Background: Destructive aortic prosthetic valve endocarditis portends a high morbidity and mortality, and requires complex high-risk surgery. Homograft root replacement is the most radical and biocompatible operation and, thus, the preferred option. Methods: A retrospective analysis was conducted on 61 consecutive patients who underwent a cardiac reoperation comprising homograft aortic root replacement since 2010. The probabilities of survival were calculated with the Kaplan-Meier method, whereas multivariable regression served to outline the predictors of adverse events. The endpoints were operative/late death, perioperative low cardiac output and renal failure, and reoperations. Results: The operative (cumulative hospital and 30-day) mortality was 13%. The baseline aspartate transaminase (AST) and associated mitral procedures were predictive of operative death (p = 0.048, OR [95% CIs] = 1.03 [1-1.06]) and perioperative low cardiac output, respectively (p = 0.04, OR [95% CIs] = 21.3 [2.7-168.9] for valve replacement). The latter occurred in 12 (20%) patients, despite a normal ejection fraction. Survival estimates (±SE) at 3 months, 6 months, 1 year, and 3 years after surgery were 86.3 ± 4.7%, 82.0 ± 4.9%, 75.2 ± 5.6, and 70.0 ± 6.3%, respectively. Survival was significantly lower in the case of AST ≥ 40 IU/L (p = 0.04) and aortic cross-clamp time ≥ 180 min (p = 0.01), but not when excluding operative survivors. Five patients required early (two out of the five, within 3 months) or late (three out of the five) reoperation. Conclusions: Homograft aortic root replacement for destructive prosthetic valve endocarditis can currently be performed with a near 90% operative survival and reasonable 3-year mortality and reoperation rate. AST might serve to additionally stratify the operative risk.

Systemic inflammation generally coexists with functional limitations that seriously affect quality of life. This study aimed to investigate the association between systemic inflammation in midlife and the risk of functional limitations in late-life. A total of 10,044 participants with an average age of 53.9 ± 5.7 years at baseline were included in a cohort study. At the last follow-up, the prevalence of impaired activities of daily living (ADLs), instrumental activities of daily living (IADLs), and lower extremity function (LEF) was 14.7%, 21.6%, and 50.3%, respectively. The values of four inflammatory biomarkers were used to calculate the inflammation composite score. Compared with the participants in the lowest quartile of the inflammation composite score (Q1), those in the highest quartile (Q4) exhibited an odds ratio (OR) of 1.589 and a 95% confidence interval (CI) of 1.335-1.892 for impaired ADLs, an OR of 1.426 and a 95% CI of 1.228-1.657 for impaired IADLs, and an OR of 1.728 and a 95% CI of 1.526-1.957 for impaired LEF. The association between systemic inflammation and functional limitations was partly mediated by cardiac and brain function. The present study provides evidence that systemic inflammation in midlife is associated with a higher risk of late-life functional limitations. Protecting vital organ functions in midlife may have a positive impact on reducing the risk of future functional limitations.Trial registration: www.clinicaltrials.gov ; Unique identifier: NCT00005131.

OBJECTIVE: Early diagnosis and prediction of organ dysfunction are critical for intervening and improving the outcomes of septic patients. The study aimed to find novel diagnostic and predictive biomarkers of organ dysfunction for perioperative septic patients.
METHODS: This is a prospective, controlled, preliminary, and single-center study of emergency surgery patients. Mass spectrometry, Gene Ontology (GO) functional analysis, and the protein-protein interaction (PPI) network were performed to identify the differentially expressed proteins (DEPs) from sepsis patients, which were selected for further verification via enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was used to estimate the relative correlation of selected serum protein levels and clinical outcomes of septic patients. Calibration curves were plotted to assess the calibration of the models.
RESULTS: Five randomized serum samples per group were analyzed via mass spectrometry, and 146 DEPs were identified. GO functional analysis and the PPI network were performed to evaluate the molecular mechanisms of the DEPs. Six DEPs were selected for further verification via ELISA. Cathepsin B (CatB), vascular cell adhesion protein 1 (VCAM-1), neutrophil gelatinase-associated lipocalin (NGAL), protein S100-A9, prosaposin, and thrombospondin-1 levels were significantly increased in the patients with sepsis compared with those of the controls (p < 0.001). Logistic regression analysis showed that CatB, S100-A9, VCAM-1, prosaposin, and NGAL could be used for preoperative diagnosis and postoperative prediction of organ dysfunction. CatB and S100-A9 were possible predictive factors for preoperative diagnosis of renal failure in septic patients. Internal validation was assessed using the bootstrapping validation. The preoperative diagnosis of renal failure model displayed good discrimination with a C-index of 0.898 (95% confidence interval 0.843-0.954) and good calibration.
CONCLUSIONS: Serum CatB, S100-A9, VCAM-1, prosaposin, and NGAL may be novel markers for preoperative diagnosis and postoperative prediction of organ dysfunction. Specifically, S100-A9 and CatB were indicators of preoperative renal dysfunction in septic patients. Combining these two biomarkers may improve the accuracy of predicting preoperative septic renal dysfunction.
BACKGROUND: The study was registered at the Chinese Clinical Trials Registry (ChiCTR2200060418) on June 1, 2022.

BACKGROUND: Heatstroke is a critical heat-related condition characterized by coagulopathy and multiple organ dysfunction. One of the most severe complications of heatstroke is disseminated intravascular coagulation. This condition manifests as excessive clot formation and bleeding that are primarily due to platelet depletion and dysfunction. Fibrinogen plays a crucial role in hemostasis because it links integrin αIIbβ3 on adjacent platelets, thereby promoting the platelet activation and aggregation necessary for clot formation. However, reduced fibrinogen levels may impair the formation of the initial platelet plug and increase the risk of bleeding. The current study explored the effect of fibrinogen on platelet dysfunction in a heatstroke model.
METHODS: Male Wistar rats were subjected to heat stress, and subsequent changes in hemodynamic, biochemical, and coagulation parameters were analyzed. Platelet viability, aggregation, adhesion, spreading and fibrin clot retraction were assessed.
RESULTS: The rats with heatstroke exhibited a variety of clinical symptoms, including hypotension, tachycardia, multiple organ dysfunction, and coagulopathy. Platelet viability in the heatstroke group was comparable to that in the healthy control group. However, the heatstroke group exhibited significant reductions in plasma fibrinogen levels and platelet aggregation, adhesion, spreading, and fibrin clot retraction. Notably, fibrinogen supplementation markedly augmented the aggregation responses of platelets in the heatstroke group. The impairment of platelet adhesion, spreading, and fibrin clot retraction in the rats with heatstroke was partially ameliorated by fibrinogen supplementation.
CONCLUSIONS: An early use of fibrinogen replacement may serve as a therapeutic intervention to alleviate platelet hyporeactivity and prevent the complications in patients with heatstroke.

OBJECTIVE: Multiple murine studies modelling the immuno-pathophysiological consequences of trauma, shock, burn or sepsis were performed during the last decades. Almost every animal model requires anesthesia for practical and ethical reasons. Furthermore, often, corresponding control groups involve untreated animals without or with a limited exposure to anesthetics. However, the influences of anesthetic drugs on immuno-pathophysiological reactions remain insufficiently investigated. Therefore, we aimed to closer characterize the anesthetic impact exemplified by sevoflurane on the organ performance in mice and thereby investigate the influence of anesthesia itself on major outcome parameters in animal studies.
METHODS: C57/BL6 mice were subjected either to 270 min of sevoflurane narcosis or directly euthanized. Plasma, BAL-fluids, lungs, kidneys, liver and intestine were collected and examined for immunological, functional and morphological changes.
RESULTS: Systemic levels of the cytokine keratinocyte chemoattractant (KC) were raised in the narcosis group, while concentrations of high mobility group box protein 1 (HMGB-1) as a major inflammatory marker were reduced. In the lungs, levels of HMGB-1 and interleukin 6 (IL-6) were reduced. In contrast, systemic concentrations of intestinal fatty acid binding-protein (i-FABP) as an intestinal damage marker were elevated. Furthermore, liver-type fatty acid binding-protein (L-FABP) levels were lower in the narcosis animals, and inflammatory markers were reduced in liver tissues. Anesthesia also ameliorated the inflammatory reaction in renal tissues, while plasma levels of urea and creatinine were elevated, reflecting either dehydration and/or impaired renal function.
CONCLUSIONS: As anesthesia with sevoflurane exhibited distinct effects in different organs, it is difficult to predict its specific impact on targets of interest in in vivo studies. Therefore, further studies are required to clarify the effects of different anesthetic drugs. Overall, the inclusion of a control group subjected to the same anesthesia protocol as the experimental groups of interest seems helpful to precisely define the inherent impact of the anesthetic when investigating immuno-pathophysiologic conditions in vivo.

BACKGROUND: Dysregulated host response to infection causes life-threatening organ dysfunction. Excessive inflammation and abnormal blood coagulation can lead to disseminated intravascular coagulation (DIC) and multiple-organ failure in the late sepsis stages. Platelet function impairment in sepsis contributes to bleeding, secondary infection, and tissue injury. Platelet transfusion is considered in patients with sepsis with DIC and bleeding; however, its benefits are limited and of low quality. Fibrinogen plays a crucial role in platelet function, and establishing a fibrin network binds to activated integrin αIIbβ3 and promotes outside-in signaling that amplifies platelet functions. However, the role of fibrinogen in sepsis-induced platelet dysfunction remains unclear.
METHODS: We evaluated the effects of fibrinogen on platelet hyporeactivity during septic shock in adult male Wistar rats using lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP) surgery. Changes in the hemodynamic, biochemical, and coagulation parameters were examined. Platelet activation and aggregation were measured using whole-blood assay, 96-well plate-based aggregometry, and light-transmission aggregometry. Additionally, platelet adhesion, spreading, and fibrin clot retraction were evaluated.
RESULTS: Rats with LPS- and CLP-induced sepsis displayed considerable decreases in plasma fibrinogen levels and platelet aggregation, adhesion, spreading, and clot retraction. The aggregation of platelets obtained from rats with sepsis was markedly augmented by fibrinogen supplementation. Additionally, fibrinogen administration improved platelet adhesion, spreading, and clot retraction in rats with sepsis.
CONCLUSIONS: Fibrinogen supplementation could serve as a potential therapeutic intervention for alleviating platelet hyporeactivity in patients with sepsis and bleeding.

Patients admitted to a pediatric intensive care unit (PICU) need individualized nutrition support that is tailored to their particular disease severity, nutritional status, and therapeutic interventions. We aim to evaluate how calories and proteins are provided during the first seven days of hospitalization for children in critical condition with organ dysfunction (OD). A single-center retrospective cohort study of children aged 2-18 years, mechanically ventilated > 48 h, and admitted > 7 days to a PICU from 2016 to 2017 was carried out. Nutrition support included enteral and parenteral nutrition. We calculated scores for the Pediatric Sequential Organ Failure Assessment (pSOFA) on days 1 and 3 of admission, with OD defined as a score > 5. Of 4199 patient admissions, 164 children were included. The prevalence of OD for days 1 and 3 was 79.3% and 78.7%, respectively. On day 3, when pSOFA scores trended upward, decreased, or remained unchanged, median (IQR) caloric intake was 0 (0-15), 9.2 (0-25), and 22 (1-43) kcal/kg/day, respectively (p = 0.0032); when pSOFA scores trended upward, decreased, or remained unchanged, protein intake was 0 (0-0.64), 0.44 (0-1.25), and 0.66 (0.04-1.67) g/kg/day, respectively (p = 0.0023). Organ dysfunction was prevalent through the first 72 h of a PICU stay. When the pSOFA scores trended downward or remained unchanged, caloric and protein intakes were higher than those that trended upward.

Tissue hypoxia is associated with the development of organ dysfunction and death in critically ill patients commonly captured using blood lactate. The kinetic parameters of serial lactate evaluations are superior at predicting mortality compared with single values. S-adenosylhomocysteine (SAH), which is also associated with hypoxia, was recently established as a useful predictor of septic organ dysfunction and death. We evaluated the performance of kinetic SAH parameters for mortality prediction compared with lactate parameters in a cohort of critically ill patients. For lactate and SAH, maxima and means as well as the normalized area scores were calculated for two periods: the first 24 h and the total study period of up to five days following ICU admission. Their performance in predicting in-hospital mortality were compared in 99 patients. All evaluated parameters of lactate and SAH were significantly higher in non-survivors compared with survivors. In univariate analysis, the predictive power for mortality of SAH was higher compared with lactate in all forms of application. Multivariable models containing SAH parameters demonstrated higher predictive values for mortality than models based on lactate parameters. The optimal models for mortality prediction incorporated both lactate and SAH parameters. Compared with lactate, SAH displayed stronger predictive power for mortality in static and dynamic application in critically ill patients.

This study aimed to investigate the incidence and significance of disseminated intravascular coagulation (DIC) in coronavirus disease 2019 (COVID-19). A multicenter cohort study was conducted using large-scale COVID-19 registry data. The patients were classified into DIC and non-DIC groups based on the diagnosis on admission (day 1) and on any of the days 1, 4, 8, and 15. In total, 23,054 patients were divided into DIC (n = 264) and non-DIC (n = 22,790) groups on admission. Thereafter, 1654 patients were divided into 181 patients with DIC and 1473 non-DIC patients based on the DIC diagnosis on any of the days from 1 to 15. DIC incidence was 1.1% on admission, increasing to 10.9% by day 15. DIC diagnosis on admission had moderate predictive performance for developing multiple organ dysfunction syndrome (MODS) on day 4 and in-hospital death and was independently associated with MODS and in-hospital death. DIC diagnosis on any of the days from 1 to 15, especially days 8 and 15, was associated with lower survival probability than those without DIC and showed significant association with in-hospital death. In conclusion, despite its low incidence, DIC, particularly late-onset DIC, plays a significant role in the pathogenesis of poor prognosis in patients with COVID-19.

BACKGROUND: Sepsis is a life-threatening disorder with no definitive cure. Preclinical studies suggest that extracellular vesicles derived from mesenchymal stromal cells (EV-MSCs) can mitigate inflammatory conditions, potentially leading to increased survival and reduced organ dysfunction during sepsis. Our aim to conduct this systematic review and meta-analysis is assessing the EV-MSCs therapeutic efficacy in sepsis.
METHODS: PubMed, Embase, Scopus, WOS and ProQuest databases and also Google Scholar search engine were searched for published articles. We used hazard ratio (HR) and standardized mean difference (SMD) as effect sizes to evaluate the therapeutic effect of EV-MSCs on survival rate and determine their effect on reducing organ dysfunction, respectively. Finally, we employed GRADE tool for preclinical animal studies to evaluate certainty of the evidence.
RESULTS: 30 studies met the inclusion criteria for our article. Our meta-analysis results demonstrate that animals treated with MSC-EVs have better survival rate than untreated animals (HR = 0.33; 95% CI: 0.27-0.41). Our meta-analysis suggests that EV-MSCs can reduce organ dysfunctions in sepsis, such as the lung, kidney, and liver. Additionally, EV-MSCs decrease pro-inflammatory mediators like TNF-α, IL-1β, and IL-6.
CONCLUSIONS: Our results indicate that EV-MSCs can be as promising therapy for sepsis management in animal models and leading to increased survival rate and reduced organ dysfunction. Furthermore, our study introduces a novel tool for risk of bias assessment and provides recommendations based on various analysis. Future studies with aiming to guide clinical translation can utilize the results of this article to establish stronger evidence for EV-MSC effectiveness.