Pre-pandemic Social Integration: Protection or Risk for Older Adults in the Time of COVID-19?

OBJECTIVES: To examine the association between pre-pandemic social integration and post-traumatic stress disorder (PTSD) symptoms during the COVID-19 pandemic and test whether the association is mediated by social support received and social events missed during the pandemic. We also explored age, race, gender, and socioeconomic differences in the association. METHODS: We adopted a prospective design. Path analysis was conducted using data from the COVID-19 supplement (2020) and the 2019 wave of the National Health and Aging Trends Study. The sample represents Medicare beneficiaries age 70+ (N = 2,694). Social integration was measured using a 6-item index. A 6-item standardized scale assessed PTSD symptoms. Both social support received and social events missed were single-item measures. The analysis controlled for sociodemographic characteristics, pre-pandemic physical and mental health, and coronavirus exposure during the pandemic. RESULTS: Pre-pandemic social integration was positively associated with PTSD symptoms during the pandemic. The association was primarily mediated by social events missed- high levels of social integration were associated with missing more social events during the pandemic resulting in more PTSD symptoms. Social support received was also a mediator-social integration was positively associated with social support received during the pandemic, with more received support associated with greater PTSD symptoms. Pre-pandemic social integration had no significant direct effect on PTSD symptoms. The direct, indirect, and total effects of social integration on PTSD symptoms did not significantly differ by age, race, gender, education or poverty status. DISCUSSION: Social integration may carry mental health risks in times of infectious disease outbreaks.

Enhanced inflammation and suppressed adaptive immunity in COVID-19 with prolonged RNA shedding.

Little is known regarding why a subset of COVID-19 patients exhibited prolonged positivity of SARS-CoV-2 infection. Here, we found that patients with long viral RNA course (LC) exhibited prolonged high-level IgG antibodies and higher regulatory T (Treg) cell counts compared to those with short viral RNA course (SC) in terms of viral load. Longitudinal proteomics and metabolomics analyses of the patient sera uncovered that prolonged viral RNA shedding was associated with inhibition of the liver X receptor/retinoid X receptor (LXR/RXR) pathway, substantial suppression of diverse metabolites, activation of the complement system, suppressed cell migration, and enhanced viral replication. Furthermore, a ten-molecule learning model was established which could potentially predict viral RNA shedding period. In summary, this study uncovered enhanced inflammation and suppressed adaptive immunity in COVID-19 patients with prolonged viral RNA shedding, and proposed a multi-omic classifier for viral RNA shedding prediction.

Treatment of COVID-19 in Hemodialysis Patients Using Traditional Chinese Medicine: A Single-Center, Retrospective Study.

Background: To explore the effect of combining traditional Chinese medicine (TCM) and Western medicine in hemodialysis patients with coronavirus disease 2019 (COVID-19). Methods: This study was conducted from 27 January 2020 to 17 March 2020 in Wuhan Third Hospital Guanggu Branch, Wuhan, China. Fifty-three patients were included and divided into a control group (CG), which received Western medicine and a combined treatment group, which received TCM and Western medicine (TG). Clinical and laboratory data, TCM symptom scores, and chest computed tomography results were extracted and compared between the two groups. Results: The TG included 21 (67.7%) men and 10 (32.3%) women with a mean age of 61.02 (standard deviation [SD] 15.07, range 26-89) years. The mean dialysis duration in the TG was 49 (SD 31) months. Of all patients in the TG, 27 (87.1%) had fatigue, 18 (58.1%) had dry cough, 16 (51.6%) had anorexia, 11 (35.5%) had dyspnea, and 11 (35.5%) had fever. The CG included 14 (63.6%) men and 8 (36.4%) women with a mean age of 61.45 (SD 13.78, range 36-84) years. The mean dialysis duration in the CG was 63 (SD 46) months. Of all patients in the CG, 21 (95.5%) had fatigue, 12 (54.5%) had dry cough, 17 (77.3%) had anorexia, 12 (54.5%) had dyspnea, and 7 (31.8%) had fever. After treatment, the TCM symptom scores of the two groups decreased; the anorexia scores were lower in the TG than in the CG (p < 0.05). After treatment, albumin increased and D-dimer, C-reactive protein, and lactate dehydrogenase levels decreased in the TG. The d-dimer levels were lower and the albumin level was higher in the TG than in the CG after treatment (p < 0.05). The cure rate was higher, and the mortality rate was lower in the TG than in the CG (p < 0.05). Conclusion: A combination of TCM and Western medicine in hemodialysis patients with COVID-19 could relieve symptoms and help recovery. Further evidence from larger randomized controlled trials is needed to confirm our results.

MutCov: A pipeline for evaluating the effect of mutations in spike protein on infectivity and antigenicity of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing an outbreak of coronavirus disease 2019 (COVID-19), is a major threat to public health worldwide. Previous studies have shown that the spike protein of SARS-CoV-2 determines viral infectivity and major antigenicity. However, the spike protein has been undergoing various mutations, which bring a great challenge to the prevention and treatment of COVID-19. Here we present the MutCov, a pipeline for evaluating the effect of mutations in spike protein on infectivity and antigenicity of SARS-CoV-2 by calculating the binding free energy between spike protein and angiotensin-converting enzyme 2 (ACE2) or neutralizing monoclonal antibody (mAb). The predicted infectivity and antigenicity were highly consistent with biologically experimental results, and demonstrated that the MutCov achieved good prediction performance. In conclusion, the MutCov is of high importance for systematically evaluating the effect of novel mutations and improving the prevention and treatment of COVID-19. The source code and installation instruction of MutCov are freely available at http://jianglab.org.cn/MutCov.

DLpTCR: an ensemble deep learning framework for predicting immunogenic peptide recognized by T cell receptor.

Accurate prediction of immunogenic peptide recognized by T cell receptor (TCR) can greatly benefit vaccine development and cancer immunotherapy. However, identifying immunogenic peptides accurately is still a huge challenge. Most of the antigen peptides predicted in silico fail to elicit immune responses in vivo without considering TCR as a key factor. This inevitably causes costly and time-consuming experimental validation test for predicted antigens. Therefore, it is necessary to develop novel computational methods for precisely and effectively predicting immunogenic peptide recognized by TCR. Here, we described DLpTCR, a multimodal ensemble deep learning framework for predicting the likelihood of interaction between single/paired chain(s) of TCR and peptide presented by major histocompatibility complex molecules. To investigate the generality and robustness of the proposed model, COVID-19 data and IEDB data were constructed for independent evaluation. The DLpTCR model exhibited high predictive power with area under the curve up to 0.91 on COVID-19 data while predicting the interaction between peptide and single TCR chain. Additionally, the DLpTCR model achieved the overall accuracy of 81.03% on IEDB data while predicting the interaction between peptide and paired TCR chains. The results demonstrate that DLpTCR has the ability to learn general interaction rules and generalize to antigen peptide recognition by TCR. A user-friendly webserver is available at http://jianglab.org.cn/DLpTCR/. Additionally, a stand-alone software package that can be downloaded from https://github.com/jiangBiolab/DLpTCR.

N439K Variant in Spike Protein Alter the Infection Efficiency and Antigenicity of SARS-CoV-2 Based on Molecular Dynamics Simulation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing an outbreak of coronavirus disease 2019 (COVID-19), has been undergoing various mutations. The analysis of the structural and energetic effects of mutations on protein-protein interactions between the receptor binding domain (RBD) of SARS-CoV-2 and angiotensin converting enzyme 2 (ACE2) or neutralizing monoclonal antibodies will be beneficial for epidemic surveillance, diagnosis, and optimization of neutralizing agents. According to the molecular dynamics simulation, a key mutation N439K in the SARS-CoV-2 RBD region created a new salt bridge with Glu329 of hACE2, which resulted in greater electrostatic complementarity, and created a weak salt bridge with Asp442 of RBD. Furthermore, the N439K-mutated RBD bound hACE2 with a higher affinity than wild-type, which may lead to more infectious. In addition, the N439K-mutated RBD was markedly resistant to the SARS-CoV-2 neutralizing antibody REGN10987, which may lead to the failure of neutralization. The results show consistent with the previous experimental conclusion and clarify the structural mechanism under affinity changes. Our methods will offer guidance on the assessment of the infection efficiency and antigenicity effect of continuing mutations in SARS-CoV-2.

Traditional Chinese Medicine Decoctions Significantly Reduce the Mortality in Severe and Critically Ill Patients with COVID-19: A Retrospective Cohort Study.

Coronavirus disease (COVID-19) is a new infectious disease associated with high mortality, and traditional Chinese medicine decoctions (TCMDs) have been widely used for the treatment of patients with COVID-19 in China; however, the impact of these decoctions on severe and critical COVID-19-related mortality has not been evaluated. Therefore, we aimed to address this gap. In this retrospective cohort study, we included inpatients diagnosed with severe/critical COVID-19 at the Tongren Hospital of Wuhan University and grouped them depending on the recipience of TCMDs (TCMD and non-TCMD groups). We conducted a propensity score-matched analysis to adjust the imbalanced variables and treatments and used logistic regression methods to explore the risk factors associated with in-hospital death. Among 282 patients with COVID-19 who were discharged or died, 186 patients (66.0%) received TCMD treatment (TCMD cohort) and 96 (34.0%) did not (non-TCMD cohort). After propensity score matching at a 1:1 ratio, 94 TCMD users were matched to 94 non-users, and there were no significant differences in baseline clinical variables between the two groups of patients. The all-cause mortality was significantly lower in the TCMD group than in the non-TCMD group, and this trend remained valid even after matching (21.3% [20/94] vs. 39.4% [37/94]). Multivariable logistic regression model showed that disease severity (odds ratio: 0.010; 95% CI: 0.003, 0.037; [Formula: see text]¡ 0.001) was associated with increased odds of death and that TCMD treatment significantly decreased the odds of in-hospital death (odds ratio: 0.115; 95% CI: 0.035, 0.383; [Formula: see text]¡ 0.001), which was related to the duration of TCMD treatment. Our findings show that TCMD treatment may reduce the mortality in patients with severe/critical COVID-19.

Global characterization of B cell receptor repertoire in COVID-19 patients by single-cell V(D)J sequencing.

The world is facing a pandemic of Corona Virus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Adaptive immune responses are essential for SARS-CoV-2 virus clearance. Although a large body of studies have been conducted to investigate the immune mechanism in COVID-19 patients, we still lack a comprehensive understanding of the BCR repertoire in patients. In this study, we used the single-cell V(D)J sequencing to characterize the BCR repertoire across convalescent COVID-19 patients. We observed that the BCR diversity was significantly reduced in disease compared with healthy controls. And BCRs tend to skew toward different V gene segments in COVID-19 and healthy controls. The CDR3 sequences of heavy chain in clonal BCRs in patients were more convergent than that in healthy controls. In addition, we discovered increased IgG and IgA isotypes in the disease, including IgG1, IgG3 and IgA1. In all clonal BCRs, IgG isotypes had the most frequent class switch recombination events and the highest somatic hypermutation rate, especially IgG3. Moreover, we found that an IgG3 cluster from different clonal groups had the same IGHV, IGHJ and CDR3 sequences (IGHV4-4-CARLANTNQFYDSSSYLNAMDVW-IGHJ6). Overall, our study provides a comprehensive characterization of the BCR repertoire in COVID-19 patients, which contributes to the understanding of the mechanism for the immune response to SARS-CoV-2 infection.

COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas.

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.

Multi-organ proteomic landscape of COVID-19 autopsies.

The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report a proteomic analysis of 144 autopsy samples from seven organs in 19 COVID-19 patients. We quantified 11,394 proteins in these samples, in which 5,336 were perturbed in the COVID-19 patients compared to controls. Our data showed that cathepsin L1, rather than ACE2, was significantly upregulated in the lung from the COVID-19 patients. Systemic hyperinflammation and dysregulation of glucose and fatty acid metabolism were detected in multiple organs. We also observed dysregulation of key factors involved in hypoxia, angiogenesis, blood coagulation, and fibrosis in multiple organs from the COVID-19 patients. Evidence for testicular injuries includes reduced Leydig cells, suppressed cholesterol biosynthesis, and sperm mobility. In summary, this study depicts a multi-organ proteomic landscape of COVID-19 autopsies that furthers our understanding of the biological basis of COVID-19 pathology.

Comprehensive analysis of TCR repertoire in COVID-19 using single cell sequencing.

T-cell receptor (TCR) is crucial in T cell-mediated virus clearance. To date, TCR bias has been observed in various diseases. However, studies on the TCR repertoire of COVID-19 patients are lacking. Here, we used single-cell V(D)J sequencing to conduct comparative analyses of TCR repertoire between 12 COVID-19 patients and 6 healthy controls, as well as other virus-infected samples. We observed distinct T cell clonal expansion in COVID-19. Further analysis of VJ gene combination revealed 6 VJ pairs significantly increased, while 139 pairs significantly decreased in COVID-19 patients. When considering the VJ combination of α and ß chains at the same time, the combination with the highest frequency on COVID-19 was TRAV12-2-J27-TRBV7-9-J2-3. Besides, preferential usage of V and J gene segments was also observed in samples infected by different viruses. Our study provides novel insights on TCR in COVID-19, which contribute to our understanding of the immune response induced by SARS-CoV-2.

Reflection on the Reform of China's Emergency Medical Insurance System based on the Prevention and Control of COVID-19 (preprint)

Objective: Based on the Prevention and Control of  COVID-19, this paper points out the shortcomings of China's current medical insurance system, and puts forward the concept of establishing emergency medical insurance system.Methods: This paper analyzes the characteristics of the modern epidemic and its special requirements for medical insurance. Putting forward the idea of mechanism construction.Results:The operation of China's national medical insurance system is mainly operated by the insured, the government, medical institutions and medical institutions. However, the rapid spread of the epidemic has caused great disasters to the society. In the face of major public health events, medical insurance should have four characteristics: the "normalization" of the emergency medical insurance system, the fairness of guarantees, the public quality of treatment and positive externalities. China should establish an emergency system in line with these four characteristics from the four parties. Therefore, this paper analyzes the characteristics of modern epidemic risk, its development process and the requirements for the insurance industry in combination with the situation of China's response to dealing with COVID-19, and puts forward that China should further improve the universal medical insurance system and establish an emergency medical security system to better deal with all kinds of sudden public health events, which will still happen in the future.Conclusions:China's national medical insurance system should not be limited to meet people's conventional medical needs. When public health emergencies occur, it is also necessary to establish a sound medical insurance system to operate.The establishment of emergency medical security system is one of the important development directions of our country in the future.