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Abstract Background The triglyceride-glucose (TyG) index, identified as a reliable indicator of insulin resistance (IR), was reported to be associated with stroke recurrence and morbidity in the general population and critically ill patients. However, the relationship in liver transplantation (LT) recipients remains unknown. This study aimed to investigate the correlation between the TyG index and post-LT stroke along with all-cause mortality and further assess the influence of IR on the LT recipients’ prognosis. Methods The retrospective cohort study enrolled 959 patients who underwent LT at a university-based medical centre between January 2015 and January 2021. The participants were divided into three groups according to their TyG index tertiles. The primary outcome was post-LT stroke. Multivariate logistic regression, COX proportional hazards regression, and restricted cubic spline RCS were used to examine the association between the TyG index and outcomes in LT recipients. Results With a median TyG index of 8.23 (7.78–8.72), 780 (87.18% males) patients were eventually included. The incidence of post-LT stroke was 5.38%, and the in-hospital, 1-year, and 3-year mortality rates were 5.54%, 13.21%, and 15.77%, respectively. Multivariate regression analysis showed an independent association between the TyG index and an increased risk of post-LT stroke [adjusted odds ratio (aOR), 3.398 (95% confidence interval [CI]: 1.371–8.426) P = 0. 008], in-hospital mortality [adjusted hazard ratio (aHR), 2.326 (95% CI: 1.089–4.931) P = 0.025], 1-year mortality [aHR, 1.668 (95% CI: 1.024–2.717) P = 0.039], and 3-year mortality [aHR, 1.837 (95% CI: 1.445–2.950) P = 0.012]. Additional RCS analysis also suggested a linear increase in the risk of postoperative stroke with elevated TyG index (P for nonlinearity = 0.480). Conclusions The TyG index may be a valuable and reliable indicator for assessing stroke risk and all-cause mortality in patients undergoing LT, suggesting its potential relevance in improving risk stratification during the peri-LT period.

Background: We aimed to explore the potential risk factors and short-term prognosis for SIRS after thermal ablation of hepatocellular carcinoma (HCC). Methods: Data from patients with HCC who underwent thermal ablation in the Third Affiliated Hospital of Sun Yat-sen University between January 2015 and August 2021 were retrieved from the perioperative database. Pre-, intra- and postoperative data between SIRS group and non-SIRS group were compared and multivariate logistic regression analysis was performed to identify the risk factors for SIRS after thermal ablation. Results: A total of 1491 patients were enrolled and 234 (15.7 %) patients developed SIRS after thermal ablation. Compared with those without SIRS, patients with SIRS had a longer hospital stay, higher hospitalization costs and higher risk of more severe postoperative complications. In the multivariate logistic regression analysis, current smoking (OR 1.58, 95 %CI 1.09–2.29), decreased HCT (OR 1.51,95 %CI 1.11–2.04), NEUT < 1.5 × 109/L(OR 1.74, 95 %CI 1.14–2.65), NEUT% < 0.5 or > 0.7 (OR 1.36, 95 %CI 1.01–1.83) and PT > 16.3s (OR 2.42, 95 %CI 1.57–3.74) were significantly associated with postoperative SIRS. Conclusions: Current smoking, decreased HCT, neutropenia, abnormal percentage of neutrophils and prolonged PT are the independent risk factors for SIRS after thermal ablation of HCC, which worsens outcomes of patients. This study can help identify high-risk population and guide appropriate care so as to reduce the incidence of postoperative SIRS.

Abstract Background Early prediction of acute kidney injury (AKI) after liver transplantation (LT) facilitates timely recognition and intervention. We aimed to build a risk predictor of post-LT AKI via supervised machine learning and visualize the mechanism driving within to assist clinical decision-making. Methods Data of 894 cases that underwent liver transplantation from January 2015 to September 2019 were collected, covering demographics, donor characteristics, etiology, peri-operative laboratory results, co-morbidities and medications. The primary outcome was new-onset AKI after LT according to Kidney Disease Improving Global Outcomes guidelines. Predicting performance of five classifiers including logistic regression, support vector machine, random forest, gradient boosting machine (GBM) and adaptive boosting were respectively evaluated by the area under the receiver-operating characteristic curve (AUC), accuracy, F1-score, sensitivity and specificity. Model with the best performance was validated in an independent dataset involving 195 adult LT cases from October 2019 to March 2021. SHapley Additive exPlanations (SHAP) method was applied to evaluate feature importance and explain the predictions made by ML algorithms. Results 430 AKI cases (55.1%) were diagnosed out of 780 included cases. The GBM model achieved the highest AUC (0.76, CI 0.70 to 0.82), F1-score (0.73, CI 0.66 to 0.79) and sensitivity (0.74, CI 0.66 to 0.8) in the internal validation set, and a comparable AUC (0.75, CI 0.67 to 0.81) in the external validation set. High preoperative indirect bilirubin, low intraoperative urine output, long anesthesia time, low preoperative platelets, and graft steatosis graded NASH CRN 1 and above were revealed by SHAP method the top 5 important variables contributing to the diagnosis of post-LT AKI made by GBM model. Conclusions Our GBM-based predictor of post-LT AKI provides a highly interoperable tool across institutions to assist decision-making after LT. Graphic abstract

BackgroundTo assess the frequency of major complications after thermal ablation of liver tumours and to determine risk factors for adverse events.MethodsA retrospective study was conducted between January 2015 and January 2021. A total of 2,084 thermal ablation sessions in 1,592 patients with primary and metastatic liver tumours were evaluated. The frequency of major complications was evaluated according to the Society of Interventional Radiology Standards, and putative predictors of adverse events were analysed using simple and multivariate logistic regression.ResultsThermal ablation-related mortality was 0.1% (2/2,084), with an overall major complication rate of 5.6% (117/2,084). The most frequent major complication was symptomatic pleural effusion (2.9%, 60/2,084). Multivariate logistic regression analysis revealed that a total maximum diameter of lesions >3 cm, microwave ablation (MWA) and MWA combined with radiofrequency ablation, intrahepatic cholangiocarcinoma and postoperative systemic inflammatory response syndrome were independent prognostic factors for major complications.ConclusionsThermal ablation of liver tumours is a safe procedure with an acceptable incidence of major complications. The risk factors identified in this study will help to stratify high-risk patients.

Abstract Background To investigate whether transmuscular quadratus lumborum block (TQLB) combined with oxycodone-based patient-controlled intravenous analgesia (PCIA) compared with sufentanil-based patient-controlled intravenous analgesia could reduce postoperative pain and opioid consumption in patients undergoing laparoscopic hepatectomy. Methods Eighty patients undergoing laparoscopic hepatectomy surgery were randomly divided into Group S (Sufentanil for PCIA group), Group O (Oxycodone for PCIA group) and Group QO (transmuscular quadratus lumborum block + oxycodone for PCIA group). Primary outcome was Numerical Rating Scale (NRS) pain score when coughing at 6th hour after the operation. We summarized opioid consumption and recorded complications, opioid drug adverse reaction and analgesia satisfaction. Results NRS pain scores were significantly lower in Group QO while patients coughing at 6th hour after the operation compared with Group S and Group O (median (interquartile range [IQR]):Group S vs. Group O vs. Group QO 4.0 [3.0, 5.0] vs. 4.0[3.0,5.0]vs.3.0 [2.0, 3.0], p

N6-methyladenosine (m6A) modification plays a pivotal role in cell fate determination. Previous studies show that eliminating m6A using Mb1-Cre dramatically impairs B cell development. However, whether disturbing m6A modification at later stages affects B cell development and function remains elusive. Here, we deleted m6A methyltransferase Mettl3 from the pro-B stage on using Cd19-Cre (Mettl3 cKO) and found that the frequency of total B cells in peripheral blood, peritoneal cavity, and liver is comparable between Mettl3 cKO mice and wild-type (WT) littermates, while the percentage of whole splenic B cells slightly increases in Mettl3 cKO individuals. The proportion of pre-pro-B, pro-B, pre-B, immature, and mature B cells in the bone marrow were minimally affected. Loss of Mettl3 resulted in increased apoptosis but barely affected B cells’ proliferation and IgG production upon LPS, CD40L, anti-IgM, or TNF-α stimulation. Different stimuli had different effects on B cell activation. In addition, B cell-specific Mettl3 knockout had no influence on the pro-fibrogenic activity of B cells in liver fibrosis, evidenced by comparable fibrosis in carbon tetrachloride- (CCl4-) treated Mettl3 cKO mice and WT controls. In summary, our study demonstrated that deletion of Mettl3 from the pro-B stage on has minimal effects on B cell development and function, as well as profibrogenic activity of B cells in liver fibrosis, revealing a stage-specific dependence on Mettl3-mediated m6A of B cell development.

Acute lung injury (ALI) is a severe complication of orthotopic liver transplantation (OLT) with unclear underline mechanism. Toll-like receptor 4 (TLR4) has been identified as a key receptor mediating inflammation. We hypothesized that TLR4-mediated pulmonary inflammation may contribute to development of ALI during OLT. Patients with or without ALI were observed for serum cytokines and expression of TLR4 on peripheral blood polymorphonuclear leukocytes (PMNs). Next, rats which underwent orthotopic autologous liver transplantation (OALT) were divided into sham and model groups. Pulmonary function and the level of TLR4 expression and cytokines were analyzed. Furthermore, the role of TLR4 in OALT-mediated ALI was assessed in rats treated with TLR4-siRNA before OALT. The PMNs TLR4 expression and the serum TNF-α and IL-β level were higher in patients with ALI than those with non-ALI. Interestingly, lung TLR4 expression was significantly increased after 8 hours of OALT with increased levels of TNF-α and IL-β, which lead to lung pathological damage and an increase of lung myeloperoxidase content. Moreover, knockdown of TLR4 reduced lung cytokines release and reversed the above pathologic changes after OALT and finally improved rats’ survival rate. In conclusion, TLR4 overexpression, potentially by stimulating proinflammatory cytokine overproduction, contributes to the development of ALI after OLT.

Résumé: L’étude que nous envisageons s’intéresse à l’instance de réception dans le système de communication. Dans le champ qui est le nôtre, l’analyse du discours, l’accent est plus mis sur l’instance émettrice et sa production. Même lorsqu’on s’occupe du récepteur, c’est dans le discours du locuteur qu’on va chercher ses traces. Il nous semble qu’il est tout aussi important de voir dans quelle mesure et selon quelles modalités le discours du locuteur impacte réellement l’auditoire auquel il est adressé. Nous postulons que cette analyse est possible en nous penchant sur les retours de l’auditoire par rapport au discours du locuteur. Dans cette contribution, nous verrons comment le feedback du discours de candidature pour un troisième mandat de Ouattara en 2020 se structure en deux catégories quasi antagoniques : l’une validant l’argumentation et l’autre se posant en contre argumentation. Mots-clés : Argumentation ; Feedback ; Réfutation.

Résumé : Le Forum pour la Réconciliation Nationale en Côte d’Ivoire visait, comme stipulé par le triptyque qui le sous-tendait, la Vérité, la Repentance et le Pardon, afin d’aboutir à la Réconciliation. La question du pardon est donc centrale. Notre contribution ambitionne de montrer que par une étude des différentes sémiotisations du pardon, il est possible d’entrevoir que cette grande rencontre était vouée à l’échec. Mots-clés : Acte illocutionnaire, Pardon, Postures énonciatives, Stratégies argumentatives, Victimisation

Objective Our previous retrospective study demonstrated that perioperative dexmedetomidine (Dex) administration was associated with low systemic inflammatory response syndrome (SIRS) incidence. The present study was designed to investigate whether perioperative administration of Dex decreases the incidence of postpercutaneous nephrolithotomy lithotripsy (PCNL) SIRS in patients who undergo PCNL. Design A randomised controlled trial was designed. Participants A total of 190 patients were randomly assigned to receive Dex (DEX group, n=95) or saline control (CON group, n=95) and completed the study. In the DEX group, Dex was loaded (1 µg/kg) before anaesthesia induction and was infused (0.5 µg/kg/h) during surgery. Outcomes The incidences of postoperative SIRS were recorded. Serum interleukin-6 (IL-6) and tumour necrosis factor α(TNF-α) were measured. Results The incidence rates of SIRS were significantly lower in the DEX group than in the CON group (35.8% vs 50.5%, p=0.04). No patients developed sepsis in either group. These results might be attributed to inhibition of inflammatory responses and the resulting lower serum levels of IL-6 and TNF-α, caused by Dex administration. However, compared with the CON group, the lower incidence rate of SIRS in the DEX group did not result in better outcomes, such as shorter postoperative hospitalisation stays and lower costs. Conclusion The present study showed that Dex administration during PCNL might be beneficial for decreasing the incidence of SIRS through inhibiting the release of inflammatory mediators, but not clinical consequences such as postoperative hospitalisation duration and costs. Further effects of Dex administration on SIRS in patients who are scheduled for PCNL should be explored in future studies. Trial registration number ChiCTR-ICR-15006167. [ABSTRACT FROM AUTHOR]

Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling plays a dominant role in the pathogenesis of liver ischemia-reperfusion (IR) injury. Dexmedetomidine (Dex) protects the liver against IR injury via 2-adrenoceptor activation, but the contribution of TLR4 signaling remains unknown. The authors aimed to examine whether pretreatment with Dex produces hepatic protection and investigate the influence of Dex on TLR4/NF-κB signaling. Dex was given via intraperitoneal injection 30 min prior to orthotopic autologous liver transplantation (OALT) in rats, and three 2-adrenoceptor antagonists including atipamezole (a nonselective 2 receptor blocker), ARC-239 (a specific α2B/C blocker) and BRL-44408 (a specific α2A blocker) were injected intraperitoneally 10 min before Dex administration. Histopathologic evaluation of the liver and the measurement of serum alanine aminotransferase activity, TLR4/NF-κB expression in the liver, and pro-inflammatory factors (serum tumor necrosis factor-α, interleukin-1β and hepatic myeloperoxidase) concentrations were performed 8 h after OALT. Dex ameliorated liver injury after OALT probably by suppressing the TLR4/NF-κB pathway and decreasing inflammatory mediator levels. The protective effects of Dex were reversed by atipamezole and BRL-44408, but not by ARC-239, suggesting that these effects were mediated in part by the α2A subtype. In conclusion, Dex attenuates liver injury partly via the 2A-adrenoceptor subtype, and the mechanism is due to the suppression of the TLR4/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Intestinal motility and barriers are often impaired due to intestinal congestion during liver transplantation. Intestinal bacteria and enterogenous endotoxins enter into the blood stream or lymphatic system and translocate to other organs, which can result in postoperative multi-organ dysfunction (MODF) and systemic inflammatory reaction syndrome (SIRS) severely affecting patient survival. However, the mechanisms underlying liver transplantation-induced intestinal injury remain unclear and effective therapies are lacking. Thus, the present study investigated whether these effects were associated with endotoxin-mediated apoptosis. Rat autologous orthotopic liver transplantation (AOLT) models were established to observe dynamic intestinal injuries at different time-points following reperfusion. Changes in the levels of endotoxins and the primary receptor, toll-like receptor 4 (TLR4), as well as its downstream signaling molecule, nuclear factor-?B (NF-?B) were all determined. Finally, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were conducted to detect caspase-3 expression and intestinal cell apoptosis, respectively. AOLT resulted in significant pathological intestinal injury, with the most serious intestine damage apparent four or eight hours following reperfusion. Furthermore, the levels of endotoxins and inflammatory cytokines, such as tumor necrosis factor-a and interleukin-6, peaked during this time period and gradually decreased to the normal level. Notably, TLR4 and downstream NF-?B expression, as well as NF-?B-mediated caspase-3 activation and intestinal cell aapoptosis coincided with the intestinal pathological damage. Thus, the possible mechanism of post-liver transplantation intestinal injury was demonstrated to be associated with NF-?B activation-induced cell apoptosis. [ABSTRACT FROM AUTHOR]

Tryptase exacerbates intestinal ischemia-reperfusion injury, however, the direct role of tryptase in intestinal mucosal injury and the underlying mechanism remains largely unknown. Protease-activated receptor 2 (PAR-2), commonly activated by tryptase, interacts with various adaptor proteins, including β-arrestin-2. The present study aimed to determine whether tryptase is capable of inducing intestinal mucosal cell injury via PAR-2 activation and to define the role of β-arrestin-2 in the process of injury. The IEC-6 rat intestinal epithelial cell line was challenged by tryptase stimulation. Cell viability, lactate dehydrogenase (LDH) activity and apoptosis were analyzed to determine the severity of cell injury. Injury was also evaluated following treatments with specific PAR-2 and extracellular signal-related kinases (ERK) inhibitors, and knockdown of β-arrestin-2. PAR-2, ERK and β-arrestin-2 protein expression levels were evaluated. Tryptase treatment (100 and 1,000 ng/ml) resulted in IEC-6 cell injury, as demonstrated by significant reductions in cell viability, accompanied by concomitant increases in LDH activity and levels of cleaved caspase-3 protein expression. Furthermore, tryptase treatment led to a marked increase in PAR-2 and phosphorylated-ERK expression, and exposure to specific PAR-2 and ERK inhibitors eliminated the changes induced by tryptase. Knockdown of β-arrestin-2 blocked tryptase-mediated cell injury, whereas tryptase exerted no influence on β-arrestin-2 expression in IEC-6 cells. These data indicate that tryptase may directly damage IEC-6 cells via PAR-2 and the downstream activation of ERK, and demonstrate that the signaling pathway requires β-arrestin-2. [ABSTRACT FROM AUTHOR]

Adhesion between circulating monocytes and vascular endothelial cells is a key initiator of atherosclerosis. In our previous studies, it was demonstrated that the expression of connexin (Cx)43 in monocytes modulates cell adhesion, however, the effects of the expression of Cx43 in endothelial cells remains to be elucidated. Therefore, the present study investigated the role of the expression of Cx43 in endothelial cells in the process of cell adhesion. A total of four different methods with distinct mechanisms were used to change the function and expression of Cx43 channels in human umbilical vein endothelial cells: Cx43 channel inhibitor (oleamide), enhancer (retinoic acid), overexpression of Cx43 by transfection with pcDNA-Cx43 and knock-down of the expression of Cx43 by small interfering RNA against Cx43. The results indicated that the upregulation of the expression of Cx43 enhanced monocyte-endothelial adhesion and this was markedly decreased by downregulation of Cx43. This mechanism was associated with Cx43-induced expression of vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1. The effects of Cx43 in endothelial cells was independent of Cx37 or Cx40. These experiments suggested that local regulation of endothelial Cx43 expression within the vasculature regulates monocyte-endothelial adhesion, a critical event in the development of atherosclerosis and other inflammatory pathologies, with baseline adhesion set by the expression of Cx43. This balance may be crucial in controlling leukocyte involvement in inflammatory cascades. [ABSTRACT FROM AUTHOR]

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical regulator of the cellular-defense response in protection against oxidative injury. Several studies have demonstrated that propofol ameliorates ischemia/reperfusion injury in a number of organs. However, whether propofol exerts renal protection against liver transplantation via Nrf2 activation remains to be elucidated. The aim of the present study was to investigate the effects of orthotopic liver autotransplantation (OLAT) on renal Nrf2 expression and to determine whether propofol protects against kidney injury induced by OLAT via Nrf2 activation. A total of 24 male Sprague Dawley rats were randomly divided into four groups: sham surgery + normal saline (sham group); OLAT + normal saline (OLAT group); OLAT + propofol 50 mg/kg (L-Prop group) and OLAT + propofol 100 mg/kg (H-Prop group). Normal saline and propofol were administered for 3 consecutive days through an intraperitoneal injection prior to surgery. Kidney pathology, blood urea nitrogen (BUN), creatinine (Cr), superoxide anion (O2 •-), hydroxyl radical (.OH), maleic dialdehyde (MDA) and expression levels of Nrf2, Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1) and NADP quinine oxidoreductase 1 (NQO1) were assessed 8 h after OLAT. It was demonstrated that OLAT induced remote kidney damage. Pretreatment with propofol significantly ameliorated renal pathology and abrogated the increase of the Cr and BUN concentrations, O2 •- and .OH activities, and MDA levels induced by OLAT. In the H-Prop group, Keap1 expression in the cytoplasm was decreased and Nrf2 expression in the nucleus was upregulated, accompanied by an increase of HO-1 and NQO1 expression. The present results suggest that propofol pretreatment exerted renal protection against OLAT, with the upregulation of nuclear Nrf2 expression as a potential mechanism. [ABSTRACT FROM AUTHOR]

Liver transplantation is known to trigger intestinal injuries. Oxidative damage that is induced by reactive oxygen species (ROS) plays a crucial role in ischemia-reperfusion injuries. NF-E2-related factor-2 (Nrf2) and its modulated antioxidant enzymes form the critical endogenous antioxidant system to scavenge ROS. The present study investigated the dynamic changes of intestinal ROS levels, Nrf2 expression and antioxidant enzyme activity following orthotopic liver autotransplantation (OLAT). Sprague-Dawley rats were randomly divided into five groups consisting of one sham group and four groups with rats that underwent OLAT and were evaluated following 4, 8, 16 and 24 h, respectively. The intestinal specimens were collected for histopathological examination and the detection of hydrogen peroxide (H2O2), hydroxyl radical (*OH), malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels and the expression of Nrf2. The present study demonstrated that OLAT resulted in severe intestinal injury, which manifested as a significant change in the intestine pathological scores as early as 4 h and peaking at 8 h post-treatment. Oxidative stress was also revealed by the increase of the H2O2, *OH and MDA levels. Significant decreases were observed in the activity of SOD and CAT and a dramatic decrease occurred in the levels of GSH at 4 and 8 h post-treatment. All the parameters were restored gradually at 16 and 24 h post-treatment. The expression of Nrf2 in the intestinal tissues increased significantly at 4, 16 and 24 h following OLAT. The present study shows that an imbalance between oxidants and antioxidants contributes to intestinal oxidative injury, and that the upregulation of Nrf2 is not sufficient to withstand intestinal oxidative injury following OLAT. [ABSTRACT FROM AUTHOR]