Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity.

The CD4(+) and CD8(+) T cell dichotomy is essential for effective cellular immunity. How individual T cell identity is established remains poorly understood. Here we show that the high-mobility group (HMG) transcription factors Tcf1 and Lef1 are essential for repressing CD4(+) lineage-associated genes including Cd4, Foxp3 and Rorc in CD8(+) T cells. Tcf1- and Lef1-deficient CD8(+) T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1. Mutation of five conserved amino acids in the Tcf1 HDAC domain diminishes HDAC activity and the ability to suppress CD4(+) lineage genes in CD8(+) T cells. These findings reveal that sequence-specific transcription factors can utilize intrinsic HDAC activity to guard cell identity by repressing lineage-inappropriate genes.

SERS Sensor for Acetylcholine Detection Based on Covalent Organic Framework Hybridized Gold Nanoparticles As Nanozymes.

An innovative and potent nanozyme with reductase-like activity was developed by integrating the in situ synthesis of gold nanoparticles (Au NPs) onto the surface of a covalent organic framework (COF). Based on the reductase-like activity of the COF-hybridized Au NPs, this nanozyme could efficiently catalyze the reduction of 4-nitrophenol (4-NPH). Moreover, the prepared nanohybrid was utilized as an excellent surface-enhanced Raman scattering (SERS) substrate for highly sensitive SERS detection by combining the excellent adsorption properties of COFs and the large number of Raman hotspots between the high-density Au NPs. For the first time, 4-NPH was used as an SERS marker to detect the electron receptor acetylcholine (Ach), with high sensitivity; Ach acted as an inhibitor in this catalytic reaction. The linear range of Ach was 1.0 pM to 10 nM, the correlation coefficient was 0.993, the detection limit was approximately 0.3 pM with a signal-to-noise ratio (s/n) of 3, and the acceptable recovery in the serum was 97.2% to 104.5%. The results from this study show that the nanozyme-SERS system has great potential for chemical and bioassay applications.

BRCC36 regulates ß-catenin ubiquitination to alleviate vascular calcification in chronic kidney disease.

BACKGROUND: The prevalence of vascular calcification (VC) in chronic kidney disease (CKD) patients remains substantial, but currently, there are no effective pharmaceutical therapies available. BRCA1/BRCA2-containing complex subunit 36 (BRCC36) has been implicated in osteoblast osteogenic conversion; however, its specific role in VC remains to be fully elucidated. The aim of this study was to investigate the role and underlying mechanisms of BRCC36 in VC. METHODS: The association between BRCC36 expression and VC was examined in radial arteries from patients with CKD, high-adenine-induced CKD mice, and vascular smooth muscle cells (VSMCs). Western blotting, real-time polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to analyse gene expression. Gain- and loss-of-function experiments were performed to comprehensively investigate the effects of BRCC36 on VC. Coimmunoprecipitation and TOPFlash luciferase assays were utilized to further investigate the regulatory effects of BRCC36 on the Wnt/ß-catenin pathway. RESULTS: BRCC36 expression was downregulated in human calcified radial arteries, calcified aortas from CKD mice, and calcified VSMCs. VSMC-specific BRCC36 overexpression alleviated calcium deposition in the vasculature, whereas BRCC36 depletion aggravated VC progression. Furthermore, BRCC36 inhibited the osteogenic differentiation of VSMCs in vitro. Rescue experiments revealed that BRCC36 exerts the protective effects on VC partly by regulating the Wnt/ß-catenin signalling pathway. Mechanistically, BRCC36 inhibited the Wnt/ß-catenin pathway by decreasing the K63-linked ubiquitination of ß-catenin. Additionally, pioglitazone attenuated VC partly through upregulating BRCC36 expression. CONCLUSIONS: Our research results emphasize the critical role of the BRCC36-ß-catenin axis in VC, suggesting that BRCC36 or ß-catenin may be promising therapeutic targets to prevent the progression of VC in CKD patients.

Phase III clinical trial comparing the efficacy and safety of adamgammadex with sugammadex for reversal of rocuronium-induced neuromuscular block.

BACKGROUND: Preliminary clinical trials of adamgammadex, a new cyclodextrin-based selective reversal agent, have demonstrated its efficacy in reversing neuromuscular block by rocuronium. METHODS: This multicentre, randomised, double-blind, positive-controlled, non-inferiority phase III clinical trial compared the efficacy and safety of adamgammadex and sugammadex. We randomised 310 subjects to receive adamgammadex (4 mg kg-1) or sugammadex (2 mg kg-1) at reappearance of the second twitch of the train-of-four (TOF), and standard safety data were collected. RESULTS: For the primary outcome, the proportion of patients with TOF ratio ≥0.9 within 5 min was 98.7% in the adamgammadex group vs 100% in the sugammadex group, with a point estimate and 95% confidence interval (CI) of 1.3% (-4.6%, +1.3%); the lower limit was greater than the non-inferiority margin of -10%. For the key secondary outcome, the median (inter quartile range) time from the start of administration of adamgammadex or sugammadex to recovery of TOF ratio to 0.9 was 2.25 (1.75, 2.75) min and 1.75 (1.50, 2.00) min, respectively. The difference was 0.50 (95% CI: 0.25, 0.50); the upper limit was lower than the non-inferiority margin of 5 min. In addition, there were no inferior results observed in secondary outcomes. Adamgammadex had a lower incidence of adverse drug reactions compared with sugammadex (anaphylactic reaction, recurarisation, decreased heart rate, and laryngospasm; P=0.047). CONCLUSIONS: Adamgammadex was non-inferior to sugammadex with a possible lower incidence of adverse drug reactions compared with sugammadex. Adamgammadex may have a potential advantage in terms of its overall risk-benefit profile. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000039525. Registered October 30, 2020. https://www.chictr.org.cn/showproj.html?proj=56825.

METTL3 and IGF2BP1-Mediated m6A Modification of ZHX2 Promotes Tumor Property of Renal Cell Carcinoma.

INTRODUCTION: Renal cell carcinoma (RCC) is a common type of kidney cancer with limited treatment options and a high mortality rate. Therefore, it is essential to understand the role and mechanism of key genes in RCC development and progression. This study aimed to analyze the role of zinc fingers and homeoboxes 2 (ZHX2) in RCC and the underlying mechanism. METHODS: RNA expression was analyzed by quantitative real-time polymerase chain reaction, while protein expression was analyzed by Western blotting assay and immunohistochemistry assay. Cell viability was evaluated using CCK-8 assay, and cell proliferation was assessed by EdU assay. The rate of cell apoptosis was quantified by flow cytometry. Transwell assays were conducted to analyze cell migration and invasion. The sphere formation assay was performed to assess the formation of microspheres. Additionally, m6A RNA immunoprecipitation assay and RNA immunoprecipitation assay were utilized to investigate the relationship between ZHX2 and two proteins, methyltransferase like 3 (METTL3) and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1). The stability of ZHX2 mRNA was analyzed through the Actinomycin D assay. Furthermore, a xenograft mouse model assay was conducted to analyze the effect of ZHX2 overexpression and METTL3 silencing on RCC cell tumor properties in vivo. RESULTS: ZHX2 expression was upregulated in both RCC tissues and cells when compared with healthy renal tissues and human renal cortex proximal convoluted tubule epithelial cells. Depletion of ZHX2 inhibited RCC cell proliferation, migration, invasion, and spheroid-forming capacity but promoted cell apoptosis. Moreover, it was found that METTL3-mediated m6A methylation of ZHX2 and IGF2BP1 also stabilized ZHX2 through m6A methylation modification. Furthermore, ZHX2 overexpression showed a potential for attenuating the effects induced by METTL3 silencing and counteracted the inhibitory effect of METTL3 depletion on tumor formation in vivo. CONCLUSION: METTL3 and IGF2BP1-mediated m6A modification of ZHX2 promoted RCC progression. The finding suggests that ZHX2 may serve as a potential therapeutic target in RCC, providing valuable insights for future clinical interventions.

Comparison of Prone With Lithotomy Position in Removal of Posterior Myoma in Transvaginal Natural Orifice Endoscopic Surgery: A Prospective Cohort Study.

OBJECTIVE: Vaginal natural orifice transluminal endoscopic surgery (vNOTES) is considered to have the advantages of completely scarless, less postoperative pain, earlier flatus, and faster postoperative recovery. However, posterior myoma are relatively difficult to operate through vNOTES in the conventional lithotomy position. Thus, we innovated the application of prone position in the removal of posterior myoma in vNOTES. The aim of this study is the comparison of myomectomy outcomes of patient for single posterior myoma in prone and lithotomy position. DESIGN: A single-center, prospective study. SETTING: A university teaching hospital. PATIENTS: A total of 81 patients with posterior myoma who underwent myomectomy in vNOTES from January 2021 to December 2022. INTERVENTIONS: The patients underwent myomectomy in vNOTES in prone or lithotomy position. MEASUREMENTS AND MAIN RESULTS: Among the patients who underwent vNOTES myomectomy, 29 (35.8%) were in the lithotomy position group, and 52 (64.2%) in the prone position group. Of note, 4 (4.9%) patients underwent a conversion to LESS during the operation-3 in the lithotomy and 1 in the prone position group. And a patient in the lithotomy position group underwent resurgery for hemostasis due to postoperative pelvic bleeding. Compared with the lithotomy position, prone position significantly shortens the operation time (12.3, 95% CI: 6.811, 17.761. p = .009) without increasing the complications and postoperative discomfort of patients. CONCLUSION: Compared to the lithotomy position, the prone position provides greater convenience for operation and exhibits a lower rate of surgical conversion during the removal of single posterior myomas via vNOTES. Further, for patients selecting vNOTES, surgeons need to conduct sufficient preoperative evaluation, timely hemostasis during surgery, and timely surgical conversion if necessary to ensure patient safety.

Liquiritin targeting Th17 cells differentiation and abnormal proliferation of keratinocytes alleviates psoriasis via NF-κB and AP-1 pathway.

Psoriasis is a common immune-mediated inflammatory skin disease, caused by disturbed interactions between keratinocytes and immune cells. Chinese medicine shows potential clinical application for its treatment. Liquiritin is a flavone compound extracted from licorice and shows potential antitussive, antioxidant and antiinflammatory effects, and therefore may have potential as a psoriasis therapeutic. The aim of this work was to examine the possible roles that liquiritin may have in treating psoriasis. HaCaT cells were stimulated by TNF-α with or without liquiritin, harvested for analysis by western blots and RT-qPCR, and the cellular supernatants were collected and analyzed by ELISA for cytokines. In addition, 4 groups of mice were examined: Normal, Vehicle, LQ-L and LQ-H. The mice were sacrificed after 6 days and analyzed using IHC, ELISA, RT-qPCR and flow cytometry. The results showed that liquiritin could significantly inhibit the progression of psoriasis both in vitro and in vivo. Liquiritin strongly suppressed the proliferation of HaCaT keratinocytes but did not affect cell viability. Moreover, liquiritin alleviated imiquimod-induced psoriasis-like skin inflammation and accumulation of Th17 cells and DCs in vivo. In TNF-α-induced HaCaT keratinocytes, both protein and mRNA expression levels of inflammatory cytokines were sharply decreased. In imiquimod-induced mice, the activation of NF-κB and AP-1 was reduced after treatment with liquiritin. Collectively, our results show that liquiritin might act as a pivotal regulator of psoriasis via modulating NF-κB and AP-1 signal pathways.

Overexpression of Aurora Kinase B Is Correlated with Diagnosis and Poor Prognosis in Hepatocellular Carcinoma.

Aurora kinase B (AURKB) overexpression promotes tumor initiation and development by participating in the cell cycle. In this study, we focused on the mechanism of AURKB in hepatocellular carcinoma (HCC) progression and on AURKB's value as a diagnostic and prognostic biomarker in HCC. We used data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) to analyze AURKB expression in HCC. We found that the expression levels of AURKB in HCC samples were higher than those in the corresponding control group. R packages were used to analyze RNA sequencing data to identify AURKB-related differentially expressed genes (DEGs), and these genes were found to be significantly enriched during the cell cycle. The biological function of AURKB was verified, and the results showed that cell proliferation was slowed down and cells were arrested in the G2/M phase when AURKB was knocked down. AURKB overexpression resulted in significant differences in clinical symptoms, such as the clinical T stage and pathological stage. Kaplan-Meier survival analysis, Cox regression analysis, and Receiver Operating Characteristic (ROC) curve analysis suggested that AURKB overexpression has good diagnostic and prognostic potential in HCC. Therefore, AURKB may be used as a potential target for the diagnosis and cure of HCC.

Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes.

AIMS/HYPOTHESIS: This study aimed to assess the causal relationship between visceral obesity and type 2 diabetes and subsequently to screen visceral adipose tissue (VAT)-specific targets for type 2 diabetes. METHODS: We examined the causal relationship between VAT and type 2 diabetes using bidirectional Mendelian randomisation (MR) followed by multivariable MR. We conducted a transcriptome-wide association study (TWAS) leveraging prediction models and a large-scale type 2 diabetes genome-wide association study (74,124 cases and 824,006 controls) to identify candidate genes in VAT and used summary-data-based MR (SMR) and co-localisation analysis to map causal genes. We performed enrichment and single-cell RNA-seq analyses to determine the cell-specific localisation of the TWAS-identified genes. We also conducted knockdown experiments in 3T3-L1 pre-adipocytes. RESULTS: MR analyses showed a causal relationship between genetically increased VAT mass and type 2 diabetes (inverse-variance weighted OR 2.48 [95% CI 2.21, 2.79]). Ten VAT-specific candidate genes were associated with type 2 diabetes after Bonferroni correction, including five causal genes supported by SMR and co-localisation: PABPC4 (1p34.3); CCNE2 (8q22.1); HAUS6 (9p22.1); CWF19L1 (10q24.31); and CCDC92 (12q24.31). Combined with enrichment analyses, clarifying cell-type specificity with single-cell RNA-seq data indicated that most TWAS-identified candidate genes appear more likely to be associated with adipocytes in VAT. Knockdown experiments suggested that Pabpc4 likely contributes to regulating differentiation and energy metabolism in 3T3-L1 adipocytes. CONCLUSIONS/INTERPRETATION: Our findings provide new insights into the genetic basis and biological processes of the association between VAT accumulation and type 2 diabetes and warrant investigation through further functional studies to validate these VAT-specific candidate genes.

A machine learning framework develops a DNA replication stress model for predicting clinical outcomes and therapeutic vulnerability in primary prostate cancer.

Recent studies have identified DNA replication stress as an important feature of advanced prostate cancer (PCa). The identification of biomarkers for DNA replication stress could therefore facilitate risk stratification and help inform treatment options for PCa. Here, we designed a robust machine learning-based framework to comprehensively explore the impact of DNA replication stress on prognosis and treatment in 5 PCa bulk transcriptomic cohorts with a total of 905 patients. Bootstrap resampling-based univariate Cox regression and Boruta algorithm were applied to select a subset of DNA replication stress genes that were more clinically relevant. Next, we benchmarked 7 survival-related machine-learning algorithms for PCa recurrence using nested cross-validation. Multi-omic and drug sensitivity data were also utilized to characterize PCa with various DNA replication stress. We found that the hyperparameter-tuned eXtreme Gradient Boosting model outperformed other tuned models and was therefore used to establish a robust replication stress signature (RSS). RSS demonstrated superior performance over most clinical features and other PCa signatures in predicting PCa recurrence across cohorts. Lower RSS was characterized by enriched metabolism pathways, high androgen activity, and a favorable prognosis. In contrast, higher RSS was significantly associated with TP53, RB1, and PTEN deletion, exhibited increased proliferation and DNA replication stress, and was more immune-suppressive with a higher chance of immunotherapy response. In silico screening identified 13 potential targets (e.g. TOP2A, CDK9, and RRM2) from 2249 druggable targets, and 2 therapeutic agents (irinotecan and topotecan) for RSS-high patients. Additionally, RSS-high patients were more responsive to taxane-based chemotherapy and Poly (ADP-ribose) polymerase inhibitors, whereas RSS-low patients were more sensitive to androgen deprivation therapy. In conclusion, a robust machine-learning framework was used to reveal the great potential of RSS for personalized risk stratification and therapeutic implications in PCa.

Prenatal Exposure to General Anesthesia Drug Esketamine Impaired Neurobehavior in Offspring.

Prenatal exposure to anesthetics has raised increasing attention about the neuronal development in offspring. Animal models are usually used for investigation. As a new drug, esketamine is the s-isoform of ketamine and is twice as potent as the racemic ketamine with less reported adverse effects. Esketamine is currently being used and become more favorable in clinical anesthesia work, including surgeries during pregnancy, yet the effect on the offspring is unknown. The present study aimed to elucidate the effects of gestational administration of esketamine on neuronal development in offspring, using a rat model. Gestational day 14.5 pregnant rats received intravenous injections of esketamine. The postnatal day 0 (P0) hippocampus was digested and cultured in vitro to display the neuronal growth morphology. On Day 4 the in vitro experiments revealed a shorter axon length and fewer dendrite branches in the esketamine group. The results from the EdU- imaging kit showed decreased proliferative capacity in the subventricular zone (SVZ) and dentate gyrus (DG) in both P0 and P30 offspring brains in the esketamine group. Moreover, neurogenesis, neuron maturity and spine density were impaired, resulting in attenuated long-term potentiation (LTP). Compromised hippocampal function accounted for the deficits in neuronal cognition, memory and emotion. The evidence obtained suggests that the neurobehavioral deficit due to prenatal exposure to esketamine may be related to the decrease phosphorylation of CREB and abnormalities in N-methyl-D-aspartic acid receptor subunits. Taken together, these results demonstrate the negative effect of prenatal esketamine exposure on neuronal development in offspring rats. G14.5 esketamine administration influenced the neurobehavior of the offspring in adolescence. Poorer neuronal growth and reduced brain proliferative capacity in late gestation and juvenile pups resulted in impaired P30 neuronal plasticity and synaptic spines as well as abnormalities in NMDAR subunits. Attenuated LTP reflected compromised hippocampal function, as confirmed by behavioral tests of cognition, memory and emotions. This figure was completed on the website of Figdraw.

Nuclear localization signal peptides enhance genetic transformation of Dunaliella salina.

BACKGROUND: Dunaliella salina (D. salina) expression system shows a very attractive application prospect, but it currently has a technical bottleneck, namely the low or unstable expression of recombinant proteins. Given the characteristics of cell-penetrating peptides or/and nuclear localization signal (NLS) peptides, this study is the first attempt to improve the transformation rate of foreign gene with trans-activating transcriptional (TAT) protein or/and NLS peptides. METHODS AND RESULTS: Using salt gradient method, exogenous plasmids were transferred into D. salina cells with TAT or TAT/NLS complexes simultaneously. The ß-glucuronidase gene expression was identified by means of histochemical stain and RT-qPCR detection. Through observation with light microscope, TAT-mediating cells exhibit an apparent cytotoxicity even at ratios of 0.5, no significant toxicity was noted in the TAT/plasmid/NLS complex group. It is obvious that with the addition of peptides the toxicity decreases significantly. Histochemical staining showed that the transformants presented blue color under light microscope, but the negative control and blank control are not. Furthermore, based on a TAT/plasmids ratio of 4 with 10 µg NLS peptides mediation, RT-qPCR results demonstrated that the transcripts of target gene were increased by 269 times than that of control group. CONCLUSIONS: This study demonstrated that combination of TAT and NLS peptides can significantly improve the transformation rate and expression level of foreign gene in D. salina system. It offers a promising way for promoting the application and development of D. salina bioreactor.

A potential paradigm in CRISPR/Cas systems delivery: at the crossroad of microalgal gene editing and algal-mediated nanoparticles.

Microalgae as the photosynthetic organisms offer enormous promise in a variety of industries, such as the generation of high-value byproducts, biofuels, pharmaceuticals, environmental remediation, and others. With the rapid advancement of gene editing technology, CRISPR/Cas system has evolved into an effective tool that revolutionised the genetic engineering of microalgae due to its robustness, high target specificity, and programmability. However, due to the lack of robust delivery system, the efficacy of gene editing is significantly impaired, limiting its application in microalgae. Nanomaterials have become a potential delivery platform for CRISPR/Cas systems due to their advantages of precise targeting, high stability, safety, and improved immune system. Notably, algal-mediated nanoparticles (AMNPs), especially the microalgae-derived nanoparticles, are appealing as a sustainable delivery platform because of their biocompatibility and low toxicity in a homologous relationship. In addition, living microalgae demonstrated effective and regulated distribution into specified areas as the biohybrid microrobots. This review extensively summarised the uses of CRISPR/Cas systems in microalgae and the recent developments of nanoparticle-based CRISPR/Cas delivery systems. A systematic description of the properties and uses of AMNPs, microalgae-derived nanoparticles, and microalgae microrobots has also been discussed. Finally, this review highlights the challenges and future research directions for the development of gene-edited microalgae.

Global burden of type 2 diabetes attributable to non-high body mass index from 1990 to 2019.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) currently was increased in some countries of the world like China. However, the epidemiological trends of T2DM attributable to non-high body mass index (BMI) remain unclear. Thus, we aimed to describe the burden of T2DM attributable to non-high BMI. METHODS: To estimate the burden of T2DM attributable to non-high BMI, data from the Global Burden of Disease Study 2019 were used to calculate the deaths and disability-adjusted life years (DALYs) by age, sex, year, and location. The estimated annual percentage change (EAPC) was applied in the analysis of temporal trends in T2DM from 1990 to 2019. RESULTS: Globally in 2019, the number of death cases and DALYs of T2DM attributable to non-high BMI accounted for 57.9% and 48.1% of T2DM-death from all risks, respectively. Asia accounted for 59.5% and 63.6% of the global non-high-BMI-related death cases and DALYs of T2DM in 2019, respectively. From 1990 to 2019, regions in the low-income experienced a rise in DALYs attributable to non-high BMI. As compared to other age groups, older participants had higher deaths and DALYs of T2DM attributable to non-high BMI. The death and DALY rates of T2DM due to non-high BMI were higher in males and people in regions with low socio-demographic index (SDI) countries. CONCLUSIONS: The burden of T2DM attributable to non-high BMI is higher in the elderly and in people in regions with low- and middle-SDI, resulting in a substantial burden on human health and the social cost of healthcare.

Neonatal outcomes when intravenous esketamine is added to the parturients transferred from labor analgesia to emergency cesarean section: a retrospective analysis report.

OBJECTIVES: The use of intravenous analgesics during emergency cesarean section may lead to adverse neonatal outcomes. In our study, we investigated whether a single intravenous (i.v.) dose of 25 mg esketamine administered to parturients with inadequate analgesia during epidural anesthesia for cesarean section would affect the neonate. DESIGN: We reviewed the records of parturients who were transferred from labor analgesia to epidural anesthesia for emergency cesarean section from January 2021 to April 2022. Parturients were grouped by whether they received esketamine infusions during the incision-delivery interval. Neonatal outcomes, including umbilical arterial-blood gas analysis (UABGA), Apgar score, and total days spent by the neonate in the hospital, were compared between the two groups. The secondary outcomes of this study included BP, heart rate (HR), SPO2 and the incidence of adverse effects in parturients during operation. SETTING: China. RESULTS: After propensity score matching, 31 patients remained in each of the non-esketamine and esketamine groups. There were no significant differences in neonatal outcomes, including UABGA, Apgar score, and total days in the hospital, between the two groups. Additionally, our study showed a similar hemodynamic performance in parturients between the two groups during operation. CONCLUSIONS: Intravenous esketamine (25 mg) is safe for neonates when it is given to parturients transferred from labor analgesia to emergency cesarean section.

Intravenous lidocaine improves postoperative cognition in patients undergoing laparoscopic colorectal surgery: a randomized, double-blind, controlled study.

BACKGROUND: The risk of postoperative cognitive dysfunction(POCD) in laparoscopic surgery should not be overlooked. Intravenous lidocaine can reduce perioperative inflammatory response in patients undergoing laparoscopic surgery, while the effect of intraoperative intravenous lidocaine on postoperative cognitive function in patients undergoing laparoscopic colorectal cancer surgery has not been well studied. We investigated whether intraoperative lidocaine improves postoperative cognitive function after laparoscopic radical resection for colorectal cancer. METHODS: We conducted a prospective, randomized double blinded controlled trial to investigate the effect of intravenous lidocaine on rapid postoperative recovery in patients undergoing laparoscopic radical resection of colorectal cancer. The patients were randomly assigned to receive either intravenous lidocaine or saline. The primary outcome was cognitive dysfunction defined by a decrease from pre- to postoperative ≥ 2 of the Mini-Mental State Examination (MMSE) score, at the 3rd and the 7th postoperative days. Secondary outcomes were the MMSE raw score and parameters of the patients' postoperative recovery such as agitation and length of stay in the post-anaesthesia care unit (PACU), length of hospital stay, markers of inflammation (white blood cell count and CRP), and incidence of complications. RESULTS: Seventy-three patients in the lidocaine group and 77 patients in the control group completed the trial. The rate of cognitive dysfunction was lower in the lidocaine group than that in the control group, both at the 3rd (18.57% vs. 63.64% for each group respectively; RR = 0.26, 95%CI = 0.19-0.32; p < 0.0001) and at the 7th postoperative day (12.33% vs. 53.25% for each group respectively; RR = 0.28, 95%CI = 0.22-0.35; P < 0.001). The postoperative MMSE scores were also higher in the lidocaine group than in the control group both at the 3rd (median 25 vs. 24 respectively) and at the 7th postoperative day (26 vs. 24 respectively). Also, patients in the lidocaine group displayed a lower white blood cell count than the control group at the 1st postoperative day (8.5 ± 2.7 vs. 10.4 ± 3.3; p < 0. 001). No differences were evidenced for the other secondary outcomes. CONCLUSIONS: Intraoperative intravenous lidocaine can significantly improve postoperative cognitive function in patients undergoing laparoscopic radical resection of colorectal cancer. TRIAL REGISTRATION: Chinese Clinical Trial Registry (16/1/2022, registration number: ChiCTR2200055683).

Assessing the Impact of Prone Positioning on Mortality and Adverse Events Among Patients with Acute Respiratory Distress Syndrome: A Meta-Analysis.

Background: Prone positioning has evolved as a therapeutic intervention for patients with acute respiratory distress syndrome (ARDS). ARDS remains a critical condition, with a mortality rate of approximately 40%. Prone positioning, which involves placing patients in a face-down position, has the potential to enhance gas exchange and improve lung mechanics, possibly leading to better patient outcomes. Objectives: This comprehensive review aims to evaluate the impact of prone positioning on mortality (primary outcome) and the occurrence of adverse events (secondary outcome) in patients with ARDS compared to conventional supine positioning. Methods: We conducted an extensive systematic review, including studies published from 2000 to 2022. We searched databases including PUBMED, MEDLINE, EMBASE, CENTRAL, and WEB OF SCIENCE. Only randomized controlled trials (RCTs) that compared the outcomes of patients with ARDS in prone and supine positions were included. We employed the Cochrane risk of bias instrument to assess the methodological quality of the included RCTs. Results: Our review included a total of twelve RCTs involving 2736 patients, with 1401 patients in the prone position. The meta-analysis demonstrated a lower mortality rate among patients in the prone position compared to those in the supine position (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.52-0.98; P = .04). Notably, there was a higher incidence of pressure sores in patients placed in the prone position (OR, 0.15; 95% CI, 0.09-0.20) compared to those in the supine position. However, there were no statistically significant differences in the occurrence of arrhythmias, unplanned extubation, or pneumothorax between the two positioning strategies. Conclusions: Prone positioning offers potential benefits for patients with ARDS by reducing mortality rates. However, it is important to note that there is an associated risk of pressure sores. Further research and clinical consideration are needed to optimize the use of prone positioning in ARDS management.

Neurological Dysfunction and Serum Levels of IL-6 and IL-1ß in Patients Undergoing Isoflurane Inhalation Anesthesia: A Correlation Study.

Objective: This study aims to explore the association between neurological dysfunction and serum levels of Interleukin-6 (IL-6) and Interleukin-1ß (IL-1ß) in patients undergoing isoflurane inhalation anesthesia. Methods: This prospective observational study enrolled a total of 88 patients who underwent isoflurane anesthesia, between April 2019 and April 2020 in our hospital's operating room. The Mini-Mental State Examination scale (MMSE) was administered on the first preoperative day (T0), the 1st postoperative day (T1), the 3rd postoperative day (T2), and the 7th postoperative day (T3). Based on the MMSE score obtained on the 1st postoperative day, patients were categorized into the neurological dysfunction group (n = 23) and the normal group (n = 65). Serum levels of IL-6 and IL-1ß were measured at T0, T1, T2, and T3, and their relationship with MMSE scores was analyzed. Results: Compared to the normal group, the neurological dysfunction group exhibited significantly higher levels of serum IL-6 and IL-1ß at all time points except T0, accompanied by notably lower MMSE scores (P < .001). Combined diagnostic parameters, including area under the curve (AUC) value, sensitivity, and specificity, showed improved performance compared to individual tests. Pearson correlation analysis revealed a negative correlation between serum IL-6 and IL-1ß levels and MMSE scores (r = -0.719, -0.408, all P < .05). Conclusions: Our findings highlight a correlation between neurological dysfunction and serum IL-6 and IL-1ß levels in patients undergoing isoflurane inhalation anesthesia. These cytokines could serve as valuable indicators for the early detection of neurological dysfunction following anesthesia.

Efficacy and safety of ciprofol vs. propofol for the induction and maintenance of general anaesthesia: A multicentre, single-blind, randomised, parallel-group, phase 3 clinical trial.

BACKGROUND: HSK3486 (ciprofol) is a 2,6-disubstituted phenol derivative that acts like propofol as an agonist at the gamma-aminobutyric acid-A (GABA A ) receptor. OBJECTIVE: To investigate the efficacy and safety of HSK3486 for general anaesthesia induction and maintenance. DESIGN: A single-blinded, randomised, parallel-group, phase 3 trial. SETTING: Involving 10 study centres, from November 24, 2020 to January 25, 2021. PATIENTS: A total of 129 patients undergoing nonemergency, noncardiothoracic, and nonneurosurgical elective surgery. INTERVENTION: Patients were randomly assigned at a 2:1 ratio into HSK3486 or propofol groups, to receive HSK3486 (0.4 mg kg -1 ) or propofol (2.0 mg kg -1 ) for induction before a maintenance infusion at initial rates of 0.8 and 5.0 mg kg -1 h -1 , and were adjusted to maintain a bispectral index (BIS) of 40-60 until the end of surgery. MAIN OUTCOME MEASURES: Noninferiority between the drugs was evaluated as the lower limit of the 95% confidence interval (CI) for the between-group difference in the success rate of anesthetic maintenance (primary outcome) >-8%. Secondary outcomes included successful anaesthetic induction, full alertness and spontaneous breathing recovery, time until leaving the postanaesthesia care unit and changes in BIS. Safety profiles were also measured. RESULTS: Of 129 enrolled patients, 128 completed the trial, with 86 in the HSK3486 group and 42 in the propofol group. The success rate for the maintenance of general anaesthesia was 100% for both groups, and noninferiority of HSK3486 was confirmed (95% CI -4.28% to 8.38%). No significant differences were found between the two groups of patients with regard to secondary outcomes (all P  > 0.05). There appeared to be a comparable incidence of treatment for emergency adverse events (TEAEs) (80.2% vs. 81.0%, P  = 1.000) and drug-related TEAEs (57.0% vs. 64.3%, P  = 0.451) in the HSK3486 and propofol groups. CONCLUSION: HSK3486 had a noninferior efficacy profile compared to propofol, exhibiting excellent tolerance. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT04511728.

Benzoylaconitine Alleviates Progression of Psoriasis via Suppressing STAT3 Phosphorylation in Keratinocytes.

Psoriasis is a chronic and multifactorial skin disease which is caused by inflammatory infiltrates, keratinocyte hyperproliferation, and accumulation of immune cells. As part of the Aconitum species, Benzoylaconitine (BAC) shows potential antiviral, anti-tumor, and anti-inflammatory effects. In this study, we investigated the effects and mechanisms of BAC on tumor necrosis factor-alpha (TNF-α)/LPS-induced HaCaT keratinocytes in a imiquimod(IMQ)-induced mice model. The results showed that BAC could relieve the symptoms of psoriasis by inhibiting cell proliferation, the release of inflammatory factors, and the accumulation of Th17 cells, while no obvious effect on cell viability and safety was observed both in vitro and in vivo. Additionally, BAC can markedly inhibit the protein and mRNA levels of inflammatory cytokines in TNF-α/LPS-induced HaCaT keratinocytes by inhibiting the phosphorylation of STAT3. In brief, our data indicated that BAC could alleviate the progression of psoriasis and may be a potential therapeutic agent for treating psoriasis in clinical practice.