Propofol improves survival in a murine model of sepsis via inhibiting Rab5a-mediated intracellular trafficking of TLR4.

BACKGROUND: Propofol is a widely used anesthetic and sedative, which has been reported to exert an anti-inflammatory effect. TLR4 plays a critical role in coordinating the immuno-inflammatory response during sepsis. Whether propofol can act as an immunomodulator through regulating TLR4 is still unclear. Given its potential as a sepsis therapy, we investigated the mechanisms underlying the immunomodulatory activity of propofol. METHODS: The effects of propofol on TLR4 and Rab5a (a master regulator involved in intracellular trafficking of immune factors) were investigated in macrophage (from Rab5a-/- and WT mice) following treatment with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) in vitro and in vivo, and peripheral blood monocyte from sepsis patients and healthy volunteers. RESULTS: We showed that propofol reduced membrane TLR4 expression on macrophages in vitro and in vivo. Rab5a participated in TLR4 intracellular trafficking and both Rab5a expression and the interaction between Rab5a and TLR4 were inhibited by propofol. We also showed Rab5a upregulation in peripheral blood monocytes of septic patients, accompanied by increased TLR4 expression on the cell surface. Propofol downregulated the expression of Rab5a and TLR4 in these cells. CONCLUSIONS: We demonstrated that Rab5a regulates intracellular trafficking of TLR4 and that propofol reduces membrane TLR4 expression on macrophages by targeting Rab5a. Our study not only reveals a novel mechanism for the immunomodulatory effect of propofol but also indicates that Rab5a may be a potential therapeutic target against sepsis.

Preoperative risk prediction models for acute kidney injury after noncardiac surgery: an independent external validation cohort study.

BACKGROUND: Numerous models have been developed to predict acute kidney injury (AKI) after noncardiac surgery, yet there is a lack of independent validation and comparison among them. METHODS: We conducted a systematic literature search to review published risk prediction models for AKI after noncardiac surgery. An independent external validation was performed using a retrospective surgical cohort at a large Chinese hospital from January 2019 to October 2022. The cohort included patients undergoing a wide range of noncardiac surgeries with perioperative creatinine measurements. Postoperative AKI was defined according to the Kidney Disease Improving Global Outcomes creatinine criteria. Model performance was assessed in terms of discrimination (area under the receiver operating characteristic curve, AUROC), calibration (calibration plot), and clinical utility (net benefit), before and after model recalibration through intercept and slope updates. A sensitivity analysis was conducted by including patients without postoperative creatinine measurements in the validation cohort and categorising them as non-AKI cases. RESULTS: Nine prediction models were evaluated, each with varying clinical and methodological characteristics, including the types of surgical cohorts used for model development, AKI definitions, and predictors. In the validation cohort involving 13,186 patients, 650 (4.9%) developed AKI. Three models demonstrated fair discrimination (AUROC between 0.71 and 0.75); other models had poor or failed discrimination. All models exhibited some miscalibration; five of the nine models were well-calibrated after intercept and slope updates. Decision curve analysis indicated that the three models with fair discrimination consistently provided a positive net benefit after recalibration. The results were confirmed in the sensitivity analysis. CONCLUSIONS: We identified three models with fair discrimination and potential clinical utility after recalibration for assessing the risk of acute kidney injury after noncardiac surgery.

Novel tripeptide RKH derived from Akkermansia muciniphila protects against lethal sepsis.

OBJECTIVE: The pathogenesis of sepsis is complex, and the sepsis-induced systemic proinflammatory phase is one of the key drivers of organ failure and consequent mortality. Akkermansia muciniphila (AKK) is recognised as a functional probiotic strain that exerts beneficial effects on the progression of many diseases; however, whether AKK participates in sepsis pathogenesis is still unclear. Here, we evaluated the potential contribution of AKK to lethal sepsis development. DESIGN: Relative abundance of gut microbial AKK in septic patients was evaluated. Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) injection were employed to establish sepsis in mice. Non-targeted and targeted metabolomics analysis were used for metabolites analysis. RESULTS: We first found that the relative abundance of gut microbial AKK in septic patients was significantly reduced compared with that in non-septic controls. Live AKK supplementation, as well as supplementation with its culture supernatant, remarkably reduced sepsis-induced mortality in sepsis models. Metabolomics analysis and germ-free mouse validation experiments revealed that live AKK was able to generate a novel tripeptide Arg-Lys-His (RKH). RKH exerted protective effects against sepsis-induced death and organ damage. Furthermore, RKH markedly reduced sepsis-induced inflammatory cell activation and proinflammatory factor overproduction. A mechanistic study revealed that RKH could directly bind to Toll-like receptor 4 (TLR4) and block TLR4 signal transduction in immune cells. Finally, we validated the preventive effects of RKH against sepsis-induced systemic inflammation and organ damage in a piglet model. CONCLUSION: We revealed that a novel tripeptide, RKH, derived from live AKK, may act as a novel endogenous antagonist for TLR4. RKH may serve as a novel potential therapeutic approach to combat lethal sepsis after successfully translating its efficacy into clinical practice.

Gut microbiota-derived succinate aggravates acute lung injury after intestinal ischaemia/reperfusion in mice.

INTRODUCTION: Acute lung injury (ALI) is a major cause of morbidity and mortality after intestinal ischaemia/reperfusion (I/R). The gut microbiota and its metabolic byproducts act as important modulators of the gut-lung axis. This study aimed to define the role of succinate, a key microbiota metabolite, in intestinal I/R-induced ALI progression. METHODS: Gut and lung microbiota of mice subjected to intestinal I/R were analysed using 16S rRNA gene sequencing. Succinate level alterations were measured in germ-free mice or conventional mice treated with antibiotics. Succinate-induced alveolar macrophage polarisation and its effects on alveolar epithelial apoptosis were evaluated in succinate receptor 1 (Sucnr1)-deficient mice and in murine alveolar macrophages transfected with Sucnr1-short interfering RNA. Succinate levels were measured in patients undergoing cardiopulmonary bypass, including intestinal I/R. RESULTS: Succinate accumulated in lungs after intestinal I/R, and this was associated with an imbalance of succinate-producing and succinate-consuming bacteria in the gut, but not the lungs. Succinate accumulation was absent in germ-free mice and was reversed by gut microbiota depletion with antibiotics, indicating that the gut microbiota is a source of lung succinate. Moreover, succinate promoted alveolar macrophage polarisation, alveolar epithelial apoptosis and lung injury during intestinal I/R. Conversely, knockdown of Sucnr1 or blockage of SUCNR1 in vitro and in vivo reversed the effects of succinate by modulating the phosphoinositide 3-kinase-AKT/hypoxia-inducible factor-1α pathway. Plasma succinate levels significantly correlated with intestinal I/R-related lung injury after cardiopulmonary bypass. CONCLUSION: Gut microbiota-derived succinate exacerbates intestinal I/R-induced ALI through SUCNR1-dependent alveolar macrophage polarisation, identifying succinate as a novel target for gut-derived ALI in critically ill patients.

Microbiota-derived tryptophan metabolites indole-3-lactic acid is associated with intestinal ischemia/reperfusion injury via positive regulation of YAP and Nrf2.

BACKGROUND: Lactobacillus has been demonstrated to serve a protective role in intestinal injury. However, the relationship between Lactobacillus murinus (L. murinus)-derived tryptophan metabolites and intestinal ischemia/reperfusion (I/R) injury yet to be investigated. This study aimed to evaluate the role of L. murinus-derived tryptophan metabolites in intestinal I/R injury and the underlying molecular mechanism. METHODS: Liquid chromatograph mass spectrometry analysis was used to measure the fecal content of tryptophan metabolites in mice undergoing intestinal I/R injury and in patients undergoing cardiopulmonary bypass (CPB) surgery. Immunofluorescence, quantitative RT-PCR, Western blot, and ELISA were performed to explore the inflammation protective mechanism of tryptophan metabolites in WT and Nrf2-deficient mice undergoing intestinal I/R, hypoxia-reoxygenation (H/R) induced intestinal organoids. RESULTS: By comparing the fecal contents of three L. murinus-derived tryptophan metabolites in mice undergoing intestinal I/R injury and in patients undergoing cardiopulmonary bypass (CPB) surgery. We found that the high abundance of indole-3-lactic acid (ILA) in the preoperative feces was associated with better postoperative intestinal function, as evidenced by the correlation of fecal metabolites with postoperative gastrointestinal function, serum I-FABP and D-Lactate levels. Furthermore, ILA administration improved epithelial cell damage, accelerated the proliferation of intestinal stem cells, and alleviated the oxidative stress of epithelial cells. Mechanistically, ILA improved the expression of Yes Associated Protein (YAP) and Nuclear Factor erythroid 2-Related Factor 2 (Nrf2) after intestinal I/R. The YAP inhibitor verteporfin (VP) reversed the anti-inflammatory effect of ILA, both in vivo and in vitro. Additionally, we found that ILA failed to protect epithelial cells from oxidative stress in Nrf2 knockout mice under I/R injury. CONCLUSIONS: The content of tryptophan metabolite ILA in the preoperative feces of patients is negatively correlated with intestinal function damage under CPB surgery. Administration of ILA alleviates intestinal I/R injury via the regulation of YAP and Nrf2. This study revealed a novel therapeutic metabolite and promising candidate targets for intestinal I/R injury treatment.

Gut microbiota dysbiosis is associated with sepsis-induced cardiomyopathy in patients: A case-control study.

BACKGROUND: Myocardial injury is a major complication of sepsis and a key factor affecting prognosis. Therefore, early and accurate diagnosis and timely management of sepsis-induced cardiomyopathy (SICM) are of great significance for the prevention and treatment of sepsis. The gut microbiota has been shown to be closely associated with sepsis or myocardial injury, but the association between the gut microbiota and SICM is not fully understood. This study aimed to explore the link between gut microbiota composition and SICM. METHODS: A case-control and single-center study of clinical features and gut microbiota profiles by Metagenome and Virome was conducted in SICM patients (n = 15) and sepsis-uninduced cardiomyopathy patients (SNICM, n = 16). RESULTS: Compared with SNICM patients, SICM patients showed significant myocardial injury and higher 28-day mortality, SOFA scores, lactate levels, and infection levels on admission. Meanwhile, differences in the composition of gut bacteria, archaea, fungi, and viruses were analyzed between the two groups. Differential gut bacteria or viruses were found to have a good predictive effect on SICM. Furthermore, gut bacteria and viruses that differed between the two groups were strongly related. The abundance of Cronobacter and Cronobacter phage was higher in the SICM group than in the SNICM group, and the receiver operating characteristic curve showed that Cronobacter and Cronobacter phage both had a good predictive effect on SICM. CONCLUSIONS: SICM patients may have specific gut microbiota signatures, and Cronobacter and Cronobacter phages have a good ability to identify and diagnose SICM.

Acute Kidney Injury After General Thoracic Surgery: A Systematic Review and Meta-analysis.

INTRODUCTION: The clinical importance of postoperative acute kidney injury (AKI) in patients undergoing general thoracic surgery is unclear. We aimed to systematically review the incidence, risk factors, and prognostic implications of AKI as a complication after general thoracic surgery. METHODS: We searched PubMed, EMBASE, and the Cochrane Library from January 2004 to September 2021. Observational or interventional studies that enrolled ≥50 patients undergoing general thoracic surgery and reported postoperative AKI defined using contemporary consensus criteria were included for meta-analysis. RESULTS: Thirty-seven articles reporting 35 unique cohorts were eligible. In 29 studies that enrolled 58,140 consecutive patients, the pooled incidence of postoperative AKI was 8.0% (95% confidence interval [CI]: 6.2-10.0). The incidence was 3.8 (2.0-6.2) % after sublobar resection, 6.7 (4.1-9.9) % after lobectomy, 12.1 (8.1-16.6) % after bilobectomy/pneumonectomy, and 10.5 (5.6-16.7) % after esophagectomy. Considerable heterogeneity in reported incidences of AKI was observed across studies. Short-term mortality was higher (unadjusted risk ratio: 5.07, 95% CI: 2.99-8.60) and length of hospital stay was longer (weighted mean difference: 3.53, 95% CI: 2.56-4.49, d) in patients with postoperative AKI (11 studies, 28,480 patients). Several risk factors for AKI after thoracic surgery were identified. CONCLUSIONS: AKI occurs frequently after general thoracic surgery and is associated with increased short-term mortality and length of hospital stay. For patients undergoing general thoracic surgery, AKI may be an important postoperative complication that needs early risk evaluation and mitigation.

Sex-Specific Associations Between Preoperative Hemoglobin and Outcomes After Major Noncardiac Surgery: A Retrospective Cohort Study.

BACKGROUND: Preoperative anemia is an established risk factor for morbidity and mortality after surgery. Men and women have different hemoglobin concentrations and are at different risks of postoperative complications. However, sex-stratified analysis on the association between preoperative hemoglobin and outcomes after noncardiac surgery has been limited in previous studies. METHODS: This was a retrospective cohort study of adult patients undergoing elective major noncardiac surgery in a large academic hospital. The primary outcome was a collapsed composite of postoperative mortality or cardiovascular, renal, pulmonary, and infectious complications during hospitalization. Sex-specific univariable associations between preoperative hemoglobin and the composite outcome were visualized using moving-average and cubic-spline smoothing plots. Multivariable regression models adjusting for patient demographics, comorbidities, medication uses, laboratory tests, and anesthesia/surgery features were used to estimate confounder-adjusted associations. Restricted cubic spline and piecewise linear functions were used to assess the possible nonlinear relationships between preoperative hemoglobin and the outcomes. The interaction between patient sex and hemoglobin on outcomes was assessed using a likelihood-ratio test. RESULTS: We included 22,550 patients, with 6.7% (622 of 9268) of women and 9.7% (1293 of 13,282) of men developing the primary outcome. Lower preoperative hemoglobin was associated with a higher incidence of the primary composite outcome in both men and women. Nonlinearity for the association was not statistically significant in either women ( P = .539) or men ( P = .165). The multivariable-adjusted odds ratios per 1 g/dL increase in hemoglobin were 0.93 (95% confidence interval [CI], 0.87-0.98; P = .013) for women and 0.94 (95% CI, 0.90-0.97; P < .001) for men, with no interaction by sex ( Pinteraction = .923). No hemoglobin thresholds were confirmed at which the associations with the primary outcome changed significantly. CONCLUSIONS: Low preoperative hemoglobin was associated with a higher risk of complications or mortality after elective noncardiac surgery in both men and women. No differences in the strength of associations between sexes were found. Further studies are needed to assess whether these associations are linear or there are sex-specific thresholds of preoperative hemoglobin concentrations below which postoperative risks begin to increase.

Association between cumulative duration of deep anesthesia and postoperative acute kidney injury after noncardiac surgeries: a retrospective observational study.

BACKGROUND: Bispectral index (BIS) is a processed electroencephalography monitoring tool and is widely used in anesthetic depth monitoring. Deep anesthesia exposure may be associated with multiple adverse outcomes. However, the relationship between anesthetic depth and postoperative acute kidney injury (AKI) remains unclear. We sought to determine the effect of BIS-based deep anesthesia duration on postoperative AKI following noncardiac surgery. METHODS: This retrospective study used data from the Vital Signs DataBase, including patients undergoing noncardiac surgeries with BIS monitoring. The BIS values were collected every second during anesthesia. Restricted cubic splines and logistic regression were used to assess the association between the cumulative duration of deep anesthesia and postoperative AKI. RESULTS: 4774 patients were eligible, and 129 (2.7%) experienced postoperative AKI. Restricted cubic splines showed that a cumulative duration of BIS < 45 was nonlinearly associated with postoperative AKI (P-overall = 0.033 and P-non-linear = 0.023). Using the group with the duration of BIS < 45 less than 15 min as the reference, ORs of postoperative AKI were 2.59 (95% confidence interval [CI]:0.60 to 11.09, p = 0.200) in the 15-100 min group, and 4.04 (95%CI:0.92 to 17.76, p = 0.064) in the ≥ 100 min group after adjusting for preoperative and intraoperative covariates in multivariable logistic regression. CONCLUSIONS: The cumulative duration of BIS < 45 was independently and nonlinearly associated with the risk of postoperative AKI in patients undergoing noncardiac surgery.

MicroRNA-26b-5p Targets DAPK1 to Reduce Intestinal Ischemia/Reperfusion Injury via Inhibition of Intestinal Mucosal Cell Apoptosis.

BACKGROUND: Emerging evidence has suggested that miRNAs are important regulators of intestinal I/R injury, but their function in this context remains elusive. AIMS: To evaluate the role of miR-26b-5p in intestinal I/R injury. METHODS: We utilized in vivo murine models of intestinal I/R and in vitro Mode-K cell-based models of oxygen and glucose deprivation/reperfusion (OGD/R) to examine the function of miR-26b-5p in intestinal I/R injury. The expression of miR-26b-5p in intestinal mucosa and Mode-K cell was detected by RT-PCR. HE staining and Chiu's score were used to evaluate intestinal mucosa injury severity. Apoptosis was detected by TUNEL stain, flow cytometry, and western blot. TargetScan and StarBase prediction algorithms were applied to predict putative target genes of miR-26b-5p and validated by luciferase reporter analyses. RESULTS: We found that the expression of miR-26b-5p in intestinal mucosa was markedly decreased during I/R injury. We additionally found miR-26b-5p overexpression to markedly disrupt intestinal I/R- or OGD/R-induced injury in vivo and in vitro, whereas inhibiting this miRNA had an adverse impact and resulted in increased intestinal tissue injury and Mode-K cell damage. From a mechanistic perspective, miR-26b-5p was predicted to target DAPK1, which was related to cellular apoptosis. Luciferase reporter assay results confirmed that miR-26b-5p directly targets DAPK1 in Mode-K cells, thereby suppressing OGD/R-induced cell apoptosis. CONCLUSION: Our findings show that miR-26b-5p may prevent intestinal I/R injury via targeting DAPK1 and inhibiting intestinal mucosal cell apoptosis, suggesting that this miRNA may be a viable target for the treatment of intestinal I/R injury.

Predictive and Preventive Potential of Preoperative Gut Microbiota in Chronic Postoperative Pain in Breast Cancer Survivors.

BACKGROUND: Evidence suggests a potential relationship between gut microbiota and chronic postoperative pain (CPP). This study aimed to explore the predictive and preventive potential of preoperative gut microbiota in CPP in breast cancer survivors. METHODS: In the clinical experiments, we designed a nested case-control study to compared preoperative gut microbiota of breast cancer survivors with and without CPP using 16s rRNA sequencing. The primary outcome was clinically meaningful pain in or around the operative area 3 months after surgery. Logistic prediction models based on previously identified risk factors for CPP in breast cancer survivors were tested with and without differential bacteria to evaluate the model's potential for improvement with the addition of gut microbiota information. In the animal experiments, preoperative fecal microbiota was transplanted from patients with and without CPP to mice, and a spared nerve injury (SNI) model was used to mimic neuropathic pain in CPP. Mechanical hyperalgesia and the expression of markers of spinal microglia and peroxisome proliferator-activated receptor-γ (PPAR-γ) were assessed. RESULTS: Sixty-six CPP patients and 66 matched controls were analyzed. Preoperative gut microbiota composition was significantly different in the 2 groups at phylus, family, and genera levels. The discrimination of the clinical prediction model (determined by area under the receiver operating characteristic curve) improved by 0.039 and 0.099 after the involvement of differential gut microbiota at the family and genus levels, respectively. After fecal microbiota transplantation (FMT), "CPP microbiota" recipient mice exhibited significantly increased mechanical hyperalgesia and decreased expression of Ppar-γ and arginase-1 (Arg-1) in the spinal cord. CONCLUSIONS: Preoperative gut microbiota has the potential to predict and prevent the development of CPP and plays a causal role in its development via the PPAR-γ-microglia pathway in the spinal cord. Thus, it could be targeted to develop a prevention strategy for CPP in breast cancer survivors.

Microarray Profiling and Functional Identification of LncRNA in Mice Intestinal Mucosa Following Intestinal Ischemia/Reperfusion.

BACKGROUND: Intestinal ischemia-reperfusion (I/R) injury is a common clinical event with high mortality, but its mechanism is elusive. Although long noncoding RNAs (lncRNAs) have recently emerged as critical molecules in I/R damage in other organs, the changes in their expression and potential roles in intestinal I/R remain unclear. METHODS: The expression profiles of both lncRNAs and mRNAs in mouse intestinal mucosa after intestinal I/R were explored by a microarray approach, and their biological functions were elucidated by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Then, some lncRNAs were further verified by qRT-PCR. Based on the coding-noncoding gene coexpression (CNC) network analyses, the role of lncRNA AK089510 in intestinal I/R-induced intestinal mucosa apoptosis was investigated by knockdown assay in vitro. RESULTS: A total of 3602 aberrantly expressed lncRNAs (1503 upregulated and 2099 downregulated) and 3158 mRNAs (1528 upregulated and 1630 downregulated) were identified. The dysregulated transcripts were enriched in the lipid metabolic process, apoptotic process, reactive oxygen species metabolic process, MAPK, TNF, ErbB, mTOR, and FoxO signaling pathways, and so on. The overexpression of lncRNA AK089510 was validated by qRT-PCR, and the CNC analysis revealed its target mRNAs. AK089510-siRNA reduced Casp6 and Casp7 expression and suppressed intestinal epithelial cell apoptosis after oxygen-glucose deprivation treatment. CONCLUSIONS: Our study revealed the lncRNA and mRNA expression patterns in mouse intestinal mucosa after intestinal I/R and predicted their potential functions and pathways. We identified AK089510 as a novel lncRNA involved in the apoptosis of intestinal mucosa, advancing our understanding of the molecular mechanisms of intestinal I/R injury.

Assessment of prognostic value of intraoperative oliguria for postoperative acute kidney injury: a retrospective cohort study.

BACKGROUND: Oliguria is often viewed as a sign of renal hypoperfusion and an indicator for volume expansion during surgery. However, the prognostic association and the predictive utility of intraoperative oliguria for postoperative acute kidney injury (AKI) are unclear. METHODS: We conducted a retrospective cohort study on patients undergoing major thoracic surgery in an academic hospital to assess the association of intraoperative oliguria with postoperative AKI and its predictive value. To contextualise our findings, we included our results in a meta-analysis of observational studies on the importance of oliguria during noncardiac surgery. RESULTS: In our cohort study, 3862 patients were included; 205 (5.3%) developed AKI after surgery. Intraoperative urine output of 0.3 ml kg-1 h-1 was the optimal threshold for oliguria in multivariable analysis. Patients with oliguria had an increased risk of AKI (adjusted odds ratio: 2.60; 95% confidence interval: 1.24-5.05). However, intraoperative oliguria had a sensitivity of 5.9%, specificity of 98%, positive likelihood ratio of 2.74, and negative likelihood ratio of 0.96, suggesting poor predictive ability. Moreover, it did not improve upon the predictive performance of a multivariable model, based on discrimination and reclassification indices. Our findings were generally consistent with the results of a systematic review and meta-analysis, including six additional studies. CONCLUSIONS: Intraoperative oliguria has moderate association with, but poor predictive ability for, postoperative AKI. It remains of clinical interest as a risk factor potentially modifiable to interventions.

Dexmedetomidine attenuates one-lung ventilation associated lung injury by suppressing inflammatory responses: A systematic review and meta-analysis.

One-lung ventilation (OLV), a common ventilation technique, is associated with perioperative lung injury, tightly connected with inflammatory responses. Dexmedetomidine has shown positive anti-inflammatory effects in lung tissues in pre-clinical models. This study investigated the efficacy of dexmedetomidine for suppressing inflammatory responses in patients requiring OLV. We searched PubMed, MEDLINE, Embase, Scopus, Ovid, and Cochrane Library for randomized controlled trials focusing on dexmedetomidine's anti-inflammatory effects on patients requiring OLV without any limitation on the year of publication or languages. 20 clinical trials were assessed with 870 patients in the dexmedetomidine group and 844 in the control group. Our meta-analysis investigated the anti-inflammatory property of dexmedetomidine perioperatively [T1 (30-min OLV), T2 (90-min OLV), T3 (end of surgery) and T4 (postoperative day 1)], demonstrating that dexmedetomidine's intraoperative administration resulted in a significant reduction in serum concentration of interleukin-6, tumor necrosis factor-α and other inflammatory cytokines perioperatively. By calculating specific I2 index, significant heterogeneity was observed on all occasions, with I2 index ranging from 95% to 99%. For IL-6 changes, sensitivity analysis showed that the exclusion of a single study led to a significant decrease of heterogeneity (96%-0%; p < 0.00001). Besides, pulmonary oxygenation was ameliorated in the dexmedetomidine group comparing with the control group. In conclusion, perioperative administration of dexmedetomidine can attenuate OLV induced inflammation, ameliorate pulmonary oxygenation, and may be conducive to a decreased occurrence of postoperative complications and better prognosis. However, the results should be prudently interpreted due to the evidence of heterogeneity and the limited number of studies.

Relationships of sleep disturbance, intestinal microbiota, and postoperative pain in breast cancer patients: a prospective observational study.

PURPOSE: Our study was designed to examine the possible relationship between gut microbiota, sleep disturbances, and acute postoperative pain. METHODS: Using 16S rRNA sequencing, we analyzed preoperative fecal samples from women undergoing breast cancer surgery. Preoperative sleep disturbance was evaluated with the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Peak and average pain at rest and movement were evaluated 24 h after surgery, using a numerical rating scale (NRS). Preoperative symptoms of depression and anxiety were assessed with the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7), respectively. Inflammation was measured using white blood cell and neutrophil counts, together with platelet-lymphocyte ratio, and neutrophil-lymphocyte ratio. RESULTS: Preoperative sleep disturbance was associated with more severe acute postoperative pain. At the phylum level, women with poor sleep quality had higher relative abundance of Firmicutes (p = 0.021) and lower relative abundance of Bacteroidetes (p = 0.013). At the genus level, women with poor sleep quality harbored higher relative abundance of Acidaminococcus and lower relative abundance of several genera. The genus Alloprevotella was negatively associated with peak pain at movement during the first 24 h (r = - 0.592, p < 0.001). The genus Desulfovibrio was negatively associated with symptoms of anxiety (r = - 0.448, p = 0.006). However, partial correlations suggested that the relationship between Alloprevotella and peak pain at movement during the first 24 h was not statistically significant after controlling for sleep (r = - 0.134, p = 0.443). CONCLUSION: These findings suggest that the changed gut microbiota may be involved in sleep-pain interaction and could be applied as a potential preventive method for postoperative pain. TRIAL REGISTRATION: The present clinical study has been registered on Chinese Clinical Trial Registry ( www.chictr.org.cn ); the clinical trial registration number is ChiCTR1900021730; the date of registration is March 7, 2019.

Pre-operative N-terminal pro-B-type natriuretic peptide for prediction of acute kidney injury after noncardiac surgery: A retrospective cohort study.

BACKGROUND: Acute kidney injury (AKI) is associated with poor outcomes after noncardiac surgery. Whether pre-operative N-terminal pro-B-type natriuretic peptide (NT-proBNP) predicts AKI after noncardiac surgery is unclear. OBJECTIVE: To investigate the predictive role of pre-operative NT-proBNP on postoperative AKI. DESIGN: Retrospective cohort study. SETTING: Nanfang Hospital, Southern Medical University, China. PATIENTS: Adult patients who had a serum creatinine and NT-proBNP measurement within 30 pre-operative days and at least one serum creatinine measurement within 7 days after noncardiac surgery between February 2008 and May 2018 were identified. MAIN OUTCOME MEASURES: The primary outcome was postoperative AKI, defined by the kidney disease: improving global outcomes creatinine criteria. RESULTS: In all, 6.1% (444 of 7248) of patients developed AKI within 1 week after surgery. Pre-operative NT-proBNP was an independent predictor of AKI after adjustment for clinical variables (OR comparing top to bottom quintiles 2.29, 95% CI, 1.47 to 3.65, P < 0.001 for trend; OR per 1-unit increment in natural log transformed NT-proBNP 1.27, 95% CI, 1.16 to 1.39). Compared with clinical variables alone, the addition of NT-proBNP improved model fit, modestly improved the discrimination (change in area under the curve from 0.764 to 0.773, P = 0.005) and reclassification (continuous net reclassification improvement 0.210, 95% CI, 0.111 to 0.308, improved integrated discrimination 0.0044, 95% CI, 0.0016 to 0.0072) of AKI and non-AKI cases, and achieved higher net benefit in decision curve analysis. CONCLUSIONS: Pre-operative NT-proBNP concentrations provided predictive information for AKI in a cohort of patients undergoing noncardiac surgery, independent of and incremental to conventional risk factors. Prospective studies are required to confirm this finding and examine its clinical impact. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900024056. www.chictr.org.cn/showproj.aspx?proj=40385.

6-Gingerol attenuates macrophages pyroptosis via the inhibition of MAPK signaling pathways and predicts a good prognosis in sepsis.

BACKGROUND: Sepsis is a major cause of death for ICU patients. Sepsis development depends heavily on the presence of mature IL-1ß cytokine. This study evaluates the potential therapeutic properties of a bioactive compound known as 6-gingerol on sepsis. This compound has previously been demonstrated to possess anti-inflammatory properties both in vivo and in vitro. METHODS: C57BL/6 mice was used to establish models of sepsis by means of cecal ligation and puncture (CLP). Upon treatment with 6-gingerol, we assessed the survival rate of mice and measured the levels of key pro-inflammatory cytokines in serum and colon tissues. Sepsis pathogenesis was further explored using the RAW264.7 cell line and bone marrow-derived macrophages (BMDMs) treated with ATP and lipopolysaccharide (LPS). The impact of 6-gingerol on pyroptosis was also examined. In addition, we assessed the role of MAPK signaling in 6-gingerol-induced effects in BMDMs and RAW264.7 cells. RESULTS: In CLP mice, 6-gingerol significantly ameliorated sepsis development, which was associated with the reduction of serum IL-1ß. In BMDMs and RAW264.7 cells, 6-gingerol strongly attenuated pyroptosis as well as the release of caspase-1p20, HMGB1, mature IL-1ß, IL-18 in response to ATP and LPS treatment. 6-Gingerol conferred these effects by blocking MAPK activation. Exposure to an ERK agonist (EGF) reversed effects of 6-gingerol, causing pyroptosis, LDH and caspase-1p20 release. CONCLUSIONS: By targeting MAPK signaling, 6-gingerol significantly suppressed secretion of pro-inflammatory cytokines and inhibited macrophage cells pyroptosis resulting in overall inhibition of sepsis development.

Incidence and risk factors of postoperative ileus after hysterectomy for benign indications.

PURPOSE: Postoperative ileus (POI) after abdominal surgery is associated with prolonged hospital stay and increased costs. The aim of this study is to investigate the incidence of, risk factors for, and outcomes associated with POI in patients undergoing hysterectomy for benign indications. METHODS: A retrospective review of 1017 consecutive patients undergoing benign hysterectomy over the period 2012-2017 in a single center was performed. POI was predefined as absence of flatus and defecation for more than 2 days with the presence of one or more of the following symptoms: nausea, vomiting, and abdominal distention. The association between perioperative variables and the risk of POI was evaluated by univariate analysis. Independent risk factors were identified by multivariate logistic regression analysis. RESULTS: Overall incidence of POI was 9.2%. Incidence of POI did not differ significantly among three different surgical approaches (abdominal hysterectomy, 10.6%; laparoscopic hysterectomy, 7.8%; vaginal hysterectomy, 11.3%; P = 0.279). Independent risk factors of POI identified by multivariate analysis included anesthesia technique (odds ratio [OR] 2.662, 95% interval [CI] 1.533-4.622, P = 0.001), adhesiolysis (odds ratio [OR] 1.818, 95% interval [CI] 1.533-4.622, P = 0.011), duration of operation (odds ratio [OR] 1.005, 95% interval [CI] 0.942-6.190, P = 0.029), previous cancer (odds ratio [OR] 4.789, 95% interval [CI] 1.232-18.626, P = 0.024), and dysmenorrhea (odds ratio [OR] 1.859, 95% interval [CI] 1.182-2.925, P = 0.007). CONCLUSION: POI is a common complication after hysterectomy. This study identified risk factors of POI specifically for gynecologic patients. Patients exposed to these factors should be monitored closely for the development POI.

Amelioration of Coagulation Disorders and Inflammation by Hydrogen-Rich Solution Reduces Intestinal Ischemia/Reperfusion Injury in Rats through NF-κB/NLRP3 Pathway.

Intestinal ischemia/reperfusion (I/R) injury often causes inflammatory responses and coagulation disorders, which is further promoting the deterioration of the disease. Hydrogen has anti-inflammatory, antioxidative, and antiapoptotic properties against various diseases. However, the effect of hydrogen on coagulation dysfunction after intestinal I/R and the underlying mechanism remains unclear. The purpose of this study was to explore whether hydrogen-rich solution (HRS) could attenuate coagulation disorders and inflammation to improve intestinal injury and poor survival following intestinal I/R. The rat model of intestinal I/R injury was established by clamping the superior mesenteric artery for 90 min and reperfusion for 2 h. HRS (10 or 20 mL/kg) or 20 mL/kg 0.9% normal saline was intravenously injected at 10 min before reperfusion, respectively. The samples were harvested at 2 h after reperfusion for further analyses. Moreover, the survival rate was observed for 24 h. The results showed that HRS improved the survival rate and alleviated serum diamine oxidase activities, intestinal injury, edema, and apoptosis. Interestingly, HRS markedly improved intestinal I/R-mediated coagulation disorders as evidenced by abnormal conventional indicators of coagulation and thromboelastography. Additionally, HRS attenuated inflammatory responses and the elevated tissue factor (TF) and inhibited nuclear factor kappa beta (NF-κB) and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in peripheral blood mononuclear cells. Moreover, inflammatory factors and myeloperoxidase were closely associated with TF level. This study thus emphasized upon the amelioration of coagulation disorders and inflammation by HRS as a mechanism to improve intestinal I/R-induced intestinal injury and poor survival, which might be partially related to inhibition of NF-κB/NLRP3 pathway.