Efficacy and safety of paxlovid (nirmatrelvir/ritonavir) in the treatment of COVID-19: An updated meta-analysis and trial sequential analysis.

Our study is aimed to access the efficacy and safety outcomes for coronavirus disease 2019 (COVID-19) patients treated with Paxlovid. According to inclusion and exclusion criteria, databases were used to retrieve articles from 1 January 2020 to 1 January 2023. Article screening, quality evaluation and data extraction were completed and cross-checked. The meta-analysis and trial sequential analysis (TSA) were conducted using RevMan, StataMP, and TSA software. A total of 42 original articles were included. Overall meta-analysis results showed that for death, hospitalisation, death or hospitalisation, emergency department (ED) visit, intensive care unit (ICU) admission, and extra oxygen requirement outcomes, every odds ratio (OR) was <1 and p < 0.05. For rebound outcome, the OR was >1 and p > 0.05. For adverse events (AEs) outcome, the OR was >1 and p < 0.05. In conclusion, Paxlovid effectively reduced the risks of death, hospitalisation, death or hospitalisation, ED visit, ICU admission, and extra oxygen requirement. There was no significant statistical difference considering rebound, but people should pay attention to possible AEs. However, for rebound and AEs outcomes, observations in certain subgroups suggested conclusions contrary to the overall meta-analysis. Trial sequential analysis indicated these two outcomes have a risk of false negative or false positive conclusions, so additional original studies are needed for further validation.

Imperatorin Improves Obesity-Induced Cardiac Sympathetic Nerve Injury Mediated by P2X4 Receptor in Stellate Sympathetic Ganglion.

Obesity can activate the inflammatory signal pathway, induce in the body a state of chronic inflammation, and increase the excitability of the sympathetic nervous system, which may induce sympathetic neuropathic injury. The stellate sympathetic ganglia (SG) can express the P2X4 receptor, and the abnormal expression of the P2X4 receptor is related to inflammation. Imperatorin (IMP) is a kind of furan coumarin plant which has anti-inflammatory effects. This project aimed to investigate whether IMP can affect the expression of P2X4 receptors in the SG of obese rats to display a protective effect from high-fat-triggered cardiac sympathetic neuropathic injury. Molecular docking through homology modelling revealed that IMP had good affinity for the P2X4 receptor. Our results showed that compared with the normal group, the administration of IMP or P2X4 shRNA decreased sympathetic excitement; reduced the serum levels of triglyceride, total cholesterol, and lactate dehydrogenase; downregulated the expression of P2X4 receptors in SG; and inhibited the expression of inflammatory factors in the SG and serum of obese rats significantly. In addition, the expression of factors associated with the cell pyroptosis GSDMD, caspase-1, NLRP-3, and IL-18 in obese rats were significantly higher than those of the normal rats, and such effects were decreased after treatment with IMP or P2X4 shRNA. Furthermore, IMP significantly reduced the ATP-activated currents in HEK293 cells transfected with P2X4 receptor. Thus, the P2X4 receptor may be a key target for the treatment of obesity-induced cardiac sympathetic excitement. IMP can improve obesity-induced cardiac sympathetic excitement, and its mechanism of action may be related to the inhibition of P2X4 receptor expression and activity in the SG, suppression of cellular pyroptosis in the SG, and reduction of inflammatory factor levels.

Gallic Acid Alleviates Visceral Pain and Depression via Inhibition of P2X7 Receptor.

Chronic visceral pain can occur in many disorders, the most common of which is irritable bowel syndrome (IBS). Moreover, depression is a frequent comorbidity of chronic visceral pain. The P2X7 receptor is crucial in inflammatory processes and is closely connected to developing pain and depression. Gallic acid, a phenolic acid that can be extracted from traditional Chinese medicine, has been demonstrated to be anti-inflammatory and anti-depressive. In this study, we investigated whether gallic acid could alleviate comorbid visceral pain and depression by reducing the expression of the P2X7 receptor. To this end, the pain thresholds of rats with comorbid visceral pain and depression were gauged using the abdominal withdraw reflex score, whereas the depression level of each rat was quantified using the sucrose preference test, the forced swimming test, and the open field test. The expressions of the P2X7 receptor in the hippocampus, spinal cord, and dorsal root ganglion (DRG) were assessed by Western blotting and quantitative real-time PCR. Furthermore, the distributions of the P2X7 receptor and glial fibrillary acidic protein (GFAP) in the hippocampus and DRG were investigated in immunofluorescent experiments. The expressions of p-ERK1/2 and ERK1/2 were determined using Western blotting. The enzyme-linked immunosorbent assay was utilized to measure the concentrations of IL-1ß, TNF-α, and IL-10 in the serum. Our results demonstrate that gallic acid was able to alleviate both pain and depression in the rats under study. Gallic acid also reduced the expressions of the P2X7 receptor and p-ERK1/2 in the hippocampi, spinal cords, and DRGs of these rats. Moreover, gallic acid treatment decreased the serum concentrations of IL-1ß and TNF-α, while raising IL-10 levels in these rats. Thus, gallic acid may be an effective novel candidate for the treatment of comorbid visceral pain and depression by inhibiting the expressions of the P2X7 receptor in the hippocampus, spinal cord, and DRG.

Clamping force prediction based on deep spatio-temporal network for machining process of deformable parts.

As an important component of the machining system, the influence of fixtures on the machining deformation of the workpiece cannot be ignored. By controlling the clamping force during the machining process is an effective means to suppress or improve the machining deformation. However, due to the dynamic coupling of part geometry, clamping method, manufacturing process and time-varying cutting forces, it is difficult to obtain accurate clamping forces, which hinders the realization of fixture-based deformation control. In this paper, the variation of clamping force is considered as the response of the joint action of cutting force and other working conditions in spatial and temporal terms, and a clamping force prediction method based on deep spatio-temporal network is proposed. The part geometry model is first parameterized based on voxels, after which the cutting forces are dynamically correlated with the clamping forces in spatial and temporal terms. Then, a convolutional network was designed to capture the spatial correlation between the working conditions such as cutting force and clamping force, and a gated recurrent cell network to capture the temporal correlation to predict the clamping force during machining. Finally, an experiment of milling a cylindrical thin-walled part illustrates the effectiveness of the proposed method.

Association of CCL4 rs10491121 and rs1634507 gene polymorphisms with cancer susceptibility: trial sequential analysis and meta-analysis.

Background: Although numerous case-control studies have explored the association between CC cytokine ligand-4 (CCL4) expression and cancer susceptibility, their results have been conflicting. This study aimed to determine the still-unknown connection of CCL4 rs10491121 and rs163450 polymorphisms with cancer susceptibility. Methods: Several databases, such as Web of Science, PubMed, and EMBASE, were searched for papers published since the creation of the database until November 2, 2022. Using RevMan 5.4 and StataMP 17 softwares, meta-analysis and subgroup analysis were performed after article screening and data extraction. For sensitivity analyses, one-by-one exclusion method was used, and then, the comprehensive effect was estimated and compared with that before exclusion. Trial sequential analysis (TSA)was performed using TSA 0.9.5.10 beta software. Results: Seven case-control studies encompassing 3559 cases and 4231 controls were included. The P value was greater than 0.05 for all models, indicating the absence of an evident relationship of CCL4 gene rs10491121 and rs1634507 polymorphisms with cancer susceptibility. However, in the subgroup analysis of rs10491121, the P values in all models studied by us except GA vs. AA were <0.05 considering the Chinese subgroup, suggesting that the G allele is a risk factor for cancer in the Chinese population. Besides, in the subgroup analysis of rs1634507 considering oral cancer, the co-dominant model GG vs. TT, dominant model GG + GT vs. TT, and allele model G vs. T groups showed OR < 1 and P < 0.05, indicating that the G allele was a protective factor of oral cancer. However, for other cancer types, all the models studied by us except GG vs. GT showed OR > 1 and P < 0.05, indicating that the G allele was a risk factor for these other cancers. Despite the statistically significant results, sensitivity analysis had some stability limitations, and TSA results suggested the possibility of false positives. Conclusion: For rs10491121, we identified an association between the G allele and increased cancer risk in the Chinese population. For rs1634507, the G allele was not found to be associated with reduced risk of oral cancer and increased risk of other cancers studied by us.

Local-feature and global-dependency based tool wear prediction using deep learning.

Evaluation of tool wear is vital in manufacturing system, since early detections on worn-out condition can ensure workpiece quality, improve machining efficiency. With the development of intelligent manufacturing, tool wear prediction technology plays an increasingly important role. However, traditional tool wear prediction methods rely on experience and knowledge of experts and are labor-extensive. Deep learning provides an effective way to extract features of raw data and establish the mapping relationship between features and targets automatically. In this paper, a new local-feature and global-dependency based tool wear prediction method is proposed. It is a hybrid approach combining manual features with automatic features. Firstly, an enhanced CNN network is designed and applied on the transformed wavelet scalogram to learn the local single-scale specific features and multi-scale correlation features automatically. Secondly, sequence of local feature vectors combining manual features with automatic features are fed into multi-layer LSTM step by step for the global dependency. A fully connected layer is then trained to predict tool wear. Finally, two statistics are proposed to illustrate the overall prediction performance and generalization ability of the model. An experiment illustrates the effectiveness of our proposed method under multiple working conditions.

Association of PTPN22 SNP1858 (rs2476601) and Gene SNP1123 (rs2488457) Polymorphism With Primary Immune Thrombocytopenia Susceptibility: A Meta-Analysis of Case-Control Studies and Trial Sequential Analysis.

Objective: Systematic review of the association of protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene 1858 and 1123 sites single nucleotide polymorphism (SNP) with the susceptibility of primary immune thrombocytopenia (ITP). Method: Database searched includes PubMed, Embase, Web of Science, CNKI, CBM, VIP and WanFang Data. The retrieval period is from the establishment of the database to 30 June 2021. After screening articles according to inclusion and exclusion criteria, the data were extracted and methodological quality of the included studies was evaluated. Meta-analysis was performed using RevMan 5.4 and Stata 16.0 software. The combined OR value and its 95%CI were calculated. Sensitivity analysis and publication bias assessment were performed. Trial sequential analysis (TSA) was performed using TSA 0.9.5.10 Beta software. Results: A total of 10 studies with 10 articles were included, with a total of 932 cases and 2,112 controls. The results of meta-analysis showed that for SNP1858, the susceptibility of TT genotype to ITP was 5.01 times higher than CC genotype [95%CI (1.81, 13.86), p = 0.002]. For SNP1123, G allele carriers were more susceptible to ITP than C allele carriers [OR = 1.23, 95%CI (1.05, 1.45), p = 0.01], and GG genotype carriers were 1.51 times more susceptible to ITP than CC genotype carriers [95%CI (1.11, 2.06), p = 0.009]. Although the results are statistically significant, the results of sensitivity analysis showed certain limitations of stability, and the TSA analysis still indicated the possibility of false positive. No significant publication bias was observed. Conclusion: PTPN22 gene SNP1858 (rs2476601) and SNP1123 (rs2488457) polymorphisms are associated with susceptibility to primary immune thrombocytopenia. Due to the limitation of the number and quality of the included studies, the above conclusions need to be verified by more high-quality studies.

Association of TLR3 gene 1377C/T (rs3775290) and TLR7 gene C/G (rs3853839) polymorphism with hand, foot, and mouth disease caused by human enterovirus 71 infection susceptibility and severity in the Chinese Han population: A meta-analysis of case-control studies.

BACKGROUND: Several case-control studies have been conducted on the relationship between rs3775290 C/T and rs3853839 C/G single nucleotide polymorphisms of the Toll-like receptor (TLR) gene and hand, foot, and mouth disease (HFMD) susceptibility and severity. This meta-analysis aimed to offer a systemic review of HFMD susceptibility and severity among the Chinese Han population associated with the C/T (rs3775290) polymorphism of the TLR3 gene or C/G (rs3853839) polymorphism of the TLR7 gene. METHODS: A computer search was conducted using PubMed, Web of Science, Embase, CNKI, CBM, VIP, and WanFang databases. The time ranges were from database establishment to 30/7/2021. Articles selected according to the inclusion and exclusion criteria underwent data extraction and methodological quality evaluation. RevMan 5.4 and Stata 16.0 were adopted for meta-analysis, and the incorporated odds ratio (OR) values and 95% confidence intervals (CIs) were calculated. Sensitivity and publication bias assessments were performed. RESULTS: 8 articles with 9 studies were selected. Among them, there were 858 cases and 577 controls in TLR3 rs3775290 studies as well as 2151 cases and 1554 controls in TLR7 rs3853839 studies. Regarding rs3775290 of TLR3, susceptibilities of the severe type of T-possessing individuals were larger than those of C-possessing individuals [OR = 1.34, 95%CI (1.10, 1.64), P = .004]. The susceptibility of individuals with the severe TT genotype was 1.61 times that of individuals with the CC genotype [95%CI (1.07, 2.43), P=0.02], while susceptibility to HFMD was not influenced by the genotype. In terms of the rs3853839 of the TLR7 gene, C allele carriers have a higher risk of developing HFMD than G allele carriers. The susceptibility to HFMD in CC+CG individuals was 1.24 times than that in GG individuals [95%CI (1.07, 1.43), P = .004]. However, no relationship was found between this polymorphism and severity of the severe type. No significant publication bias was observed in this study. CONCLUSIONS: rs3775290 (C/T) of TLR3 is associated with susceptibility to the severe type, whereas rs3853839 (C/G) of TLR7 is associated with susceptibility to HFMD. However, owing to the limited quantity and quality of the research, the aforementioned conclusions are yet to be justified by more high-quality research.

Some results of Heron mean and Young's inequalities.

In this paper, we will show some improvements of Heron mean and the refinements of Young's inequalities for operators and matrices with a different method based on others' results.