Safety and immunogenicity of heterologous boosting with orally aerosolised or intramuscular Ad5-nCoV vaccine and homologous boosting with inactivated vaccines (BBIBP-CorV or CoronaVac) in children and adolescents: a randomised, open-label, parallel-controlled, non-inferiority, single-centre study.

BACKGROUND: Heterologous booster immunisation with orally administered aerosolised Ad5-nCoV vaccine (AAd5) has been shown to be safe and highly immunogenic in adults. Here, we aimed to assess the safety and immunogenicity of heterologous booster immunisation with orally administered AAd5 in children and adolescents aged 6-17 years who had received two doses of inactivated vaccine (BBIBP-CorV or CoronaVac). METHODS: We did a randomised, open-label, parallel-controlled, non-inferiority study to assess the safety and immunogenicity of heterologous booster immunisation with AAd5 (0·1 mL) or intramuscular Ad5-nCoV vaccine (IMAd5; 0·3 mL) and homologous booster immunisation with inactivated vaccine (BBIBP-CorV or CoronaVac; 0·5 mL) in children (aged 6-12 years) and adolescents (aged 13-17 years) who had received two doses of inactivated vaccine at least 3 months earlier in Hunan, China. Children and adolescents who were previously immunised with two-dose BBIBP-CorV or CoronaVac were recruited for eligibility screening at least 3 months after the second dose. A stratified block method was used for randomisation, and participants were stratified by age and randomly assigned (3:1:1) to receive AAd5, IMAd5, or inactivated vaccine. The study staff and participants were not masked to treatment allocation. Laboratory and statistical staff were masked during the study. In this interim analysis, adverse events within 14 days and geometric mean titre (GMT) of serum neutralising antibodies on day 28 after the booster vaccination, based on the per-protocol population, were used as the primary outcomes. The analysis of non-inferiority was based on comparison using a one-sided 97·5% CI with a non-inferiority margin of 0·67. This study was registered at ClinicalTrials.gov, NCT05330871, and is ongoing. FINDINGS: Between April 17 and May 28, 2022, 436 participants were screened and 360 were enrolled: 220 received AAd5, 70 received IMAd5, and 70 received inactivated vaccine. Within 14 days after booster vaccination, vaccine-related adverse reactions were reported: 35 adverse events (in 13 [12%] of 110 children and 22 [20%] of 110 adolescents) in 220 individuals in the AAd5 group, 35 (in 18 [51%] of 35 children and 17 [49%] of 35 adolescents) in 70 individuals in the IMAd5 group, and 13 (in five [14%] of 35 children and eight [23%] of 35 adolescents) in 70 individuals in the inactivated vaccine group. Solicited adverse reactions were also reported: 34 (13 [12%] of 110 children and 21 [10%] of 110 adolescents) in 220 individuals in the AAd5 group, 34 (17 [49%] of 35 children and 17 [49%] of 35 adolescents) in 70 individuals in the IMAd5 group, and 12 (five [14%] of 35 children and seven [20%] of 35 adolescents) in 70 individuals in the inactivated vaccine group. The GMTs of neutralising antibodies against ancestral SARS-CoV-2 Wuhan-Hu-1 (Pango lineage B) in the AAd5 group were significantly higher than the GMTs in the inactivated vaccine group (adjusted GMT ratio 10·2 [95% CI 8·0-13·1]; p<0·0001). INTERPRETATION: Our study shows that a heterologous booster with AAd5 is safe and highly immunogenic against ancestral SARS-CoV-2 Wuhan-Hu-1 in children and adolescents. FUNDING: National Key R&D Program of China.

Impact of Divalent Metal Ions on Regulation of Trans-Cleavage Activity of CRISPR-Cas13a: A Combined Experimental and Computational Study.

CRISPR-LbuCas13a has emerged as a revolutionary tool for in vitro diagnosis. Similar to other Cas effectors, LbuCas13a requires Mg2+ to maintain its nuclease activity. However, the effect of other divalent metal ions on its trans-cleavage activity remains less explored. Herein, we addressed this issue by combining experimental and molecular dynamics simulation analysis. In vitro studies showed that both Mn2+ and Ca2+ could replace Mg2+ as cofactors of LbuCas13a. In contrast, Ni2+ , Zn2+ , Cu2+ , or Fe2+ inhibits the cis- and trans-cleavage activity, while Pb2+ does not affect it. Importantly, molecular dynamics simulations confirmed that calcium, magnesium, and manganese hydrated ions have a strong affinity to nucleotide bases, thus stabilizing the conformation of crRNA repeat region and enhancing the trans-cleavage activity. Finally, we showed that combination of Mg2+ and Mn2+ can further enhance the trans-cleavage activity to allow amplified RNA detection, revealing its potential advantage for in vitro diagnosis.

Harnessing the CRISPR-Cas13d System for Protein Detection via Dual-aptamer-based Transcription Amplification.

CRISPR-based biosensing technology has been emerging as a revolutionary diagnostics for many diseases-related biomarkers. In particular, RspCas13d, a newly identified RNA-guided Cas13d ribonuclease derived from Ruminococcus sp., has shown great promise for accurate and sensitive detection of RNA due to its RNA sequence-specific recognition and robust collateral trans-cleavage activity. However, its diagnostic utility is limited to detect nucleic-acid-related biomarkers. To address this limitation, we herein present a proof-of-concept demonstration of a target-responsive CRISPR-Cas13d sensing system for protein biomarkers. Such a system is rationally designed by integrating a Dual-Aptamer-based Transcription Amplification Strategy with CRISPR-Cas13d (DATAS-Cas13d), in which the protein binding initiates the in vitro RNA transcription followed by the activation of RspCas13d. Using a short fluorescent ssRNA as the signal reporter and cardiac troponin I (cTnI) as the model analyte, the DATAS-Cas13d system showed a wide linear range, low detection limit and high specificity for the detection of cTnI in buffer and human serum. Thanks to the facile integration of various bioreceptors into the DATAS-Cas13d system, the method could be adapted to detecting a broad range of clinically relevant protein biomarkers, and thus broaden the medical applications of Cas13d-based diagnostics.

COVID-19 and liver dysfunction in children: Current views and new hypotheses.

Coronavirus disease 2019 (COVID-19) poses an extremely serious global impact on public healthcare for individuals of all ages, including children. Increasing evidence has shown that liver abnormalities are commonly found in children with COVID-19, and age-related features in innate and adaptive response have been demonstrated. However, there are few reports and studies on COVID-19 related liver injury in children, and the data are scattered. So that many contradictions have arose. This situation is not only due to the serious ethical issues in studying pediatric patients with COVID-19, but also because of the short duration and wide coverage of the COVID-19 epidemic, the severity and complexity of clinical cases varied, as did the inclusion criteria for case reporting and patient outcomes. Therefore, we totaled the incidences, characteristics and pathomechanism of liver injury in children since the COVID-19 outbreak. The etiology of COVID-19-related liver injury is divided into three categories: (1) The direct mechanism involves severe acute respiratory syndrome coronavirus 2 binding to angiotensin-converting enzyme 2 in the liver or bile duct to exert direct toxicity; (2) the indirect mechanisms include an inflammatory immune response and hypoxia; and (3) COVID-19-related treatments, such as mechanical ventilation and antiviral drugs, may cause liver injury. In summary, this minireview provides fundamental insights into COVID-19 and liver dysfunction in children.

Dynamic lead–lag relationship between Chinese carbon emission trading and stock markets under exogenous shocks

Using the non-parametric thermal optimal path method, we investigate the dynamic lead–lag relationship between carbon emission trading and stock markets in China, and further consider the impact of different types of exogenous shocks on the lead–lag relationship. The empirical results show that the stock market leads the carbon market on most trading days, and the relationship reverses when the mean values of carbon market return are significantly smaller than zero. In addition, the lead–lag relationships when the carbon market leads the high energy-consuming stock market sectors are more obvious. We also find that there exist significant heterogeneous effects of different types of exogenous shocks on the lead–lag relationship between the two markets, including government policy, the Sino-US trade war and the Covid-19 outbreak. These findings have the potential to help regulators understand the interrelationship between components of the financial market, and be of great value for investors to optimize portfolio allocation by incorporating carbon assets into the portfolio.

Dynamic characteristics of a COVID-19 outbreak in Nanjing, Jiangsu province, China.

Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage B.1.617.2 (also named the Delta variant) was declared as a variant of concern by the World Health Organization (WHO). This study aimed to describe the outbreak that occurred in Nanjing city triggered by the Delta variant through the epidemiological parameters and to understand the evolving epidemiology of the Delta variant. Methods: We collected the data of all COVID-19 cases during the outbreak from 20 July 2021 to 24 August 2021 and estimated the distribution of serial interval, basic and time-dependent reproduction numbers (R0 and Rt), and household secondary attack rate (SAR). We also analyzed the cycle threshold (Ct) values of infections. Results: A total of 235 cases have been confirmed. The mean value of serial interval was estimated to be 4.79 days with the Weibull distribution. The R0 was 3.73 [95% confidence interval (CI), 2.66-5.15] as estimated by the exponential growth (EG) method. The Rt decreased from 4.36 on 20 July 2021 to below 1 on 1 August 2021 as estimated by the Bayesian approach. We estimated the household SAR as 27.35% (95% CI, 22.04-33.39%), and the median Ct value of open reading frame 1ab (ORF1ab) genes and nucleocapsid protein (N) genes as 25.25 [interquartile range (IQR), 20.53-29.50] and 23.85 (IQR, 18.70-28.70), respectively. Conclusions: The Delta variant is more aggressive and transmissible than the original virus types, so continuous non-pharmaceutical interventions are still needed.

Dynamic characteristics of a COVID-19 outbreak in Nanjing, Jiangsu province, China

Objectives Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage B.1.617.2 (also named the Delta variant) was declared as a variant of concern by the World Health Organization (WHO). This study aimed to describe the outbreak that occurred in Nanjing city triggered by the Delta variant through the epidemiological parameters and to understand the evolving epidemiology of the Delta variant. Methods We collected the data of all COVID-19 cases during the outbreak from 20 July 2021 to 24 August 2021 and estimated the distribution of serial interval, basic and time-dependent reproduction numbers (R0 and Rt), and household secondary attack rate (SAR). We also analyzed the cycle threshold (Ct) values of infections. Results A total of 235 cases have been confirmed. The mean value of serial interval was estimated to be 4.79 days with the Weibull distribution. The R0 was 3.73 [95% confidence interval (CI), 2.66–5.15] as estimated by the exponential growth (EG) method. The Rt decreased from 4.36 on 20 July 2021 to below 1 on 1 August 2021 as estimated by the Bayesian approach. We estimated the household SAR as 27.35% (95% CI, 22.04–33.39%), and the median Ct value of open reading frame 1ab (ORF1ab) genes and nucleocapsid protein (N) genes as 25.25 [interquartile range (IQR), 20.53–29.50] and 23.85 (IQR, 18.70–28.70), respectively. Conclusions The Delta variant is more aggressive and transmissible than the original virus types, so continuous non-pharmaceutical interventions are still needed.

Feasibility analysis and mechanism exploration of Rhei Radix et Rhizome-Schisandrae Sphenantherae Fructus (RS) against COVID-19.

Introduction. As a novel global epidemic, corona virus disease 2019 (COVID-19) caused by SARS-CoV-2 brought great suffering and disaster to mankind. Recently, although significant progress has been made in vaccines against SARS-CoV-2, there are still no drugs for treating COVID-19. It is well known that traditional Chinese medicine (TCM) has achieved excellent efficacy in the treatment of COVID-19 in China. As a treasure-house of natural drugs, Chinese herbs offer a promising prospect for discovering anti-COVID-19 drugs.Hypothesis/Gap Statement. We proposed that Rhei Radix et Rhizome-Schisandrae Sphenantherae Fructus (RS) may have potential value in the treatment of COVID-19 patients by regulating immune response, protecting the cardiovascular system, inhibiting the production of inflammatory factors, and blocking virus invasion and replication processes.Aim. We aimed to explore the feasibility and molecular mechanisms of RS against COVID-19, to provide a reference for basic research and clinical applications.Methodology. Through literature mining, it is found that a Chinese herbal pair, RS, has potential anti-COVID-19 activity. In this study, we analysed the feasibility of RS against COVID-19 by high-throughput molecular docking and molecular dynamics simulations. Furthermore, we predicted the molecular mechanisms of RS against COVID-19 based on network pharmacology.Results. We proved the feasibility of RS anti-COVID-19 by literature mining, virtual docking and molecular dynamics simulations, and found that angiotensin converting enzyme 2 (ACE2) and 3C-like protease (3 CL pro) were also two critical targets for RS against COVID-19. In addition, we predicted the molecular mechanisms of RS in the treatment of COVID-19, and identified 29 main ingredients, 21 potential targets and 16 signalling pathways. Rhein, eupatin, (-)-catechin, aloe-emodin may be important active ingredients in RS. ALB, ESR1, EGFR, HMOX1, CTSL, and RHOA may be important targets against COVID-19. Platelet activation, renin secretion, ras signalling pathway, chemokine signalling pathway, and human cytomegalovirus infection may be important signalling pathways against COVID-19.Conclusion. RS plays a key role in the treatment of COVID-19, which may be closely related to immune regulation, cardiovascular protection, anti-inflammation, virus invasion and replication processes.

Advances in treatment of COVID-19

The novel coronavirus pneumonia is an acute infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The global pandemic of this novel coronavirus pneumonia has greatly threatened human health and brought enormous economy losses. By the end of May 20, 2020, the pandemic of this disease had caused more than 2.70 million infections and more than 320 thousand deaths. This paper reviewed the recent advances in the treatment of the novel coronavirus pneumonia to provide basic references for disease control.

Clinical significance of detection of SARS-CoV-2 nucleic acid in patients with COVID-19

Objective: To investigate the significance of the detection results of different types of samples in the clinical diagnosis and treatment of new coronavirus pneumonia (COVID-19) and the prevention and control of epidemic situation.

Current trends and future prediction of novel coronavirus disease (COVID-19) epidemic in China: a dynamical modeling analysis.

The novel coronavirus disease 2019 (COVID-19) infection broke out in December 2019 in Wuhan, and rapidly overspread 31 provinces in mainland China on 31 January 2020. In the face of the increasing number of daily confirmed infected cases, it has become a common concern and worthy of pondering when the infection will appear the turning points, what is the final size and when the infection would be ultimately controlled. Based on the current control measures, we proposed a dynamical transmission model with contact trace and quarantine and predicted the peak time and final size for daily confirmed infected cases by employing Markov Chain Monte Carlo algorithm. We estimate the basic reproductive number of COVID-19 is 5.78 (95%CI: 5.71-5.89). Under the current intervention before 31 January, the number of daily confirmed infected cases is expected to peak on around 11 February 2020 with the size of 4066 (95%CI: 3898-4472). The infection of COVID-19 might be controlled approximately after 18 May 2020. Reducing contact and increasing trace about the risk population are likely to be the present effective measures.