NEDD4 lactylation promotes APAP induced liver injury through Caspase11 dependent non-canonical pyroptosis.

Caspase-11 detection of intracellular lipopolysaccharide mediates non-canonical pyroptosis, which could result in inflammatory damage and organ lesions in various diseases such as sepsis. Our research found that lactate from the microenvironment of acetaminophen-induced acute liver injury increased Caspase-11 levels, enhanced gasdermin D activation and accelerated macrophage pyroptosis, which lead to exacerbation of liver injury. Further experiments unveiled that lactate inhibits Caspase-11 ubiquitination by reducing its binding to NEDD4, a negative regulator of Caspase-11. We also identified that lactates regulated NEDD4 K33 lactylation, which inhibits protein interactions between Caspase-11 and NEDD4. Moreover, restraining lactylation reduces non-canonical pyroptosis in macrophages and ameliorates liver injury. Our work links lactate to the exquisite regulation of the non-canonical inflammasome, and provides a basis for targeting lactylation signaling to combat Caspase-11-mediated non-canonical pyroptosis and acetaminophen-induced liver injury.

Association between sarcopenia and new-onset chronic kidney disease among middle-aged and elder adults: findings from the China Health and Retirement Longitudinal Study.

BACKGROUND: Sarcopenia is a senile syndrome of age-related muscle loss. It is thought to affect the development of chronic kidney disease and has a serious impact on the quality of life of the elder adults. Little is known about the association between sarcopenia and new-onset chronic kidney disease in middle-aged and elder adults. Using nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS), we conducted a longitudinal analysis to investigate the association between sarcopenia status and new-onset chronic kidney disease in middle-aged and elder adults in China. METHODS: The study population consisted of 3676 participants aged 45 or older selected from 2011 CHARLS database who had no history of chronic kidney disease at the baseline and completed the follow-up in 2015. A multivariate cox regression model was employed to examine the association between sarcopenia and the incidence of new-onset chronic kidney disease. RESULTS: Followed up for 4 years, a total of 873 (22.5%) new cases of chronic kidney disease occurred. Among them, participants diagnosed with sarcopenia (HR1.45; 95% CI 1.15-1.83) were more likely to develop new-onset chronic kidney disease than those without sarcopenia. Similarly, patients with sarcopenia were more likely to develop new-onset chronic kidney disease than those with possible sarcopenia (HR 1.27; 95%CI 1.00-1.60). Subgroup analysis revealed that elder adults aged between 60 and 75 years old (HR 1.666; 95%CI 1.20-22.28), with hypertension (HR 1.57; 95%CI 1.02-2.40), people with sarcopenia had a significantly higher risk of developing new-onset chronic kidney disease than those without sarcopenia (all P < 0.05). CONCLUSION: Middle-aged and elder adults diagnosed with sarcopenia have a higher risk of developing new-onset chronic kidney disease.

Sarcopenia index based on serum creatinine and cystatin C is associated with mortality in middle-aged and older adults in Chinese: A retrospective cohort study from the China Health and Retirement Longitudinal Study.

Background: The sarcopenia index (SI, serum creatinine/serum cystatin C × 100) is recommended for predicting sarcopenia. There were several studies showing that lower SI is associated with poorer outcomes in the older adults. However, the cohorts studied in these researches were mainly patients hospitalized. The aim of this study was to evaluate the correlation between SI and all-cause mortality among middle-aged and older adults from the China Health and Retirement Longitudinal Study (CHARLS). Materials and methods: A total of 8,328 participants meeting the criteria were enrolled in this study from CHARLS between 2011 and 2012. SI was calculated as [serum creatinine (mg/dL)/cystatin C (mg/L)] × 100. Mann-Whitney U-test and Fisher's exact test were used to assess balance in baseline characteristics. Kaplan-Meier, log-rang analysis, univariate and multivariate Cox hazard ratio regression models were used to compare the mortality between different SI levels. The dose relationship between sarcopenia index and all-cause mortality was further assessed by the cubic spline functions and smooth curve fitting. Results: After adjustment for potential covariates, we found SI was significantly correlated with all-cause mortality [Hazard Ratio (HR) = 0.983, 95% confidence interval (CI) 0.977-0.988, P < 0.001]. Similarly, as SI was used as a categorical variable according to quartiles, higher SI was associated with lower mortality [Hazard Ratio (HR) = 0.44, 95% CI 0.34-0.57, P < 0.001] after adjustment for confounders. Conclusions: Lower sarcopenia index was associated with higher mortality among middle-aged and older adults in China.

Waist-to-height ratio and new-onset hypertension in middle-aged and older adult females from 2011 to 2015: A 4-year follow-up retrospective cohort study from the China Health and Retirement Longitudinal Study.

Background: Central obesity was closely associated with hypertension. Middle-aged and older adult females, defined as those aged 45 and above, were more likely to suffer from central obesity. For waist-to-height ratio (WHtR) was used as central obesity assessment, the object of this study was to illustrate the relationship between WHtR and the incidence of hypertension in middle-aged and older adult females in China. Methods: Data used in this prospective cohort study was derived from the China Health and Retirement Longitudinal Study (CHARLS) in a baseline survey from 2011 to 2012 with a follow-up duration of 4 years. The waist-to-height ratio was calculated as waist circumstance divided by height, and the cohort was divided into different groups based on WHtR level. The outcome variable was new-onset hypertension. Results: Of the 2,438 participants included in the study, 1,821 (74.7%) had high WHtR levels (WHtR ≥ 0.5). As WHtR was closely related to new-onset hypertension in a multivariable logistics regression mode [OR: 7.89 (95% CI: 2.10-29.67)], individuals with high WHtR were also more likely to suffer from hypertension compared with low WHtR levels [OR: 1.34 (95% CI: 1.06-1.69)]. Conclusion: WHtR is positively related to the risk of hypertension incidents among middle-aged and older adult females. Individuals with WHtR ≥ 0.5 were more likely to suffer from hypertension.

Interaction between Acute Hepatic Injury and Early Coagulation Dysfunction on Mortality in Patients with Acute Myocardial Infarction.

BACKGROUND: In acute myocardial infarction (AMI), acute hepatic injury is an independent risk factor for prognosis and is associated with complex coagulation dynamics. This study aims to determine the interaction between acute hepatic injury and coagulation dysfunction on outcomes in AMI patients. METHODS: The Medical Information Mart for Intensive Care (MIMIC-III) database was used to identify AMI patients who underwent liver function testing within 24 h of admission. After ruling out previous hepatic injury, patients were divided into the hepatic injury group and the nonhepatic injury group based on whether the alanine transaminase (ALT) level at admission was >3 times the upper limit of normal (ULN). The primary outcome was intensive care unit (ICU) mortality. RESULTS: Among 703 AMI patients (67.994% male, median age 65.139 years (55.757-76.859)), acute hepatic injury occurred in 15.220% (n = 107). Compared with the nonhepatic injury group, patients with hepatic injury had a higher Elixhauser comorbidity index (ECI) score (12 (6-18) vs. 7 (1-12), p < 0.001) and more severe coagulation dysfunction (85.047% vs. 68.960%, p < 0.001). In addition, acute hepatic injury was associated with increased in-hospital mortality (odds ratio (OR) = 3.906; 95% CI: 2.053-7.433; p < 0.001), ICU mortality (OR = 4.866; 95% CI: 2.489-9.514; p < 0.001), 28-day mortality (OR = 4.129; 95% CI: 2.215-7.695; p < 0.001) and 90-day mortality (OR = 3.407; 95% CI: 1.883-6.165; p < 0.001) only in patients with coagulation disorder but not with normal coagulation. Unlike patients with coagulation disorder and normal liver, patients with both coagulation disorder and acute hepatic injury had greater odds of ICU mortality (OR = 8.565; 95% CI: 3.467-21.160; p < 0.001) than those with normal coagulation. CONCLUSIONS: The effects of acute hepatic injury on prognosis are likely to be modulated by early coagulation disorder in AMI patients.

Construction and validation of a nomogram for predicting survival in elderly patients with cardiac surgery.

Background: In recent years, the number of elderly patients undergoing cardiac surgery has rapidly increased and is associated with poor outcomes. However, there is still a lack of adequate models for predicting the risk of death after cardiac surgery in elderly patients. This study sought to identify independent risk factors for 1-year all-cause mortality in elderly patients after cardiac surgery and to develop a predictive model. Methods: A total of 3,752 elderly patients with cardiac surgery were enrolled from the Medical Information Mart for Intensive Care III (MIMIC-III) dataset and randomly divided into training and validation sets. The primary outcome was the all-cause mortality at 1 year. The Least absolute shrinkage and selection operator (LASSO) regression was used to decrease data dimensionality and select features. Multivariate logistic regression was used to establish the prediction model. The concordance index (C-index), receiver operating characteristic curve (ROC), and decision curve analysis (DCA) were used to measure the predictive performance of the nomogram. Results: Our results demonstrated that age, sex, Sequential Organ Failure Assessment (SOFA), respiratory rate (RR), creatinine, glucose, and RBC transfusion (red blood cell) were independent factors for elderly patient mortality after cardiac surgery. The C-index of the training and validation sets was 0.744 (95%CI: 0.707-0.781) and 0.751 (95%CI: 0.709-0.794), respectively. The area under the curve (AUC) and decision curve analysis (DCA) results substantiated that the nomogram yielded an excellent performance predicting the 1-year all-cause mortality after cardiac surgery. Conclusions: We developed a novel nomogram model for predicting the 1-year all-cause mortality for elderly patients after cardiac surgery, which could be an effective and useful clinical tool for clinicians for tailored therapy and prognosis prediction.

A Predictive Model Based on Inflammatory and Coagulation Indicators for Sepsis-Induced Acute Kidney Injury.

Background: Sepsis-induced acute kidney injury (S-AKI) is associated with systemic inflammatory responses and coagulation system dysfunction, and it is associated with an increased risk of mortality. However, there was no study to explore the predictive value of inflammatory and coagulation indicators for S-AKI. Methods: In this retrospective study, 1051 sepsis patients were identified and divided into a training cohort (75%, n = 787) and a validation cohort (25%, n = 264) in chronological order according to the date they were admitted. Univariate analyses and multivariate logistic regression analyses were performed to identify the independent predictors of S-AKI. The logistic regression analyses (enter methods) were used to conducted the prediction models. The ROC curves were used to determine the predictive value of the constructed models on S-AKI. To test whether the increase in the AUC is significant, we used a two-sided test for ROC curves available online (http://vassarstats.net/roc_comp.html). The secondary outcome was different AKI stages and major adverse kidney events within 30 days (MAKE30). Stage 3B of S-AKI was defined as both meeting the stage 3 criteria [increase of Cr level by > 300% (≥ 4.0 mg/dL with an acute increase of ≥ 0.5 mg/dL) and/or UO < 0.3 mL/kg/h for > 24 h or anuria for > 12 h and/or acute kidney replacement therapy] and having cystatin C positive. MAKE30 were a composite of death, new renal replacement therapy (RRT), or persistent renal dysfunction (PRD). Results: We discovered that cardiovascular disease, white blood cell (WBC), mean arterial pressure (MAP), platelet (PLT), serum procalcitonin (PCT), prothrombin time activity (PTA), and thrombin time (TT) were independent predictors for S-AKI. The predictive value (AUC = 0.855) of the simplest model 3 (constructed with PLT, PCT, and PTA), with a sensitivity of 77.6% and a specificity of 82.4%, had a similar predictive value comparing with the model 1 (AUC = 0.872) and the model 2 (AUC = 0.864) in the training cohort (P > 0.05). Compared with the model 1 (AUC = 0.888) and the model 2 (AUC = 0.887), the model 3 (AUC = 0.887) had a similar predictive value in the validation cohort. Moreover, model 3 had the best predictive power for predicting S-AKI in the stage 3 (AUC = 0.777), especially in stage 3B (AUC = 0.771). Finally, the model 3 (AUC = 0.843) had perfect predictive power for predicting MAKE30 in sepsis patients. Conclusion: Within 24 hours after admission, the simplest model 3 (constructed with PLT, PCT, and PTA) might be a robust predictor of the S-AKI in sepsis patients, providing information for timely and efficient intervention.

NSAID Treatment Before and on the Early Onset of Acute Kidney Injury Had an Opposite Effect on the Outcome of Patients With AKI.

Background: NSAIDs are one of the most frequently used medications and a risk factor for AKI. However, the optimal time of NSAIDs in patients with AKI is unknown. Methods: A secondary analysis of a multicenter, randomized clinical trial including adult inpatients with acute kidney injury was performed. Univariate, multivariate, and subgroup analyses were used to explore the impact of NSAIDs during the early onset of AKI on the outcome of patients with AKI. Results: A total of 6,030 patients with AKI were enrolled in the study. Following are the findings of the multi-factor analysis: NSAID treatments within 72 and 24 h before the onset of AKI were not associated with AKI progression, dialysis, or discharge from dialysis; only NSAID treatment within the 24-h onset of AKI was associated with these outcomes, and their OR values were independently 1.50 (95% CI: 1.02-2.19, p = 0.037), 4.20 (95% CI: 1.47-11.97, p = 0.007), and 0.71 (95% CI: 0.54-0.92, p = 0.011); only NSAID treatment within the 24-h onset of AKI would decrease the 14-day mortality, and the OR value was 0.52 (95% CI: 0.33-0.82, p = 0.005). The subgroup analysis revealed that in patients with age ≥65 years, CKD (chronic kidney disease), congestive heart failure, hypertension, and liver disease, NSAID treatments within the 24-h onset of AKI would deteriorate the outcome of patients with AKI. Conclusion: Before an early onset of AKI, NSAID treatment might be safe, but during the onset of AKI, even early NSAID treatment would deteriorate the outcome of patients with AKI.

Antimicrobial and Microbiological Characteristics of Critically Ill Patients with Complicated Intra-Abdominal Infection: Observational Data from Beth Israel Deaconess Medical Center.

PURPOSE: We describe the clinical characteristics, isolated microorganisms and antibiotics used in patients with cIAIs during ICU stay. METHODS: A retrospective analysis of data from Beth Israel Deaconess Medical Center was performed. RESULTS: A total of 316 patients with cIAIs were included, 57.0% of them were male and the median age was 63 years. A total of 239 patients did have cultures taken, and 74 patients had a positive microbial result. The main pathogens were Escherichia coli, Staphylococci (coagulase negative), Enterococcus sp. and Bacteroides fragilis. The main antibiotics given were vancomycin, metronidazole, piperacillin tazobactam and ciprofloxacin. Univariable and multivariable Cox regression analyses showed that receiving more antibiotics reduced ICU mortality, but the same results were not obtained in the analysis of hospital mortality. CONCLUSION: The main Gram-positive microorganisms for empirical antimicrobial therapy were Staphylococci (coagulase negative), Enterococcus sp. and Staphylococcus aureus, and Gram-negative microorganisms were Escherichia coli, Bacteroides fragilis and Klebsiella pneumoniae. The use of more antibiotics reduced ICU mortality, but the same results were not obtained in the analysis of hospital mortality.

PPARγ Alleviates Sepsis-Induced Liver Injury by Inhibiting Hepatocyte Pyroptosis via Inhibition of the ROS/TXNIP/NLRP3 Signaling Pathway.

Sepsis is a systemic inflammatory response syndrome caused by a dysregulated host response to infection. Peroxisome proliferator-activated receptor gamma (PPARγ) exerts anti-inflammatory and antioxidative properties. To investigate the potential effects of PPARγ on sepsis-induced liver injury and determine the related mechanisms, C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to create a sepsis model which was treated with GW1929 or GW9662 to upregulate or downregulate the expression of PPARγ. We found that upregulation of PPARγ decreased the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), and liver pathological damage and improved the 5-day survival rate. Increased expression of PPARγ also decreased sepsis-induced reactive oxygen species (ROS) by promoting the expression of Nrf2. In addition, upregulated PPARγ inhibited the expression of the TXNIP/NLRP3 signaling pathway by reducing ROS-induced injury in the liver during sepsis, which further reduced NLRP3-mediated pyroptosis and the inflammatory response. The role of PPARγ was further examined in in vitro experiments, where lipopolysaccharide- (LPS-) treated HepG2 and Hep3B cells were incubated with GW1929 or GW9662 to upregulate or downregulate the expression of PPARγ. We found that upregulated PPARγ ameliorated LDH release and improved cell viability. Our results indicated that increased expression of PPARγ reduced ROS levels and inhibited the TXNIP/NLRP3 signaling pathway, resulting in decreased pyroptosis and reduced liver dysfunction during sepsis.

An Interpretable Early Dynamic Sequential Predictor for Sepsis-Induced Coagulopathy Progression in the Real-World Using Machine Learning.

Sepsis-associated coagulation dysfunction greatly increases the mortality of sepsis. Irregular clinical time-series data remains a major challenge for AI medical applications. To early detect and manage sepsis-induced coagulopathy (SIC) and sepsis-associated disseminated intravascular coagulation (DIC), we developed an interpretable real-time sequential warning model toward real-world irregular data. Eight machine learning models including novel algorithms were devised to detect SIC and sepsis-associated DIC 8n (1 ≤ n ≤ 6) hours prior to its onset. Models were developed on Xi'an Jiaotong University Medical College (XJTUMC) and verified on Beth Israel Deaconess Medical Center (BIDMC). A total of 12,154 SIC and 7,878 International Society on Thrombosis and Haemostasis (ISTH) overt-DIC labels were annotated according to the SIC and ISTH overt-DIC scoring systems in train set. The area under the receiver operating characteristic curve (AUROC) were used as model evaluation metrics. The eXtreme Gradient Boosting (XGBoost) model can predict SIC and sepsis-associated DIC events up to 48 h earlier with an AUROC of 0.929 and 0.910, respectively, and even reached 0.973 and 0.955 at 8 h earlier, achieving the highest performance to date. The novel ODE-RNN model achieved continuous prediction at arbitrary time points, and with an AUROC of 0.962 and 0.936 for SIC and DIC predicted 8 h earlier, respectively. In conclusion, our model can predict the sepsis-associated SIC and DIC onset up to 48 h in advance, which helps maximize the time window for early management by physicians.

Early Coagulation Disorder Is Associated With an Increased Risk of Atrial Fibrillation in Septic Patients.

Background: Atrial fibrillation (AF) and coagulation disorder, two common complications of sepsis, are associated with the mortality. However, the relationship between early coagulation disorder and AF in sepsis remains elusive. This study aimed to evaluate the interaction between AF and early coagulation disorder on mortality. Methods: In this retrospective study, all data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. Septic patients with coagulation tests during the first 24 h after admission to intensive care units (ICUs) meeting study criteria were included in the analysis. Early coagulation disorder is defined by abnormalities in platelet count (PLT), international normalized ratio (INR) and activated partial thromboplastin time (APTT) within the first 24 h after admission, whose score was defined with reference to sepsis-induced coagulopathy (SIC) and coagulopathy. Patients meeting study criteria were divided into AF and non-AF groups. Results: In total, 7,528 septic patients were enrolled, including 1,243 (16.51%) with AF and 5,112 (67.91%) with early coagulation disorder. Compared with patients in the non-AF group, patients in the AF group had higher levels of INR and APTT (P < 0.001). Multivariable logistic regression analyses showed that stroke, early coagulation disorder, age, gender, congestive heart failure (CHF), chronic pulmonary disease, renal failure, and chronic liver disease were independent risk factors for AF. In addition, AF was related to in-hospital mortality and 90-day mortality. In the subgroup analysis stratified by the scores of early coagulation disorder, AF was associated with an increased risk of 90-day mortality when the scores of early coagulation disorder were 1 or 2 and 3 or 4. Conclusion: In sepsis, coagulation disorder within the first 24 h after admission to the ICUs is an independent risk factor for AF. The effect of AF on 90-day mortality varies with the severity of early coagulation disorder.

Association between body mass index and short-term mortality in patients with intra-abdominal infections: a retrospective, single-centre cohort study using the Medical Information Mart for Intensive Care database.

OBJECTIVES: This study aimed to determine the relationship between the body mass index (BMI) and short-term mortality of patients with intra-abdominal infection (IAI) using the Medical Information Mart for Intensive Care (MIMIC-III) database. DESIGN: Retrospective cohort study. SETTING: Adult intensive care units (ICUs) at a tertiary hospital in the USA . PARTICIPANTS: Adult IAI ICU patients from 2001 to 2012 in the MIMIC-III database. INTERVENTIONS: In univariate analysis, we compared the differences in the characteristics of patients in each BMI group. Cox regression models were used to evaluate the relationships between BMI and short-term prognosis. PRIMARY AND SECONDARY OUTCOME MEASURES: 90-day survival. RESULTS: In total, 1161 patients with IAI were included. There were 399 (34.4%) patients with a normal BMI (<25 kg/m2), 357 (30.8%) overweight patients (25-30 kg/m2) and 405 (34.9%) obese patients (>30 kg/m2) who tended to be younger (p<0.001) and had higher Sequential Organ Failure Assessment scores (p<0.05). The mortality of obese patients at 90 days was lower than that of patients with a normal BMI (20.74% vs 23.25%, p<0.05), but their length of stay in the ICU was higher (4.9 days vs 3.6 days, p<0.001); however, their rate of mechanical ventilation utilisation was higher (61.48% vs 56.86%, p<0.05). In the Cox regression model, we also confirmed that BMI was a protective factor in patients with IAIs, and the adjusted mortality rate of patients with a higher BMI was 0.97 times lower than that of patients with a lower BMI (p<0.001, HR=0.97, 95% CI 0.96 to 0.99). CONCLUSIONS: IAI patients with an overweight or obese status might have lower 90-day mortality than patients with a normal BMI.

Ulinastatin protects against acetaminophen-induced liver injury by alleviating ferroptosis via the SIRT1/NRF2/HO-1 pathway.

Acetaminophen (APAP) overdose has been considered responsible for the drug-induced liver injury for many years. Ferroptosis is defined as an iron-dependent form of cell death associated with lipid peroxide accumulation. Ferroptosis is involved in APAP-induced acute liver failure, and UTI is an effective drug treatment for acute liver failure. Thus, we aimed to determine whether UTI protects the liver against APAP-induced acute liver failure by decreasing ferroptosis-induced lipid peroxide accumulation. C57BL/6 mice and LO2 cell line were treated with UTI before and after the exposure to APAP. Liver tissues and LO2 cells were collected for biochemical assessment of molecular parameters. APAP-induced upregulation of ferroptotic events (iron content), lipid hydroperoxides (ROS production, MDA, and 4-HNE), and depletion of GSH were effectively relieved by ferrostatin-1 (Fer-1), a ferroptosis inhibitor, and UTI. UTI blocked ferroptosis-induced lipid peroxide accumulation by promoting nuclear translocation of NRF2 to activate its downstream targets (HO-1). An increased expression or knockdown of of SIRT1 influenced the UTI effect on the NRF2 pathway and had an impact on lipid accumulation. Overall, UTI plays a role in mitigation of APAP-induced acute liver injury by inhibiting ferroptosis-induced lipid peroxide accumulation, and the effect of UT1 was mediated by the NRF2/HO-1 pathway and SIRT1 expression.

Origin of Sepsis Associated with the Short-Term Mortality of Patients: A Retrospective Study Using the eICU Collaborative Research Database.

OBJECTIVE: The aim of this study was to compare the clinical characteristics and short-term mortality of patients with abdominal and pulmonary sepsis. DESIGN: Retrospective cohort study. SETTING: Adult intensive care units (ICUs) at tertiary hospitals. PARTICIPANTS: Adult ICU patients from 2014 to 2015 in the eICU Collaborative Research Database. INTERVENTIONS: In univariate analysis, we compared the differences in the characteristics of patients in each group. Logistic regression models were used to evaluate the relationships between primary site of sepsis and short-term prognosis. PRIMARY AND SECONDARY OUTCOME MEASURES: Hospital and ICU survival. RESULTS: The final dataset included 7023 pulmonary and 2360 abdominal sepsis patients, who accounted for 74.84% and 25.16%, respectively. We compared the results of the baseline characteristics, vital signs and laboratory indicators between the two groups. In the logistic regression models, we found that the hospital and ICU mortality of patients with abdominal sepsis was higher than that with pulmonary sepsis (p < 0.05, OR = 1.15, p < 0.05, OR = 1.19, respectively), although these results were no longer significantly after adjustment for confounders, but in the subgroups with SOFA score ≧ 8, the adjusted hospital mortality rate of patients with abdominal sepsis was 1.30 times higher than that of patients with pulmonary sepsis (p < 0.005, OR = 1.30, 95% CI 1.09-1.55), while there was no significant difference in the subgroups that SOFA score < 8. CONCLUSION: In the patients with SOFA score ≧ 8, the adjusted hospital mortality of patients with abdominal sepsis was higher than patients with pulmonary sepsis.

Comparison of survival between adolescent and young adult vs older patients with hepatocellular carcinoma.

BACKGROUND: Due to the special clinical features and biologic characteristics of adolescent and young adult (AYA) cancers, AYA cancers are different from cancers in children and elderly individuals. However, there are few reports on AYA hepatocellular carcinoma (HCC). AIM: To investigate the overall survival (OS) of AYA (15-39 years) and elderly (40-74 years) patients with HCC. METHODS: The data of all the HCC cases were extracted from the Surveillance, Epidemiology, and End Results database from 2004 to 2015 and were then divided into two groups based on age: AYA group (15-39 years) and older group (40-74 years). Kaplan-Meier curves and log-rank tests were used to compare the OS of the two groups. Propensity score matching (PSM) was employed to analyze the OS difference between the two groups. The Cox proportional hazards regression model was used to perform multivariate analysis to explore the risk factors for OS of HCC patients. RESULTS: Compared to elderly cancer patients, AYA patients with HCC had a worse Surveillance, Epidemiology, and End Results stage, including the distant stage (22.1% vs 15.4%, P < 0.001), and a more advanced American Joint Committee on Cancer (AJCC) stage, including AJCC III and IV (49.2% vs 38.3%, P < 0.001), and were more likely to receive surgery (64.5% vs 47.5%, P < 0.001). Before PSM, the AYA group had a longer survival in months (median: 20.00, interquartile range [IQR]: 5.00-62.50) than the older group (median: 15.00, IQR: 4.00-40.00) (P < 0.001). After PSM, the AYA group still had a longer survival in months (median: 21.00, IQR: 5.00-64.50) than the older group (median: 18.00, IQR: 6.00-53.00) (P < 0.001). The Cox proportional hazards regression model showed that advanced age (hazard ratio [HR] = 1.405, 95%CI: 1.218-1.621, P < 0.001) was a risk factor for OS of HCC patients. In the subgroup analysis, the Cox proportional hazards regression model showed that in AJCC I/II HCC patients, advanced age (HR = 1.749, 95%CI: 1.352-2.263, P < 0.001) was a risk factor for OS, while it was not a risk factor in AJCC III/IV HCC patients (HR = 1.186, 95%CI: 0.997-1.410, P = 0.054) before PSM. After PSM, advanced age (HR = 1.891, 95%CI: 1.356-2.637, P < 0.001) was still a risk factor for OS in AJCC I/II HCC patients, but was not a risk factor for OS in AJCC III/IV HCC patients (HR = 1.192, 95%CI: 0.934-1.521, P = 0.157) after PSM. CONCLUSION: AYA patients with HCC have different clinical characteristics from older adults. In different AJCC stages, the two groups of patients have different OS: In AJCC I/II HCC patients, advanced age is a risk factor for OS, but it is not a risk factor for OS in the AJCC III/IV HCC patient group.

Methane-Rich Saline Alleviates CA/CPR Brain Injury by Inhibiting Oxidative Stress, Microglial Activation-Induced Inflammatory Responses, and ER Stress-Mediated Apoptosis.

Brain injury induced by cardiac arrest/cardiopulmonary resuscitation (CA/CPR) is the leading cause of death among patients who have recovery of spontaneous circulation (ROSC). Inflammatory response, apoptosis, and oxidative stress are proven pathological mechanisms implicated in neuronal damage. Methane-rich saline (MRS) has been proven that exerts a beneficial protectiveness impact in several models of ischemia-reperfusion injury. The goal of this paper is to ascertain the role of MRS in CA/CPR-induced brain injury and its potential mechanisms. The tracheal intubation of Sprague-Dawley (SD) rats was clamped for 6 min to establish an asphyxiating cardiac arrest model. After that, chest compressions were applied; then, MRS or saline was administered immediately post-ROSC, the rats were sacrificed, and brain tissue was collected at the end of 6 hours. We observed that MRS treatment attenuated neuronal damage in the hippocampal CA1 region by inhibiting microglial activation, leading to a decrease in the overexpression of proinflammatory cytokines such as TNF-α, IL-6, and iNOS. The results also illustrated that MRS treatment diminished apoptosis in the hippocampal CA1 region , reduced the expression of apoptosis-associated proteins Bax and cleaved caspase9, and increased Bcl-2 expression, as well as inhibited the expression of endoplasmic reticulum (ER) stress pathway-related proteins GRP78, ATF4, and CHOP. Further findings showed that MRS treatment significantly attenuated hippocampal ROS and MDA levels and increased GSH and SOD antioxidant factor levels, which indicated that MRS treatment could inhibit oxidative stress. Our results suggest that MRS exerts a protective effect against CA/CPR brain injury, by inhibiting oxidative stress, microglial activation-induced inflammatory responses, and ER stress-mediated apoptosis.

Metformin protects against intestinal ischemia-reperfusion injury and cell pyroptosis via TXNIP-NLRP3-GSDMD pathway.

Intestinal ischemia-reperfusion (I/R) injury is a life-threatening vascular emergency and has long been a disturbing problem for surgeons. Oxidative stress is considered a vital factor in I/R injury. Metformin has anti-oxidative properties and protects against I/R injury. The present study aimed to investigate whether Metformin protects against intestinal I/R injury and reveal the protective mechanism of Metformin. I/R injury was induced in mice by temporary superior mesenteric artery occlusion, and Caco-2 cells were subjected to OGD/R to establish an in vitro model. Different doses of Metformin were administered in vivo and in vitro. We found that I/R injury led to intestinal barrier disruption and cell death by examining histopathological results and the intestinal barrier index, including TER, tight junction proteins and serum biomarkers. We confirmed the existence of pyroptosis in intestinal I/R injury. Moreover, we confirmed the role of pyroptosis in intestinal I/R injury by silencing the gasdermin D (GSDMD). Then, we confirmed that Metformin treatment protected barrier function against intestinal I/R injury and reduced oxidative stress and the inflammatory response. Importantly, Metformin reduced pyroptosis-related proteins, including NLRP3, cleaved caspase-1, and the N-terminus of GSDMD. Knocking down the GSDMD could reversed the protective effects of Metformin, which showed pyroptosis was one of the major cell death pathways controlled by Metformin treatment in setting of intestinal I/R injury. We also discovered that Metformin suppressed the expression of TXNIP and the interaction between TXNIP and NLRP3. We performed siRNA knockdown and found that the protective effects were abolished, which further confirmed our findings. In conclusion, we believe that Metformin protects against intestinal I/R injury in a TXNIP-NLRP3-GSDMD-dependent manner.

Methane-Rich Saline: A Potential Resuscitation Fluid for Hemorrhagic Shock.

Hemorrhagic shock is caused by massive blood loss. If the patient is not fully resuscitated in time, this may eventually lead to multiple organ failure and even death. Previous studies on methane-rich saline in animal models showed that it confers resistance against many diseases. In this study, we explored the protective effect of methane-rich saline, used as a resuscitation fluid, in hemorrhagic shock. Hemorrhagic shock was induced in SD rats by bloodletting via intubation of the right femoral artery. The rats were divided into three groups: a sham control group (sham control), a shock group resuscitated by an infusion of autologous blood and an equivalent volume of normal saline (Shock+NS), and a shock group resuscitated by an infusion of autologous blood and an equivalent volume of methane-rich saline (Shock+MRS). Assessment of blood pressure and levels of plasma lactate showed that resuscitation using methane-rich saline (MRS) restored systemic blood pressure and reduced the levels of lactate in the plasma. Meanwhile, lower levels of serum IL-6 and TNF-α were also observed in the group resuscitated with MRS. In the heart, liver, and kidney, MRS reduced inflammation and oxidative stress levels. Analysis of organ function via levels of biochemical indicators revealed that the group resuscitated with MRS had reduced serum levels of AST and CK, indicating a potential cardioprotective effect. The expression levels of apoptosis-related proteins, including those of Bcl-2/Bax, and the results of TUNEL-labeling assay indicated that MRS significantly reduced apoptosis in the heart. Methane also had a positive effect on the expression of the PGC-1α/SIRT3/SOD2 signaling pathway. Our results showed that MRS can potentially serve as a novel resuscitation fluid because of its anti-inflammatory, antioxidative, and antiapoptotic properties.

Methane-Rich Saline Counteracts Cholestasis-Induced Liver Damage via Regulating the TLR4/NF-κB/NLRP3 Inflammasome Pathway.

Cholestatic liver injury, due to obstruction of the biliary tract or genetic defects, is often accompanied by progressive inflammation and liver fibrosis. Methane-rich saline (MRS) has anti-inflammatory properties. However, whether MRS can provide protective effect in cholestatic liver injury is still unclear. In this study, Sprague-Dawley rats received bile duct ligation (BDL) to generate a cholestatic model followed by MRS treatment (10 mL/kg, ip treatment) every 12 h after the operation to explore the potential protective mechanism of MRS in cholestatic liver injury. We found that MRS effectively improved liver function, alleviated liver pathological damage, and localized infiltration of inflammatory cells. MRS treatment decreased the expression of hepatic fibrosis-associated proteins to alleviate liver fibrosis. Furthermore, MRS treatment suppressed the TLR4/NF-κB pathway and further reduced the levels of proinflammatory factors. Downregulation of NF-κB subsequently reduced the NLRP3 expression to inhibit pyroptosis. Our data indicated that methane treatment prevented cholestatic liver injury via anti-inflammatory properties that involved the TLR4/NF-κB/NLRP3 signaling pathway.