Oral VV116 versus placebo in patients with mild-to-moderate COVID-19 in China: a multicentre, double-blind, phase 3, randomised controlled study.

BACKGROUND: Spread of SARS-CoV-2 led to a global pandemic, and there remains unmet medical needs in the treatment of Omicron infections. VV116, an oral antiviral agent that has potent activity against SARS-CoV-2, was compared with a placebo in this phase 3 study to investigate its efficacy and safety in patients with mild-to-moderate COVID-19. METHODS: This multicentre, double-blind, phase 3, randomised controlled study enrolled adults in hospitals for infectious diseases and tertiary general hospitals in China. Eligible patients were randomly assigned in a 1:1 ratio using permuted block randomisation to receive oral VV116 (0·6 g every 12 h on day 1 and 0·3 g every 12 h on days 2-5) or oral placebo (on the same schedule as VV116) for 5 days. Randomisation stratification factors included SARS-CoV-2 vaccination status and the presence of high-risk factors for progression to severe COVID-19. Inclusion criteria were a positive SARS-CoV-2 test, an initial onset of COVID-19 symptoms 3 days or less before the first study dose, and a score of 2 or more for any target COVID-19-related symptoms in the 24 h before the first dose. Patients who had severe or critical COVID-19 or who had taken any antiviral drugs were excluded from the study. The primary endpoint was the time to clinical symptom resolution for 2 consecutive days. Efficacy analyses were performed on a modified intention-to-treat population, comprising all patients who received at least one dose of VV116 or placebo, tested positive for SARS-CoV-2 nucleic acid, and did not test positive for influenza virus before the first dose. Safety analyses were done on all participants who received at least one dose of VV116 or placebo. This study was registered with ClinicalTrials.gov, NCT05582629, and has been completed. FINDINGS: A total of 1369 patients were randomly assigned to treatment groups and 1347 received either VV116 (n=674) or placebo (n=673). At the interim analysis, VV116 was superior to placebo in reducing the time to sustained clinical symptom resolution among 1229 patients (hazard ratio [HR] 1·21, 95% CI 1·04-1·40; p=0·0023). At the final analysis, a substantial reduction in time to sustained clinical symptom resolution was observed for VV116 compared with placebo among 1296 patients (HR 1·17, 95% CI 1·04-1·33; p=0·0009), consistent with the interim analysis. The incidence of adverse events was similar between groups (242 [35·9%] of 674 patients vs 283 [42·1%] of 673 patients). INTERPRETATION: Among patients with mild-to-moderate COVID-19, VV116 significantly reduced the time to sustained clinical symptom resolution compared with placebo, with no observed safety concerns. FUNDING: Shanghai Vinnerna Biosciences, Shanghai Science and Technology Commission, and the National Key Research and Development Program of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Incidence, causes, and risk factors for unplanned readmission in patients admitted with pulmonary tuberculosis in China.

INTRODUCTION: To investigate the incidence, causes, and risk factors for unplanned readmission within 30 days of discharge in patients with pulmonary tuberculosis (TB). METHODOLOGY: The clinical data of 1,062 patients with confirmed pulmonary TB who were admitted to our hospital from October 2018 to October 2021 were analysed retrospectively. The subjects were divided into a readmission group (354 cases) and a non-readmission group (708 cases) according to whether there was an unplanned admission within 30 days of discharge. We analysed the risk factors for unplanned readmission within 30 days after discharge with pulmonary TB. RESULTS: The incidence of unplanned readmission in patients with pulmonary TB was 5.2%. Being female (OR = 0.63, 95% CI: 0.434-0.942) and living in cities (OR = 0.218, 95% CI: 0.151-0.315) were protective factors for the readmission of patients with TB (p < 0.05). However, being ≥ 65 years old (OR = 2.574, 95% CI: 1.709-3.870), being a smoker (OR = 2.773, 95% CI: 1.751-4.390), having chronic obstructive pulmonary disease (COPD) (OR = 3.373, 95% CI: 1.708-6.660), having viral hepatitis (OR= 2.079, 95% CI: 1.067-4.052), receiving non-standard treatment (OR = 15.620, 95% CI: 10.413-23.431), having medical side effects (OR = 6.138, 95% CI: 3.798-9.922) and l unauthorised discharge (OR = 2.570, 95% CI: 1.509-4.376) were risk factors for the readmission to hospital of patients with TB (p < 0.05). CONCLUSIONS: Gender, age, place of residence, smoking, COPD, hepatitis, non-standard treatment, adverse drug reactions and unauthorised discharge were risk factors of TB for unplanned readmission.

Clinical Manifestation, Imaging Features and Treatment Follow-up of 29 Cases with Hepatic Tubercolosis.

To understand the clinical and imaging manifestations and the treatment and follow-up of hepatic tuberculosis (HTB), we retrospectively analysed the clinical and imaging data of 29 patients with HTB who had been diagnosed clinically or by biopsy, and the clinical and imaging data had been summarised. Patient characteristics were followed up after anti-TB drug treatment. The median age of the 29 patients with HTB was 37 years, and most were male (58.6%). The patient's symptoms included fever (48.2%), respiratory symptoms (27.5%), abdominal pain (24.1%), and abdominal distension (10.3%). Elevated erythrocyte sedimentation rate (79.3%), elevated serum C-reactive protein (75.8%) and hypoalbuminemia (62.0%) were common features. Three patients were serologically positive for acquired human immunodeficiency syndrome, and two were serologically positive for hepatitis B surface antigen with normal tumour markers. The 29 patients with HTB included 17 with serous HTB, 9 with parenchymal HTB (8 with parenchymal nodular HTB and 1 with parenchymal miliary HTB), 1 with intrahepatic abscess type HTB, and 2 with hilar HTB. Approximately 86% of the patients also had pulmonary TB. Most of the serous HTB patients also had tuberculous peritonitis. Enhanced computerized tomography scans of the serous and parenchymal HTB cases showed the progressive development of lesions. Abnormal blood perfusion was observed in the hepatic artery, and the clearest evidence of TB was observed in the hepatic portal vein. Magnetic resonance imaging indicated that the lesions returned a high signal in the diffusion-weighted imaging sequence. However, the lesions' apparent diffusion coefficient values reflected high signals. The Xpert MTB/RIF test detected Mycobacterium TB complex in the liver biopsy fluid from 10 patients. Regarding histopathology, one patient showed granulomatous inflammation, and one patient's acid-fast bacillus (AFB) stain was positive. The treatment of two patients was stopped due to their adverse reactions to the drugs and the risk of creating drug-resistant TB. The remaining patients received anti-TB treatment, but one subsequently died, and two were unavailable for follow-up. The clinical symptoms of HTB are difficult to detect, and it has diverse manifestations by imaging, with no obvious specificity in terms of pathological results. Therefore, follow-up of liver lesions for checking anti-TB therapy is another method for diagnosing HTB. In addition, early active anti-TB treatment can achieve good curative results.

Efficacy and safety of Fuzheng Huayu tablet on persistent advanced liver fibrosis following 2 years entecavir treatment: A single arm clinical objective performance criteria trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Antiviral therapy can alleviate liver fibrosis in chronic hepatitis B, but it has a limited effect on advanced liver fibrosis/cirrhosis. Traditional Chinese medicine (TCM), particularly FuZheng HuaYu (FZHY) tablet, appears to have an antifibrotic effect, but its improving resolution of hepatitis b virus (HBV) -associated advanced fibrosis and experienced anti-viral treatment has not been investigated. AIM OF THE STUDY: To observe the safety and efficacy of adjunctive FZHY on the HBV-associated cirrhosis patients who received 2 years of entecavir but still with advanced fibrosis. METHODS: An open-label, multicentre, single arm trial. 251 patients were included and treated with TCM consisted of FZHY tablets 1.6 g and granules, three times a day in addition to entecavir 0.5 mg daily for an additional 48 weeks. Primary outcome was regression of fibrosis (the proportion of patients with a 1-point decrease in the Ishak liver fibrosis score from baseline to week 48). RESULTS: Fibrosis regression occurred in 94 of 184 patients with paired liver biopsy (51.09%, 95% CI: 43.9～58.0). In 132 compensated cirrhosis patients (Ishak score ≥5), 56.06% (74/132, 95% CI: 47.5～64.2) showed fibrosis regression and reached the goal of 54% (15% more than entecavir mono-therapy). 10 patients occurred adverse reaction, most of them were mild, and all recovered or achieved remission. CONCLUSIONS: The combination therapy of FZHY, TCM granules and ETV could regress the liver fibrosis in the patients with HBV cirrhosis, who experienced 2 years of ETV treatment, and it is safe and well tolerated.

Differential diagnosis for suspected cases of coronavirus disease 2019: a retrospective study.

BACKGROUND: Since December 2019, the coronavirus disease 2019 (COVID-19) has infected more than 12,322,000 people and killed over 556,000 people worldwide. However, Differential diagnosis remains difficult for suspected cases of COVID-19 and need to be improved to reduce misdiagnosis. METHODS: Sixty-eight cases of suspected COVID-19 treated in Wenzhou Central Hospital from January 21 to February 20, 2020 were divided into confirmed and COVID-19-negative groups based on the results of real-time reverse transcriptase polymerase chain reaction (RT-PCR) nucleic acid testing of the novel coronavirus in throat swab specimens to compare the clinical symptoms and laboratory and imaging results between the groups. RESULTS: Among suspected patients, 17 were confirmed to COVID-19-positive group and 51 were distinguished to COVID-19-negative group. Patients with reduced white blood cell (WBC) count were more common in the COVID-19-positive group than in the COVID-19-negative group (29.4% vs 3.9%, P = 0.003). Subsequently, correlation analysis indicated that there was a significant inverse correlation existed between WBC count and temperature in the COVID-19-positive patients (r = - 0.587, P = 0.003), instead of the COVID-19-negative group. But reduced lymphocyte count was no different between the two groups (47.1% vs 25.5%, P = 0.096). More common chest imaging characteristics of the confirmed COVID-19 cases by high-resolution computed tomography (HRCT) included ground-glass opacities (GGOs), multiple patchy shadows, and consolidation with bilateral involvement than COVID-19-negative group (82.4% vs 31.4%, P = 0.0002; 41.2% vs 17.6% vs P = 0.048; 76.5% vs 43.1%, P = 0.017; respectively). The rate of clustered infection was higher in COVID-19-positive group than COVID-19-negative group (64.7% vs 7.8%, P = 0.001). Through multiplex PCR nucleic acid testing, 2 cases of influenza A, 3 cases of influenza B, 2 cases of adenovirus, 2 cases of Chlamydia pneumonia, and 7 cases of Mycoplasma pneumoniae were diagnosed in the COVID-19-negative group. CONCLUSIONS: WBC count inversely correlated with the severity of fever, GGOs, multiple patchy shadows, and consolidation in chest HRCT and clustered infection are common but not specific features in the confirmed COVID-19 group. Multiplex PCR nucleic acid testing helped differential diagnosis for suspected COVID-19 cases.

Rottlerin inhibits cell growth, induces apoptosis and cell cycle arrest, and inhibits cell invasion in human hepatocellular carcinoma.

Rottlerin, a polyphenolic compound, has been demonstrated to exhibit antitumor activity in various types of human cancer. Several studies have revealed that rottlerin exerts its anticancer function through PKC­dependent and independent pathways. The transcriptional co­activator with PDZ­binding motif (TAZ) oncopreotein is an important molecule in regulation of the Hippo pathway in human cancer. The present study investigated whether rottlerin has a tumor suppressive role via inhibiting the expression of TAZ, using cell viability assay, apoptosis and cell cycle analyses, western blot analysis and Tanswell invasion assay. The results demonstrated that rottlerin suppressed cell growth, triggered cell apoptosis and induced cell cycle arrest. In addition, rottlerin inhibited cell migration and invasion in hepatocellular carcinoma (HCC) cells. Mechanistically, the results demonstrated that rottlerin exerted its antitumor activity partly through the inhibition of TAZ. In addition, the depletion of TAZ led to inhibited cell growth and invasion, whereas the overexpression of TAZ enhanced cell growth and invasion in the HCC cells. Taken together, these findings indicated that the inhibition of TAZ by rottlerin may be a novel strategy for treating HCC.

ZNRF3 contributes to the growth of lung carcinoma via inhibiting Wnt/ß-catenin pathway and is regulated by miR-93.

Lung carcinoma is the most common cancer with increasing morbidity, inefficient therapeutic modality, and poor prognosis, due to the lack of understanding of its related molecular mechanism. ZNRF3 is a newly identified negative regulator of Wnt signaling. In this study, we found that ZNRF3 level is reduced in lung carcinoma compared with normal lung tissue and its expression level is positively correlated with the survival of lung cancer patients. Restoration of ZNRF3 suppressed the proliferation and cell cycle progression of lung cancer cell lines. Suppression of ZNRF3 expression in normal lung cells increased the proliferation rates. In an animal model, ZNRF3 was shown to suppress the growth of lung cancer xenografts. ZNRF3 was shown to negatively regulate the activation of Wnt signaling in lung cancerous and normal cells. Further studies revealed that ZNRF3 is a target of miR-93, an oncogenic microRNA (miRNA) for lung cancer progression. Collectively, we found that miR-93/ZNRF3/Wnt/ß-catenin regulatory network contributes to the growth of lung carcinoma. Targeting this pathway may be a promising strategy for lung cancer therapy.