Epitope-anchored contrastive transfer learning for paired CD8+ T cell receptor-antigen recognition (preprint)

Understanding the mechanisms of T-cell antigen recognition that underpin adaptive immune responses is critical for the development of vaccines, immunotherapies, and treatments against autoimmune diseases. Despite extensive research efforts, the accurate identification of T cell receptor (TCR)-antigen binding pairs remains a significant challenge due to the vast diversity and cross-reactivity of TCRs. Here, we propose a deep-learning framework termed Epitope-anchored Contrastive Transfer Learning (EPACT) tailored to paired human CD8+ TCRs from single-cell sequencing data. Harnessing the pre-trained representations and the contrastive co-embedding space, EPACT demonstrates state-of-the-art model generalizability in predicting TCR binding specificity for unseen epitopes and distinct TCR repertoires, offering potential values for practical outcomes in real-world scenarios. The contrastive learning paradigm achieves highly precise predictions for immunodominant epitopes and facilitates interpretable analysis of epitope-specific T cells. The TCR binding strength predicted by EPACT aligns well with the surge in spike-specific immune responses targeting SARS-CoV-2 epitopes after vaccination. We further fine-tune EPACT on TCR-epitope structural data to decipher the residue-level interactions involved in T-cell antigen recognition. EPACT not only exhibits superior capabilities in quantifying inter-chain distance matrices and identifying contact residue pairs but also corroborates the presence of molecular mimicry across multiple tumor-associated antigens. Together, EPACT can serve as a useful AI approach with significant potential in practical applications and contribute toward the development of TCR-based diagnostics and immunotherapies.

A phase I/II clinical trial of intradermal, controllable self-replicating RNA vaccine EXG 5003 against SARS-CoV-2 (preprint)

mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have played a key role in reducing morbidity and mortality from coronavirus disease 2019 (COVID 19). We conducted a double-blind, placebo-controlled phase I/II trial to evaluate the safety, tolerability, and immunogenicity of EXG 5003, a two-dose, controllable self-replicating RNA vaccine against SARS-CoV-2. EXG 5003 encodes the receptor binding domain (RBD) of SARS-CoV-2 and was administered intradermally without lipid nanoparticles (LNP). The participants were followed for 12 months. Forty healthy participants were enrolled in Cohort 1 (5 g per dose, n = 16; placebo, n = 4) and Cohort 2 (25 g per dose, n = 16; placebo, n = 4). No safety concerns were observed with EXG 5003 administration. SARS-CoV-2 RBD antibody titers and neutralizing antibody titers were not elevated in either cohort. Elicitation of antigen-specific cellular immunity was observed in the EXG 5003 recipients in Cohort 2. At the 12-month follow-up, participants who had received an approved mRNA vaccine (BNT162b2 or mRNA-1273) >1 month after receiving the second dose of EXG 5003 showed higher cellular responses compared to equivalently vaccinated participants in the placebo group. The findings suggest a priming effect by EXG-5003 on the long-term cellular immunity of approved SARS-CoV-2 mRNA vaccines.

A transformer-based representation-learning model with unified processing of multimodal input for clinical diagnostics.

During the diagnostic process, clinicians leverage multimodal information, such as the chief complaint, medical images and laboratory test results. Deep-learning models for aiding diagnosis have yet to meet this requirement of leveraging multimodal information. Here we report a transformer-based representation-learning model as a clinical diagnostic aid that processes multimodal input in a unified manner. Rather than learning modality-specific features, the model leverages embedding layers to convert images and unstructured and structured text into visual tokens and text tokens, and uses bidirectional blocks with intramodal and intermodal attention to learn holistic representations of radiographs, the unstructured chief complaint and clinical history, and structured clinical information such as laboratory test results and patient demographic information. The unified model outperformed an image-only model and non-unified multimodal diagnosis models in the identification of pulmonary disease (by 12% and 9%, respectively) and in the prediction of adverse clinical outcomes in patients with COVID-19 (by 29% and 7%, respectively). Unified multimodal transformer-based models may help streamline the triaging of patients and facilitate the clinical decision-making process.

A Transformer-based representation-learning model with unified processing of multimodal input for clinical diagnostics (preprint)

During the diagnostic process, clinicians leverage multimodal information, such as chief complaints, medical images, and laboratory-test results. Deep-learning models for aiding diagnosis have yet to meet this requirement. Here we report a Transformer-based representation-learning model as a clinical diagnostic aid that processes multimodal input in a unified manner. Rather than learning modality-specific features, the model uses embedding layers to convert images and unstructured and structured text into visual tokens and text tokens, and bidirectional blocks with intramodal and intermodal attention to learn a holistic representation of radiographs, the unstructured chief complaint and clinical history, structured clinical information such as laboratory-test results and patient demographic information. The unified model outperformed an image-only model and non-unified multimodal diagnosis models in the identification of pulmonary diseases (by 12% and 9%, respectively) and in the prediction of adverse clinical outcomes in patients with COVID-19 (by 29% and 7%, respectively). Leveraging unified multimodal Transformer-based models may help streamline triage of patients and facilitate the clinical decision process.

Clinicopathological and immunological features of new onset kidney disease: a rare event after SARS-CoV-2 vaccination.

The onset of various kidney diseases has been reported after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. However, detailed clinical and pathological features are lacking. We screened and analyzed patients with newly diagnosed kidney diseases after inactivated SARS-CoV-2 vaccination in Peking University First Hospital from January 2021 to August 2021, and compared them with the reported cases in the literature. We obtained samples of blood, urine and renal biopsy tissues. Clinical and laboratory information, as well as light microscopy, immunostaining and ultrastructural observations, were described. The SARS-CoV-2 spike protein and nucleoprotein were stained using the immunofluorescence technique in the kidney biopsy samples. SARS-CoV-2 specific antibodies were tested using magnetic particle chemiluminescence immunoassay. The study group included 17 patients with a range of conditions including immune-complex-mediated kidney diseases (IgA nephropathy, membranous nephropathy and lupus nephritis), podocytopathy (minimal change disease and focal segmental glomerulosclerosis) and others (antineutrophil-cytoplasmic-antibody-associated vasculitis, anti-glomerular basement membrane nephritis, acute tubulointerstitial nephritis and thrombotic microangiopathy). Seven patients (41.18%) developed renal disease after the first dose and ten (58.82%) after the second dose. The kidney disease spectrum as well as clinicopathological features are similar across different types of SARS-CoV-2 vaccines. We found no definitive evidence of SARS-CoV-2 spike protein or nucleoprotein deposition in the kidney biopsy samples. Seropositive markers implicated abnormal immune responses in predisposed individuals. Treatment and follow-up (median = 86 days) showed that biopsy diagnosis informed treatment and prognosis in all patients. In conclusion, we observed various kidney diseases following SARS-CoV-2 vaccine administration, which show a high consistency across different types of SARS-CoV-2 vaccines. Our findings provide evidence against direct vaccine protein deposition as the major pathomechanism, but implicate abnormal immune responses in predisposed individuals. These findings expand our understanding of SARS-CoV-2 vaccine renal safety.

Trend of research on the medical use of molecular hydrogen: a bibliometric analysis.

The medical use of molecular hydrogen, including hydrogen-rich water and hydrogen gas, has been extensively explored since 2007. This article aimed to demonstrate the trend in medical research on molecular hydrogen. A total of 1126 publications on hydrogen therapy were retrieved from the PubMed database until July 30, 2021. From 2007 to 2020, the number of publications in this field had been on an upward trend. Medical Gas Research, Scientific Report and Shock have contributed the largest number of publications on this topic. Researchers by the name of Xue-Jun Sun, Ke-Liang Xie and Yong-Hao Yu published the most studies in the field. Analysis of the co-occurrence of key words indicated that the key words "molecular hydrogen," "hydrogen-rich water," "oxidative stress," "hydrogen gas," and "inflammation" occurred most frequently in these articles. "Gut microbiota," "pyroptosis," and "COVID-19" occurred the most recently among the keywords. In summary, the therapeutic application of molecular hydrogen had attracted much attention in these years. The advance in this field could be caught up by subscribing to relevant journals or following experienced scholars. Oxidative stress and inflammation were the most important research directions currently, and gut microbiota, pyroptosis, and coronavirus disease 2019 might become hotspots in the future.

Glycemic Control in Critically Ill COVID-19 Patients: Systematic Review and Meta-Analysis.

Background: Given the mortality risk in COVID-19 patients, it is necessary to estimate the impact of glycemic control on mortality rates among inpatients by designing and implementing evidence-based blood glucose (BG) control methods. There is evidence to suggest that COVID-19 patients with hyperglycemia are at risk of mortality, and glycemic control may improve outcomes. However, the optimal target range of blood glucose levels in critically ill COVID-19 patients remains unclear, and further research is needed to establish the most effective glycemic control strategies in this population. Methods: The investigation was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Data sources were drawn from Google Scholar, ResearchGate, PubMed (MEDLINE), Cochrane Library, and Embase databases. Randomized controlled trials, non-randomized controlled trials, retrospective cohort studies, and observational studies with comparison groups specific to tight glycemic control in COVID-19 patients with and without diabetes. Results: Eleven observational studies (26,953 patients hospitalized for COVID-19) were included. The incidence of death was significantly higher among COVID-19 patients diagnosed with diabetes than those without diabetes (OR = 2.70 [2.11, 3.45] at a 95% confidence interval). Incidences of death (OR of 3.76 (3.00, 4.72) at a 95% confidence interval) and complications (OR of 0.88 [0.76, 1.02] at a 95% confidence interval) were also significantly higher for COVID-19 patients with poor glycemic control. Conclusion: These findings suggest that poor glycemic control in critically ill patients leads to an increased mortality rate, infection rate, mechanical ventilation, and prolonged hospitalization.

Comparison of the prophylactic antithrombotic effect of indobufen and warfarin in patients with nephrotic syndrome: a randomized controlled trial.

PURPOSE: The risk of thromboembolic events is elevated in patients with nephrotic syndrome, and warfarin use has been associated with an increased risk of bleeding. Indobufen, a selective cyclooxygenase-1 inhibitor, is currently being evaluated for the prevention of thromboembolic events in nephrotic syndrome. This study aimed to compare the efficacy and safety of indobufen with that of warfarin in patients with nephrotic syndrome. MATERIALS AND METHODS: This multicenter, randomized, three-arm, open-label, parallel controlled trial involved a total of 180 adult patients with nephrotic syndrome from four centers in China. Patients were randomly assigned to receive 100 mg indobufen (bid), 200 mg indobufen (bid), and 3 mg warfarin (qd) daily for 12 weeks. The primary endpoints included thromboembolic and bleeding events, while laboratory results and adverse events constituted secondary endpoints. RESULTS: No thromboembolic events occurred in the high-/low-dose indobufen and warfarin groups. Moreover, the use of a low dose of indobufen significantly reduced the risk of minor bleeding events compared with warfarin use (2% versus 18%, p < .05). Finally, adverse events were more frequent in warfarin-treated patients. CONCLUSIONS: This study found that indobufen therapy provided equivalent effects in preventing thromboembolic events compared with warfarin therapy, while low dose of indobufen was associated with a reduced risk of bleeding events, thus it should be recommended for the prevention of thromboembolic events in clinical practice in patients with nephrotic syndrome. TRIAL REGISTRATION NUMBER: ChiCTR-IPR-17013428.

Vertigo/dizziness following COVID-19 vaccination.

PURPOSE: This study assessed the vertigo/dizziness in patients following COVID-19 vaccination. PATIENTS AND METHODS: From July 2021 to June 2022, totaling 50 patients with dizzy spells following COVID-19 vaccination by AZ (AstraZeneca-Oxford University, AZD1222), BNT (Pfizer-BioNTech, BNT162b2) or Moderna (Moderna, mRNA-1273) vaccine were enrolled in this study. The interval from vaccination to the onset of vertigo/dizziness was compared with inter-episodic interval of vertigo/dizziness in the same patients, but without vaccination, during past one year (2020). RESULTS: The incidences of severe systemic complication per 106 shots were 0.86 for Moderna vaccine, 1.22 for AZ vaccine, and 1.23 for BNT vaccine. Conversely, rate of post-vaccination vertigo/dizziness was noted in the Moderna group (66 %), followed by the AZ group (20 %) and the BNT (14 %) group, meaning that type of COVID-19 vaccine may affect various organ systems. The median time to the onset of vertigo/dizziness following vaccination is 10d, which is consistent with the onset of IgG production, and significantly less than inter-episodic interval (84d) in the same patients without vaccination. CONCLUSION: Post-vaccination vertigo/dizziness can manifest as exacerbation of previous neurotological disorder. The median time to the onset of vertigo/dizziness following COVID-19 vaccination is 10d. Since the outcome is fair after supportive treatment, the immunomodulatory effect of the vaccines does not undermine the necessity of the COVID-19 vaccination.

Taxonomical and ontological analysis of verified natural and laboratory human coronavirus hosts (preprint)

To fully understand COVID-19, it is critical to identify and analyze all the possible hosts of SARS-CoV-2 (the pathogen of COVID-19) and compare them with the hosts of other human coronaviruses. In this study, we collected, annotated, and performed taxonomical and ontological analysis of all the reported and verified hosts for all human coronaviruses including SARS-CoV, MERS-CoV, SARS-CoV-2, and four others that cause the common cold. A total of 37 natural hosts and 19 laboratory animal hosts of host human coronaviruses were identified based on experimental or clinical evidence. Our taxonomical ontology-based analysis found that all the verified susceptible natural and laboratory animals belong to therian mammals. Specifically, these 37 natural therian hosts include one wildlife marsupial mammal (i.e., Didelphis virginiana) and 36 Eutheria mammals (a.k.a. placental mammals). The 19 laboratory animal hosts are also classified as placental mammals. While several non-therian animals (including snake, housefly, zebrafish) were reported to be likely SARS-CoV-2 hosts, our analysis excluded them due to the lack of convincing evidence. Genetically modified mouse models with human Angiotensin-converting enzyme 2 (ACE2) or dipeptidyl peptidase-4 (DPP4) protein were more susceptible to virulent human coronaviruses with clear symptoms. Coronaviruses often became more virulent and adaptive in the mouse hosts after a series of viral passages in the mice. To support knowledge standardization and analysis, we have also represented the annotated host knowledge in the Coronavirus Infectious Disease Ontology (CIDO) and provided ways to automatically query the knowledge.

Peripheral Nervous System Adverse Events after the Administration of mRNA Vaccines: A Systematic Review and Meta-Analysis of Large-Scale Studies.

Although neurological complications after the administration of vaccines against coronavirus disease 2019 (COVID-19) are rare, they might result in long-term morbidity. This study was designed to determine the risk of peripheral nervous system (PNS) adverse events after the administration of mRNA vaccines against COVID-19. Large-scale randomized controlled trials (RCTs) and cohort studies were systematically searched in databases, and 15 cohort studies were included in the synthesis. Among all PNS adverse events, only Bell's palsy and Guillain-Barré syndrome (GBS) had sufficient data and were included for further analysis. Individuals who received mRNA vaccines had a higher risk of Bell's palsy than the unvaccinated group, and the risk of Bell's palsy after BNT162b2 was significantly higher than after mRNA-1273. Regarding GBS, no significant difference in the risk was observed between BNT162b2 and the unvaccinated group, but BNT126b2 introduced a higher risk of post-vaccinated GBS than mRNA-1273. In conclusion, PNS adverse events, especially Bell's palsy, should be carefully observed after mRNA vaccination against COVID-19. With the opportunity of vaccination campaigns on such a large scale, further investigation and surveillance of post-vaccination neurological adverse events should also be established.

The association between duration of muscle exercise and psychological symptoms is higher in boys than in girls: A cross-sectional study based on Chinese college students during COVID-19.

Objective: The COVID-19 pandemic has had many negative effects on the physical and mental health of college students. Although many studies have analyzed the association between muscular fitness and psychological symptoms in children and adolescents, research during the COVID-19 pandemic is limited. Our study focused on analyzing the association between duration of muscle exercise and psychological symptoms among Chinese college students during the COVID-19 pandemic. Method: A four-stage stratified whole-group sampling method was used to investigate basic demographic information, duration of muscle exercise and psychological symptoms in 5,559 college students aged 19-22 years in China. Chi-square test (categorical variables) and one-way ANOVA (continuous variables) were used to compare the psychological symptoms of college students with different durations of muscle exercise. Logistic regression analysis was used to analyze the association between duration of muscle exercise and psychological symptoms. Result: The detection rate of psychological symptoms among Chinese college students was 9.0%; the detection rate was 10.7% for boys and 7.6% for girls. The proportions of duration of muscle exercise at <30 min/d, 30-60 min/d, and >60 min/d were 75.0%, 20.4%, and 4.6%, respectively. After adjusting for relevant confounding variables, taking Chinese college students with duration of muscle exercise >60 min/d as the reference group, duration of muscle exercise <30 min/d was positively correlated with the occurrence of psychological symptoms (OR: 4.19, 95%CI: 1.82, 9.61) (P < 0.001). In emotional symptoms (OR: 4.56, 95%CI: 1.99, 10.44), behavioral symptoms (OR: 3.44, 95%CI: 1.79, 6.60), social adaptation difficulties (OR: 3.04, 95%CI: 1.62, 5.68) dimensions, there is also a positive correlation (P < 0.01). Conclusions: The negative association between duration of muscle exercise and psychological symptoms among Chinese college students also suggests that longer duration of muscle exercise among college students is associated with a lower prevalence of psychological symptoms. The association between duration of muscle exercise and psychological symptoms was higher in boys compared to girls.

Vaccination with SARS-CoV-2 inactivated vaccines reduced the risk of anxiety and depression in a population majored by health care workers during the recent omicron variant outbreak

Background The mental health status of the population majored by health care workers in China during the omicron variant outbreak remains unknown. Furthermore, the effect of COVID-19-inactivated vaccines on mental health is yet to be investigated. Methods A cross-sectional, online survey study was conducted from 12–20 April, 2022. The prevalence of symptoms of depression and anxiety were evaluated using the Hospital Anxiety and Depression Scale. Results Responses from a total of 1,387 participants were analyzed, 39.7% of which reported symptoms of mental health illness. The incidence of anxiety (30.4% vs. 48.4%, p < 0.001) and depression (27.1% vs. 46.3%, p < 0.001) decreased with COVID-19 inactivated vaccination. From multivariate analysis, living in Shanghai (anxiety: Odds ratio [OR]: 1.58, 95% confidence interval [CI]: 1.14–2.19, p = 0.006;depression: OR: 1.61, 95% CI: 1.16–2.25, p = 0.005), with a mental illness (anxiety: OR: 8.97, 95% CI: 1.01–79.56, p = 0.049;depression: OR: 9.32, 95% CI: 1.06–82.30, p = 0.045) increased the incidence of anxiety and depression. Elderly participants (anxiety: OR: 0.986, 95% CI: 0.975–0.997, p = 0.012;depression: OR: 0.976, 95% CI: 0.965–0.987, p < 0.001) who had been vaccinated against COVID-19 (anxiety: OR: 0.49, 95% CI: 0.32–0.75, p = 0.001;depression: OR: 0.45, 95% CI: 0.29–0.69, p < 0.001) had decreased incidences of anxiety and depression. Conclusion Our findings increase the awareness of the high incidence of mental health illness symptoms during the omicron variant outbreak despite previous experiences with the COVID-19 pandemic, and vaccination is suggested to reduce the risk of anxiety and depression.

SARS-CoV-2 Variants, Current Vaccines and Therapeutic Implications for COVID-19.

Over the past two years, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of infections, resulting in an unprecedented pandemic of coronavirus disease 2019 (COVID-19). As the virus spreads through the population, ongoing mutations and adaptations are being discovered. There is now substantial clinical evidence that demonstrates the SARS-CoV-2 variants have stronger transmissibility and higher virulence compared to the wild-type strain of SARS-CoV-2. Hence, development of vaccines against SARS-CoV-2 variants to boost individual immunity has become essential. However, current treatment options are limited for COVID-19 caused by the SARS-CoV-2 variants. In this review, we describe current distribution, variation, biology, and clinical features of COVID-19 caused by SARS-CoV-2 variants (including Alpha (B.1.1.7 Lineage) variant, Beta (B.1.351 Lineage) variant, Gamma (P.1 Lineage) variant, Delta (B.1.617.2 Lineage) variant, and Omicron (B.1.1.529 Lineage) variant and others. In addition, we review currently employed vaccines in clinical or preclinical phases as well as potential targeted therapies in an attempt to provide better preventive and treatment strategies for COVID-19 caused by different SARS-CoV-2 variants.

Controllable self-replicating RNA vaccine delivered intradermally elicits predominantly cellular immunity (preprint)

Intradermal delivery of self-replicating RNA (srRNA) is a promising vaccine platform. Considering that human skin temperature is around 33{degrees}C, lower than core body temperature of 37{degrees}C, we have developed an srRNA that functions optimally at skin temperature and is inactivated at or above 37{degrees}C as a safety switch. This temperature-controllable srRNA (c-srRNA), when tested as an intradermal vaccine against SARS-CoV-2, functions when injected naked without lipid nanoparticles. Unlike most currently available vaccines, c-srRNA vaccines predominantly elicit cellular immunity with little or no antibody production. Interestingly, c-srRNA-vaccinated mice produced antigen-specific antibodies upon subsequent stimulation with antigen protein. Antigen-specific antibodies were also produced when B-cell stimulation using antigen protein was followed by c-srRNA booster vaccination. Using c-srRNA, we have designed a pan-coronavirus booster vaccine that incorporates both spike receptor binding domains as viral surface proteins and evolutionarily conserved nucleoproteins as viral non-surface proteins, from both SARS-CoV-2 and MERS-CoV. It can thereby potentially immunize against SARS-CoV-2, SARS-CoV, MERS-CoV, and their variants. c-srRNA may provide a route to activate cellular immunity against a wide variety of pathogens.

Grassroots Mirroring under COVID-19: Does Community Resilience Affect Residents' Responses? The Case of Shenzhen, China

In the face of the sudden outbreak of COVID-19, the community has played a large role in stemming the impact of COVID-19, and community resilience has become a key part of community governance. Community resilience is the ability of a community to respond effectively to risk and keep the community functioning by strengthening governance and leveraging community relationships in the face of external-disaster disruptions;this gives community participants a real sense that the community is equipped to face adversity and challenges. However, the evasive response of some residents is an important factor that hinders the community's emergency response capabilities. Therefore, this study selected different types of communities in Shenzhen, China, from 9–23 July 2021, conducted a field survey, and obtained 2256 questionnaires using multi-segment random sampling. Based on the questionnaire data, this study uses factor analysis, correlation analysis, multiple linear regression analysis, and cluster analysis to explore the mechanisms of community resilience on residents' risk coping styles, and the differences between community resilience and residents' risk coping styles in different types of communities. The study found that, first, community resilience has a significant positive impact on proactive risk response, among which governance performance has a more significant impact;second, community resilience has a negative correlation with evasive coping styles, in which governance performance has a more significant impact;third, there are obvious differences in the level of resilience between different types of communities, with urban communities being the best, mixed communities being second, and transition communities being last. The government's role in guiding and organizing the population was extremely significant during the COVID-19 pandemic, highlighting the superiority of the socialist system. The role of the community in social management has become increasingly prominent, and community resilience has become a key factor in controlling COVID-19.

Virtual Reality in Treatment for Psychological Problems in First-Line Health Care Professionals Fighting COVID-19 Pandemic: A Case Series.

ABSTRACT: Virtual reality therapy (VRT) is a new psychotherapeutic approach integrating virtual reality technology and psychotherapy. This case series aimed to study effectiveness of VRT in treating psychological problems. We described four cases of first-line health care professionals with emerging clinically significant early psychological problems during the COVID-19 outbreak, and specifically received the VRT treatment. We compared the Patient Health Questionnaire 9 items (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), PHQ-15, and Athens Insomnia Scale to evaluate psychological symptoms and sleep quality before and after sessions. All four cases showed a reduction in scale comparison. General scores of the PHQ-9 reduced 65%, GAD-7 reduced 52.17%, PHQ-15 decreased 38.17%, and scores of the Athens Insomnia Scale reduced 67.44%. Meanwhile, a reduction in depression, anxiety, psychosomatic, and sleeping symptoms was also found, which decreased 76.92% in general. These results are highly significant statistically. This case series demonstrated the effectiveness of VRT on psychological problems as a promising approach to apply on various psychological distress and disorders.