Evaluation of efficacy and safety of Qiangzhu-qinggan formula as an adjunctive therapy in adult patients with severe influenza: study protocol for a randomized parallel placebo-controlled double-blind multicenter trial.

BACKGROUND: Influenza can fall into three categories according to severity: mild influenza, severe influenza, and critical influenza. Severe influenza can result in critical illness and sometimes death particularly in patients with comorbidities, advanced age, or pregnancy. Neuraminidase inhibitors (NAIs) are the only antiviral drugs in widespread use for influenza. However, the effectiveness of NAIs against severe influenza is uncertain. New effective drugs or regimens are therefore urgently needed. Qiangzhu-qinggan (QZQG) formula has been found to be effective against influenza virus infection during long-term application in China, which lacks support of evidence-based clinical trial till now. This study is designed to assess the efficacy and safety of QZQG formula as an adjuvant therapy in adult patients with severe influenza. METHODS: This protocol is drawn up in accordance with the SPIRIT guidelines and CONSORT Extension for Chinese herbal medicine formulas. This is a randomized, placebo-controlled, double-blind, multicenter trial. Two hundred twenty-eight adults with severe influenza are randomly assigned in a 1:1 ratio to QZQG or placebo for 7 days. All participants need to receive 1 day of screening before randomization, 7 days of intervention, and 21 days of observation after randomization. The primary outcome is the proportion of clinical improvement, defined as the proportion of patients who met the criteria of 3 points or less in the seven-category ordinal scale or 2 points or less in National Early Warning Score 2 within 7 days after randomization. DISCUSSION: This is the first randomized, controlled, parallel, double-blind clinical trial to evaluate the efficacy and safety of traditional Chinese herbal formula granules as an adjuvant therapy in adult patients with severe influenza. This study aims to redefine the value of traditional Chinese herbal medicines in the treatment of virus-related respiratory infectious diseases and serves as an example of evidence-based clinical trials of other Chinese herbal medicines.

Hesitancy to Undergo SARS-CoV-2 Rapid Antigen Testing in China: Nationwide Cross-sectional Study.

BACKGROUND: SARS-CoV-2 rapid antigen testing (RAT) could be a useful supplementary test to diagnose larger numbers of acute asymptomatic infections and alleviate the limitations of polymerase chain reaction testing. However, hesitancy to undergo SARS-CoV-2 RAT may compromise its implementation. OBJECTIVE: We aimed to understand the prevalence and correlates of hesitancy to undergo RAT among adults not infected with SARS-CoV-2 in mainland China. METHODS: A nationwide cross-sectional survey on hesitancy to undergo SARS-CoV-2 RAT was conducted among adults not infected with SARS-CoV-2 in mainland China between April 29, 2022, and May 10, 2022. Participants completed an online questionnaire that covered the following COVID-19-related factors: sociodemographic characteristics, experiences of COVID-19 restrictions and knowledge of COVID-19, and attitude toward COVID-19 and its screening. This study was a secondary analysis of data from the survey. We compared the characteristics of participants by hesitancy to undergo SARS-CoV-2 RAT. Thereafter, logistic regression with a sparse group minimax concave penalty was used to identify correlates of hesitancy to undergo RAT. RESULTS: We recruited 8856 individuals with diverse demographic, socioeconomic, and geographic characteristics in China. Eventually, 5388 participants (valid response rate of 60.84%; 52.32% [2819/5388] women; median age 32 years) were included in the analysis. Among the 5388 participants, 687 (12.75%) expressed hesitancy to undergo RAT and 4701 (87.25%) were willing to undergo RAT. Notably, those who were from the central region (adjusted odds ratio [aOR] 1.815, 95% CI 1.441-2.278) and those who received COVID-19 information from traditional media (aOR 1.544, 95% CI 1.279-1.863) were significantly more likely to report hesitancy to undergo RAT (both P<.001). However, those who were women (aOR 0.720, 95% CI 0.599-0.864), were older (aOR 0.982, 95% CI 0.969-0.995), had postgraduate education (aOR 0.612, 95% CI 0.435-0.858), had children (<6 years old) and elders (>60 years old) in the family (aOR 0.685, 95% CI 0.510-0.911), had better knowledge about COVID-19 (aOR 0.942, 95% CI 0.916-0.970), and had mental health disorders (aOR 0.795, 95% CI 0.646-0.975) were less likely to report hesitancy to undergo RAT. CONCLUSIONS: Hesitancy to undergo SARS-CoV-2 RAT was low among individuals who were not yet infected with SARS-CoV-2. Efforts should be made to improve the awareness and acceptance of RAT among men, younger adults, individuals with a lower education or salary, families without children and elders, and individuals who access COVID-19 information via traditional media. In a reopening world, our study could inform the development of contextualized mass screening strategies in general and the scale-up of RAT in particular, which remains an indispensable option in emergency preparedness.

Impact of combination preventative interventions on hospitalization and death under the pandemic of SARS-CoV-2 Omicron variant in China.

With a large population most susceptible to Omicron and emerging SARS-CoV-2 variants, China faces uncertain scenarios if reopening its border. Thus, we aimed to predict the impact of combination preventative interventions on hospitalization and death. An age-stratified susceptible-infectious-quarantined-hospitalized-removed-susceptible (SIQHRS) model based on the new guidelines of COVID-19 diagnosis and treatment (the ninth edition) was constructed to simulate the transmission dynamics of Omicron within 365 days. At baseline, we assumed no interventions other than 60% booster vaccination in individuals aged <=60 years and 80% in individuals aged >60 years, quarantine and hospitalization. Oral antiviral medications for COVID-19 (e.g. BRII-196/BRII-198) and non-pharmaceutical interventions (NPIs) such as social distancing and antigen self-testing were considered in subsequent scenarios. Sensitivity analyses were conducted to reflect different levels of interventions. A total of 0.73 billion cumulative quarantines (95% CI 0.53-0.83), 33.59 million hospitalizations (22.41-39.31), and 0.62 million deaths (0.40-0.75) are expected in 365 days. The case fatality rate with pneumonia symptoms (moderate, severe and critical illness) is expected to be 1.83% (1.68-1.99%) and the infected fatality rate 0.38‰ (0.33-0.42‰). The highest existing hospitalization and ICU occupations are 3.11 (0.30-3.85) and 20.33 (2.01-25.20) times of capacity, respectively. Sensitivity analysis showed that interventions can be adjusted to meet certain conditions to reduce the total number of infections and deaths. In conclusion, after sufficient respiratory and ICU beds are prepared and the relaxed NPIs are in place, the SARS-CoV-2 Omicron variant would not seriously impact the health system. This article is protected by copyright. All rights reserved.

A live attenuated virus-based intranasal COVID-19 vaccine provides rapid, prolonged, and broad protection against SARS-CoV-2.

Remarkable progress has been made in developing intramuscular vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, they are limited with respect to eliciting local immunity in the respiratory tract, which is the primary infection site for SARS-CoV-2. To overcome the limitations of intramuscular vaccines, we constructed a nasal vaccine candidate based on an influenza vector by inserting a gene encoding the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, named CA4-dNS1-nCoV-RBD (dNS1-RBD). A preclinical study showed that in hamsters challenged 1 d after single-dose vaccination or 9 months after booster vaccination, dNS1-RBD largely mitigated lung pathology, with no loss of body weight. Moreover, such cellular immunity is relatively unimpaired for the most concerning SARS-CoV-2 variants, especially for the latest Omicron variant. In addition, this vaccine also provides cross-protection against H1N1 and H5N1 influenza viruses. The protective immune mechanism of dNS1-RBD could be attributed to the innate immune response in the nasal epithelium, local RBD-specific T cell response in the lung, and RBD-specific IgA and IgG response. Thus, this study demonstrates that the intranasally delivered dNS1-RBD vaccine candidate may offer an important addition to the fight against the ongoing coronavirus disease 2019 pandemic and influenza infection, compensating limitations of current intramuscular vaccines.

Alterations in the Composition of Intestinal DNA Virome in Patients With COVID-19.

Patients with Coronavirus Disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection mainly present with respiratory issues and related symptoms, in addition to significantly affected digestive system, especially the intestinal tract. While several studies have shown changes in the intestinal flora of patients with COVID-19, not much information is available on the gut virome of such patients. In this study, we used the viromescan software on the latest gut virome database to analyze the intestinal DNA virome composition of 15 patients with COVID-19 and investigated the characteristic alternations, particularly of the intestinal DNA virome to further explore the influence of COVID-19 on the human gut. The DNA viruses in the gut of patients with COVID-19 were mainly crAss-like phages (35.48%), Myoviridae (20.91%), and Siphoviridae (20.43%) family of viruses. Compared with healthy controls, the gut virome composition of patients with COVID-19 changed significantly, especially the crAss-like phages family, from the first time of hospital admission. A potential correlation is also indicated between the change in virome and bacteriome (like Tectiviridae and Bacteroidaceae). The abundance of the viral and bacterial population was also analyzed through continuous sample collection from the gut of patients hospitalized due to COVID-19. The gut virome is indeed affected by the SARS-CoV-2 infection, and along with gut bacteriome, it may play an important role in the disease progression of COVID-19. These conclusions would be helpful in understanding the gut-related response and contribute to the treatment and prevention strategies of COVID-19.

Alterations in the Composition of Intestinal DNA Virome in Patients With COVID-19

Patients with Coronavirus Disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection mainly present with respiratory issues and related symptoms, in addition to significantly affected digestive system, especially the intestinal tract. While several studies have shown changes in the intestinal flora of patients with COVID-19, not much information is available on the gut virome of such patients. In this study, we used the viromescan software on the latest gut virome database to analyze the intestinal DNA virome composition of 15 patients with COVID-19 and investigated the characteristic alternations, particularly of the intestinal DNA virome to further explore the influence of COVID-19 on the human gut. The DNA viruses in the gut of patients with COVID-19 were mainly crAss-like phages (35.48%), Myoviridae (20.91%), and Siphoviridae (20.43%) family of viruses. Compared with healthy controls, the gut virome composition of patients with COVID-19 changed significantly, especially the crAss-like phages family, from the first time of hospital admission. A potential correlation is also indicated between the change in virome and bacteriome (like Tectiviridae and Bacteroidaceae). The abundance of the viral and bacterial population was also analyzed through continuous sample collection from the gut of patients hospitalized due to COVID-19. The gut virome is indeed affected by the SARS-CoV-2 infection, and along with gut bacteriome, it may play an important role in the disease progression of COVID-19. These conclusions would be helpful in understanding the gut-related response and contribute to the treatment and prevention strategies of COVID-19.

Human carboxylesterase 1A plays a predominant role in the hydrolytic activation of remdesivir in humans.

Remdesivir, an intravenous nucleotide prodrug, has been approved for treating COVID-19 in hospitalized adults and pediatric patients. Upon administration, remdesivir can be readily hydrolyzed to form its active form GS-441524, while the cleavage of the carboxylic ester into GS-704277 is the first step for remdesivir activation. This study aims to assign the key enzymes responsible for remdesivir hydrolysis in humans, as well as to investigate the kinetics of remdesivir hydrolysis in various enzyme sources. The results showed that remdesivir could be hydrolyzed to form GS-704277 in human plasma and the microsomes from human liver (HLMs), lung (HLuMs) and kidney (HKMs), while the hydrolytic rate of remdesivir in HLMs was the fastest. Chemical inhibition and reaction phenotyping assays suggested that human carboxylesterase 1 (hCES1A) played a predominant role in remdesivir hydrolysis, while cathepsin A (CTSA), acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) contributed to a lesser extent. Enzymatic kinetic analyses demonstrated that remdesivir hydrolysis in hCES1A (SHUTCM) and HLMs showed similar kinetic plots and much closed Km values to each other. Meanwhile, GS-704277 formation rates were strongly correlated with the CES1A activities in HLM samples from different individual donors. Further investigation revealed that simvastatin (a therapeutic agent for adjuvant treating COVID-19) strongly inhibited remdesivir hydrolysis in both recombinant hCES1A and HLMs. Collectively, our findings reveal that hCES1A plays a predominant role in remdesivir hydrolysis in humans, which are very helpful for predicting inter-individual variability in response to remdesivir and for guiding the rational use of this anti-COVID-19 agent in clinical settings.

Viral and Antibody Kinetics of COVID-19 Patients with Different Disease Severities in Acute and Convalescent Phases: A 6-Month Follow-Up Study.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly around the world, posing a major threat to human health and the economy. Currently, long-term data on viral shedding and the serum antibody responses in COVID-19 patients are still limited. Herein, we report the clinical features, viral RNA loads, and serum antibody levels in a cohort of 112 COVID-19 patients admitted to the Honghu People's Hospital, Hubei Province, China. Overall, 5.36% (6/112) of patients showed persistent viral RNA shedding (> 45 days). The peak viral load was higher in the severe disease group than in the mild group (median cycle threshold value, 36.4 versus 31.5; P = 0.002). For most patients the disappearance of IgM antibodies occurred approximately 4-6 weeks after symptoms onset, while IgG persisted for over 194 days after the onset of symptoms, although patients showed a 46% reduction in antibodies titres against SARS-CoV-2 nucleocapsid protein compared with the acute phase. We also studied 18 asymptomatic individuals with RT-qPCR confirmed SARS-CoV-2 infection together with 17 symptomatic patients, and the asymptomatic individuals were the close contacts of these symptomatic cases. Delayed IgG seroconversion and lower IgM seropositive rates were observed in asymptomatic individuals. These data indicate that higher viral loads and stronger antibody responses are related to more severe disease status in patients with SARS-CoV-2 infection, and the antibodies persisted in the recovered patient for more than 6 months so that the vaccine may provide protection against SARS-CoV-2 infection.

Efficacy of the combination of modern medicine and traditional Chinese medicine in pulmonary fibrosis arising as a sequelae in convalescent COVID-19 patients: a randomized multicenter trial.

BACKGROUND: The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a significant number of mortalities worldwide. COVID-19 poses a serious threat to human life. The clinical manifestations of COVID-19 are diverse and severe and 20% of infected patients are reported to be in a critical condition. A loss in lung function and pulmonary fibrosis are the main manifestations of patients with the severe form of the disease. The lung function is affected, even after recovery, thereby greatly affecting the psychology and well-being of patients, and significantly reducing their quality of life. METHODS: Participants must meet the following simultaneous inclusion criteria: over 18 years of age, should have recovered from severe or critical COVID-19 cases, should exhibit pulmonary fibrosis after recovery, and should exhibit Qi-Yin deficiency syndrome as indicated in the system of traditional Chinese medicine (TCM). The eligible candidates will be randomized into treatment or control groups. The treatment group will receive modern medicine (pirfenidone) plus TCM whereas the control group will be administered modern medicine plus TCM placebo. The lung function index will be continuously surveyed and recorded. By comparing the treatment effect between the two groups, the study intend to explore whether TCM can improve the effectiveness of modern medicine in patients with pulmonary fibrosis arising as a sequelae after SARS-CoV-2 infection. DISCUSSION: Pulmonary fibrosis is one of fatal sequelae for some severe or critical COVID-19 cases, some studies reveal that pirfenidone lead to a delay in the decline of forced expiratory vital capacity, thereby reducing the mortality partly. Additionally, although TCM has been proven to be efficacious in treating pulmonary fibrosis, its role in treating pulmonary fibrosis related COVID-19 has not been explored. Hence, a multicenter, parallel-group, randomized controlled, interventional, prospective clinical trial has been designed and will be conducted to determine if a new comprehensive treatment for pulmonary fibrosis related to COVID-19 is feasible and if it can improve the quality of life of patients. TRIAL REGISTRATION: This multicenter, parallel-group, randomized controlled, interventional, prospective trial was registered at the Chinese Clinical Trial Registry (ChiCTR2000033284) on 26th May 2020 (prospective registered).

Potential molecular targets of nonstructural proteins for the development of antiviral drugs against SARS-CoV-2 infection.

Outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 have produced high pathogenicity and mortality rates in human populations. However, to meet the increasing demand for treatment of these pathogenic coronaviruses, accelerating novel antiviral drug development as much as possible has become a public concern. Target-based drug development may be a promising approach to achieve this goal. In this review, the relevant features of potential molecular targets in human coronaviruses (HCoVs) are highlighted, including the viral protease, RNA-dependent RNA polymerase, and methyltransferases. Additionally, recent advances in the development of antivirals based on these targets are summarized. This review is expected to provide new insights and potential strategies for the development of novel antiviral drugs to treat SARS-CoV-2 infection.

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.

Safety and efficacy of inferoposterior access approach to the renal pedicle during transperitoneal laparoscopic radical nephrectomy: A retrospective comparative analysis at a single institution

Purpose: To assess the safety and efficacy of transperitoneal laparoscopic radical nephrectomy using an inferoposterior approach to the renal pedicle. Materials and methods: A retrospective review of 89 patients who underwent transperitoneal laparoscopic radical nephrectomy by a single surgeon between June 2014 and December 2019 at a single urological unit was carried out. Access to the renal pedicle was via the inferoposterior approach in 48 cases (study group) and 41 were approached via the conventional anterior approach (control group). Patient demographics, intra-operative anatomical findings, and procedural details including operative time on renal pedicles and post-operative outcomes were recorded. Post-operative complications were recorded and classified according to the Clavien-Dindo classification. A comparative analysis between the two groups was performed using Chi-square test and t-test. Results: The inferoposterior approach group had a shorter operative time (132.85±26.65 min vs 153.46±39.94 min;p<0.01), which could be attributed to the shorter time spent operating on the renal vasculature (46.31±6.16 min vs 64.46±7.64 min;p<0.01). Lower average blood loss was also observed in the inferoposterior approach group (42 ml vs 62 ml;p<0.05). No significant difference was identified concerning the mean patient age, body mass index, tumor size, number of renal vessels identified, and post-operative length of stay between the two groups. None of the patients required conversion to open. Conclusion: Inferoposterior approach to access the renal pedicle during transperitoneal laparoscopic radical nephrectomy is a safe and effective technique, which shortens the operative time when compared to the conventional anterior approach. Level of evidence_ Level 3b.

Efficacy and safety of Chinese patent medicine injection for COVID-19: A protocol for systematic review and meta-analysis.

BACKGROUND: Corona Virus Disease 2019 (COVID-19) has caused a worldwide epidemic since its discovery. The outbreak of virus infection has aroused great concern of the World Health Organization (WHO). COVID-19 is highly infectious and has a high infection rate. So far, no specific drug has been found to cure it. China as one of the first countries attacked by epidemic has shown outstanding in fighting against the COVID-19. The contribution of traditional Chinese medicine can not be ignored. As a kind of representative of traditional Chinese medicine, the Chinese patent medicine injection has significant effect in reducing the clinical symptoms of patients and preventing the deterioration of the disease. However, there is no systematic review of its efficacy and safety. The purpose of this study is to evaluate the efficacy and safety of Chinese patent medicine injection in the treatment of COVID-19. METHODS: All randomized controlled trials of Chinese patent medicine injection for COVID-19 will be included. The following electronic databases will be searched: PubMed, Web of Science, the Cochrane Library, EMBASE, China National Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journal Database, Chinese Biomedical Literature database and some clinical trial registration websites. Two researchers will independently screen titles, abstracts, full texts, and extract data, then assess the bias risk of each study. We will conduct meta-analyses to assess all the available evidence of the efficacy and safety. RESULTS: Systematic review of current evidence will be provided from the indexes of efficacy and safety. CONCLUSION: Evidence regarding the efficacy and safety of Chinese patent medicine injection in the treatment of COVID-19 will be provided to clinicians.PROSPERO registration number: CRD42020182725.