Creutzfeldt-Jakob Disease with Initial Typical Parkinsonism Precipitated by COVID-19? A Case Report (preprint)

Background Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disease caused by the accumulation of PrPSc. While COVID-19-induced sporadic CJD (sCJD) with parkinsonism as the initial symptom is extremely uncommon, this report aims to raise awareness of sCJD cases that present with parkinsonism that are not associated with genetic mutations or pathological α-synuclein (α-Syn) accumulation. Case presentation This report presents the case of a 72-year-old man with probable sporadic Creutzfeldt-Jakob disease (sCJD) who initially showed symptoms of parkinsonism, which worsened rapidly after contracting COVID-19. Despite a history of responsive tremor and bradykinesia, his condition deteriorated following the viral infection, leading to rapid consciousness decline and diffuse myoclonus. Diagnostic tests, including brain MRI, cerebrospinal fluid analysis, and EEG, pointed towards prion disease. PrPSc, a marker for CJD, was detected in both the cerebrospinal fluid and skin samples using RT-QuIC, further confirming the diagnosis. Notably, skin analysis revealed PrPSc but no pathological α-synuclein deposits, ruling out typical Parkinson's disease.  Conclussion This case underscores the importance of considering sCJD in patients with parkinsonism, especially if they experience sudden neuropsychiatric symptoms, especially if they do not exhibit pathological α-Syn accumulation or have genetic mutations.

Integration of human organoids single-cell transcriptomic profiles and human genetics repurposes critical cell type-specific drug targets for severe COVID-19 (preprint)

Human organoids recapitulate the cell type diversity and function of their primary organs holding tremendous potentials for basic and translational research. Advances in single-cell RNA sequencing (scRNA-seq) technology and genome-wide association study (GWAS) have accelerated the biological and therapeutic interpretation of trait-relevant cell types or states. Here, we constructed a computational framework to integrate atlas-level organoid scRNA-seq data, GWAS summary statistics, expression quantitative trait loci, and gene-drug interaction data for distinguishing critical cell populations and drug targets relevant to COVID-19 severity. We found that 39 cell types across eight kinds of organoids were significantly associated with COVID-19 outcomes. Notably, subset of lung mesenchymal stem cells (MSCs) increased proximity with fibroblasts predisposed to repair COVID-19-damaged lung tissue. Brain endothelial cell subset exhibited significant associations with severe COVID-19, and this cell subset showed a notable increase in cell-to-cell interactions with other brain cell types, including microglia. We repurposed 33 druggable genes, including IFNAR2, TYK2, and VIPR2, and their interacting drugs for COVID-19 in a cell-type-specific manner. Overall, our results showcase that host genetic determinants have cellular specific contribution to COVID-19 severity, and identification of cell type-specific drug targets may facilitate to develop effective therapeutics for treating severe COVID-19 and its complications.

Clinical characteristics and remission of nine cases with coronavirus disease 2019 infection in Zunyi, Southwest of China: A retrospective study

The outbreak of coronavirus disease 2019 (COVID-19) has become a rock-ribbed public pandemic and caused substantial health concerns worldwide. In addition to therapeutic strategies, the epidemiologic features and clinical characteristics of patients responded to COVID-19 infection are of equal importance. The study aims to systematically evaluate the clinical presentations and remission of cases with COVID-19 infection in Zunyi, Southwest of China, and to determine the similarities and variations for further clinical classification and comprehensive treatment. Herein, we conducted a retrospective study upon 9 patients in Zunyi, southwest of China, including 1 mild (LPA), 5 severe (SPA) and 3 critical (CPA) types of COVID-19 infection. In details, the demographic data, historical epidemiology, previous medical history, clinical symptoms and complications, laboratory examination, chest imaging, treatment and outcomes of the patients were throughout explored. The non-normal distribution of the data was conducted by utilizing the SPSS software, and significant statistical differences were identified when P < .05. By retrospective analysis of the 9 cases, we found there were multifaceted similarities and differences among them in clinical representation. The patients collectively showed negative for nucleic acid test (NAT) and favorable prognosis after receiving comprehensive therapy such as hormonotherapy, hemopruification, and antiviral administration as well as respiratory support. On the basis of the information, we systematically dissected the clinical features and outcomes of the enrolled patients with COVID-19 and the accompanied multiple syndromes, which would serve as new references for clinical classification and comprehensive treatment. Analysis of clinical characteristics and therapeutic effect of 9 cases of novel coronavirus pneumonia (COVID-19), ChiCTR2000031930. Registered April 15, 2020 (retrospective registration).

Bayesian inference

Bayesian statistical methods have become more popular in different applications of scientific research over the past several decades. This is mainly due to the computing capacity of modern machines and the recent advances in Bayesian computational methodologies. In this chapter, we give a brief introduction to Bayesian analysis and discuss the difference between Bayesian and classical frequentist statistics. To illustrate Bayesian methodologies, a diagnostic COVID-19 test is used to present the basic principles of the Bayesian approach, prior distribution, likelihood function, and posterior distribution. As an application of the Bayesian methodologies, we introduce Bayesian linear regression and Gaussian process regression and their Bayesian inference framework.

Deep learning identified genetic variants associated with COVID-19 related mortality (preprint)

Analysis of host genetic components provides insights into the susceptibility and response to viral infection such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). To reveal genetic determinants of susceptibility to COVID-19 related mortality, we train a deep learning model to identify groups of genetic variants and their interactions that contribute to the COVID-19 related mortality risk using the UK Biobank data. We refer to such groups of variants as super variants. We identify 15 super variants with various levels of significance as susceptibility loci for COVID-19 mortality. Specifically, we identify a super variant (OR=1.594, p=5.47E-9) on Chromosome 7 that consists of the minor allele of rs76398985, rs6943608, rs2052130, 7:150989011_CT_C, rs118033050 and rs12540488. We also discover a super variant (OR=1.353, p=2.87E-8) on Chromosome 5 that contains rs12517344, rs72733036, rs190052994, rs34723029, rs72734818, 5:9305797_GTA_G and rs180899355.

Identification and Characterization of a Novel Cell Binding and Cross-reactive Region on Spike Protein of SARS-CoV-2 (preprint)

Given that COVID-19 continues to wreak havoc around the world, it is imperative to search for a conserved region involved in viral infection so that effective vaccines can be developed to prevent the virus from rapid mutations. We have established a twelve-fragment library of recombinant proteins covering the entire region of spike protein of both SARS-CoV-2 and SARS-CoV from E. coli. IgGs from murine antisera specifically against six spike protein fragments of SARS-CoV-2 were produced, purified, and characterized. We found that one specific IgG against the fusion process region, named COVID19-SF5, serologically cross-reacted with all twelve S-protein fragments. COVID19-SF5, with amino acid sequences from 880 to 1084, specifically bound to VERO-E6 and BEAS-2B cells, with Kd values of 449.1 ± 21.41 and 381.9 ± 31.53 nM, and IC50 values of 761.2 ± 28.2 nM and 862.4 ± 32.1 nM, respectively. In addition, COVID19-SF5 greatly enhanced binding of the full-length CHO cell-derived spike protein to the host cells in a concentration-dependent manner. Furthermore, COVID19-SF5 and its IgGs inhibited the infection of the host cells by pseudovirus. The combined data from our studies reveal that COVID19-SF5, a novel cell-binding fragment, may contain a common region(s) for mediating viral binding during infection. Our studies also provide valuable insights into how virus variants may evade host immune recognition. Significantly, the observation that the IgGs against COVID19-SF5 possesses a cross-reactivity to all other fragments of S protein suggests that it is possible to develop universal neutralizing monoclonal antibodies to curb rapid mutations of COVID-19. 

Advances in the design and development of SARS-CoV-2 vaccines.

Since the end of 2019, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The RNA genome of SARS-CoV-2, which is highly infectious and prone to rapid mutation, encodes both structural and nonstructural proteins. Vaccination is currently the only effective method to prevent COVID-19, and structural proteins are critical targets for vaccine development. Currently, many vaccines are in clinical trials or are already on the market. This review highlights ongoing advances in the design of prophylactic or therapeutic vaccines against COVID-19, including viral vector vaccines, DNA vaccines, RNA vaccines, live-attenuated vaccines, inactivated virus vaccines, recombinant protein vaccines and bionic nanoparticle vaccines. In addition to traditional inactivated virus vaccines, some novel vaccines based on viral vectors, nanoscience and synthetic biology also play important roles in combating COVID-19. However, many challenges persist in ongoing clinical trials.

Clinical Efficacy of Convalescent Plasma Therapy on Treating COVID-19 Patients: Evidence from Matched Study and a Meta-Analysis (preprint)

Background: COVID-19 has infected tens of millions of people worldwide since its pandemic. CPT is one of the promising treatment methods and is favored by more and more researchers. However, the clinical efficacy and safety of CPT in COVID-19 remains unclear.Methods: We performed a matched control study by PSM analysis (including 163 cases with CPT and 163 controls with the standard treatment) and meta-analysis (including 498 cases and 557 controls) estimate the clinical efficacy and security of CPT and COVID-19, which will help inform clinical management of COVID-19 infection.Results: We found that days of hospital stay in case with CPT groups were significantly higher than matched control group (P< 0.0001). A significant reduction in mortality (OR= 0.496, 95%CI= 0.342-0.719, P< 0.0001) was found in the CPT group compared with the standard treatment group, and a true positive result was also found in sequential analysis. In terms of adverse events, sequential analysis found a false positive, although meta-analysis found a significant increase in the incidence of adverse events in patients treated with CPT compared to the control group. No differences between the two groups in terms of length of stay, improvement of clinical symptoms, and discharge were found.Conclusions: This study is the first to systematically review and meta-analysis the efficacy and safety of CPT in patients with COVID-19 in the largest sample size. Our results showed that CPT could significantly reduce the mortality rate of COVID-19 patients, and there was no significant increase in the incidence of adverse events. These data provide evidence favoring the efficacy and safety of CPT as a therapeutic agent in COVID-19 patients and provide comprehensive reference for COVID-19 treatment.Funding Statement: This work was supported by Scientific Research Project of Jiangsu Commission of Health (H2019065), Key Foundation of Wuhan Huoshenshan Hospital (2020[18]), Key Research & Development Program of Jiangsu Province (BE2018713), Medical Innovation Project of Logistics Service (18JS005).Declaration of Interests: The authors declare no conflicts of interest with this work.Ethics Approval Statement: The authors were approved by the ethics committee of Huoshenshan hospital, and were conducted in accordance with the tenets of the Declaration of Helsinki and its amendments. All participants provided written informed consent for the collection of samples and their subsequent analysis.

Aspergillus But Not Candida: Fatal Fungus Infection in COVID-19 Critical Patients (preprint)

Objectives: Earlier researches suggested patients should be routinely screened for bacteria and fungi infection after COVID-19 being confirmed. Here, we enrolled 236 patients with COVID-19 to analyze the clinical characteristics, fungal strains, mortality, and laboratory data of different groups.Design: Single center retrospective studyPatients: A total of 236 COVID-19 patients from Huoshenshan Hospital were included in this study, consisting of 14(6%) died cases, 222(94%) discharged cases.Results: The result revealed that 5 mortality in positive group were all related to aspergillus infection while candida infection rarely caused death. Aspergillus was most common in non-survivors while candida was most common in survivors. In terms of interleukin-6 (IL6), viral loads, nucleic acid clearance time, etc, fungal serologically positive group had a higher level than negative group.Conclusions: Non-survivors of Covid-19 with fungal infection were almost associated with aspergillus infection. Aspergillus infection, instead of candida infection might be fatal for critical ill patients with COVID-19. There is great significance to carry out routine screening for fungal infection especially for critical patients to enable early treatment to be implemented.Funding Statement: This study was financially supported by grants Key Foundation of Wuhan Huoshenshan Hospital (2020[18]), Key Research& Development Program of Jiangsu Province (BE2018713), Medical Innovation Project of Logistics Service (18JS005).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: This study was approved by the Medical Ethical Committee of Wuhan Huoshenshan Hospital (No. HSSLL011). Written informed consent was obtained from each patient.

Diabetes Patients of COVID-19 Infection Treated with Convalescent Plasma Transfusion in Wuhan, China (preprint)

Background: The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 had spread all over the world, causing public health emergency. Although the diagnosis for COVID-19 such as nucleic acid test and antibody detection have been well defined, there is still a big gap of knowledge regarding for COVID-19 patients receiving convalescent plasma transfusion (CPT) therapy, especially patients with comorbidity of diabetes. Method: In this study, out of 3059 COVID-19 patients admitted in Wuhan Huoshenshan Hospital of China, we described the characteristics of 39 diabetes patients receiving the transfusion of ABO-compatible convalescent plasma, and compared the baseline information and clinical outcome with that of 328 diabetes patients receiving traditional treatment. Results: It was found that the intervention of CPT therapy was effective and beneficial for COVID-19 patients, including severe or critical patients with comorbidity of diabetes, without obvious adverse effects observing during the treatments. The CPT therapy significantly improved the clinical outcome of diabetes patients with COVID-19 infection, especially the duration based on six categories compared to the patients with traditional therapy. Conclusions: This study not only provided a better understanding of COVID-19 in diabetes people receiving CPT, but also highlighted the CPT therapy was helpful for COVID-19 patients with comorbidity of diabetes.

Effect of ambient air pollutants and meteorological factors on COVID-19 transmission (preprint)

The authors have withdrawn this preprint due to author disagreement.