Causal associations between thyroid dysfunction and COVID-19 susceptibility and severity: A bidirectional Mendelian randomization study.

Background: Observational studies have reported an association between coronavirus disease 2019 (COVID-19) risk and thyroid dysfunction, but without a clear causal relationship. We attempted to evaluate the association between thyroid function and COVID-19 risk using a bidirectional two-sample Mendelian randomization (MR) analysis. Methods: Summary statistics on the characteristics of thyroid dysfunction (hypothyroidism and hyperthyroidism) were obtained from the ThyroidOmics Consortium. Genome-wide association study statistics for COVID-19 susceptibility and its severity were obtained from the COVID-19 Host Genetics Initiative, and severity phenotypes included hospitalization and very severe disease in COVID-19 participants. The inverse variance-weighted (IVW) method was used as the primary analysis method, supplemented by the weighted-median (WM), MR-Egger, and MR-PRESSO methods. Results were adjusted for Bonferroni correction thresholds. Results: The forward MR estimates show no effect of thyroid dysfunction on COVID-19 susceptibility and severity. The reverse MR found that COVID-19 susceptibility was the suggestive risk factor for hypothyroidism (IVW: OR = 1.577, 95% CI = 1.065-2.333, P = 0.022; WM: OR = 1.527, 95% CI = 1.042-2.240, P = 0.029), and there was lightly association between COVID-19 hospitalized and hypothyroidism (IVW: OR = 1.151, 95% CI = 1.004-1.319, P = 0.042; WM: OR = 1.197, 95% CI = 1.023-1.401, P = 0.023). There was no evidence supporting the association between any phenotype of COVID-19 and hyperthyroidism. Conclusion: Our results identified that COVID-19 might be the potential risk factor for hypothyroidism. Therefore, patients infected with SARS-CoV-2 should strengthen the monitoring of thyroid function.

CAR-T cell-induced cytokine release syndrome is rapidly alleviated by tripterygium glycosides (preprint)

Background Cytokine release syndrome (CRS) is a life-threatening complication of chimeric antigen receptor T cell (CAR-T) therapy. Macrophages/ monocytes are mediators of CRS. Tripterygium glycosides is an immunomodulator which could inhibit macrophages/ monocytes in animal models.Methods Two patients with relapsed and refractory hematological malignancies developed CRS after receiving CAR-T therapy. They received short-term tripterygium glycosides orally.Results Both patients showed rapid mitigation of fever with evidently decrease in elevated inflammatory cytokines within 72 hours. The patients' monocytes diminished remarkably, while CAR-T cells were neglectably affected. Treatment of 30 ng/mL triptolide in ex vivo cultured patients' blood for 24 hours selectively deplete over half of monocytes. Single cell RNA sequencing suggested selective depletion of CD14+CD16+ monocytes with decreased pro-inflammatory cytokines.Conclusions The low-cost and orally available tripterygium glycosides could be a promising alternative for CAR-T induced CRS, as well as other diseases complicated with CRS, e.g., coronavirus disease 2019.

Causal associations between thyroid dysfunction and COVID-19 susceptibility and severity: A bidirectional Mendelian randomization study

Background Observational studies have reported an association between coronavirus disease 2019 (COVID-19) risk and thyroid dysfunction, but without a clear causal relationship. We attempted to evaluate the association between thyroid function and COVID-19 risk using a bidirectional two-sample Mendelian randomization (MR) analysis. Methods Summary statistics on the characteristics of thyroid dysfunction (hypothyroidism and hyperthyroidism) were obtained from the ThyroidOmics Consortium. Genome-wide association study statistics for COVID-19 susceptibility and its severity were obtained from the COVID-19 Host Genetics Initiative, and severity phenotypes included hospitalization and very severe disease in COVID-19 participants. The inverse variance-weighted (IVW) method was used as the primary analysis method, supplemented by the weighted-median (WM), MR-Egger, and MR-PRESSO methods. Results were adjusted for Bonferroni correction thresholds. Results The forward MR estimates show no effect of thyroid dysfunction on COVID-19 susceptibility and severity. The reverse MR found that COVID-19 susceptibility was the suggestive risk factor for hypothyroidism (IVW: OR = 1.577, 95% CI = 1.065–2.333, P = 0.022;WM: OR = 1.527, 95% CI = 1.042–2.240, P = 0.029), and there was lightly association between COVID-19 hospitalized and hypothyroidism (IVW: OR = 1.151, 95% CI = 1.004–1.319, P = 0.042;WM: OR = 1.197, 95% CI = 1.023-1.401, P = 0.023). There was no evidence supporting the association between any phenotype of COVID-19 and hyperthyroidism. Conclusion Our results identified that COVID-19 might be the potential risk factor for hypothyroidism. Therefore, patients infected with SARS-CoV-2 should strengthen the monitoring of thyroid function.

Thyroid Function and COVID-19 Susceptibility and Its Severity: A Two-Sample Mendelian Randomization Study.

Several observational studies have confirmed the relationship between thyroid hormones and coronavirus disease 2019 (COVID-19), but this correlation remains controversial. We performed a two-sample Mendelian randomization (MR) analysis based on the largest publicly available summary datasets. Summary statistics with 49 269 individuals for free thyroxine (FT4) and 54 288 for thyroid stimulating hormone (TSH) were used as exposure instruments. Genome-wide association studies of susceptibility (cases = 38 984; controls = 1 644 784), hospitalization (cases: 9986 = controls = 1 877 672), and very severe disease (cases = 5101; controls = 1 383 241) of COVID-19 were used as the outcome. We used the inverse-variance weighted (IVW) method as the primary analysis, and utilized MR-Egger regression, weighted median, and robust adjusted profile score (RAPS) for sensitivity analysis. Genetic predisposition to higher serum levels of FT4 within the normal range was negatively associated with the risk of COVID-19 hospitalization (odds ratio [OR] = 0.818; 95% CI, 0.718-0.932; P = 2.6 × 10-3) and very severe disease (OR = 0.758; 95% CI, 0.626-0.923; P = 5.8 × 10-3), but not susceptibility. There is no evidence that genetically predicted circulating TSH levels are associated with COVID-19 susceptibility and severity risk. Neither apparent pleiotropy nor heterogeneity were detected in the sensitivity analysis. In summary, we found that higher FT4 levels may reduce the risk of COVID-19 severity, suggesting that thyroid function testing may be required for patients with COVID-19.

S373P Mutation of Spike Protein in SARS-CoV-2 Stabilizes Omicron (preprint)

Recently, a cluster of several newly occurring mutations on Omicron, which is currently the dominant SARS-CoV-2 variant, are found at the (mechanically) stable {beta}-core region of spike protein's receptor-binding domain (RBD), where mutation rarely happened before. Notably, the binding of SARS-CoV-2 to human receptor ACE2 via RBD happens in a dynamic airway environment, where mechanical force caused by coughing or sneezing occurs and applies to the proteins. Thus, we used atomic force microscopy-based single-molecule force spectroscopy (AFM-SMFS) to measure the stability of RBDs and found that the unfolding force of Omicron RBD increased by 20% compared with the wild-type. Molecular dynamics simulations revealed that Omicron RBD showed more hydrogen bonds in the {beta}-core region due to the closing of the -helical motif caused primarily by the S373P mutation, which was further confirmed by the experiment. This work reveals the stabilizing effect of the S373P mutation and suggests mechanical stability becomes another important factor in SARS-CoV-2 mutation selection.

Evaluation of Factors Affecting Online Teaching of Medical Courses for MBBS Students During the Novel Coronavirus Epidemic (preprint)

Background: Bachelor of Medicine and Bachelor of Surgery (MBSS) students are the largest group of international students. Due to the breakout of COVID-19, most international students have returned to their home countries. From March 2020, the MBBS undergraduate students of Yangzhou University were taught online since March 2020. For MBBS students，the effect of online teaching remains unknown. Methods: This study was conducted in Yangzhou University in June 2021, including 295 MBBS international undergraduate students. The objective conditions, environment, teacher factors, personal factors, advantages, and disadvantages of online teaching were evaluated for each student by using a self-completed structured anonymous questionnaire. At the same time, Pearson chi-square analysis was conducted to evaluate the factors affecting online teaching satisfaction (teaching attitude, teacher-student interaction, teacher evaluation, learning effect, online teaching management). Results: Most students’ hardware was well equipped and their network could meet the need of online learning (240 of 280, 85.71%). Most students (263 of 280, 93.93%) had a quiet environment during online teaching. With respect to factors conducive to online teaching, students rated the importance of teachers from the aspects of knowledge level, teaching methods, class attitude, interaction with students, English proficiency, homework correction and pre-class guidance. In terms of students' attention, 76.78% students' attention was concentrated and 85.36% students had a positive attitude towards online teaching. Four factors (teaching attitude, teacher-student interaction, learning effect and management of online teaching) appeared to be associated with teaching effect satisfaction. Conclusion: This study investigates the various factors involved in conducting online education during the pandemic and provides suggestions for improving the quality and effectiveness of online education for MBBS students.

Epidemiological Characteristics of Traumatic Spinal Cord Injuries in Multi-Center Retrospective Study in Northwest China, 2017-2020. (preprint)

Introduction: Traumatic spinal cord injuries (TSCI) are worldwide public health problems. There has been a lack of extensive multi-center study of TSCI epidemiology in Northwest China in pre- and post-pandemic period of COVID-19. Materials: and Methods: A multi-center retrospective study of 14 hospitals of Northwest China was conducted on patients with TSCI between 2017 and 2020. Variables assessed included patient demographics, etiology, segmental distribution, treatment, waiting time for treatment and outcomes. Results: : The number of patients with TSCI showed an increasing trend from 2017 to 2019 while there were fewer patients in 2020 than in 2019. The male-to-female ratio was 3.67:1 and the mean age was 48±14.9. The major cause of TSCI was high fall (38.8%), low fall (27.7%), traffic accidents (23.9%), sports (2.6%) and others (7.0%). The segmental distribution showed a bimodal pattern, peak segments were C6 and Tl1, L1(14.7%) was the most frequently injured segments. Incomplete injury (72.8%) occurred more often than complete injury (27.2%). ASIA scale of most patients did not change before and after treatment both in operational or conservative group. 975 patients from urban and 1646 patients from rural areas were conducted, most urban residents could rush to get treatment after injured immediately (<1 h), whereas most rural patients get treatment spend several hours since injured. The rough annual incidence from 2017-2020 are 112.4, 143.4,152.2 and 132.6 per million people calculated by the population-coverage-rate. Conclusion: The incidence of TSCI in Northwest China is high and growing. However, under the pandemic policy reasons, it has decreased in 2020. The promotion of online work may be an effective primary prevention measures for trauma. Also, due to the distance from the hospitals with proper conditions, rural patients need to spend long time to there, the timely treatment of them should be paid attention.

Restrospective analysis and pharmaceutical care of immunotherapeutic drug tocilizumab for COVID-19

Since December 2019, COVID-19 had spread many countries, attracting high attention from the world. Its infectivity is strong, harm is big, at present there is no definite effective antiviral drug. Recently, the national health commission released the latest "new coronavirus pneumonia diagnosis and treatment program (trial seventh edition)", which for the first time proposed immunotherapy program based on Tocilizumab (TCZ). In this paper, firstly, a review of articles on the treatment of immune system diseases with TCZ at home and abroad was conducted to analyze the effectiveness of TCZ in the treatment of severe and critical COVID-19. Then, from the safety point of view, the drug interactions, drug use in special population, adverse reactions and medication precautions were presented in detail, which can be used as a medication reference for the treatment of COVID-19 severe and critical patients.

Mutation N501Y in RBD of Spike Protein Strengthens the Interaction between COVID-19 and its Receptor ACE2 (preprint)

Coronavirus disease-19 (COVID-19) is spreading around the world for the past year. Enormous efforts have been taken to understand its mechanism of transmission. It is well established now that the SARS-CoV-2 receptor-binding domain (RBD) of the spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) as its first step of entry. Being a single-stranded RNA virus, SARS-CoV-2 is evolving rapidly. Recently, two variants, B.1.1.7 and B.1.351, both with a key mutation N501Y on the RBD, appear to be more infectious to humans. To understand its mechanism, we combined kinetics assay, single-molecule technique, and computational method to compare the interaction between these RBD (mutations) and ACE2. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger inter-action characterized from all these methodologies, while the other two mutations from B.1.351 contributed to a less effect. Surface plasmon resonance and fluorescence-activated cell scan (FACS) assays found that both RBD mutations are of higher binding affinity to ACE2 than the wild type. In addition, atomic force microscopy-based single-molecule force microscopy quantify their strength on living cells, showing a higher binding probability and unbinding force for both mutations. Finally, Steered Molecular Dynamics (SMD) simulations on the dissociation of RBD-ACE2 complexes revealed the possible structural details for the higher force/interaction. Taking together, we suggested that the stronger inter-action from N501Y mutation in RBD should play an essential role in the higher transmission of COVID-19 variants.

Tripterygium glycosides as a potential treatment for CAR-T induced cytokine release syndrome: implication of monocyte depletion (preprint)

Summary Background Cytokine release syndrome (CRS) is a potentially life-threatening complication of chimeric antigen receptor T (CAR-T) cell therapy. Recent studies indicated critical roles of macrophages and monocytes in CAR-T induced CRS. Here, we report rapid dissipation of CAR-T induced CRS in two patients after receiving Tripterygium glycosides (TG). Effects of triptolide, the major active component of TG, on macrophages and monocytes were examined in animal models. Methods Two patients with CRS after CAR-T cell therapy (for hematological malignancy) received TG (50 mg, p.o.). Flow cytometry analysis and single cell RNA sequencing (scRNAseq) were conducted to examine the effects of TG on immune cells. Potential effects of triptolide were also examined ex vivo using patient-derived monocytes, as well as in mice. Findings Rapid alleviation of fever and cytokine storm was observed within 72 hours after TG treatment. Blood concentration of triptolide ranged from 21 to 154 ng/mL during treatment. Flow cytometry and scRNAseq showed selective depletion of monocytes with minimal impact on CAR-T cells in both patients. In ex vivo experiments with patient-derived monocytes, triptolide dramatically inhibited the synthesis of pro-inflammatory cytokines (e.g., IL-6, IL-10, and IP-10). Triptolide also rapidly and selectively depleted peritoneal concanavalin A activated macrophages and monocytes in mice. Interpretation TG could be a promising treatment for CAR-T induced CRS, as well as other diseases with similar mechanisms, e.g., hemophagocytic lymphohistiocytosis and COVID-19. Our preliminary findings require further verification with properly designed clinical trials.

Roles of meteorological conditions in COVID-19 transmission on a worldwide scale (preprint)

The novel coronavirus (SARS-CoV-2/ 2019-nCoV) identified in Wuhan, China, in December 2019 has caused great damage to public health and economy worldwide with over 140,000 infected cases up to date. Previous research has suggested an involvement of meteorological conditions in the spread of droplet-mediated viral diseases, such as influenza. However, as for the recent novel coronavirus, few studies have discussed systematically about the role of daily weather in the epidemic transmission of the virus. Here, we examine the relationships of meteorological variables with the severity of the outbreak on a worldwide scale. The confirmed case counts, which indicates the severity of COVID-19 spread, and four meteorological variables, i.e., air temperature, relative humidity, wind speed, and visibility, were collected daily between January 20 and March 11 (52 days) for 430 cities and districts all over China, 21 cities/ provinces in Italy, 21 cities/ provinces in Japan, and 51 other countries around the world. Four different time delays of weather (on the day, 3 days ago, 7 days ago, and 14 days ago) as to the epidemic situation were taken for modeling and we finally chose the weather two weeks ago to model against the daily epidemic situation as its correlated with the outbreak best. Taken Chinese cities as a discovery dataset, it was suggested that temperature, wind speed, and relative humidity combined together could best predict the epidemic situation. The meteorological model could well predict the outbreak around the world with a high correlation (r2>0.6) with the real data. Using this model, we further predicted the possible epidemic situation in the future 12 days in several high-latitude cities with potential outbreak. This model could provide more information for government's future decisions on COVID-19 outbreak control.