CoV‐2 VOCs were first downloaded from NCBI, including the prototypic strain, Alpha (B.1.1.7) strain, Beta (B.1.351) strain, Delta (B.1.617.2), and Omicron (B1.1.529) strain. Bioinformatics analysis revealed that the D614G mutation led to formation of a protruding spike (S) in the tertiary structure of spike protein, which could be responsible for the enhanced binding to angiotensin‐converting enzyme 2 (ACE2) receptor. The epitope analysis further showed that the S protein antigenicity of the Omicron variant changed dramatically, which was possibly associated with its enhanced ability of immune escape. To verify the bioinformatics results, we performed experiments of pseudovirus infection and protein affinity assay. Notably, we found that the spike protein of Omicron variant showed the weakest infectivity and binding ability among all tested strains. Finally, we also proved this through virus infection experiments, and found that the cytotoxicity of Omicron seems to be not strong enough. The results in this study provide guidelines for prevention and control of COVID‐19. In this study, we first predicted and compared the structure of the S protein and B‐cell epitopes of different SARS‐CoV‐2 variants. Then, the binding ability of different SARS‐CoV‐2 variant S proteins to angiotensin‐converting enzyme 2 (ACE2) cells and the affinity of RBD region to ACE2 were further compared through pseudovirus infection and intermolecular binding ability test. Finally, cell infection experiments were performed. The results unexpectedly showed that Omicron possesses lower ACE2 binding capacity, and lower replication capacity than Delta strain.

Characteristic analysis of Omicron-included SARS-CoV-2 variants of concern.

In view of the rapid development of the COVID-19 pandemic and SARS-CoV-2 mutation, we characterized the emerging SARS-CoV-2 variants of concern (VOCs) by both bioinformatics methods and experiments. The representative genomic sequences of SARS-CoV-2 VOCs were first downloaded from NCBI, including the prototypic strain, Alpha (B.1.1.7) strain, Beta (B.1.351) strain, Delta (B.1.617.2), and Omicron (B1.1.529) strain. Bioinformatics analysis revealed that the D614G mutation led to formation of a protruding spike (S) in the tertiary structure of spike protein, which could be responsible for the enhanced binding to angiotensin-converting enzyme 2 (ACE2) receptor. The epitope analysis further showed that the S protein antigenicity of the Omicron variant changed dramatically, which was possibly associated with its enhanced ability of immune escape. To verify the bioinformatics results, we performed experiments of pseudovirus infection and protein affinity assay. Notably, we found that the spike protein of Omicron variant showed the weakest infectivity and binding ability among all tested strains. Finally, we also proved this through virus infection experiments, and found that the cytotoxicity of Omicron seems to be not strong enough. The results in this study provide guidelines for prevention and control of COVID-19.

Circular RNA vaccines against SARS-CoV-2 and emerging variants.

As the emerging variants of SARS-CoV-2 continue to drive the worldwide pandemic, there is a constant demand for vaccines that offer more effective and broad-spectrum protection. Here, we report a circular RNA (circRNA) vaccine that elicited potent neutralizing antibodies and T cell responses by expressing the trimeric RBD of the spike protein, providing robust protection against SARS-CoV-2 in both mice and rhesus macaques. Notably, the circRNA vaccine enabled higher and more durable antigen production than the 1mΨ-modified mRNA vaccine and elicited a higher proportion of neutralizing antibodies and distinct Th1-skewed immune responses. Importantly, we found that the circRNARBD-Omicron vaccine induced effective neutralizing antibodies against the Omicron but not the Delta variant. In contrast, the circRNARBD-Delta vaccine protected against both Delta and Omicron or functioned as a booster after two doses of either native- or Delta-specific vaccination, making it a favorable choice against the current variants of concern (VOCs) of SARS-CoV-2.

Mental health conditions and academic burnout among medical and non-medical undergraduates during the mitigation of COVID-19 pandemic in China.

The outbreak of the novel coronavirus disease 2019 (COVID-19) has posed a great impact on people's mental health, especially for undergraduate students. This study aimed to compare the mental health conditions and academic burnout between medical and non-medical undergraduates in China when the COVID-19 pandemic is mitigating. A cross-sectional online survey was conducted among 4,972 undergraduates between October 2020 and April 2021, when the pandemic was basically under control. The survey included basic demographics information and standardized scales to evaluate depression, anxiety, perceived stress, daytime sleepiness, alcohol abuse/dependence, quality of life, fatigue, and academic burnout. Compared with medical undergraduates, non-medical undergraduates had higher rates of moderate to severe depression symptoms (29.1% vs. 17.9%, P < 0.001), moderate to severe anxiety symptoms (19.7% vs. 8.9%, P < 0.001), alcohol abuse/dependence (16.3% vs.10.3%, P < 0.001), excessive daytime sleepiness (47.4% vs. 43.4%, P = 0.018), high perceived stress (34.7% vs. 22.2%, P < 0.001), high level of fatigue (51.8% vs. 42.2%, P < 0.001), low QOL (35.8% vs. 21.4%, P < 0.001), and higher academic burnout score (59.4 vs. 57.5, P < 0.001). Being non-medical undergraduates, depression, alcohol abuse/dependence, excessive daytime sleepiness, and high perceived stress were positively associated with academic burnout, while high QOL was negatively associated with the burnout (all P < 0.001). Excessive daytime sleepiness was the strongest predictor for academic burnout.

Three doses of prototypic SARS-CoV-2 inactivated vaccine induce cross-protection against its variants of concern.

Variants are globally emerging very quickly following pandemic prototypic SARS-CoV-2. To evaluate the cross-protection of prototypic SARS-CoV-2 vaccine against its variants, we vaccinated rhesus monkeys with three doses of prototypic SARS-CoV-2 inactivated vaccine, followed by challenging with emerging SARS-CoV-2 variants of concern (VOCs). These vaccinated animals produced neutralizing antibodies against Alpha, Beta, Delta, and Omicron variants, although there were certain declinations of geometric mean titer (GMT) as compared with prototypic SARS-CoV-2. Of note, in vivo this prototypic vaccine not only reduced the viral loads in nasal, throat and anal swabs, pulmonary tissues, but also improved the pathological changes in the lung infected by variants of Alpha, Beta, and Delta. In summary, the prototypic SARS-CoV-2 inactivated vaccine in this study protected against VOCs to certain extension, which is of great significance for prevention and control of COVID-19.

Immunogenicity and protective efficacy of a recombinant protein subunit vaccine and an inactivated vaccine against SARS-CoV-2 variants in non-human primates.

Emerging SARS-CoV-2 variants and the gradually decreasing neutralizing antibodies over time post vaccination have led to an increase in incidents of breakthrough infection across the world. To investigate the potential protective effect of the recombinant protein subunit COVID-19 vaccine targeting receptor-binding domain (RBD) (PS-RBD) and whole inactivated virus particle vaccine (IV) against the variant strains, in this study, rhesus macaques were immunized with PS-RBD or IV vaccine, followed by a Beta variant (B.1.351) challenge. Although neutralizing activity against the Beta variant was reduced compared with that against the prototype, the decreased viral load in both upper and lower respiratory tracts, milder pathological changes, and downregulated inflammatory cytokine levels in lung tissues after challenge demonstrated that PS-RBD and IV still provided effective protection against the Beta variant in the macaque model. Furthermore, PS-RBD-induced macaque sera possessed general binding and neutralizing activity to Alpha, Beta, Delta, and Omicron variants in our study, though the neutralizing antibody (NAb) titers declined by varying degrees, demonstrating potential protection of PS-RBD against current circulating variants of concern (VOCs). Interestingly, although the IV vaccine-induced extremely low neutralizing antibody titers against the Beta variant, it still showed reduction for viral load and significantly alleviated pathological change. Other correlates of vaccine-induced protection (CoP) like antibody-dependent cellular cytotoxicity (ADCC) and immune memory were both confirmed to be existing in IV vaccinated group and possibly be involved in the protective mechanism.

Benefit finding: understanding the impact and public health factors among COVID-19 patients in China.

BACKGROUND: This study aimed to determine the level of benefit finding among COVID-19 patients in a hospital in mainland China, and to identify its associated impact and public health factors. METHODS: Using a cross-sectional design, a total of 288 COVID-19 patients were recruited in Huoshenshan Hospital in Wuhan, China to complete a survey on benefit finding. The level of benefit finding evaluated by the Benefit Finding Scale (BFS), mental resilience evaluated by the Connor-Davidson Resilience Scale (CD-RISC), social support evaluated by the Multidimensional Scale of Perceived Social Support (MSPSS), medical coping modes evaluated by the Medical Coping Modes Questionnaire (MCMQ), and general information was collected by self-designed questionnaires. T-test and chi-square test were used for single-factor analyses. For multiple factor analyses, multivariate regression analyses were performed. RESULT: The mean BFS score of 288 participants was 61.26±10.25. Multivariate regression analysis showed that the factors associated with the level of benefit finding among COVID-19 patients in China included education level, having experienced major event, social support, optimism, confrontive coping and resigned coping mode. CONCLUSIONS: In general, the patients with COVID-19 in this study had a middle level of benefit finding. Health professionals should take measures to identify the influencing factors on the quality of the life and take targeted intervention measures.

Doctor-patient relationship improved during COVID-19 pandemic, but weakness remains.

OBJECTIVE: To assess the quality of the doctor-patient relationship (DPR) in China and possible influencing factors during the COVID-19 period from the patient's perspective. METHODS: An online survey was carried out nationwide from March 12, 2020 to March 30, 2020 in China via a convenience sampling strategy. Patients who met the inclusion criteria were invited to complete a questionnaire regarding the quality of DPR, including sociodemographic information, the Patient-Doctor Relationship Questionnaire (PDRQ-9), and influencing factors for DPR during the pandemic. RESULTS: A total of 1903 patients were included. Our result showed that participants had a higher PDRQ-9 score during the COVID-19 pandemic (4.18 ± 0.51) than that before the COVID-19 pandemic (3.86 ± 0.67). Importance-performance analysis (IPA) revealed that doctor-patient communication, patient satisfaction, consultation time, doctor's attitude, and medical knowledge were specific aspects that needed to be prioritized to improve the DPR. Multiple linear regression analysis suggested that positive media reports, telemedicine, and national policies had a significantly positive effect on the DPR during the pandemic (P < 0.05). CONCLUSION: In general, the DPR had been improved during the COVID-19 pandemic. Our research found the key points that needed to be prioritized to improve the DPR during the pandemic, which may provide effective suggestions for building a harmonious DPR in the future.

A Comparison of COVID-19 Stigma and AIDS Stigma During the COVID-19 Pandemic: A Cross-Sectional Study in China.

Objective: To understand the current situation of stigmatizing attitudes toward Coronavirus Disease 2019 (COVID-19) in China and compare it with acquired immunodeficiency syndrome (AIDS). Methods: Convenient sampling and vignette-based methods were used to recruit participants on WeChat. A demographic form and adopted stigma scale were used to collect participants' demographic information and stigmatizing attitudes toward COVID-19 and AIDS. Results: A total of 13,994 questionnaires were included in this study. A high portion of participants tend to avoid contact with individuals affected with COVID-19 (74.3%) or AIDS (59.0%), as well as their family members (70.4% for COVID-19 and 47.9% for AIDS). About half of the participants agreed that affected persons could not only cause problems to their own family but also have adverse effects on others (59.6% and 55.6% for COVID-19, 56.9 and 47.0% for AIDS). The agreements with statements about perceived stigma were similar but slightly higher than those about personal stigma in both COVID-19 and AIDS. Participants' agreements with all statements regarding personal and perceived stigma attitudes between COVID-19 and AIDS were all statistically significant (p < 0.001). Participants obtained COVID-19-related information mainly from social media (91.3%) and newspaper or television (77.1%) during the epidemic, and 61.0% of them thought information from newspapers or television was the most reliable. Conclusion: Several similarities and differences of people's attitude toward COVID-19 and AIDS were found. Avoidance, blame, and secondary discrimination to diagnosed persons and their surrounding persons were the main representations of COVID-19-related stigma. Stigma of COVID-19 had less moral link but more public panic. Experience from HIV-related stigma reduction and prevention can be applied to reduce COVID-19-related stigma.

Doctor-Patient Relationship in the Eyes of Medical Professionals in China During the COVID-19 Pandemic: A Cross-Sectional Study.

Background: Doctor-patient relationship (DPR) is very important for patient outcomes, especially during a public health emergency like the COVID-19 pandemic. However, few studies have evaluated DPR and related sentiments from medical professionals' perspectives. Thus, the aim of the study is to provide a better understanding of DPR from medical professionals' perspectives during the COVID-19 pandemic in China. Methods: A total of 979 medical professionals, including doctors, nurses, technicians, and other workers have completed a series of questionnaires to evaluate their attitudes toward DPR, trust, violence against doctors, factors that affected and improved DPR, and the importance of these factors on DPR. Analyses of variances (ANOVA) and linear regressions were used to analyze the effects of the pandemic, demographic variables, and various elements on DPR. Results: One-way ANOVA revealed a significant effect of education on recent DPR [F (2, 976) = 6.17, p < 0.001 and trust at F (2, 976) = 9.54, p < 0.001], indicating that individuals with higher level of education (bachelor's degree, Master's degree and above) showed poorer recent DPR and lower level of trust. The level of hospital also showed a significant effect on trust [F (5, 973) = 3.79, p = 0.0021]. Cochran's Q test revealed a significant difference in factors that affected [Q(11) = 3,997.83, p < 0.001] and improved [Q(8) = 3,304.53, p < 0.001] DPR. Backward stepwise linear regressions revealed predictors for changes during [F (9, 969) = 21.17, p < 0.001, R 2 = 0.16], shortly after [F (7, 971) = 54.98, p < 0.001, R 2 = 0.28], and long after [F (10, 968) = 37.83, p < 0.001, R 2 = 0.29] the pandemic. Conclusions: Medical professionals' perceptions of DPR is important as they provide basis for the improvement in working environment of medical professionals and hospital visiting experience of patients, as well as healthcare policy making and preparation for future public health emergencies.

Spatiotemporal patterns of the COVID-19 control measures impact on industrial production in Wuhan using time-series earth observation data.

Understanding the spatiotemporal patterns of the COVID-19 impact on industrial production could improve the estimation of the economic loss and sustainable work resumption policies in cities. In this study, assuming and checking a correlation between the land surface temperature (LST) and industrial production, we applied the BFAST algorithm and linear regression models on multi-temporal MODIS data to derive monthly time-series deviation of LST with a spatial resolution of 1 × 1 km, to quantificationally explore the fine-scale spatiotemporal patterns of the COVID-19 control measures impact on industrial production, within Wuhan city. The results demonstrate that (1) the trend of time-series LST could partly reflect the impact of the COVID-19 pandemic on industrial production, and the year-around industrial production was less than expectations, with a fall of 14.30%; (2) the most serious COVID-19 impact on industrial production appeared in Mar. and Apr., then, after the lifting of lockdown, some regions (approximate 4.90%) firstly returned to expected levels in Jun, and almost all regions (98.49%) have completed the resumption of work and production before Nov.; (3) the southwest and south-central had more serious impact of the COVID-19 pandemic, approximate twice as much as that in the north and suburban, in Wuhan. The results and findings elaborated the spatiotemporal distribution and their changes during 2020 within Wuhan, which could provide a beneficial support for assessment of the COVID-19 pandemic and implementation of resumption plans for sustainable development.