Cytosolic mtDNA-cGAS-STING axis contributes to sepsis-induced acute kidney injury via activating the NLRP3 inflammasome.

BACKGROUND: NLRP3 inflammasome activation is significantly associated with sepsis-induced acute kidney injury (S-AKI). Cytosolic DNA derived from damaged mitochondria has been reported to activate NLRP3 inflammasome via upregulating the cyclic GMP-AMP synthase (cGAS)-the stimulator of interferon genes (STING) axis in nucleus pulposus cell and cardiomyocytes. However, the regulatory effect of mitochondria DNA (mtDNA)-cGAS-STING axis on the NLRP3 inflammasome in S-AKI remains unclear. METHODS: In the current study, we established an in vivo model of S-AKI by intraperitoneally injecting male C57BL/6 J mice with lipopolysaccharide (LPS). Next, selective cGAS inhibitor RU.521, and STING agonist DMXAA were intraperitoneally injected in the mice; then, blood urea nitrogen (BUN), serum creatinine (CRE), urinary kidney injury molecular-1 (KIM-1), pathological changes, and infiltrated neutrophils were detected to assess kidney injury. We also performed western blot and immunofluorescence assays to evaluate STING, cGAS, TBK-1, p-TBK-1, IRF3, p-IRF3, NF-kB, p-NF-kB, NLRP3, cleaved caspase-1, caspase-1, GSDMD-N, and GSDMD expression levels in kidney tissues. IL-18 and IL-1ß in renal tissue were identified by ELISA. In vitro, we treated HK-2 cells with LPS to establish a cell model of S-AKI. Furthermore, ethidium bromide (EtBr) was administered to deplete mitochondria DNA (mtDNA). LPS-induced cytotoxicity was evaluated by LDH release assay. Protein expression of cGAS, STING, and NLRP3 in was quantified by western blot. Cytosolic mtDNA was detected by immunofluorescence and q-PCR. Released IL-1ß and IL-18 in HK-2 supernatants were detected by ELISA. RESULTS: LPS injection induced S-AKI in mice, as evidenced by neutrophil infiltration, tubular vacuolation, and increased levels of serum creatinine (CRE), blood urea nitrogen (BUN), and urinary KIM-1. In addition, LPS activated the cGAS-STING axis and NLRP3 inflammasome in vivo, illustrated by increased phosphorylation levels of TBK-1, IRF3, and NF-kB protein, increased ratio of cleaved caspase-1 to caspase-1 and GSDMD-N to GSDMD, and increased IL-1ß and IL-18 levels. Moreover, the cGAS inhibitor RU.521 effectively attenuated NLRP3 inflammasome and S-AKI; however, these effects were abolished by treatment with the STING agonist DMXAA. Furthermore, cytosolic release of mtDNA and activation of the cGAS-STING-NLRP3 axis were observed in LPS-treated HK-2 cells. Inhibiting mtDNA replication by Ethidium Bromide (EtBr) treatment reduced cytosolic mtDNA accumulation and downregulated the cGAS-STING-NLRP3 axis, ameliorating the cytotoxicity induced by LPS. CONCLUSION: This study demonstrated that the cGAS-STING axis was triggered by cytosolic mtDNA and participated in the development of S-AKI by activating NLRP3 inflammasome. Reducing cytosolic mtDNA accumulation or inhibiting the cGAS-STING axis may be potential therapeutic targets for S-AKI.

The association between mortality and door-to-antibiotic time: a systematic review and meta-analysis.

PURPOSE: Previous studies evaluating the impact of antibiotic timing on mortality in sepsis have shown conflicting results. We performed a meta-analysis to evaluate the association between door-to-antibiotic time (each hour of delay) and mortality in sepsis. METHODS: We searched PubMed and Embase through 10 November 2022 to identity cohort studies that evaluated the adjusted association between door-to-antibiotic time (each hour of delay) and mortality in adult patients with sepsis. The primary outcome was mortality. Analysis was based on inverse-variance weighting using a fixed-effects model. The variances were derived from the logarithms of the reported confidence intervals (CIs) for associations. We estimated the odds ratio, 95% CI, and number needed to treat for the pooled data. RESULTS: Fifteen cohort studies involving 106 845 patients were included in the meta-analysis. Door-to-antibiotic time (each hour of delay) was associated with increased risk of mortality (odds ratio: 1.07; 95% CI: 1.06-1.08; P < 0.0001; number needed to treat = 91), with high heterogeneity (I2 = 82.2%). The association was robust in sensitivity analyses and consistent in subgroup analyses. No publication bias was found. CONCLUSION: In adult patients with sepsis, each hour of delay in antibiotic administration is associated with increased odds of mortality. Key messages What is already known on this topic Sepsis is a common and lethal syndrome that affects millions of people worldwide. The updated 2018 Surviving Sepsis Campaign guidelines recommended initiating empirical broad-spectrum antibiotic coverage within 1 hour of identification of sepsis and septic shock. Delay in antibiotic administration may increase the risk of mortality in patients with sepsis. What this study adds This meta-analysis evaluates and quantifies the association between door-to-antibiotic time (each hour of delay) and mortality in patients with sepsis. Each hour of delay in antibiotic administration is associated with increased odds of mortality in sepsis. The number needed to treat (NNT) with delayed antibiotic administration for one additional death was 91. How this study might affect research, practice, or policy: More efforts should be made to speed up the diagnosis of sepsis or sepsis shock.

Panax notoginseng saponins induce apoptosis in retinoblastoma Y79 cells via the PI3K/AKT signalling pathway.

This study aimed to investigate the effects of Panax notoginseng saponins (PNS) on the proliferation, apoptosis, and PI3K/AKT signalling pathways of retinoblastoma Y79 cells to explore the possible mechanism of action of PNS on retinoblastoma. The effects of PNS and carboplatin on the proliferation of Y79 cells were examined using cell counting kit-8 assay. And the apoptosis rate, the mRNA and protein levels of apoptosis-related genes and the expression of PI3K/AKT pathway protein were assessed. PNS effectively inhibited the proliferation (P < 0.05) and increased apoptosis of Y79 cells (P < 0.05). Compared with the negative control, the Y79 cells treated with PNS had significantly increased (P < 0.05) mRNA and protein expression of Bax, caspase-3, caspase-8, and caspase-9 and elevated levels of cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 proteins (P < 0.05). The mRNA and protein expression of the apoptosis suppressor gene Bcl-2 was inhibited (P < 0.05), while the Bax/Bcl-2 values of the cells in the drug group were significantly higher than those in the negative group (P < 0.01). After treatment with PNS, the total protein expression of PI3K and AKT1 in the Y79 cells did not show significant differences compared with the negative group (P > 0.05), although the expression of phosphorylated proteins p-PI3K, p-AKT (Thr308), p-AKT (Ser473), and p-mTOR were significantly reduced (P < 0.05). Meanwhile, the antagonist protein of the pathway phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression was increased (P < 0.01). Cellular alterations following inhibition of the PI3K/AKT pathway using LY294002 were similar to those of PNS, the proliferation of Y79 cells was also inhibited, and cell apoptosis increased (P < 0.001). The expression of Bax, caspase-3, caspase-8, caspase-9, and activation proteins cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 was also significantly higher than that in the negative control (P < 0.05). Bcl-2 protein expression was decreased (P < 0.01), and the Bax/Bcl-2 ratio was higher than that in the negative control (P < 0.001). Overall, we demonstrated that PNS effectively inhibited the proliferation and promoted the apoptosis of retinoblastoma Y79 cells. The apoptosis-promoting effect of PNS may involve the inhibition of the PI3K/AKT signalling pathway, which subsequently regulates the expression of apoptosis-related genes.

Ultrasound-guided quadratus lumborum block for postoperative analgesia in renal surgery: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Quadratus lumborum block (QLB) guided by ultrasound is a novel local block anesthesia technique, which can be used in various surgeries for multimodal analgesia. Its analgesic effectiveness for renal surgery is still uncertain. The aim of this meta-analysis was to assess the postoperative analgesic efficacy of QLB in adult patients undergoing renal surgery. METHODS: We systematically searched randomized controlled trials (RCTs) through the databases of Cochrane Library, Embase, and PubMed until June 21, 2021. Postoperative consumption of opioid in the first 24-h was set as the primary outcome. The risk of bias was evaluated by Cochrane methodology. RESULTS: Ten RCTs involving 577 patients were eligible for our inclusion criteria. Ultrasound-guided QLB significantly reduced postoperative consumption of opioid in the first 24 h after surgery (mean differences [MD] - 17.58, 95% confidence interval [CI] - 23.14 to - 12.02, P < 0.00001, I2 = 98%). Similarly, the results were consistent in subgroups analysis of both different types of renal surgeries and different QLB approaches. The QLB also significantly decreased postoperative static pain scores at different time points, and reduced the incidence of postoperative nausea and vomiting (PONV) (risk ratio [RR] = 0.48, 95% CI 0.33 to 0.70, P = 0.0002, I2 = 0%) and the number of rescue analgesia patients (RR = 0.34, 95% CI 0.20 to 0.58, P < 0.0001, I2 = 0%). No major complications related to QLB were reported in the included studies. CONCLUSIONS: Ultrasound-guided QLB improves postoperative analgesic efficacy and reduces PONV in adult patients undergoing renal surgery. There is currently limited evidence concerning the analgesic effects of different QLB approaches after renal surgery, and further research is required in this area. PROSPERO REGISTRATION: PROSPERO Registration CRD42021260821.

Ultrasound-guided erector spinae plane block for postoperative analgesia: a meta-analysis of randomized controlled trials.

BACKGROUND: Ultrasound-guided Erector Spinae Plane Block (ESPB) has been increasingly applied in patients for postoperative analgesia. Its effectiveness remain uncertain. This meta-analysis aimed to determine the clinical efficacy of ultrasound-guided ESPB in adults undergoing general anesthesia (GA) surgeries. METHODS: A systematic databases search was conducted in PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) comparing ESPB with control or placebo. Primary outcome was iv. opioid consumption 24 h after surgery. Standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated with a random-effects model. RESULTS: A total of 12 RCTs consisting of 590 patients were included. Ultrasound-guided ESPB showed a reduction of intravenous opioid consumption 24 h after surgery (SMD = - 2.18; 95% confidence interval (CI) -2.76 to - 1.61,p < 0.00001). Considerable heterogeneity was observed (87%). It further reduced the number of patients who required postoperative analgesia (RR = 0.41,95% CI 0.25 to 0.66,p = 0,0002) and prolonged time to first rescue analgesia (SMD = 4.56,95% CI 1.89 to 7.22, p = 0.0008). CONCLUSIONS: Ultrasound-guided ESPB provides effective postoperative analgesic in adults undergoing GA surgeries.

The analgesic efficacy compared ultrasound-guided continuous transverse abdominis plane block with epidural analgesia following abdominal surgery: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: This review and meta-analysis aims to evaluate the analgesic efficacy of continuous transversus abdominis plane (TAP) block compared with epidural analgesia (EA) in adults after abdominal surgery. METHODS: The databases PubMed, Embase and Cochrane Central Register were searched from inception to June 2019 for all available randomized controlled trials (RCTs) that evaluated the analgesic efficacy of continuous TAP block compared with EA after abdominal surgery. The weighted mean differences (WMDs) were estimates for continuous variables with a 95% confidence interval (CI) and risk ratio (RR) for dichotomous data. The pre-specified primary outcome was the dynamic pain scores 24 h postoperatively. RESULTS: Eight trials including 453 patients (TAP block:224 patients; EA: 229 patients) ultimately met the inclusion criteria and seven trials were included in the meta-analysis. Dynamic pain scores after 24 h were equivalent between TAP block and EA groups (WMD:0.44; 95% CI: 0.1 to 0.99; I2 = 91%; p = 0.11). The analysis showed a significant difference between the subgroups according to regularly administering (4 trials; WMD:-0.11; 95% CI: - 0.32 to 0.09; I2 = 0%; p = 0.28) non-steroidal anti-inflammatory drugs (NSAIDs) or not (3 trials; WMD:1.02; 95% CI: 0.09 to 1.96; I2 = 94%; p = 0.03) for adjuvant analgesics postoperatively. The measured time of the urinary catheter removal in the TAP group was significantly shorter (3 trials, WMD:-18.95, 95% CI:-25.22 to - 12.71; I2 = 0%; p < 0.01), as was time to first ambulation postoperatively (4 trials, WMD:-6.61, 95% CI: - 13.03 to - 0.19; I2 = 67%; p < 0.05). CONCLUSION: Continuous TAP block, combined with NSAIDs, can provide non-inferior dynamic analgesia efficacy compared with EA in postoperative pain management after abdominal surgery. In addition, continuous TAP block is associated with fewer postoperative side effects.

Chernoff Index for Cox Test of Separate Parametric Families.

The asymptotic efficiency of a generalized likelihood ratio test proposed by Cox is studied under the large deviations framework for error probabilities developed by Chernoff. In particular, two separate parametric families of hypotheses are considered (Cox, 1961, 1962). The significance level is set such that the maximal type I and type II error probabilities for the generalized likelihood ratio test decay exponentially fast with the same rate. We derive the analytic form of such a rate that is also known as the Chernoff index (Chernoff, 1952), a relative efficiency measure when there is no preference between the null and the alternative hypotheses. We further extend the analysis to approximate error probabilities when the two families are not completely separated. Discussions are provided concerning the implications of the present result on model selection.

Recommendation System for Adaptive Learning.

An adaptive learning system aims at providing instruction tailored to the current status of a learner, differing from the traditional classroom experience. The latest advances in technology make adaptive learning possible, which has the potential to provide students with high-quality learning benefit at a low cost. A key component of an adaptive learning system is a recommendation system, which recommends the next material (video lectures, practices, and so on, on different skills) to the learner, based on the psychometric assessment results and possibly other individual characteristics. An important question then follows: How should recommendations be made? To answer this question, a mathematical framework is proposed that characterizes the recommendation process as a Markov decision problem, for which decisions are made based on the current knowledge of the learner and that of the learning materials. In particular, two plain vanilla systems are introduced, for which the optimal recommendation at each stage can be obtained analytically.

Exploratory Item Classification Via Spectral Graph Clustering.

Large-scale assessments are supported by a large item pool. An important task in test development is to assign items into scales that measure different characteristics of individuals, and a popular approach is cluster analysis of items. Classical methods in cluster analysis, such as the hierarchical clustering, K-means method, and latent-class analysis, often induce a high computational overhead and have difficulty handling missing data, especially in the presence of high-dimensional responses. In this article, the authors propose a spectral clustering algorithm for exploratory item cluster analysis. The method is computationally efficient, effective for data with missing or incomplete responses, easy to implement, and often outperforms traditional clustering algorithms in the context of high dimensionality. The spectral clustering algorithm is based on graph theory, a branch of mathematics that studies the properties of graphs. The algorithm first constructs a graph of items, characterizing the similarity structure among items. It then extracts item clusters based on the graphical structure, grouping similar items together. The proposed method is evaluated through simulations and an application to the revised Eysenck Personality Questionnaire.

The Ganglioside GM-1 Inhibits Bupivacaine-Induced Neurotoxicity in Mouse Neuroblastoma Neuro2a Cells.

OBJECTIVE: Studies indicate that bupivacaine-induced neurotoxicity results from apoptosis. Gangliosides have been shown to promote neuronal repair and recovery of neurological function after spinal cord injury. Previously, we confirmed that in vivo administration of the ganglioside GM-1 attenuated bupivacaine-induced neurotoxicity in various animal models; however, the underlying mechanism remains unclear. METHODS: Cells of the neuroblastoma line N2a (Neuro2a cells) were divided into three experimental groups: control, bupivacaine-treated, and bupivacaine-treated with GM-1 pretreatment. Cell viability and apoptosis were assessed through CCK-8 assays, Hoechst staining, and flow cytometry analysis of Annexin-V/propidium iodide double labeling. Real-time polymerase chain reaction and western blotting assessed the expression of caspase-3, caspase-8, and caspase-9. RESULTS: Bupivacaine-induced apoptosis worsened with increasing dose and exposure time. Bupivacaine induced increased expression of caspase-3 and caspase-9, but not caspase-8, indicating that the mitochondrial pathway but not the death receptor apoptosis pathway was activated. GM-1 pretreatment inhibited bupivacaine-induced apoptosis and the expression of caspase-3 and caspase-9 in a dose-dependent manner. CONCLUSION: Bupivacaine induced neurotoxicity by activating apoptosis via the mitochondrial pathway, and this was inhibited by GM-1 pretreatment.

Effect of lung-protective ventilation with lower tidal volumes on clinical outcomes among patients undergoing surgery: a meta-analysis of randomized controlled trials.

BACKGROUND: In anesthetized patients undergoing surgery, the role of lung-protective ventilation with lower tidal volumes is unclear. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of this ventilation strategy on postoperative outcomes. METHODS: We searched electronic databases from inception through September 2014. We included RCTs that compared protective ventilation with lower tidal volumes and conventional ventilation with higher tidal volumes in anesthetized adults undergoing surgery. We pooled outcomes using a random-effects model. The primary outcome measures were lung injury and pulmonary infection. RESULTS: We included 19 trials (n=1348). Compared with patients in the control group, those who received lung-protective ventilation had a decreased risk of lung injury (risk ratio [RR] 0.36, 95% confidence interval [CI] 0.17 to 0.78; I2=0%) and pulmonary infection (RR 0.46, 95% CI 0.26 to 0.83; I2=8%), and higher levels of arterial partial pressure of carbon dioxide (standardized mean difference 0.47, 95% CI 0.18 to 0.75; I2=65%). No significant differences were observed between the patient groups in atelectasis, mortality, length of hospital stay, length of stay in the intensive care unit or the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen. INTERPRETATION: Anesthetized patients who received ventilation with lower tidal volumes during surgery had a lower risk of lung injury and pulmonary infection than those given conventional ventilation with higher tidal volumes. Implementation of a lung-protective ventilation strategy with lower tidal volumes may lower the incidence of these outcomes.

Pain sensitivity: a feasible way to predict the intensity of stress reaction caused by endotracheal intubation and skin incision?

PURPOSE: Recent studies have shown that pain sensitivity has a significant relationship with clinical pain and may also predict the intensity of pain and analgesic consumption after surgery. However, the correlation between pre-operative pain sensitivity and stress response during anesthesia has not been investigated. Therefore, we aimed to explore the relationship between pre-operative pain sensitivity and stress responses during intubation and skin incision in this study. METHODS: Fifty women (ASA I-II) aged 20-55 years, undergoing elective abdominal surgery requiring at least a 10-cm-long skin incision were studied. Pain sensitivity, including pain threshold and pain tolerance was measured before surgery. In this study, experimental pain was induced by potassium ion conducted via continuous current. When patients reported feeling pain or acted to stop pain, the intensity of the current was recorded to register pain threshold and pain tolerance. The State-Trait Anxiety Inventory (STAI) was used to examine the pre-operative mental status. General anesthesia was induced with intravenous fentanyl and a target-controlled infusion of propofol. Blood samples for norepinephrine (NE) detection were collected at 10 min after entering the operating theater, immediately before intubation, 2 min after intubation, immediately before skin incision and 2 min after incision. Mean arterial blood pressure (MAP) and heart rate (HR) were recorded at the same time. Pearson's correlation test (SPSS 13.0) was then used to analyze the relationship between pain sensitivity and the changes in MAP, HR and NE level. RESULTS: A total of fifty women were enrolled in the study. Their pre-operative pain threshold and pain tolerance were 0.90 ± 0.40 mA and 2.53 ± 0.77 mA,respectively. Changes in MAP, HR and NE before and after intubation or skin incision were significantly related with pre-operative pain tolerance (P < 0.05); however, pain threshold was not correlated with changes in MAP, HR and NE (P > 0.05). The STAI score did not correlate with the stress response either (P > 0.05). CONCLUSIONS: Pain tolerance had a significant relationship with stress response during intubation and skin incision. We may initially use pain tolerance to direct opioid usage in the future.

Cumulative sojourn time in longitudinal studies: a sequential imputation method to handle missing health state data due to dropout.

Missing data are ubiquitous in longitudinal studies. In this paper, we propose an imputation procedure to handle dropouts in longitudinal studies. By taking advantage of the monotone missing pattern resulting from dropouts, our imputation procedure can be carried out sequentially, which substantially reduces the computation complexity. In addition, at each step of the sequential imputation, we set up a model selection mechanism that chooses between a parametric model and a nonparametric model to impute eachmissing observation. Unlike usual model selection procedures that aim at finding a single model fitting the entire data set well, our model selection procedure is customized to find a suitable model for the prediction of each missing observation.

The effect of goal-directed therapy on mortality in patients with sepsis - earlier is better: a meta-analysis of randomized controlled trials.

INTRODUCTION: The Surviving Sepsis Campaign guidelines recommend goal-directed therapy (GDT) for the early resuscitation of patients with sepsis. However, the findings of the ProCESS (Protocolized Care for Early Septic Shock) trial showed no benefit from GDT for reducing mortality rates in early septic shock. We performed a meta-analysis to integrate these findings with existing literature on this topic and evaluate the effect of GDT on mortality due to sepsis. METHODS: We searched the PubMed, Embase and CENTRAL (Cochrane Central Register of Controlled Trials) databases and reference lists of extracted articles. Randomized controlled trials comparing GDT with standard therapy or usual care in patients with sepsis were included. The prespecified primary outcome was overall mortality. RESULTS: In total, 13 trials involving 2,525 adult patients were included. GDT significantly reduced overall mortality in the random-effects model (relative risk (RR), 0.83; 95% confidence interval (CI), 0.71 to 0.96; P =0.01; I 2 = 56%). Predefined subgroup analysis according to the timing of GDT for resuscitation suggested that a mortality benefit was seen only in the subgroup of early GDT within the first 6 hours (seven trials; RR, 0.77; 95% CI, 0.67 to 0.89; P =0.0004; I 2 = 40%), but not in the subgroup with late or unclear timing of GDT (six trials; RR, 0.92; 95% CI, 0.69 to 1.24; P =0.59; I 2 = 56%). GDT was significantly associated with the use of dobutamine (five trials; RR, 2.71; 95% CI, 1.20 to 6.10; P =0.02). CONCLUSIONS: The results of the present meta-analysis suggest that GDT significantly reduces overall mortality in patients with sepsis, especially when initiated early. However, owing to the variable quality of the studies, strong and definitive recommendations cannot be made.

Efficacy of ultrasound-guided radial artery catheterization: a systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Ultrasound guidance has emerged as an adjunct for central vein catheterization in both adults and children. However, the use of ultrasound guidance for radial arterial catheterization has not been well established. We conducted a systematic review and meta-analysis to evaluate the efficacy of ultrasound guidance for radial artery catheterization. METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched. Randomized controlled trials (RCTs) comparing ultrasound guidance with other techniques (palpation or Doppler) in adult or pediatric patients requiring radial artery catheterization were included. The primary outcome was first-attempt success. RESULTS: Seven RCTs enrolling 546 patients met the inclusion criteria, and all the selected trials were considered as at high risk of bias. Ultrasound-guided radial artery catheterization was associated with an increased first-attempt success (relative risk (RR) 1.55, 95% confidence interval (CI) 1.02 to 2.35). There was significant heterogeneity among the studies (I2 = 74%). Ultrasound-guided radial artery catheterization in small children and infants also provided an increased chance for first-attempt success (RR 1.94, 95% CI 1.31 to 2.88). Ultrasound guidance further significantly reduced mean attempts to success (weighted mean difference (WMD) -1.13, 95% CI -1.58 to -0.69), mean time to success (WMD -72.97 seconds, 95% CI -134.41 to -11.52), and incidence of the complication of hematoma (RR 0.17, 95% CI 0.07 to 0.41). CONCLUSIONS: Ultrasound guidance is an effective and safe technique for radial artery catheterization, even in small children and infants. However, the results should be interpreted cautiously due to the heterogeneity among the studies.

Effects of intravenous lidocaine on postoperative pain and gastrointestinal function recovery following gastrointestinal surgery: a meta-analysis.

INTRODUCTION: The full extent of intravenous lidocaine's effectiveness in alleviating postoperative pain and enhancing gastrointestinal function recovery remains uncertain. EVIDENCE ACQUISITION: We conducted an exhaustive search of databases to identify randomized controlled trials that compared intravenous lidocaine infusion's efficacy to that of a placebo or routine care in patients undergoing gastrointestinal surgery. The primary outcome measure was resting pain scores 24 h postoperatively. We utilized a random-effects model based on the intention-to-treat principle for the overall results. EVIDENCE SYNTHESIS: This study included twenty-four trials with 1533 patients. Intravenous lidocaine significantly reduced resting pain scores 24 h after gastrointestinal surgery (twenty trials, SMD -0.67, 95% CI -1.09 to -0.24, P=0.002, I2 = 90%). This finding was consistent in subgroup analyses and sensitivity analyses. The benefit was also observed at other resting and moving time points (1, 2, 4, and 12 h) postoperatively. Intravenous lidocaine significantly decreased opioid consumption within 24 h after surgery (eleven trials, SMD: -1.19; 95% CI: -1.99 to -0.39; P=0.003). Intravenous lidocaine also shortened the time to bowel sound (MD: -8.51; 95% CI: -14.59 to -2.44; P=0.006), time to first flatus (MD: -6.00; 95% CI: -9.87 to -2.13; P=0.002), and time to first defecation (MD: -9.77; 95% CI: -17.19 to -2.36; P=0.01). CONCLUSIONS: Perioperative intravenous lidocaine can alleviate acute pain and expedite gastrointestinal function recovery in patients undergoing gastrointestinal surgery. However, the results should be interpreted with caution due to substantial heterogeneity. Further large-scale studies are necessary to validate these findings.

A retrospective observational study evaluating the association between vasoactive-inotropic score and mortality after major abdominal surgery.

The relationship between VISmax and mortality in patients undergoing major abdominal surgery remains unclear. This study aims to evaluate the association between VISmax and both short-term and long-term all-cause mortality in patients undergoing major abdominal surgery, VISmax was calculated (VISmax = dopamine dose [µg/kg/min] + dobutamine dose [µg/kg/min] + 100 × epinephrine dose [µg/kg/min] + 10 × milrinone dose [µg/kg/min] + 10,000 × vasopressin dose [units/kg/min] + 100 × norepinephrine dose [µg/kg/min]) using the maximum dosing rates of vasoactives and inotropics within the first 24 h postoperative ICU admission. The study included 512 patients first admitted to the intensive care unit (ICU) who were administered vasoactive drugs after major abdominal surgery. The data was extracted from the medical information mart in intensive care-IV database. VISmax was stratified into five categories: 0-5, > 5-15, > 15-30, > 30-45, and > 45. Compared to patients with the lowest VISmax (≤ 5), those with the high VISmax (> 45) had an increased risk of 30-day mortality (hazard ratio [HR] 3.73, 95% CI 1.16-12.02; P = 0.03) and 1-year mortality (HR 2.76, 95% CI 1.09-6.95; P = 0.03) in fully adjusted Cox models. The ROC analysis for VISmax predicting 30-day and 1-year mortality yielded AUC values of 0.69 (95% CI 0.64-0.75) and 0.67 (95% CI 0.62-0.72), respectively. In conclusion, elevated VISmax within the first postoperative 24 h after ICU admission was associated with increased risks of both short-term and long-term mortality in patients undergoing major abdominal surgery.

TXNIP knockdown protects rats against bupivacaine-induced spinal neurotoxicity via the inhibition of oxidative stress and apoptosis.

Bupivacaine (BUP) is an anesthetic commonly used in clinical practice that when used for spinal anesthesia, might exert neurotoxic effects. Thioredoxin-interacting protein (TXNIP) is a member of the α-arrestin protein superfamily that binds covalently to thioredoxin (TRX) to inhibit its function, leading to increased oxidative stress and activation of apoptosis. The role of TXNIP in BUP-induced oxidative stress and apoptosis remains to be elucidated. In this context, the present study aimed to explore the effects of TXNIP knockdown on BUP-induced oxidative stress and apoptosis in the spinal cord of rats and in PC12 cells through the transfection of adeno-associated virus-TXNIP short hairpin RNA (AAV-TXNIP shRNA) and siRNA-TXNIP, respectively. In vivo, a rat model of spinal neurotoxicity was established by intrathecally injecting rats with BUP. The BUP + TXNIP shRNA and the BUP + Control shRNA groups of rats were injected with an AAV carrying the TXNIP shRNA and the Control shRNA, respectively, into the subarachnoid space four weeks prior to BUP treatment. The Basso, Beattie & Bresnahan (BBB) locomotor rating score, % MPE of TFL, H&E staining, and Nissl staining analyses were conducted. In vitro, 0.8 mM BUP was determined by CCK-8 assay to establish a cytotoxicity model in PC12 cells. Transfection with siRNA-TXNIP was carried out to suppress TXNIP expression prior to exposing PC12 cells to BUP. The results revealed that BUP effectively induced neurological behavioral dysfunction and neuronal damage and death in the spinal cord of the rats. Similarly, BUP triggered cytotoxicity and apoptosis in PC12 cells. In addition, treated with BUP both in vitro and in vivo exhibited upregulated TXNIP expression and increased oxidative stress and apoptosis. Interestingly, TXNIP knockdown in the spinal cord of rats through transfection of AAV-TXNIP shRNA exerted a protective effect against BUP-induced spinal neurotoxicity by ameliorating behavioral and histological outcomes and promoting the survival of spinal cord neurons. Similarly, transfection with siRNA-TXNIP mitigated BUP-induced cytotoxicity in PC12 cells. In addition, TXNIP knockdown mitigated the upregulation of ROS, MDA, Bax, and cleaved caspase-3 and restored the downregulation of GSH, SOD, CAT, GPX4, and Bcl2 induced upon BUP exposure. These findings suggested that TXNIP knockdown protected against BUP-induced spinal neurotoxicity by suppressing oxidative stress and apoptosis. In summary, TXNIP could be a central signaling hub that positively regulates oxidative stress and apoptosis during neuronal damage, which renders TXNIP a promising target for treatment strategies against BUP-induced spinal neurotoxicity.

Comparing safety and efficacy: MemoLefort versus watchman for left atrial appendage closure.

BACKGROUND: The MemoLefort is a new plug occluder for left atrial appendage closure (LAAC) in patients with atrial fibrillation (AF). This study compares the safety and efficacy of MemoLefort and the well-established Watchman occluder for LAAC. METHODS: Between January 2021 and September 2022, a cohort of 189 consecutive patients who underwent LAAC with MemoLefort or Watchman at The Second Affiliated Hospital of Wenzhou Medical University were included. Patients with MemoLefort or Watchman devices were compared in terms of the primary safety endpoints encompassing major periprocedural complications and major bleeding events at follow-up, the primary efficacy endpoint of all-cause stroke, systemic embolism and cardiovascular/unexplained death, and the combined hazard endpoint, a composite of all the above-mentioned hazards. RESULTS: Of the MemoLefort group (n = 83) and Watchman group (n = 106), the mean age, CHA2DS2-VASc score, and HAS-BLED score were 67.6 ± 9.2 vs. 69.0 ± 10.6 years, 3.9 ± 1.9 vs. 3.8 ± 1.9, and 1.6 ± 1.0 vs. 1.7 ± 1.2, respectively. After a median follow-up duration of 198 (99-329) vs. 334 (171-497) days, the primary endpoints of efficacy [2/49, 4.1% (MemoLefort) vs. 2/97, 2.1% (Watchman); hazard ratio (HR), 1.50; 95% confidence interval (CI), 0.20-11.08; P = 0.68] and safety (1/49, 2.0% vs. 5/97, 5.2%; HR, 0.26; 95% CI, 0.05-1.31; P = 0.19), as well as the combined hazard endpoint (3/49, 61% vs. 6/97, 6.2%; HR, 0.70; 95% CI, 0.18-2.58; P = 0.59) were similar between groups. CONCLUSIONS: In the short term, LAAC with MemoLefort provided similar efficacy, safety, and net clinical benefit in comparison to Watchman devices.

Identifying therapeutic targets for breast cancer: insights from systematic Mendelian randomization analysis.

Background: Breast cancer (BC) exhibits a high incidence rate, imposing a substantial burden on healthcare systems. Novel drug targets are urgently needed for BC. Mendelian randomization (MR) has gained widespread application for identifying fresh therapeutic targets. Our endeavor was to pinpoint circulatory proteins causally linked to BC risk and proffer potential treatment targets for BC. Methods: Through amalgamating protein quantitative trait loci from 2,004 circulating proteins and comprehensive genome-wide association study data from the Breast Cancer Association Consortium, we conducted MR analyses. Employing Steiger filtering, bidirectional MR, Bayesian colocalization, phenotype scanning, and replication analyses, we further solidified MR study outcomes. Additionally, protein-protein interaction (PPI) network was harnessed to unveil latent associations between proteins and prevailing breast cancer medications. The phenome-wide MR (Phe-MR) was employed to assess potential side effects and indications for the druggable proteins of BC. Finally, we further affirmed the drugability of potential drug targets through mRNA expression analysis and molecular docking. Results: Through comprehensive analysis, we identified five potential drug targets, comprising four (TLR1, A4GALT, SNUPN, and CTSF) for BC and one (TLR1) for BC_estrogen receptor positive. None of these five potential drug targets displayed reverse causation. Bayesian colocalization suggested that these five latent drug targets shared variability with breast cancer. All drug targets were replicated within the deCODE cohort. TLR1 exhibited PPI with current breast cancer therapeutic targets. Furthermore, Phe-MR unveiled certain adverse effects solely for TLR1 and SNUPN. Conclusion: Our study uncovers five prospective drug targets for BC and its subtypes, warranting further clinical exploration.