Bidirectional causal relationships between IgA nephropathy and COVID-19: genetic evidence from Mendelian randomization (preprint)

Purpose Previous studies have suggested that patients with IgA nephropathy (IgAN) was associated with an increased risk of coronavirus disease 2019 (COVID-19) infection. However, the findings were inconsistent, and whether there was a causality between IgAN and COVID-19 infection remains unknown. This study was performed to estimate the casual effect between IgAN and COVID-19 infection with the implementation of bidirectional Mendelian randomization (MR) analysis.Methods Genetic summary data of IgAN was derived from a large genome-wide association study (GWAS) that consisted of 14,361 cases and 43,923 controls. The genetic data of COVID-19 comprised of three phenotypes, including hospitalization, severity and infection, which had a population more than 20 million. The methods of inverse variance weighting (IVW), MR-Egger, weight median and weighted mode were applied for causal inference in MR analysis.Results In the forward direction, the IVW’s results proved that IgAN did not have causal relationships with hospitalization COVID-19 (OR = 1.077, 95%CI: 0.953–1.217, P = 0.236), severe COVID-19 (OR = 1.059, 95%CI: 0.878–1.278, P = 0.547) and COVID-19 infection (OR = 0.973, 95%CI: 0.929–1.109, P = 0.243). Furthermore, reverse MR analysis showed no evidence of causal associations of hospitalization COVID-19 (OR = 1.017, 95%CI: 0.968–1.069, P = 0.499), severe COVID-19 (OR = 1.005, 95%CI: 0.979–1.078, P = 0.781) and COVID-19 infection (OR = 1.030, 95%CI: 0.909–1.169, P = 0.641) with the risk of IgAN.Conclusion Our study does not support a casual association of IgAN with the risk of COVID-19 infection, nor does the causality between COVID-19 infection and IgAN risk.

Modeling and optimization of triclosan biodegradation by the newly isolated Bacillus sp. DL4: Kinetics and metagenomics analysis (preprint)

Overusing triclosan (TCS) endangered ecological safety and human health, and the pandemic of COVID-19 aggravates the accumulation of TCS in the aquatic environment. Therefore, reducing residual TCS concentrations in the environment is an urgent issue. An aerobic bacterium, Bacillus sp. DL4 was isolated with the capability of TCS biodegradation. Response surface methodology (RSM) and artificial neural network (ANN) were carried out to optimize and verify the different condition variables. All the variables were linear and the interaction of the three factors significantly affected TCS removal at the quadratic level (p < 0.001). Under the optimal conditions (35℃, initial pH 7.31, and 5% strain DL4), the TCS removal rate of 95.89 ± 0.68% was observed and found to be consistent with the predicted values from RSM and ANN models. In addition, statistical comparisons between the models indicated that the ANN model had a stronger predictive capability than the RSM model. Kinetic studies showed that TCS degradation was consistent with a pseudo-first-order kinetic model. Whole genome sequencing indicated that many functional genes were involved in and facilitated TCS degradation. Main metabolite products were detected and identified during the biodegradation process by LC-MS, and a possible degradation pathway was tentatively hypothesized. Overall, this study provides a theoretical foundation for the characterization and mechanism of TCS biodegradation in the environment by Bacillus sp. DL4.

A loop-mediated isothermal amplification-enabled analytical assay for the detection of SARS-CoV-2: A review

The number of words: 4645, the number of figures: 4, the number of tables: 1The outbreak of COVID-19 in December 2019 caused a global pandemic of acute respiratory disease, and with the increasing virulence of mutant strains and the number of confirmed cases, this has resulted in a tremendous threat to global public health. Therefore, an accurate diagnosis of COVID-19 is urgently needed for rapid control of SARS-CoV-2 transmission. As a new molecular biology technology, loop-mediated isothermal amplification (LAMP) has the advantages of convenient operation, speed, low cost and high sensitivity and specificity. In the past two years, rampant COVID-19 and the continuous variation in the virus strains have demanded higher requirements for the rapid detection of pathogens. Compared with conventional RT–PCR and real-time RT–PCR methods, genotyping RT-LAMP method and LAMP plus peptide nucleic acid (PNA) probe detection methods have been developed to correctly identified SARS-CoV-2 variants, which is also why LAMP technology has attracted much attention. LAMP detection technology combined with lateral flow assay, microfluidic technology and other sensing technologies can effectively enhance signals by nucleic acid amplification and help to give the resulting output in a faster, more convenient and user-friendly way. At present, LAMP plays an important role in the detection of SARS-CoV-2.

Pilot genome-wide association study of antibody response to inactivated SARS-CoV-2 vaccines

Vaccines are a key weapon against the COVID-19 pandemic caused by SARS-CoV-2. However, there are inter-individual differences in immune response to SARS-CoV-2 vaccines and genetic contributions to these differences have barely been investigated. Here, we performed genome-wide association study (GWAS) of antibody levels in 168 inactivated SARS-CoV-2 vaccine recipients. A total of 177 SNPs, corresponding to 41 independent loci, were identified to be associated with IgG, total antibodies or neutral antibodies. Specifically, the rs4543780, the intronic variant of FAM89A gene, was associated with total antibodies level and was annotated as a potential regulatory variant affecting gene expression of FAM89A, a biomarker differentiating bacterial from viral infections in febrile children. These findings might advance our knowledge of the molecular mechanisms driving immunity to SARS-CoV-2 vaccine.

Lymphocyte-C-reactive protein ratio can differentiate disease severity of COVID-19 patients and serve as an assistant screening tool for hospital and ICU admission (preprint)

In this study, we aimed to explore whether Lymphocyte-C-reactive protein ratio (LCR) can differentiate disease severity of Coronavirus disease 2019 (COVID-19) patients and its value as an assistant screening tool for admission to the hospital and the intensive care unit (ICU). A total of 184 adult COVID-19 patients from the COVID-19 Treatment Center in Heilongjiang Province at the First Affiliated Hospital of Harbin Medical University between January 2020 and March 2021 were included in this study. Patients were divided into asymptomatic infection group, mild group, moderate group, severe group, and critical group according to the Diagnosis and Treatment of New Coronavirus Pneumonia (9th edition). Demographic and clinical data including gender, age, comorbidities, severity of COVID-19, white blood cell count (WBC), neutrophil proportion (NEUT%), lymphocyte count (LYMPH), lymphocyte percentage (LYM%), red blood cell distribution width (RDW), platelet (PLT), C-reaction protein (CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (SCr), albumin (ALB), total bilirubin (TB), direct bilirubin (DBIL), indirect bilirubin (IBIL), and D-Dimer were obtained and collated from medical records at admission, from which sequential organ failure assessment (SOFA) score and LCR were calculated, and all above indicators were compared among groups. Multiple clinical parameters, including LYMPH, CRP and LCR, showed significant differences among groups. The related factors to classify COVID-19 patients into moderate, severe and critical groups included age, number of comorbidities, WBC, LCR, and AST. Among these factors, number of comorbidities showed the greatest effect, and only WBC and LCR were protective factors. The area under the receiver operating characteristic (ROC) curve of LCR to classify COVID-19 patients into moderate, severe and critical groups was 0.176. The cut-off value of LCR, and the sensitivity and specificity of ROC curve were 1780.7050, 84.6% and 66.2%, respectively. The related factors to classify COVID-19 patients into severe and critical groups included number of comorbidities, PLT, LCR, and SOFA score. Among these factors, SOFA score showed the greatest effect, and LCR was the only protective factor. The area under ROC curve of LCR to classify COVID-19 patients into severe and critical groups was 0.106. The cut-off value of LCR and the sensitivity and specificity of ROC curve were 571.2200, 81.3% and 90.0%, respectively. In summary, LCR can differentiate disease severity of COVID-19 patients and serve as a simple and objective assistant screening tool for hospital and ICU admission.

Contribution of low population immunity to the severe Omicron BA.2 outbreak in Hong Kong (preprint)

Monitoring population protective immunity against SARS-CoV-2 variants is critical for risk assessment. In this serosurveillance study, older adults show much lower seropositive rates of neutralizing antibody (NAb) against ancestral virus than the younger population. The increase in NAb seopositive rate generally follows the population vaccination uptake rate, but older adults have a much lower NAb seropositive rate than vaccination uptake rate. For all age groups, the seropositive rates of NAb against Omicron variant are much lower than those against the ancestral virus. During the fifth wave of COVID-19 in Hong Kong which is dominated by Omicron sublineage BA.2, the case-fatality rate is exceptionally high in the ≥80 year-old age group (9.2%). Our study suggests that the severe BA.2 outbreak in Hong Kong can be attributed by the lack of protective immunity in the population, especially among the vulnerable older adults, and highlights the importance of continual surveillance of protective immunity against emerging variants of SARS-CoV-2.

Infection mechanism of SARS-CoV-2 and its control of transmission route

SARS-CoV-2 virus is the pathogen of COVID-19, its intermediate host, infection mechanism and transmission route need to be further studied and verified. In this study, we analyzed the mechanism of SARS-Co V-2 infecting the host, discussed the infection path and infection media of SARS-CoV-2, and put forward effective measures to control the spread of SARS-CoV-2, and we took the first unknown pneumonia case received by Doctor Zhang Jixian, a director of the Department of Infectious Diseases of Hubei Provincial Hospital of Chinese& Western Medicine as an example, illustrating how to carry out professional medical treatment and control according to professional regulations and laws and regulations, which we try to provide scientific basis for effectively controlling the virus transmission and spread of infectious diseases and quickly placing it under the control of the government and health institutions.

Respiratory rehabilitation program (draft) of integrated traditional Chinese and western medicine for novel Coronavirus pneumonia (COVID-19)

Since December 2019, a number of cases of pneumonia with unexplained reasons have been reported in Wuhan, Hubei Province, and a large number of cases have been infected. National Health Commission of the People's Republic of China has named it novel coronavirus pneumonia (COVID-19). With the strengthening of prevention and control forces, the number of mild patients in mobile cabin hospital has increased and a large number of patients have been cured and discharged from the hospital. The rehabilitation program of integrated traditional Chinese and Western medicine needs to be formulated and implemented urgently. Therefore, according to treatment protocols issued by National Health Commission of the People's Republic of China and relevant institutes, and widely discussion of relevant experts of pulmonary rehabilitation, TCM and nutrition, Respiratory Rehabilitation Program (Draft) of Integrated Traditional Chinese and Western Medicine for COVID-19 was compiled, in order to play a positive role in the follow-up epidemic prevention and control.

Laboratory parameters between multisystem inflammatory syndrome in children and Kawasaki disease (preprint)

Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) has been described to partially overlap with Kawasaki disease (KD) with regard to clinical symptoms, but they are unlikely to share the same disease entity. We conducted a systematic review and meta-analysis to characterize the laboratory parameters of MIS-C compared with those of KD and Kawasaki disease shock syndrome (KDSS). Databases were searched for studies on laboratory parameters of MIS-C (hematology, inflammatory markers, cardiac markers and biochemistry) through May 31, 2021. Twelve studies with 3073 participants yielded 969 MIS-C patients. In terms of hematology, MIS-C patients had lower levels of leukocytes, absolute lymphocyte count and platelet count (PLT) than KD patients and had similar absolute neutrophil count (ANC) and hemoglobin (Hb) levels. In terms of inflammatory markers, MIS-C patients had higher levels of C-reactive protein, D-dimer and ferritin than KD patients and had similar levels of procalcitonin and ESR. In terms of cardiac markers, MIS-C patients had higher CPK levels than KD patients. The levels of NT-proBNP, troponin and AST were not significantly different between MIS-C and KD patients. In terms of biochemistry, MIS-C patients had lower levels of albumin, sodium and ALT and higher levels of creatinine than KD patients. In addition, MIS-C patients had lower levels of PLT, Hb and ESR and higher levels of ANC than KDSS patients. Measurement of laboratory parameters might assist clinicians with accurate evaluation of MIS-C and further mechanistic research.

Analysis of s gene and protein structure difference between porcine coronavirus and SARS-CoV-2

The pandemic of COVID-19 (Corona virus disease 2019) caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) poses a huge threat to human health worldwide since December 2019. In order to study the correlation betweenSARS-CoV-2 and porcine coronavirus, the phylogenetic analysis of spike (S) protein amino acid sequence of human coronavirusand porcine coronavirus, the similarity analysis of the spatial structure of S1 subunit receptor binding domain (RBD) of S proteinwere conducted by bioinformatics analysis, moreover, the double- antigen sandwich ELISA kit was utilized to detect the SARSCoV-2 antibody in common porcine coronavirus positive serum. The results of phylogenetic analysis showed a low identity of Sprotein amino acid sequence between SARS-CoV-2 and porcine coronavirus, indicating a long distance of genetic evolution, andthe S1 subunit RBD spatial structure showed huge differences, meanwhile, all of the porcine coronavirus positive serum samplestested were negative of SARS-CoV-2 antibody. Our data suggested the huge differences in gene and protein level between SARS-CoV-2 and porcine coronavirus, which indicating that SARS-CoV-2 shows a minimal risk of achieving cross-species transmission byinfecting pigs to threaten public health security. This research provides a basis for studying COVID-19 pathogen traceability andbiosafety analysis of cross-species transmission.

The Inflammatory Markers of Multisystem Inflammatory Syndrome in children (MIS-C) and Adolescents During the COVID-19 Pandemic: A Meta-Analysis (preprint)

As per the indicated need in literature, we conducted a systematic review and meta-analysis to characterize inflammatory markers of MIS-C patients with COVID-19, Kawasaki disease (KD), and coronary artery abnormalities. We searched nine databases for studies on inflammatory markers of MIS-C. After quality check, data were pooled using a fixed- or random-effects model. Inflammatory markers included white blood cell count (WBC) or leukocytes, absolute lymphocyte count (ALC), absolute neutrophil count (ANC), platelet count (PLT), C-reactive protein (CRP), procalcitonin (PCT), ferritin, D-dimer, lactate dehydrogenase (LDH), fibrinogen and erythrocyte sedimentation rate (ESR) for comparisons by severity and age. Twenty studies with 2,990 participants yielded 684 MIS-C patients. Compared to non-severe COVID-19 patients, MIS-C patients had lower ALC and higher ANC, CRP and D-dimer levels. Compared to severe COVID-19 patients, MIS-C patients had lower LDH and PLT counts and higher ESR levels. Compared to KD patients, MIS-C patients had lower ALC and PLT, and higher CRP and ferritin levels. Severe MIS-C patients had higher levels of WBC, CRP, D-dimer and ferritin. For MIS-C, younger children had lower CRP and ferritin levels than medium-aged/older children. Measurement of inflammatory markers might assist clinicians in accurate evaluation and diagnosis of MIS-C and the associated disorders.

CD127 imprints functional heterogeneity to diversify monocyte responses in human inflammatory diseases (preprint)

Studies on human monocytes historically focused on characterization of bulk responses, whereas functional heterogeneity is largely unknown. Here, we identified an inducible population of CD127-expressing human monocytes under inflammatory conditions and named the subset M127. M127 is nearly absent in healthy individuals yet abundantly present in patients with infectious and inflammatory conditions such as COVID-19 and rheumatoid arthritis. Multiple genomic and functional approaches revealed unique gene signatures of M127 and unified anti-inflammatory properties imposed by the CD127-STAT5 axis. M127 expansion correlated with mild COVID-19 disease outcomes. Thereby, we phenotypically and molecularly characterized a human monocyte subset marked by CD127 that retained anti-inflammatory properties within the pro-inflammatory environments, uncovering remarkable functional diversity among monocytes and signifying M127 as a potential therapeutic target for human inflammatory disorders.

The hydroalcoholic extract of Uncaria tomentosa (Cat's claw) inhibits the replication of novel coronavirus (SARS-CoV-2) in vitro (preprint)

The coronavirus disease 2019 (COVID-19) has become a serious problem for public health since it was identified in the province of Wuhan (China) and spread around the world producing high mortality rates and economic losses. Nowadays, WHO recognizes traditional, complementary, and alternative medicine for treating COVID-19 symptoms. Therefore, we investigated the antiviral potential of the hydroalcoholic extract of Uncaria tomentosa stem bark from Peru against SARS-CoV-2 in vitro. The antiviral activity of U. tomentosa against SARS-CoV-2 in vitro was assessed in Vero E6 cells using cytopathic effect (CPE) and plaque reduction assay. After 48h of treatment, U. tomentosa showed an inhibition of 92.7 % of SARS-CoV-2 at 25.0 g/mL (p<0.0001) by plaque reduction assay on Vero E6 cells. In addition, U. tomentosa, induced a reduction of 98.6 % (p=0.02) and 92.7 % (p=0.03) in the CPE caused by SARS-CoV-2 on Vero E6 cells at 25 g/mL and 12.5 g/mL, respectively. The EC50 calculated for U. tomentosa extract by plaque reduction assay was 6.6 g/mL (4.89 - 8.85 g/mL) for a selectivity index of 4.1. The EC50 calculated for U. tomentosa extract by TCID50 assay was 2.57 g/mL (1.05 - 3.75 g/mL) for a selectivity index of 10.54. These results showed thatU. tomentosa known as Cat's claw has antiviral effect against SARS-CoV-2 observed as a reduction in the viral titer and CPE after 48h of treatment on Vero E6 cells. Therefore, we hypothesized that U. tomentosa stem bark, could be promissory to the development of new therapeutic strategies against SARS-CoV-2.

Protective efficacy of a SARS-CoV-2 DNA Vaccine in wild-type and immunosuppressed Syrian hamsters (preprint)

A worldwide effort to counter the COVID-19 pandemic has resulted in hundreds of candidate vaccines moving through various stages of research and development, including several vaccines in phase 1, 2 and 3 clinical trials. A relatively small number of these vaccines have been evaluated in SARS-CoV-2 disease models, and fewer in a severe disease model. Here, a SARS-CoV-2 DNA targeting the spike protein and delivered by jet injection, nCoV-S(JET), elicited neutralizing antibodies in hamsters and was protective in both wild-type and transiently immunosuppressed hamster models. This study highlights the DNA vaccine, nCoV-S(JET), we developed has a great potential to move to next stage of preclinical studies, and it also demonstrates that the transiently-immunosuppressed Syrian hamsters, which recapitulate severe and prolonged COVID-19 disease, can be used for preclinical evaluation of the protective efficacy of spike-based COVID-19 vaccine.

The Strand-biased Transcription of SARS-CoV-2 and Unbalanced Inhibition by Remdesivir (preprint)

SARS-CoV-2, a positive single-stranded RNA virus, caused the COVID-19 pandemic. Although its sense-mRNA architecture was reported, its anti-sense strand was unexplored. Here, we deeply sequenced both strands of RNA and found SARS-CoV-2 transcription is strongly biased to form the sense strand. During negative strand synthesis, apart from canonical sub-genomic ORFs, numerous non-canonical fusion transcripts are formed, driven by 3-15 nt sequence homology scattered along the genome but more prone to be inhibited by SARS-CoV-2 RNA polymerase inhibitor Remdesivir. The drug also represses more of the negative than the positive strand synthesis as supported by a mathematic simulation model and experimental quantifications. Overall, this study opens new sights into SARS-CoV-2 biogenesis and may facilitate the anti-viral drug design.

Risk Factors Related to Weight Gain for Chines During Home Confinement in COVID-19 Pandemic: An Observational Retrospective Study (preprint)

Objective: The observational study was intended to explore the weight changes and risk factors of weight gain during the self-quarantine and find available methods to lose weight. Method: This was an online retrospective observational study investigating the weight changes before and after home confinement. A total of 530 participants completed the online questionnaire. diet, sleep, self-reported depression, disease history and exercise information possibly relating to weight changes were incorporated into the questionnaire. The differences among four groups (underweight, normal weight, overweight and obesity) in BMI change and weight change were compared, and the risk factors of weight gain was also analyzed by multiple linear regression analysis. Result: Participants were mostly between 21-50 years old, getting an average weight change of 0.82±3.31kg, and an average BMI change of 0.35 [-0.37, 1.00]. 43.77% of them gained weight by 2.99±2.29kg averagely. People with normal weight were easier to gain weight than obese group (p=0.001). There were differences in food intake (p<0.001), eating habits(p<0.001), taste preference (p=0.047), daily exercise step change(p=0.007), exercise (p=0.02) between non-weight gain group and weight gain group. The multiple linear regression revealed that weight gains were associated with sex (p=0.002), food intake (p=0.004), current daily exercise step (p=0.009) and self-reported depression (p=0.002) and weight loss was related to food intake (p=0.004) and pre-BMI (p=0.001). Conclusion: Eating irregularly, increasing food intake, self-reported depression and decreased daily steps were risk factors of weight gain, yet weight loss was related to decreased food intake and pre-BMI.

ACE2 Protein-Protein Interaction Networks Reveal Potential Druggable Targets For SARS-CoV-2 (preprint)

Background: The novel coronavirus SARS-CoV-2 pandemic has infected more than 130 million people, killed over 2.3 million so far. Currently, no effective drugs are available to treat this infectious disease, due to limited knowledge of the molecular mechanisms of SARS-CoV-2 infection. ACE2 (angiotensin I converting enzyme 2) has long been identified as the major receptor for coronavirus entry the host cells. Methods: In this study, we constructed the protein-protein interaction networks (PPIN) based on ACE2 and its interacting proteins, considering with the expression alternation and co-expression relationship. The potential drugs targeting the proteins in the PPIN were explored.Results: ACE2 and its interacting proteins AAMP and HRAS are obviously increased, and their PPIN show distinguishing expression patterns during the COVID-19 progression. At least six pathways are activated for the host cell in the response to the virus. Moreover, drug-target networks were built to provide important clues to block ACE2 and its interacting proteins. Except the reported four drugs for ACE2, its interacting protein CALM1 and HRAS are great potentially druggable. We also considered the path initiated from ACE2 to nucleus by cascades of interaction, especially for the transcription factors in the PPIN which are also druggable.Conclusion: In summary, this study provides new insight into the disruption of the biological response to virus mediated by ACE2, but also its cascade interacting proteins when considering of PPIN.

The effectiveness of antiviral treatment in severe COVID-19 patients in Wuhan: a retrospective cohort study (preprint)

Background Since the outbreak of COVID-19, the application of appropriate treatment strategy for COVID-19 patients, notably for the severe patients, was a huge challenge in case management. Therefore, we aimed to evaluate the effectiveness of antiviral treatment in severe COVID-19 patients.Methods A retrospective cohort study was conducted from January 8, 2020 to March 9, 2020 in four designated hospitals of COVID-19 in Wuhan, China. 138 severe COVID-19patients with above 18 years were included in this study. 109 patients receiving the antiviral treatment were selected in antiviral group. The remaining 29 patients were in control group. The primary outcome of the study was in-hospital death and length of hospitalization. Secondary outcomes included ICU admission, length of stays in ICU, use of mechanical ventilation, length of mechanical ventilation, and the development of complications. Univariate analysis and Kaplan-Meier curves were used to examined the association between antiviral treatment and the clinical outcomes of the COVID-19 patients.Results 48 (44.0%) and 15 (51.7%) deaths were occurred in antiviral and control groups, respectively. Antiviral treatment was not associated with the rate of fatal outcome in COVID-19 patients (P > 0.05). Among the survival patients, the median length of hospitalization was 11.0 days (IQR: 6.5–18.0) and 16.0 days (IQR: 8.5–26.0) in antiviral and control groups, respectively. No significant association was identified between the antiviral treatment and the length of hospitalization in survival patients (P > 0.05). Moreover, the antiviral treatment was not statistically associated with ICU admission, mechanical ventilation and length of mechanical ventilation (P > 0.05, respectively). However, the length of ICU stays in deaths was different both groups (P < 0.05). The median length of ICU stays in deaths was 7.0 days (IQR: 3.0-14.3) and 15.5 days (IQR: 8.3–21.8) in antiviral and control groups, respectively. The occurrence of majority of complications were similar both groups. Sepsis was the single complication in which the occurrence rates were statistical different between the antiviral group and control group (40.4% vs 13.8%, P < 0.01).Conclusion No benefit of antiviral treatment in severe COVID-19 patients was observed in our study. Clinical physicians should cautiously prescribe the antiviral drugs in severe COVID-19 patients.