Murine Coronavirus Disease 2019 Lethality Is Characterized by Lymphoid Depletion Associated with Suppressed Antigen-Presenting Cell Functionality.

The disease severity of coronavirus disease 2019 (COVID-19) varies considerably from asymptomatic to serious, with fatal complications associated with dysregulation of innate and adaptive immunity. Lymphoid depletion in lymphoid tissues and lymphocytopenia have both been associated with poor disease outcomes in patients with COVID-19, but the mechanisms involved remain elusive. In this study, human angiotensin-converting enzyme 2 (hACE2) transgenic mouse models susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were used to investigate the characteristics and determinants of lethality associated with the lymphoid depletion observed in SARS-CoV-2 infection. The lethality of Wuhan SARS-CoV-2 infection in K18-hACE2 mice was characterized by severe lymphoid depletion and apoptosis in lymphoid tissues related to fatal neuroinvasion. The lymphoid depletion was associated with a decreased number of antigen-presenting cells (APCs) and their suppressed functionality below basal levels. Lymphoid depletion with reduced APC function was a specific feature observed in SARS-CoV-2 infection but not in influenza A infection and had the greatest prognostic value for disease severity in murine COVID-19. Comparison of transgenic mouse models resistant and susceptible to SARS-CoV-2 infection revealed that suppressed APC function could be determined by the hACE2 expression pattern and interferon-related signaling. Thus, we demonstrated that lymphoid depletion associated with suppressed APC function characterizes the lethality of COVID-19 mouse models. Our data also suggest a potential therapeutic approach to prevent the severe progression of COVID-19 by enhancing APC functionality.

The relationship of skin disorders, COVID-19, and the therapeutic potential of ginseng: a review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made significant impacts on global public health, including the development of several skin diseases that have arisen primarily as a result of the pandemic. Owing to the widespread expansion of coronavirus disease 19 (COVID-19), the development of effective treatments for these skin diseases is drawing attention as an important social issue. For many centuries, ginseng and its major active ingredients, ginsenosides and saponins, have been widely regarded as herbal medicines. Further, the anti-viral action of ginseng suggests its potential effectiveness as a therapeutic agent against COVID-19. Thus, the aim of this review was to examine the association of skin lesions with COVID-19 and the effect of ginseng as a therapeutic agent to treat skin diseases induced by COVID-19 infection. We classified COVID-19-related skin disorders into three categories: caused by inflammatory, immune, and complex (both inflammatory and immune) responses and evaluated the evidence for ginseng as a treatment for each category. This review offers comprehensive evidence on the improvement of skin disorders induced by SARS-CoV-2 infection using ginseng and its active constituents.

Enhancement of Online Education to the Teaching Paradigm: Taking Academic Medical Postgraduate Cultivation as an Example.

Background: The COVID-19 pandemic posed enormous challenges to postgraduate teaching in 2020. Large-scale and continuous online teaching explorations were introduced to cope with this difficult situation, which incidentally shifted the paradigm of postgraduate teaching. Purpose: A review of the online teaching of local medical schools for postgraduates was performed to identify the success factors in realizing the practice. Methods: We retrieved medical postgraduate online teaching publications mainly from the local database, the China National Knowledge Infrastructure (CNKI), via the keywords stated below and then performed a retrospective analysis. Results: We analyzed key success factors in improving online learning engagement that were considered exclusive to offline classroom teaching, including emotional interaction, the immediacy of communication, and enthusiasm for participation. With these positive effects, the integration of online and offline teaching advantages is beneficial for the initiative of academic medical postgraduates and promotes the construction and development of medical postgraduate education. Conclusion: Online education can overcome the limitations of time, space, and teaching frequency, with great advantages in terms of flexibility and mobility over traditional classroom teaching. It can effectively cope with difficulties in the education of academic medical postgraduates in challenging times. In the post-pandemic era, blended online and offline teaching approaches continue and will become the new normal pedagogy for the training of medical postgraduate students.

Associations between chronic conditions and death in hospital among adults (aged 20+ years) during first acute care hospitalizations with a confirmed or suspected COVID-19 diagnosis in Canada.

PURPOSE: We aimed to quantify life course-specific associations between death in hospital and 30 chronic conditions, and comorbidity among them, in adults (aged 20+ years) during their first acute care hospitalization with a confirmed or suspected COVID-19 diagnosis in Canada. METHODS: We identified 35,519 first acute care hospitalizations with a confirmed or suspected COVID-19 diagnosis in the Discharge Abstract Database as of March 31, 2021. For each of five life-course age groups (20-34, 35-49, 50-64, 65-79, and 80+ years), we used multivariable logistic regression to examine associations between death in hospital and 30 chronic conditions, comorbidity, period of admission, and pregnant status, after adjusting for sex and age. RESULTS: About 20.9% of hospitalized patients with COVID-19 died in hospital. Conditions most strongly associated with in-hospital death varied across the life course. Chronic liver disease, other nervous system disorders, and obesity were statistically significantly associated (α = 0.05) with in-hospital death in the 20-34 to 65-79 year age groups, but the magnitude of the associations decreased as age increased. Stroke (aOR = 5.24, 95% CI: 2.63, 9.83) and other inflammatory rheumatic diseases (aOR = 4.37, 95% CI: 1.64, 10.26) were significantly associated with in-hospital death among 35 to 49 year olds only. Among 50+ year olds, more chronic conditions were significantly associated with in-hospital death, but the magnitude of the associations were generally weaker except for Down syndrome in the 50 to 64 (aOR = 8.49, 95% CI: 4.28, 16.28) and 65 to 79 year age groups (aOR = 5.19, 95% CI: 1.44, 20.91). Associations between comorbidity and death also attenuated with age. Among 20 to 34 year olds, the likelihood of death was 19 times greater (aOR = 18.69, 95% CI: 7.69, 48.24) in patients with three or more conditions compared to patients with none of the conditions, while for 80+ year olds the likelihood of death was two times greater (aOR = 2.04, 95% CI: 1.70, 2.45) for patients with six or more conditions compared to patients with none of the conditions. CONCLUSION: Conditions most strongly associated with in-hospital death among hospitalized adults with COVID-19 vary across the life course, and the impact of chronic conditions and comorbidity attenuate with age.

Nanotechnology for ultrafast nucleic acid amplification

Nucleic acid detection has been one of the most valued tools in point-of-care diagnostics from life science, agriculture, food safety and environmental surveillance, because of its high sensitivity, great specificity and simple operation. Since polymerase chain reactions (PCR) were discovered, more and more researchers attach importance to exploring ultrafast nucleic acid amplification methods for further expediting the process of detection and curbing infectious diseases' high spread rate, especially after the coronavirus disease 2019 (COVID-19) worldwide pandemic event. Nowadays, nanotechnology as one of the most cutting-edge technologies has aroused growing attention. In this review, we describe new advances in nanotechnology research for ultrafast nucleic acid amplification. We have introduced commonly used nanotechnologies, namely nanofluidics, nanoporous materials, nanoparticles and so on. Recent advances in these nanotechnologies for ultrafast sample pretreatments, accelerated enzymatic amplification and rapid heating/cooling processes was summarized. Finally, challenges and perspectives for the future applications of ultrafast nucleic acid amplification are presented.

Immunomodulatory effects of Abelmoschus esculentus water extract through MAPK and NF-κB signaling in RAW 264.7 cells

During the current COVID-19 pandemic, the world is facing a new, highly contagious virus that suppresses innate immunity as one of its early virulence mechanisms. Therefore, finding new methods to enhance innate immunity is a promising strategy to attenuate the effects of this major global health problem. With the aim of characterizing bioactive ingredients as immune-enhancing agents, this study focuses on Abelmoschus esculentus (okra), which has several previously demonstrated bioactivities. Firstly, we investigated the immune-stimulatory effects of okra leaf ethanol extract (OLE) and okra leaf water extract (OLW) on nitric oxide (NO) production in macrophages. OLE significantly decreased nitrite accumulation in LPS-stimulated RAW 264.7 cells, indicating that it potentially inhibited NO production in a concentration-dependent manner. In contrast, OLW significantly enhanced the production of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and NO in a dose-dependent manner. OLW also increased the expression levels of NO synthase (iNOS) and cyclooxygenase (COX)-2, potentially explaining the OLW-induced increase in NO and PGE2 production. In addition, OLW stimulated the phosphorylation of mitogen-activated protein kinases (MAPKs;ERK, p38, and JNK) as well as the activation and subsequent nuclear translocation of nuclear factor κB (NF-κB). This indicated that OLW activates macrophages to secrete PGE2, TNF-α, IL-1β, and NO, inducing iNOS and COX-2 expression via activation of the NF-κB and MAPK signaling pathways. In conclusion, our results demonstrate that OLW can effectively promote the activation of macrophages, suggesting that OLW may possess potent immunomodulatory effects and should be explored as a potential health-promoting materials to boost the immune system.

T-cell responses to SARS-CoV-2 Omicron spike epitopes with mutations after the third booster dose of an inactivated vaccine.

The rapidly spreading severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant contains more than 30 mutations that mediate escape from antibody responses elicited by prior infection or current vaccines. Fortunately, T-cell responses are highly conserved in most individuals, but the impacts of mutations are not clear. Here, we showed that the T-cell responses of individuals who underwent booster vaccination with CoronaVac were largely protective against the SARS-CoV-2 Omicron spike protein. To specifically estimate the impact of Omicron mutations on vaccinated participants, 16 peptides derived from the spike protein of the ancestral virus or Omicron strain with mutations were used to stimulate peripheral blood mononuclear cells (PBMCs) from the volunteers. Compared with the administration of two doses of vaccine, booster vaccination substantially enhanced T-cell activation in response to both the ancestral and Omicron epitopes, although the enhancement was slightly weakened by the Omicron mutations. Then, the peptides derived from these spike proteins were used separately to stimulate PBMCs. Interestingly, compared with the ancestral peptides, only the peptides with the G339D or N440K mutation were detected to significantly destabilize the T-cell response. Although more participants need to be evaluated to confirm this conclusion, our study nonetheless estimates the impacts of mutations on T-cell responses to the SARS-CoV-2 Omicron variant.

Enhancement of Online Education to the Teaching Paradigm: Taking Academic Medical Postgraduate Cultivation as an Example

Background The COVID-19 pandemic posed enormous challenges to postgraduate teaching in 2020. Large-scale and continuous online teaching explorations were introduced to cope with this difficult situation, which incidentally shifted the paradigm of postgraduate teaching. Purpose A review of the online teaching of local medical schools for postgraduates was performed to identify the success factors in realizing the practice. Methods We retrieved medical postgraduate online teaching publications mainly from the local database, the China National Knowledge Infrastructure (CNKI), via the keywords stated below and then performed a retrospective analysis. Results We analyzed key success factors in improving online learning engagement that were considered exclusive to offline classroom teaching, including emotional interaction, the immediacy of communication, and enthusiasm for participation. With these positive effects, the integration of online and offline teaching advantages is beneficial for the initiative of academic medical postgraduates and promotes the construction and development of medical postgraduate education. Conclusion Online education can overcome the limitations of time, space, and teaching frequency, with great advantages in terms of flexibility and mobility over traditional classroom teaching. It can effectively cope with difficulties in the education of academic medical postgraduates in challenging times. In the post-pandemic era, blended online and offline teaching approaches continue and will become the new normal pedagogy for the training of medical postgraduate students.

Changes in Serum Neutralizing Antibodies Levels During Convalescence of COVID-19 Patients.

Detection of serum-specific SARS-CoV-2 antibody has become a complementary means for the identification of coronavirus disease 2019 (COVID-19). As we already know, the neutralizing antibody titers in patients with COVID-19 decrease during the course of time after convalescence, whereas the duration of antibody responses in the convalescent patients has not been defined clearly. In the current study, we collected 148 serum samples from 37 confirmed COVID-19 cases with different disease severities. The neutralizing antibodies (Nabs), IgM and IgG against COVID-19 were determined by CLIA Microparticle and microneutralization assay, respectively. The time duration of serum titers of SARS-CoV-2 antibodies were recorded. Our results indicate that IgG (94.44%) and Nabs (89.19%) can be detected at low levels within 190-266 days of disease onset. The findings can advance knowledge regarding the antibody detection results for COVID-19 patients and provide a method for evaluating the immune response after vaccination.

Comparing Immune Responses to Inactivated Vaccines against SARS-CoV-2 between People Living with HIV and HIV-Negative Individuals: A Cross-Sectional Study in China.

This study compared the immunogenicity of inactivated SARS-CoV-2 vaccines between people living with HIV (PLWH) and HIV-negative individuals. We recruited 120 PLWH and 53 HIV-negative individuals aged 18-59 years who had received an inactivated SARS-CoV-2 vaccine in two Chinese cities between April and June 2021. Blood samples were tested for immunogenicity of the inactivated SARS-CoV-2 vaccines. The prevalence and severity of adverse events associated with SARS-CoV-2 vaccines were similar between PLWH and HIV-negative individuals. The seropositivity of neutralizing activity against authentic SARS-CoV-2, of the total amount of antibody (total antibody) and of S-IgG were 71.3%, 81.9%, and 92.6%, respectively, among fully vaccinated PLWH. Among all participants, PLWH had lower neutralizing activity, total antibody, S-IgG, and T-cell-specific immune response levels, compared to HIV-negative individuals, after controlling for types of vaccine, time interval between first and second dose, time after receiving the second dose, and sociodemographic factors. PLWH with a longer interval since HIV diagnosis, who received their second dose 15-28 days prior to study commencement, and who had an interval of ≥21 days between first and second dose had higher neutralizing activity levels. The immunogenicity of the inactivated SARS-CoV-2 vaccines was lower among PLWH as compared to HIV-negative individuals. Vaccination guideline specific for PLWH should be developed.

Online Medical Teaching in China During the COVID-19 Pandemic: Tools, Modalities, and Challenges.

Background: The novel coronavirus disease 2019 (COVID-19) pandemic has tested the ability of universities to provide a high-quality, safe educational experience for students due to campuses shutting down. As a result, online learning could shift from a traditional classroom teaching mode and make education accessible to students. Previous studies have used individual online teaching cases to exploit a variety of online learning tools to ensure the continuation of medical education during this difficult time in China. However, for the first time, we have conducted a systematic review of local online teaching approaches, existing challenges, and potential solutions. Purpose: We present the issues and experience of conducting online medical teaching practices in China with the aim of communicating them to our peers in other countries or regions when examining the transition to e-learning during the COVID-19 pandemic and beyond. Methods: We searched the keywords below from public databases and reviewed relevant publications reporting on medical online teaching in China during the COVID-19 pandemic to analyze and summarize the online tools, modalities, and challenges. Results: We listed common online teaching tools and described a variety of online teaching modalities, as well as possible challenges. We also discussed potential solutions for those challenges, as well as the impact of the transition to online teaching on traditional education. Conclusion: By investigating local online medical teaching in China, we present useful tools and modalities that have been successfully exploited in education during the difficult time of COVID-19, although some challenges remain. The exploration of the transition to online teaching or learning will likely continue to have a profound impact on traditional classroom teaching.

Low dose of emetine as potential anti-SARS-CoV-2 virus therapy: preclinical in vitro inhibition and in vivo pharmacokinetic evidences.

The global pandemic of COVID-19 has attracted extensive drug searching interets for the new coronavirus SARS-CoV-2. Although currently several of clinically used "old" drugs have been repurposed to this new disease for the urgent clinical investigation, there is still great demand for more effective therapies for the anti-infections. Here we report the discovery that an "old" drug Emetine could potently inhibit SARS-CoV-2 virus replication and displayed virus entry blocking effect in Vero cells at low dose. In addition, Emetine could significantly reduce the lipopolysaccharide (LPS) induced interleukin-6 (IL-6) protein level and moderately reduce the tumor necrosis factor (TNF-α) protein level in the M1 polarized THP-1 macrophages. In vivo animal pharmacokinetics (PK) study revealed that Emetine was enriched in the lung tissue and had a long retention time (over 12 h). With 1 mg/kg single oral dose, the effective concentration of Emetine in lung was up to 1.8 µM (mice) and 1.6 µM (rats) at 12 h, which is over 200-fold higher than the EC50 of the drug. The potent in vitro antiviral replication efficacy and the high enrichment in target tissue, combining with the well documented safety profiles in human indicate that low dose of Emetine might be a potentially effective anti-SARS-CoV-2 infection therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s43556-020-00018-9.

Application of Nanomaterials in Isothermal Nucleic Acid Amplification.

Because of high sensitivity and specificity, isothermal nucleic acid amplification are widely applied in many fields. To facilitate and improve their performance, various nanomaterials, like nanoparticles, nanowires, nanosheets, nanotubes, and nanoporous films are introduced in isothermal nucleic acid amplification. However, the specific application, roles, and prospect of nanomaterials in isothermal nucleic acid amplification have not been comprehensively reviewed. Here, the application of different nanomaterials (0D, 1D, 2D, and 3D) in isothermal nucleic acid amplification is comprehensively discussed and recent progress in the field is summarized. The nanomaterials are mainly used for reaction enhancer, signal generation/amplification, or surface loading carriers. In addition, 3D nanomaterials can be also functioned as isolated chambers for digital nucleic acid amplification and the tools for DNA sequencing of amplified products. Challenges and future recommendations are also proposed to be better used for recent covid-19 detection, point-of-care diagnostic, food safety, and other fields.

Symptoms of major depressive disorder during the COVID-19 pandemic: results from a representative sample of the Canadian population. / Symptômes du trouble dépressif majeur pendant la pandémie de COVID 19 : résultats obtenus à partir d'un échantillon représentatif de la population canadienne.

INTRODUCTION: Since the outbreak of COVID-19, numerous studies from around the world have reported declines in mental health. However, most of these studies were of low-to-moderate quality and many were based on convenience samples or used mental health measures with low validity, or both. Consequently, it has been difficult to draw conclusions. METHODS: Both the 2020 Survey on COVID-19 and Mental Health (SCMH) and the Canadian Community Health Survey (CCHS) (2015-2019) used the Patient Health Questionnaire-9 to screen for major depressive disorder (MDD) in adults aged 18 or older. The prevalence of MDD was compared between the SCMH and the CCHS. Risk and protective factors for MDD in the SCMH were examined using bivariate and logistic regression analyses. RESULTS: Based on SCMH data, 15.2% (95% CI: 14.2-16.2) of Canadians screened positive for MDD. The prevalence of MDD was more than two times higher in the SCMH (during COVID-19) than in the CCHS (predating COVID-19). In bivariate analysis, Canadians reporting five or more COVID-19-related risk factors were close to 30 times more likely to have MDD than those reporting no risk factors. Mastery and a sense of community belonging were protective factors for MDD. CONCLUSION: After remaining stable for two decades, the prevalence of depression among Canadians increased substantially with the onset of COVID-19. Ongoing monitoring of this common condition associated with major morbidity is vital to determine if elevated levels of MDD persist as we progress through and beyond future waves of COVID-19.

Different Profiles of Antibodies and Cytokines Were Found Between Severe and Moderate COVID-19 Patients.

Objectives: Our objective was to determine the antibody and cytokine profiles in different COVID-19 patients. Methods: COVID-19 patients with different clinical classifications were enrolled in this study. The level of IgG antibodies, IgA, IgM, IgE, and IgG subclasses targeting N and S proteins were tested using ELISA. Neutralizing antibody titers were determined by using a toxin neutralization assay (TNA) with live SARS-CoV-2. The concentrations of 8 cytokines, including IL-2, IL-4, IL-6, IL-10, CCL2, CXCL10, IFN-γ, and TNF-α, were measured using the Protein Sample Ella-Simple ELISA system. The differences in antibodies and cytokines between severe and moderate patients were compared by t-tests or Mann-Whitney tests. Results: A total of 79 COVID-19 patients, including 49 moderate patients and 30 severe patients, were enrolled. Compared with those in moderate patients, neutralizing antibody and IgG-S antibody titers in severe patients were significantly higher. The concentration of IgG-N antibody was significantly higher than that of IgG-S antibody in COVID-19 patients. There was a significant difference in the distribution of IgG subclass antibodies between moderate patients and severe patients. The positive ratio of anti-S protein IgG3 is significantly more than anti-N protein IgG3, while the anti-S protein IgG4 positive rate is significantly less than the anti-N protein IgG4 positive rate. IL-2 was lower in COVID-19 patients than in healthy individuals, while IL-4, IL-6, CCL2, IFN-γ, and TNF-α were higher in COVID-19 patients than in healthy individuals. IL-6 was significantly higher in severe patients than in moderate patients. The antibody level of anti-S protein was positively correlated with the titer of neutralizing antibody, but there was no relationship between cytokines and neutralizing antibody. Conclusions: Our findings show the severe COVID-19 patients' antibody levels were stronger than those of moderate patients, and a cytokine storm is associated with COVID-19 severity. There was a difference in immunoglobulin type between anti-S protein antibodies and anti-N protein antibodies in COVID-19 patients. And clarified the value of the profile in critical prevention.

Analysis of SARS-CoV-2 variant mutations reveals neutralization escape mechanisms and the ability to use ACE2 receptors from additional species.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge during the global pandemic and may facilitate escape from current antibody therapies and vaccine protection. Here we showed that the South African variant B.1.351 was the most resistant to current monoclonal antibodies and convalescent plasma from coronavirus disease 2019 (COVID-19)-infected individuals, followed by the Brazilian variant P.1 and the United Kingdom variant B.1.1.7. This resistance hierarchy corresponded with Y144del and 242-244del mutations in the N-terminal domain and K417N/T, E484K, and N501Y mutations in the receptor-binding domain (RBD) of SARS-CoV-2. Crystal structure analysis of the B.1.351 triple mutant (417N-484K-501Y) RBD complexed with the monoclonal antibody P2C-1F11 revealed the molecular basis for antibody neutralization and escape. B.1.351 and P.1 also acquired the ability to use mouse and mink ACE2 receptors for entry. Our results demonstrate major antigenic shifts and potential broadening of the host range for B.1.351 and P.1 variants, which poses serious challenges to current antibody therapies and vaccine protection.