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Fission 1 (Fis1) plays a key role in mitochondrial division and is upregulated in pathological conditions, including trauma, sepsis, and ischemia-reperfusion injury. The goal of the study was to investigate Fis1 and other mitochondrial proteins involved in mitochondrial function and quality control as potential early biomarkers for the development of multiple organ dysfunction. We included all multiple trauma patients presenting to the hospital within 24 h of injury from September 1, 2022 to September 1, 2023. Patients were split into two groups the non-MODS group (n = 66) and the MODS group (n = 70) We obtained serum samples from all patients and using enzyme-linked immunosorbent assay (ELISA) measured concentrations of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), Fis1, mitofusin 2 (Mfn2), and Parkin. Concentrations of proteins were compared between groups and compared to a healthy control group. Additionally, demographic data and laboratory test results were collected from the patients. We used a logistic regression to identify if biomarkers were indepenteldy associated with the development of MODS. Within 24 h of injury, the median serum concentration of Parkin, Fis1, and PGC-1α, were significantly higher in the MODS group than in the control group. Similarily, compared to the non-MODS group, the median serum concentration of Fis1 and PGC-1α were significantly higher in the MODS group. Binary logistic regression analysis, adjusted for confounding factors, identified Fis1 as a predictive biomarker for MODS (OR = 1.006, 95 % CI: 1.002–1.009, P < 0.05)The area under the curve (AUC) for Fis1 in predicting MODS after multiple trauma was 0.777 (95 % CI: 0.698–0.857), indicating a moderate diagnostic value. This study found that in patients with multiple trauma, Fis1 concentrations are associated with the development of MODS. •First to evaluate serum MQC protein in multiple trauma, extending findings from sepsis studies.•Elevated Fis 1 may be an early biomarker for MODS post-trauma.•MQC proteins may offer noval therapeutic targets in trauma care.

Background Clarithromycin may act as immune-regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome. Methods We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics. Results Fifty-five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) − 15.7 to 22.7]; P  = 0.703, adjusted OR 1.03 [95%CI 0.35–3.06]; P  = 0.959). There were no statistical differences in 90-day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06–0.68]; P  = 0.012); significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non-serious adverse events were equally distributed. Conclusions Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration. Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55.

Sepsis was first described by the ancient Greek physicians over 2000 years ago. The pathophysiology of the disease, however, is still not fully understood and hence the mortality rate is still unacceptably high due to lack of specific therapies. In the last decade, great progress has been made by shifting the focus of research from systemic inflammatory response syndrome (SIRS) to multiple organ dysfunction syndrome (MODS). Sepsis has been re-defined as infection-induced MODS in 2016. How infection leads to MODS is not clear, but what mediates MODS becomes the major topic in understanding the molecular mechanisms and developing specific therapies. Recently, the mechanism of infection-induced extensive immune cell death which releases a large quantity of damage-associated molecular patterns (DAMPs) and their roles in the development of MODS as well as immunosuppression during sepsis have attracted much attention. Growing evidence supports the hypothesis that DAMPs, including high-mobility group box 1 protein (HMGB1), cell-free DNA (cfDNA) and histones as well as neutrophil extracellular traps (NETs), may directly or indirectly contribute significantly to the development of MODS. Here, we provide an overview of the mechanisms and consequences of infection-induced extensive immune cell death during the development of sepsis. We also propose a pivotal pathway from a local infection to eventual sepsis and a potential combined therapeutic strategy for targeting sepsis.

Introduction Sepsis is a devastating condition that is generally treated as a single disease. Identification of meaningfully distinct clusters may improve research, treatment and prognostication among septic patients. We therefore sought to identify clusters among patients with severe sepsis or septic shock. Methods We retrospectively studied all patients with severe sepsis or septic shock admitted directly from the emergency department to the intensive care units (ICUs) of three hospitals, 2006–2013. Using age and Sequential Organ Failure Assessment (SOFA) subscores, we defined clusters utilizing self-organizing maps, a method for representing multidimensional data in intuitive two-dimensional grids to facilitate cluster identification. Results We identified 2533 patients with severe sepsis or septic shock. Overall mortality was 17 %, with a mean APACHE II score of 24, mean SOFA score of 8 and a mean ICU stay of 5.4 days. Four distinct clusters were identified; (1) shock with elevated creatinine, (2) minimal multi-organ dysfunction syndrome (MODS), (3) shock with hypoxemia and altered mental status, and (4) hepatic disease. Mortality (95 % confidence intervals) for these clusters was 11 (8–14), 12 (11–14), 28 (25-32), and 21 (16–26) %, respectively ( p  < 0.0001). Regression modeling demonstrated that the clusters differed in the association between clinical outcomes and predictors, including APACHE II score. Conclusions We identified four distinct clusters of MODS among patients with severe sepsis or septic shock. These clusters may reflect underlying pathophysiological differences and could potentially facilitate tailored treatments or directed research.

Children with sepsis are at risk of developing life-threatening multiple organ dysfunction (MODS). We have previously described two sepsis phenotypes associated with poor prognosis: “persistent hypoxemia, encephalopathy and shock” (PHES) and “sepsis-associated persistent MODS” (PMODS). We hypothesized there are unique metabolomic and cytokine profiles associated with these phenotypes that will allow for better identification and understanding of their pathophysiology. To test this, plasma samples from 50 children with sepsis-associated MODS were categorized as meeting criteria for PHES, PMODS or assigned as controls. Concentrations of 166 lipids, 26 metabolites and 20 cytokines were measured and analyzed. Of 50 patients, 17 were classified as the PHES phenotype and had upregulation of pro-inflammatory cytokines and an endothelial activation biomarker compared to controls ( p  < 0.05). 14 patients were classified as PMODS and had significant downregulation of immune mediators compared to controls ( p  < 0.05). Both phenotypes were associated with mitochondrial dysfunction based on the metabolic profiles of lysine, carnitine, and short and long chain fatty acids. Our results demonstrate metabolomic, immune, and endothelial dysregulation associated with two high-risk sepsis phenotypes in children. If validated, our findings suggest there may be several immune modulation, endothelial repair, and metabolic support therapies that could be tested in these phenotypes.

Mitochondria release many damage-associated molecular patterns (DAMPs) when cells are damaged or stressed, with mitochondrial DNA (mtDNA) being. MtDNA activates innate immune responses and induces inflammation through the TLR-9, NLRP3 inflammasome, and cGAS-STING signaling pathways. Released inflammatory factors cause damage to intestinal barrier function. Many bacteria and endotoxins migrate to the circulatory system and lymphatic system, leading to systemic inflammatory response syndrome (SIRS) and even damaging the function of multiple organs throughout the body. This process may ultimately lead to multiple organ dysfunction syndrome (MODS). Recent studies have shown that various factors, such as the release of mtDNA and the massive infiltration of inflammatory factors, can cause intestinal ischemia/reperfusion (I/R) injury. This destroys intestinal barrier function, induces an inflammatory storm, leads to SIRS, increases the vulnerability of organs, and develops into MODS. Mitophagy eliminates dysfunctional mitochondria to maintain cellular homeostasis. This review discusses mtDNA release during the pathogenesis of intestinal I/R and summarizes methods for the prevention or treatment of intestinal I/R. We also discuss the effects of inflammation and increased intestinal barrier permeability on drugs.

To analyze the critical factors of infection-associated Hemophagocytic lymphohistiocytosis (HLH) in children, so as to provide theoretical basis for clinicians to evaluate the disease condition, formulate treatment plan and improve prognosis. This study is a retrospective analysis. 60 cases of children with infection-associated HLH were divided into critical and non-critical groups based on the presence of multiple organ dysfunction syndrome (MODS), and the clinical characteristics and laboratory data of the two groups of children were analyzed. A multifactor logistic regression analysis model was used to assess the independent risk factors affecting critical illness in children with infection-associated HLH, and the Receiver Operating Characteristic (ROC) curve analysis was used to evaluate the predictive value of risk factors for critical illness in children with infection-associated HLH. Children in the critical group with HLH had a younger age at onset. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT), D-dimer (DD), and triglycerides (TG) were significantly higher in the critical group, while albumin (ALB) was significantly lower, showing statistical significance ( P  < 0.05). Multifactorial logistic regression analysis of age, ALB, and TG showed that younger age and lower ALB were associated with a higher risk of MODS in children with infection-associated HLH, with age and ALB being independent risk factors for critical illness. ALB predicted the ROC area under the curve for critical children with infection-associated HLH was 0.765 (95% CI: 0.643–0.888, P  = 0.011), with the optimal cut-off value being 32.50 g/L (sensitivity = 68.3%, specificity = 84.2%); age predicted the ROC area under the curve for critical children with infection-associated HLH was 0.711 (95% CI: 0.570–0.851, P  = 0.009), with the optimal cut-off value being 1.50 years (sensitivity = 70.7%, specificity = 68.4%). This study suggests that younger patients and those with hypoalbuminemia among infection-related HLH patients are more likely to develop MODS. In the future, verification will be required through large-scale, multi-center studies.

Background Sepsis often led to multiple organ dysfunction (MODS) and even death. Although a variety of medicine were used to treat sepsis in clinic, there was still no specific and effective clinical medicine treatment. Exercise had been shown to work on MODS. However, in preclinical studies, there was no systematic evidence to summarize the effects of exercise training on sepsis. Objectives To investigate the effects of exercise training on sepsis in preclinical studies and explore possible mechanisms to provide reliable preclinical evidence for the use of exercise training in sepsis. Method Preclinical studies were retrieved from electronic databases (Pubmed, Embase, Cochrane Library, Scopus, Medline, Web of science) as of June 25, 2024. Our review included in vivo English studies evaluating the radioprotective effects of exercise training on sepsis. The quality of each study was assessed using the Center for Systematic Evaluation of Experimental Animal Studies (SYCLE) Animal Research Bias Risk Tool. All results were described comprehensively. Results 17 in vivo studies were included. Our comprehensive descriptive analysis showed that exercise could improve the general condition, lung injury, liver injury, kidney injury, heart and aortic injury, spleen and thymus injury, and other injuries in animals with sepsis. And its possible mechanisms were involved improving the general condition of sepsis animals, pathological and cell number of organs, anti-inflammation, anti-oxidative stress, anti-DNA damage, and so on. Conclusion Exercise training could protect sepsis by anti-inflammatory, anti-oxidative stress, increased antibacterial ability, reduced cell death, improved metabolism, vital signs and MODS.

Background Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self-perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. Principles of treatment include early antibiotic administration and operative source control. A further therapeutic option may be open abdomen (OA) management with active negative peritoneal pressure therapy (ANPPT) to remove inflammatory ascites and ameliorate the systemic damage from SCIAS. Although there is now a biologic rationale for such an intervention as well as non-standardized and erratic clinical utilization, this remains a novel therapy with potential side effects and clinical equipoise. Methods The Closed Or Open after Laparotomy (COOL) study will constitute a prospective randomized controlled trial that will randomly allocate eligible surgical patients intra-operatively to either formal closure of the fascia or use of the OA with application of an ANPTT dressing. Patients will be eligible if they have free uncontained intra-peritoneal contamination and physiologic derangements exemplified by septic shock OR a Predisposition-Infection-Response-Organ Dysfunction Score ≥ 3 or a World-Society-of-Emergency-Surgery-Sepsis-Severity-Score ≥ 8. The primary outcome will be 90-day survival. Secondary outcomes will be logistical, physiologic, safety, bio-mediators, microbiological, quality of life, and health-care costs. Secondary outcomes will include days free of ICU, ventilation, renal replacement therapy, and hospital at 30 days from the index laparotomy. Physiologic secondary outcomes will include changes in intensive care unit illness severity scores after laparotomy. Bio-mediator outcomes for participating centers will involve measurement of interleukin (IL)-6 and IL-10, procalcitonin, activated protein C (APC), high-mobility group box protein-1, complement factors, and mitochondrial DNA. Economic outcomes will comprise standard costing for utilization of health-care resources. Discussion Although facial closure after SCIAS is considered the current standard of care, many reports are suggesting that OA management may improve outcomes in these patients. This trial will be powered to demonstrate a mortality difference in this highly lethal and morbid condition to ensure critically ill patients are receiving the best care possible and not being harmed by inappropriate therapies based on opinion only. Trial registration ClinicalTrials.gov , NCT03163095 .

BackgroundTo potentially improve impaired vasomotion of patients with multiple organ dysfunction syndrome (MODS), we tested whether an electromagnetic field of low flux density coupled with a biorhythmically defined impulse configuration (Physical Vascular Therapy BEMER®, PVT), in addition to standard care, is safe and feasible and might improve disturbed microcirculatory blood flow and thereby improve global haemodynamics.MethodsIn a prospective, monocentric, one-arm pilot study, 10 MODS patients (APACHE II score 20–35) were included. Patients were treated, in addition to standard care, for 4 days with PVT (3 treatment periods of 8 min each day; day 1: field intensity 10.5 μT; day 2:14 μT, day 3:17.5 μT; day 4:21.0 μT). Primary endpoint was the effect of PVT on sublingual microcirculatory perfusion, documented by microvascular flow index (MFI). Patient safety, adverse events, and outcomes were documented.ResultsAn increase in MFI by approximately 25% paralleled 4-day PVT, with the increase starting immediately after the first PVT and lasting over the total 4-day treatment period. Concerning global haemodynamics (secondary endpoints), halving vasopressor use within 24 h, and haemodynamic stabilisation paralleled 4-day PVT with an increase in cardiac index, stroke volume index, and cardiac power index by 30%–50%. No adverse events (AEs) or serious adverse events (SAEs) were classified as causally related to the medical product (PVT) or study. Three patients died within 28 days and one patient between 28 and 180 days.ConclusionPVT treatment was feasible and safe and could be performed without obstruction of standard patient care. An increase in microcirculatory blood flow, a rapid reduction in vasopressor use, and an improvement in global haemodynamics paralleled PVT treatment. Findings of this pilot study allowed forming a concept for a randomized trial for further proof.