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Background: Intestinal ischemia-reperfusion injury is associated with both macrocirculatory and microcirculatory failure. Association of a vasoconstrictor in combination with a vasodilator such as ilomedin may improve macrocirculation parameters, microcirculation perfusion and reduce endothelial dysfunction. The primary objective was to demonstrate a difference in mean arterial pressure (MAP) after intestinal reperfusion with the concomitant administration of norepinephrine and ilomedin during ischemia compared with traditional hemodynamic treatment strategies (fluid resuscitation and vasopressors only). Secondary objectives were to demonstrate an improvement in peripheral and intestinal microcirculatory perfusion and endothelial dysfunction after intestinal reperfusion using this association.

Methods: We conducted a randomized preclinical trial in twenty-one large white pigs, in which a 2-hour small bowel ischemia was performed using a segmental mesenteric occlusion model, followed by a 2-hour reperfusion. Pigs were randomized into 3 groups: goal directed fluid therapy, early administration of norepinephrine before reperfusion and early administration of ilomedin and norepinephrine before reperfusion. Macrocirculatory (MAP and Cardiac Index (CI)), microcirculatory (Sublingual with SideStream Dark Field system and intestinal hemoglobin oxygen saturation with hyperspectral imaging (HSI)) measurements and biological analysis (biomarkers of endothelial dysfunction) were performed.

Results: There were no significant differences in the MAP (p = 0.499) and the CI (p = 0.659) between the 3 groups. Perfused Vessel Density (PVD) in sublingual microcirculation was significantly higher immediately after reperfusion and 2 hours after reperfusion in the early administration of ilomedin and norepinephrine group compared with the other 2 groups (p < 0.05). Hemoglobin oxygen saturation measured at the intestinal level was significantly higher immediately after reperfusion in the early administration of ilomedin and norepinephrine group compared with the other 2 groups (p < 0.01). There were no significant differences in biomarkers of endothelial dysfunction between the 3 groups. Creatinine, AST and alkaline phosphatases increased significantly 2 hours after reperfusion in the early administration of ilomedin and norepinephrine group compared with baseline (p < 0.05).

Conclusions: Early administration of norepinephrine and ilomedin during ischemia improved short-term post-reperfusion sublingual and intestinal microcirculation without worsening macrocirculatory parameters in an intestinal ischemia-reperfusion injury model. However, use of this strategy seemed to worsen both liver and kidney function.

Abstract: Background: Sepsis continues to pose a significant threat to human life and represents a substantial financial burden. In addition to replicative stress resulting from telomeric loss, recent studies have identified multiple factors contributing to cell cycle arrest. Furthermore, our understanding of pathways associated with cellular senescence, such as CD47-mediated suppression of efferocytosis, has expanded. However, beyond in vitro experiments, the impact of cell stress during complex systemic illnesses, including sepsis, remains poorly understood. Consequently, we conducted an investigation into molecular alterations related to senescence-associated pulmonary mechanisms during experimental non-pulmonary sepsis.Methods: Male C57BL/6JRj mice were anesthetized and subjected to either control conditions (sham) or cecal ligation and puncture (CLP) to induce sepsis. 24 h or 7 d after CLP, animals were sacrificed and blood, bronchoalveolar fluids and lungs were harvested and analyzed for morphological and biochemical changes.Results: Histological damage in pulmonary tissue, as well as increases in plasma levels of surfactant protein D, indicated development of alveolar-focused acute lung injury after CLP. Additionally, we observed a significant upregulation of the CD47-QPCTL-SHP-1-axis in lungs of septic mice. Whereas the expression of p16, a marker primarily indicating manifested forms of senescence, was decreased after CLP, the early marker of cellular senescence, p21, was increased in the lungs during sepsis. Later, at 7 d after CLP, pulmonary expression of CD47 and QPCTL-1 was decreased, whereas SHP-1 was significantly enhanced.Conclusion: Our findings suggest an activation of senescent-associated pathways during experimental sepsis. However, expanding the experiments to other organ systems and in vivo long-term models are necessary to further evaluate the sustained mechanisms and immunopathophysiological consequences of cellular senescence triggered by septic organ injury.

Background: Neutrophil extracellular traps (NETs), and its formation and release, known as NETosis, may play a role in the initiation of thrombin generation (TG) in trauma. The objective of this study was to assess whether trauma patients, who develop symptomatic venous thromboembolism (VTE), have increased levels of plasma citrullinated histone H3 (CitH3) and accelerated TG kinetics.

Methods: Patients presenting to a Level I Trauma Center as trauma activations had samples collected within 12 hours of time of injury (TOI), alongside healthy volunteers (HV). CitH3 was measured by enzyme-linked immunosorbent assay, and TG data were measured using a thrombin generation analyzer, comparing results between patients developing symptomatic VTE vs those who did not, within 90 days of injury. Data were expressed as median and quartiles [Q1, Q3], and tested using Wilcoxon rank-sum or Fisher's exact test, or 1-sample test of Spearman's correlation, p < 0.05 considered significant.

Results: 39 trauma patient samples were analyzed (10 with and 29 without VTE), and compared to 15 HV samples. CitH3 levels in patients who developed VTE were significantly greater as compared to those who did not (12.8 ng/mL [7.1, 30.8]; 3.0 ng/mL [1.8,6.8], p = 0.024), with levels in both groups greater compared to HV (1.2 [0.3, 4.1], p = 0.003, p = 0.012), respectively. TG profiles were accelerated in patients developing VTE, with differences in peak height (337.6 nM [304.4, 356.0]; 231.8 nM [180.2, 281.8], p = 0.008), endogenous thrombin potential (1718.5 nM*min [1500, 1794]; 1208.5 nM*min (1072, 1417], p = 0.003) and velocity index (213.2 nM/min [162.3, 260.5]; 124.3 nM/min [93.2, 223.1], p = 0.03), respectively.

Conclusions: Trauma patients developing VTE exhibit increased NETosis, measured by increased CitH3 levels and accelerated TG early after injury, outlining an area for further understanding VTE after trauma.

Abstract: Background: Tumor necrosis factor receptor associated factor 3 (TRAF3) and deubiquitinating enzyme ubiquitin-specific protease 33 (USP33) have been identified to play important roles in inflammatory diseases, including acute pancreatitis (AP). Here, we aimed to explore whether USP33 affected AP progression by affecting TRAF3 expression through deubiquitination.Methods: Caerulein-treated HPDE6-C7 cells were used to mimic AP conditions in vitro. Levels of mRNAs and proteins were examined by qRT-PCR and Western blot. Cell proliferation and apoptosis were evaluated using CCK-8 assay, EdU assay and flow cytometry. Cell oxidative stress was assessed by detecting the production of superoxide dismutase and malonaldehyde. ELISA analysis detected IL-6 and TNF-α levels. Macrophage M1 polarization was evaluated by flow cytometry. Cellular ubiquitination analyzed the ubiquitination effect on TRAF3. Protein interaction between USP33 and TRAF3 was identified by immunofluorescence staining.Results: Caerulein dose-dependently induced apoptosis, oxidative stress, and inflammatory response in HPDE6-C7 cells and promoted macrophage M1 polarization to enhance inflammation (P < 0.05). TRAF3 was highly expressed in AP patients (3.5±1.10 vs. 1.0 ±0.74, P < 0.05) and caerulein-induced HPDE6-C7 cells (3.3 ±0.34 vs. 1.0 ±0.10, P < 0.05). Knockdown of TRAF3 protected HPDE6-C7 cells from caerulein-induced apoptotic, oxidative and inflammatory injuries. Mechanistically, USP33 interacted with TRAF3 and induced TRAF3 deubiquitination to up-regulate its expression (P < 0.05). Further analyses showed that USP33 knockdown reversed caerulein-induced apoptosis, oxidative stress and inflammation in HPDE6-C7 cells by TRAF3 (P < 0.05). Moreover, USP33-TRAF3 activated the NF-κB pathway (P < 0.05).Conclusion: USP33 promoted caerulein-induced apoptosis, oxidative stress and inflammation in pancreatic ductal cells by deubiquitinating TRAF3, indicating a novel insight into the pathogenesis of AP.

Abstract: Purpose: This study aims to establish and validate machine learning-based models to predict death in hospital among critical orthopaedic trauma patients with sepsis or respiratory failure.Methods: This study collected 523 patients from the Medical Information Mart for Intensive Care database. All patients were randomly classified into a training cohort and a validation cohort. Six algorithms, including logistic regression (LR), extreme gradient boosting machine (eXGBM), support vector machine (SVM), random forest (RF), neural network (NN), and decision tree (DT), were used to develop and optimize models in the training cohort, and internal validation of these models were conducted in the validation cohort. Based on a comprehensive scoring system, which incorporated ten evaluation metrics, the optimal model was obtained with the highest scores. An artificial intelligence (AI) application was deployed based on the optimal model in the study.Results: The in-hospital mortality was 19.69%. Among all developed models, the eXGBM had the highest area under the curve (AUC) value (0.951, 95%CI: 0.934-0.967), and it also showed the highest accuracy (0.902), precise (0.893), recall (0.915), and F1 score (0.904). Based on the scoring system, the eXGBM had the highest score of 53, followed by the RF model (43) and the NN model (39). The scores for the LR, SVM, and DT were 22, 36, and 17, respectively. The decision curve analysis confirmed that both the eXGBM and RF models provided substantial clinical net benefits. However, the eXGBM model consistently outperformed the RF model across multiple evaluation metrics, establishing itself as the superior option for predictive modeling in this scenario, with the RF model as a strong secondary choice. The SHAP analysis revealed that SAPS II, age, respiratory rate, OASIS, and temperature were the most important five features contributing to the outcome.Conclusions: This study develops an artificial intelligence application to predict in-hospital mortality among critical orthopaedic trauma patients with sepsis or respiratory failure.

Abstract: Background: Sepsis-induced cardiomyopathy (SIC), one of the most common complications of sepsis, seriously affects the prognosis of critically ill patients. Choline metabolism is an important biological process in the organism, and the mechanism of its interaction with SIC is unclear. The aim of this study was to reveal the choline metabolism genes (CMGs) associated with SIC and to provide effective targets for the treatment of SIC.Methods: Through a comprehensive analysis of the microarray dataset GSE79962 (comprising 20 SIC patients and 11 healthy controls) from the GEO database, suspected co-expression modules and differentially expressed genes (DEGs) in SIC were identified. Hub CMGs were obtained by intersecting choline metabolism database with DEGs and key model genes. Afterward, hub CMGs most significantly involved in prognosis were further analyzed for the verification of major pathways of enrichment analysis. Finally, the expression of hub CMGs in in vivo and in vitro SIC model was verified by immunohistochemistry staining and quantitative real-time polymerase chain reaction analysis (qPCR).Results: WGCNA identified 1 hub gene panel and 3867 hub genes, which were intersected with DEGs and CMGs to obtain the same 3 hub CMGs:HIF-1α, DGKD and PIK3R1. Only HIF-1α shows significant association with mortality (P = 0.009). Subsequent differential analysis based on the high and low HIF-1α expression yielded 63 DEGs and then they were uploaded into Cytoscape software to construct a protein-protein interaction (PPI) network and 6 hub genes with the highest priority were obtained (CISH, THBS1, IMP1, MYC, SOCS3 and VCAN). Finally, a multifactorial COX analysis revealed a significant correlation between HIF-1α and survival in SIC patients, which was further validated by in vitro and in vivo experiments.Conclusion: Our findings will provide new insights into the pathogenesis of SIC, and HIF-1α may have important applications as a potential biomarker for early detection and therapeutic intervention in SIC.

Abstract: Sepsis induces intestinal hyperpermeability, which is associated with higher mortality. Occludin is a tight junction protein that plays a critical role in regulating disease-associated intestinal barrier loss. This study examined the role of intestinal occludin on gut barrier function and survival in a pre-clinical model of sepsis. Intestinal epithelial-specific occludin knockout (occludin KOIEC) mice and wild type controls were subjected to intra-abdominal sepsis and sacrificed at pre-determined endpoints for mechanistic studies or followed for survival. Occludin KOIEC mice had a significant increase in intestinal permeability, that was induced only in the setting of sepsis as knockout mice and control mice had similar baseline permeability. The worsened barrier was specific to the leak pathway of permeability, without changes in either the pore or unrestricted pathways. Increased sepsis-induced permeability was associated with increased levels of the tight junction ZO-1 in occludin KOIEC mice. Occludin KOIEC mice also had significant increases in systemic cytokines IL-6 and MCP-1and increased bacteremia. Further, occludin KOIEC mice had higher levels of jejunal IL-1β and MCP-1 as well as increased MCP-1 and IL-17A in the peritoneal fluid although peritoneal bacteria levels were unchanged. Notably, 7-day mortality was significantly higher in occludin KOIEC mice following sepsis. Occludin thus plays a critical role in preserving gut barrier function and mediating survival during sepsis, associated with alterations in inflammation and bacteremia. Agents that preserve occludin function may represent a new therapeutic strategy in the treatment of sepsis.

Abstract: Background : Severe heatstroke patients have a poor prognosis. There are few descriptions of the inflammatory response to heatstroke in clinical studies. Systemic immune-inflammation index (SII) is a new index to reflect the inflammatory state of disease. Methods : This retrospective observational study included patients who had severe heatstroke between 2010 and 2023. Multivariate logistic regression and nomogram were performed to determine the ability of the SII to predict the prognosis of these patients, and subgroup analysis was performed according to SII levels. Results : Of the 177 patients included in our study, 28 (15.8%) died. There was no difference in SII values between the first day ( P = 0.810) and the second day ( P = 0.184) in multivariate analysis. The SII value of the third day (SII 72) was elevated in patients with heatstroke who died compared to that in those who survived ( P = 0.035). In multivariable logistic regression, Sequential Organ Failure Assessment (SOFA) score (odds ratio [OR], 1.717; confidence interval [CI], 1.073-2.747; P = 0.024) and SII 72 (OR, 1.001; 95% CI, 1.000-1.002; P = 0.035) were found to be independent predictors of mortality. SII 72 combined with SOFA score distinguished between patients who died and those who survived better than did the separate SOFA score. Patients with SII 72 > 1,000 had poor clinical prognosis. Conclusions : Compared to SII results from the first and second days, third-day results more meaningfully predict poor heatstroke prognosis. SII 72 may be a good indicator and, when combined with SOFA, offers enhanced predictive value.