-
1.
Leritrelvir for the treatment of mild or moderate COVID-19 without co-administered ritonavir: a multicentre randomised, double-blind, placebo-controlled phase 3 trial.
Zhan, Y, Lin, Z, Liang, J, Sun, R, Li, Y, Lin, B, Ge, F, Lin, L, Lu, H, Su, L, et al
EClinicalMedicine. 2024;:102359
Abstract
BACKGROUND Leritrelvir is a novel α-ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease. A preclinical study has demonstrated leritrelvir poses similar antiviral activities towards different SARS-CoV-2 variants compared with nirmatrelvir. A phase 2 clinical trial has shown a comparable antiviral efficacy and safety between leritrelvir with and without ritonavir co-administration. This trial aims to test efficacy and safety of leritrelvir monotherapy in adults with mild-to-moderate COVID-19. METHODS This was a randomised, double-blind, placebo-controlled, multicentre phase 3 trial at 29 clinical sites in China. Enrolled patients were from 18 to 75 years old, diagnosed with mild or moderate COVID-19 and not requiring hospitalization. Patients had a positive SARS-CoV-2 nucleic acid test (NAT) and at least one of the COVID-19 symptoms within 48 h before randomization, and the interval between the first positive SARS-CoV-2 NAT and randomization was ≤120 h (5 days). Patients were randomly assigned in a 1:1 ratio to receive a 5-day course of either oral leritrelvir 400 mg TID or placebo. The primary efficacy endpoint was the time from the first dose to sustained clinical recovery of all 11 symptoms (stuffy or runny nose, sore throat, shortness of breath or dyspnea, cough, muscle or body aches, headache, chills, fever ≥37 °C, nausea, vomiting, and diarrhea). The safety endpoint was the incidence of adverse events (AE). Primary and safety analyses were performed in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT05620160. FINDINGS Between Nov 12 and Dec 30, 2022 when the zero COVID policy was abolished nationwide, a total of 1359 patients underwent randomization, 680 were assigned to leritrelvir group and 679 to placebo group. The median time to sustained clinical recovery in leritrelvir group was significantly shorter (251.02 h [IQR 188.95-428.68 h]) than that of Placebo (271.33 h [IQR 219.00-529.63 h], P = 0.0022, hazard ratio [HR] 1.20, 95% confidence interval [CI], 1.07-1.35). Further analysis of subgroups for the median time to sustained clinical recovery revealed that (1) subgroup with positive viral nucleic acid tested ≤72 h had a 33.9 h difference in leritrelvir group than that of placebo; (2) the subgroup with baseline viral load >8 log 10 Copies/mL in leritrelvir group had 51.3 h difference than that of placebo. Leritrelvir reduced viral load by 0.82 log10 on day 4 compared to placebo. No participants in either group progressed to severe COVID-19 by day 29. Adverse events were reported in two groups: leritrelvir 315 (46.46%) compared with placebo 292 (43.52%). Treatment-relevant AEs were similar 218 (32.15%) in the leritrelvir group and 186 (27.72%) in placebo. Two cases of COVID-19 pneumonia were reported in placebo group, and one case in leritrelvir group, none of them were considered by the investigators to be leritrelvir related. The most frequently reported AEs (occurring in ≥5% of participants in at least one group) were laboratory finding: hypertriglyceridemia (leritrelvir 79 [11.7%] vs. placebo 70 [10.4%]) and hyperlipidemia (60 [8.8%] vs. 52 [7.7%]); all of them were nonserious. INTERPRETATION Leritrelvir monotherapy has good efficacy for mild-to-moderate COVID-19 and without serious safety concerns. FUNDING This study was funded by the National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine, Guangdong Science and Technology Foundation, Guangzhou Science and Technology Planning Project and R&D Program of Guangzhou Laboratory.
-
2.
Propofol Versus Remimazolam on Cognitive Function, Hemodynamics, and Oxygenation During One-Lung Ventilation in Older Patients Undergoing Pulmonary Lobectomy: A Randomized Controlled Trial.
Kuang, Q, Zhong, N, Ye, C, Zhu, X, Wei, F
Journal of cardiothoracic and vascular anesthesia. 2023;(10):1996-2005
Abstract
OBJECTIVES To investigate the effects of remimazolam on postoperative cognitive function, intraoperative hemodynamics, and oxygenation in older patients undergoing lobectomy. DESIGN A prospective, double-blind, randomized, controlled study. SETTING A university hospital. PARTICIPANTS Eighty-four older patients with lung cancer who underwent lobectomy, aged ≥65 years. INTERVENTIONS Patients were divided randomly into the remimazolam (group R) and propofol (group P) groups. Group R underwent remimazolam anesthesia induction and maintenance, whereas group P underwent propofol anesthesia induction and maintenance. Cognitive function was assessed with neuropsychological tests 1 day before surgery and 7 days after surgery. The Clock Drawing Test, Verbal Fluency Test (VFT), Digit Symbol Switching Test (DSST), and Auditory Verbal Learning Test-Huashan (AVLT-H) assessed visuospatial ability, language function, attention, and memory, respectively. The systolic blood pressure (SBP), heart rate, mean arterial pressure (MAP), and cardiac index were recorded 5 minutes before induction of anesthesia (T0), 2 minutes after sedation (T1), 5 minutes after intubation with two-lung ventilation (T2), 30 minutes after one-lung ventilation (OLV) (T3), 60 minutes after OLV (T4), and at the end of surgery (T5), and the incidences of hypotension and bradycardia were recorded. The PaO2, oxygenation index (OI), and intrapulmonary shunt (Qs/Qt) were assessed at T0, T2, T3, T4, and T5. The levels of S-100β and interleukin 6 were measured by enzyme-linked immunosorbent assay at T0, T5, 24 hours after surgery (T6), and on day 7 after surgery (T7). MEASUREMENTS AND MAIN RESULTS The VFT, DSST, immediate recall AVLT-H, and short-delayed recall AVLT-H scores were significantly higher in group R than in group P on day 7 after surgery (p < 0.05). The SBP and MAP at T2 to T5 were significantly higher in group R than in group P, the incidence of hypotension was significantly lower in group R (9.5%) than in group P (35.7%) (p = 0.004), and remimazolam significantly reduced the dose of phenylephrine used (p < 0.05). The PaO2 and OI at T4 were significantly higher in group R than in group P, and Qs/Qt was significantly lower in group R than in group P. The levels of S-100β at T5 were significantly lower in group R than in group P (p < 0.05). CONCLUSION The results showed that remimazolam (versus propofol) may lessen the degree of short-term postoperative cognitive dysfunction measured by standard neuropsychological tests, better optimize intraoperative hemodynamics, and lead to improved oxygenation during OLV.
-
3.
Effects of strontium on the morphological and photosynthetic physiological characteristics of Vicia faba seedlings.
Chen, X, Zhong, N, Luo, Y, Ni, Y, Liu, Z, Wu, G, Zheng, T, Dang, Y, Chen, H, Li, W
International journal of phytoremediation. 2023;(7):811-821
Abstract
The adaptation of plants to strontium (Sr) stress requires a more systematic understanding. In the present study, the morphological and photosynthetic physiological characteristics of Vicia faba seedlings under Sr stress (88Sr, 0-1,000 mg·L-1) were analyzed in solution culture. The results showed that Sr treatment decreased the biomass and root activity of V. faba seedlings significantly, but fortunately, there was almost no root necrosis. In plant morphology, the taproot length, lateral root number, plant height, branching number and internodes number of V. faba were significantly inhibited, thus the apical dominance of taproot and terminal bud was more obvious. The accumulation of Sr resulted in the decrease of leaf area, dry weight, stomatal density and stomatal aperture, while the guard cell length increased, and the specific leaf weight (SLW) increased first and then decreased. These changes in stomatal morphology may be a positive regulation to reduce water loss. In addition, V. faba increased the non-photochemical quenching (NPQ) and the activities of peroxidase (POD) and ascorbate peroxidase (APX) to protect the photosynthetic structure. Low concentration of Sr (250 mg·L-1) promoted the photochemical efficiency and electron transfer of PSII (e.g., increased Fv/Fm, ΦPSII, qP and ETR). However, Sr (250-1,000 mg·L-1) inhibited the net photosynthetic rate (Pn), transpiration rate (Tr) and stomatal conductance (Gs) in leaves. In general, the Pn was affected by both stomatal and non-stomatal factors. Since Sr did not cause significant damage to the PSII function, the non-stomatal factor may be the dark reaction in photosynthesis affected, but this needs to be proved by further studies.
-
4.
Study of the Compressive Properties of Heavy Calcium Carbonate-Reinforced Epoxy Composite Spheres (HC-R-EMS) Composite Lightweight Concrete.
Ma, R, Cao, Z, Jiang, T, Wang, Y, Shi, S, Li, W, Zhao, Y, Zhong, N, Shi, D, Wu, X
Polymers. 2023;(5)
Abstract
Lightweight concrete is one of the effective means to solve the problems of structural component weight, energy efficiency, and fire safety in modern civil engineering. Heavy calcium carbonate-reinforced epoxy composite spheres (HC-R-EMS) were prepared by the ball milling method, and HC-R-EMS, cement, and hollow glass microspheres (HGMS) were mixed into the mold by the molding method to prepare composite lightweight concrete. The relationship between the HC-R-EMS volumetric fraction, the initial inner diameter of the HC-R-EMS, the number of layers of HC-R-EMS, the HGMS volume ratio, the basalt fiber length and content, and the multi-phase composite lightweight concrete density and compressive strength was studied. The experimental results show that the density of the lightweight concrete ranges between 0.953-1.679 g/cm3 and the compressive strength ranges between 1.59-17.26 MPa, where the volume fraction of HC-R-EMS is 90%, the initial internal diameter is 8-9 mm, and the number of layers of HC-R-EMS is three. The lightweight concrete can meet the requirements of high strength (12.67 MPa) and low density (0.953 g/cm3). In addition, the addition of basalt fiber (BF) can effectively improve the compressive strength of the material without changing the density of the material. From a micro-level perspective, HC-R-EMS is closely combined with the cement matrix, which is conducive to increasing the compressive strength of concrete. Basalt fibers connect the matrix into a network, improving the maximum limit force of the concrete.
-
5.
Improving Crop Nitrogen Use Efficiency Toward Sustainable Green Revolution.
Liu, Q, Wu, K, Song, W, Zhong, N, Wu, Y, Fu, X
Annual review of plant biology. 2022;:523-551
Abstract
The Green Revolution of the 1960s improved crop yields in part through the widespread cultivation of semidwarf plant varieties, which resist lodging but require a high-nitrogen (N) fertilizer input. Because environmentally degrading synthetic fertilizer use underlies current worldwide cereal yields, future agricultural sustainability demands enhanced N use efficiency (NUE). Here, we summarize the current understanding of how plants sense, uptake, and respond to N availability in the model plants that can be used to improve sustainable productivity in agriculture. Recent progress in unlocking the genetic basis of NUE within the broader context of plant systems biology has provided insights into the coordination of plant growth and nutrient assimilation and inspired the implementation of a new breeding strategy to cut fertilizer use in high-yield cereal crops. We conclude that identifying fresh targets for N sensing and response in crops would simultaneously enable improved grain productivity and NUE to launch a new Green Revolution and promote future food security.
-
6.
Metabolomics changes after rTMS intervention reveal potential peripheral biomarkers in methamphetamine dependence.
Su, H, Yang, P, Chen, T, Deng, D, Zhong, N, Jiang, H, Du, J, Peng, S, Zhao, M
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2022;:80-88
Abstract
Methamphetamine is one of the most commonly used drugs around the world, leading to serious public health and psychiatric problems. Due to the lackness of objective laboratory evaluation indicators, the molecular mechanisms of methamphetamine dependence still remain unclear. Previous evidence demonstrated that repetitive transcranial magnetic stimulation (rTMS) may be useful in treating drug addiction. The aim of this study was to identify and validate plasma metabolomics biomarkers in patients with methamphetamine use disorder before and after rTMS intervention. An untargeted gas chromatography-time-of-flight mass spectrometry (GC-TOFMS) based metabolomics approach was applied to characterize the metabolic profile of forty methamphetamine dependent subjects and thirty-eight healthy controls in peripheral blood mononuclear cells (PBMCs). Patients were randomized to receive either rTMS or sham over the DLPFC for four weeks (20 daily sessions, 900 pulses per day). Cognitive function were assessed before and after rTMS intervention. Eight PBMC metabolites responsible for distinguishing real rTMS from sham treatment were identified. These metabolites were mainly involved in energy metabolism and oxidative stress. Compared with baseline, the expression of three metabolites was reversed after rTMS intervention: alpha-tocopherol, glyceric acid and fumaric acid. Changes of the alpha-tocopherol were associated with cognitive function improvement following rTMS. These findings suggest that energy metabolism and oxidative stress system may be associated with the effect of rTMS on cognitive function in methamphetamine dependence, and warrant further investigation.
-
7.
Broad Spectrum Deubiquitinase Inhibition Induces Both Apoptosis and Ferroptosis in Cancer Cells.
Yang, L, Chen, X, Yang, Q, Chen, J, Huang, Q, Yao, L, Yan, D, Wu, J, Zhang, P, Tang, D, et al
Frontiers in oncology. 2020;:949
Abstract
Proteasomal deubiquitinase (DUB) inhibition has been found to be effective in experimental cancer therapy by inducing proteasome inhibition and apoptosis. Ferroptosis is a form of regulated cell death characterized by an iron-dependent lipid peroxidation. Antioxidant enzyme glutathione peroxidase 4 (GPX4) plays a key role in blocking ferroptosis through directly reducing phospholipid hydroperoxides production. Since cytoplasmic DUB inhibition can promote protein degradation in the cell, we hypothesize that DUB inhibition induces GPX4 degradation. Here we used palladium pyrithione complex (PdPT), a broad spectrum deubiquitinase inhibitor, to explore its cell death induction and anti-cancer effect in vitro, ex vivo, and in vivo. Mechanically, caspase activation and GPX4 protein degradation are required for PdPT-induced apoptosis and ferroptosis, respectively. Notably, PdPT-induced multiple deubiquitinase inhibition is essential for proteasomal degradation of GPX4. These findings not only identify a novel mechanism of post-translational modification of GPX4 in ferroptosis, but also suggest a potential anti-caner therapeutic strategy using Pan-DUB inhibition.
-
8.
High-dose N-acetylcysteine for long-term, regular treatment of early-stage chronic obstructive pulmonary disease (GOLD I-II): study protocol for a multicenter, double-blinded, parallel-group, randomized controlled trial in China.
Tian, H, Zhou, Y, Tang, L, Wu, F, Deng, Z, Lin, B, Huang, P, Wei, S, Zhao, D, Zheng, J, et al
Trials. 2020;(1):780
Abstract
INTRODUCTION The presence of increased oxidative stress and airway inflammation has been proven in subjects with chronic obstructive pulmonary disease (COPD). Several studies have demonstrated that drugs with antioxidant and anti-inflammatory properties such as N-acetylcysteine (NAC) can reduce the rate of exacerbations in patients with COPD. However, the beneficial effects of NAC in early-stage COPD are minimally discussed. We are investigating whether high-dose NAC has therapeutic effects in Chinese patients with early-stage COPD. METHOD AND ANALYSIS A randomized, double-blinded, placebo-controlled, parallel-group, multicenter clinical trial is evaluating the efficacy and safety of NAC for the long-term treatment of patients with early-stage COPD at 24 centers in China. Subjects aged 40-80 years and recruited by physicians or researchers with special training will be randomized to either NAC 600 mg twice daily group or matching placebo group for 2 years. Measurements will include forced expiratory volume in 1 s (FEV1), the number of COPD exacerbations, health-related quality, and pharmacoeconomic analysis. DISCUSSION Currently, there are no randomized controlled trials with high-dose N-acetylcysteine (600 mg twice daily) for patients with mild-to-moderate COPD (GOLD I-II). We designed this multicenter randomized controlled trial (RCT) to assess the effectiveness, safety, and cost-effectiveness of long-term treatment with high-dose N-acetylcysteine. The results of this trial may guide clinical practice and change the standard of early COPD management. TRIAL REGISTRATION Chinese Clinical Trial Registry ChiCTR-IIR-17012604 . Registered on 07 September 2017.
-
9.
History of the establishment of the Preterm Birth international collaborative (PREBIC).
Hobel, CJ, Dolan, SM, Hindoyan, NA, Zhong, N, Menon, R
Placenta. 2019;:3-20
Abstract
INTRODUCTION The primary aim of PREBIC is to assess the underlying mechanisms and developing strategies for preterm birth (PTB) prevention. MATERIALS AND METHODS We used concept mapping and logic models to track goals. This paper reviews our progress over 13 years using working group activities, research developments, guest speakers, and publications. RESULTS Using interactions between genetics, environment, and behaviors we identified complex interactions between biological systems. PREBIC determined that epidemiology and biomarkers should be an initial focus. In 2005, we initiated presentations by young investigators, yearly satellite meetings, working groups including nutrition and inflammation, assessment of clinical trials, and accepted an invitation by the WHO to begin yearly meetings in Geneva. DISCUSSION PREBIC used epidemiology to identify PTB factors and complex pathways. Candidate genes are associated with the environment, behavior (stress), obesity, inflammation and insulin resistance. Epigenetic changes and production of proteins can be used as biomarkers to define risk. Subsequently, we found risk factors for PTB that were also associated with the risk of cardiovascular disease (CVD) of the mother. Tanz et al. (2017) found that a history of PTB is independently predictive of CVD later in life and suggested that a modest proportion of PTB-CVD association was accounted by CVD risk factors, many of which have been identified in this paper. CONCLUSION Our findings support a relationship between genes, environment, behaviors and risk of CVD in women. The next several years must assess which factors are modifiable early in life and before pregnancy to prevent PTB.
-
10.
Setting research priorities to improve global newborn health and prevent stillbirths by 2025.
Yoshida, S, Martines, J, Lawn, JE, Wall, S, Souza, JP, Rudan, I, Cousens, S, , , Aaby, P, Adam, I, et al
Journal of global health. 2016;(1):010508
Abstract
BACKGROUND In 2013, an estimated 2.8 million newborns died and 2.7 million were stillborn. A much greater number suffer from long term impairment associated with preterm birth, intrauterine growth restriction, congenital anomalies, and perinatal or infectious causes. With the approaching deadline for the achievement of the Millennium Development Goals (MDGs) in 2015, there was a need to set the new research priorities on newborns and stillbirth with a focus not only on survival but also on health, growth and development. We therefore carried out a systematic exercise to set newborn health research priorities for 2013-2025. METHODS We used adapted Child Health and Nutrition Research Initiative (CHNRI) methods for this prioritization exercise. We identified and approached the 200 most productive researchers and 400 program experts, and 132 of them submitted research questions online. These were collated into a set of 205 research questions, sent for scoring to the 600 identified experts, and were assessed and scored by 91 experts. RESULTS Nine out of top ten identified priorities were in the domain of research on improving delivery of known interventions, with simplified neonatal resuscitation program and clinical algorithms and improved skills of community health workers leading the list. The top 10 priorities in the domain of development were led by ideas on improved Kangaroo Mother Care at community level, how to improve the accuracy of diagnosis by community health workers, and perinatal audits. The 10 leading priorities for discovery research focused on stable surfactant with novel modes of administration for preterm babies, ability to diagnose fetal distress and novel tocolytic agents to delay or stop preterm labour. CONCLUSION These findings will assist both donors and researchers in supporting and conducting research to close the knowledge gaps for reducing neonatal mortality, morbidity and long term impairment. WHO, SNL and other partners will work to generate interest among key national stakeholders, governments, NGOs, and research institutes in these priorities, while encouraging research funders to support them. We will track research funding, relevant requests for proposals and trial registers to monitor if the priorities identified by this exercise are being addressed.