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Background: Prone positioning (PP) improves survival in severe acute respiratory distress syndrome (ARDS), but its prolonged effects on pulmonary and extrapulmonary organs remain unclear. This study aimed to investigate the pathophysiological effects of 24-h PP in a porcine ARDS model.

Methods: Ten female Bama mini swine (49.5 ± 3.7 kg) underwent severe ARDS induction via repeated saline lavage and were randomized to PP (n = 5) or supine position (SP, n = 5). Respiratory parameters, electrical impedance tomography, hemodynamics, and biochemical serum analysis were performed. After 24 h, regional lung injury was assessed via histopathology and wet-dry weight ratio, and extrapulmonary injury was evaluated by histopathology, apoptosis, oxidative stress, and organ-specific injury biomarkers.

Results: Nine swine were analyzed (PP, n = 5; SP, n = 4). PP significantly improved the PaO 2 /FiO 2 ratio. Electrical impedance tomography showed sustained improvements in ventilation, perfusion, and ventilation-perfusion matching (V/Q matching), particularly in the dorsal regions. Wet-dry weight ratio in the dorsal lung was significantly lower in the PP group, with no significant differences in respiratory mechanics or histopathological lung injury. Hemodynamic parameters, intra-abdominal pressure, and serum biochemical analyses showed no significant differences. Extrapulmonary injury analysis revealed no differences, except for a higher apoptotic index in renal tissue in the PP group.

Conclusions: Prolonged PP improved oxygenation by improving ventilation, perfusion, and V/Q matching, while reducing dorsal lung edema, without significantly affecting respiratory mechanics or histopathological lung injury. Additionally, PP showed no significant damage on hemodynamics and extrapulmonary organ function. However, attention should be given to potential renal impairment during prolonged PP administration.

Background: Hemorrhagic shock (HS) is a life-threatening condition characterized by systemic hypoperfusion, which induces inflammatory responses, oxidative stress, and apoptosis, often leading to multiple organ failure. Klotho, an anti-aging protein with anti-inflammatory, anti-apoptotic, and antioxidative properties, has demonstrated therapeutic potential in chronic diseases. However, its efficacy in acute conditions, such as HS, remains unexplored.

Objective: This study investigated the protective effects of recombinant klotho protein (rKL) on the lungs and kidneys following HS and elucidated the underlying mechanisms.

Methods: Adult male Wistar rats were subjected to controlled HS, followed by resuscitation. The animals were divided into four groups: sham, sham + rKL, HS, and HS + rKL. Histopathological analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, reactive oxygen species (ROS) staining, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, cytokine array, and immunofluorescence staining for M1 and M2 macrophage markers and high mobility group box-1 protein (HMGB1) were performed to evaluate inflammation, apoptosis, and macrophage polarization.

Results: rKL administration markedly attenuated histological tissue damage in the lungs and kidneys, reduced lactate levels, and suppressed apoptosis and ROS accumulation. Furthermore, rKL inhibited the extracellular release of HMGB1 and decreased the expression of pro-inflammatory cytokines. rKL also reduced macrophage infiltration and M1 polarization while increasing the M2/M1 ratio, indicating enhanced resolution of inflammation.

Conclusion: rKL attenuates tissue injury following HS by reducing ROS, apoptosis, and inflammation, as well as modulating macrophage polarization. These findings suggest that rKL may serve as a promising adjunctive therapeutic strategy for improving HS outcomes.

Trauma-induced coagulopathy represents a serious complication of hemorrhagic shock, associated with increased mortality within the first six hours post injury. Evidence of coagulopathy is often observable at the scene or upon hospital admission, emphasizing a critical role of pre-hospital care. Since studies on the use of various blood products in pre-hospital care have shown contradictory results, we aimed to investigate the effects of different volume substitutes on the initial immune response within the intravascular immune system. In an ex vivo model of polytrauma, blood from healthy volunteers was subjected to a trauma-characteristic shock scenario including the addition of danger-associated molecular patterns, blood acidification, and volume resuscitation. Resuscitation strategies involved either sodium chloride, component therapy (a combination of fresh frozen plasma and red blood cells), or leukocyte-reduced fresh whole blood. Samples were analyzed following 60 min of incubation at 37 °C to determine clinically relevant blood parameters and the activation status of both cellular innate leukocyte and humoral cascade responses. The use of blood products demonstrated superiority over NaCl, resulting in less disruption of the hemostatic system, as evidenced by reduced platelet activation. In parallel, neutrophil granulocytes were less affected, showing decreased surface activation marker expression and lower levels of soluble activation markers. Furthermore, activation of the complement system was reduced when the volume was resuscitated with blood products. Taken together, these data indicate that the choice of volume substitution greatly impacts the stability of the intravascular innate immune system, highlighting the potential benefit of leukocyte-reduced whole blood resuscitation.

Background: This study aimed to investigate the association between the hemoglobin to red cell distribution width ratio (HRR) and 28-day and 90-day all-cause mortality in patients with chronic critical illness (CCI) in the intensive care unit (ICU).

Methods: We conducted a retrospective analysis of data from 1,541 CCI patients in the MIMIC-IV database. Kaplan-Meier survival curves were used to assess the survival probabilities of patients across different HRR quartiles, and a multivariable Cox regression model was applied to adjust for potential confounding factors and evaluate the relationship between HRR and the risk of mortality.

Results: The analysis revealed a significant inverse association between HRR and both 28-day (hazard ratio (HR)=0.74, 95%CI 0.68-0.81, P<0.001) and 90-day (HR=0.74, 95%CI 0.69-0.8, P<0.001) all-cause mortality. In the multivariable Cox regression model, HRR remained significantly associated with a lower risk of mortality even after adjusting for age, gender, and other clinical variables (28-day: HR=0.84, 95%CI 0.77-0.92, P<0.001; 90-day: HR=0.82, 95%CI 0.76-0.89, P<0.001). HRR quartile analysis showed that compared to Q1, the 28-day mortality risk was reduced by 34%, 27%, and 43% for Q2, Q3, and Q4, respectively, and the 90-day mortality risk was reduced by 32%, 38%, and 49% for Q2, Q3, and Q4, respectively.

Conclusion: HRR is an independent predictor of short-term all-cause mortality in CCI patients and may serve as a useful tool for clinical risk stratification and personalized treatment. This finding provides evidence for the potential value of HRR as a prognostic assessment tool and may have significant implications for clinical decision-making and patient management.

Background: Clostridioides difficile infection (CDI) remains a major healthcare-associated infection, leading to severe complications. Early identification of patients at high risk for unfavorable outcome remains challenging. Pancreatic Stone Protein (PSP) has emerged as a promising biomarker in sepsis; however, its role in CDI has not been investigated.

Materials and methods: We conducted a prospective multicenter study of adult patients with CDI from 13 hospitals in Greece. PSP was measured within 24 hours of CDI onset. Primary outcome was the association between PSP and unfavorable outcome, defined as at least one of the following: organ failure, severe disease progression, relapse, or death. ROC curve was performed to assess diagnostic performance, and multivariate logistic regression to evaluate independent predictors of adverse outcome.

Results: 147 patients were enrolled, and unfavorable outcome occurred in 52. PSP levels were significantly higher in these patients. PSP showed an AUC 0.648 (95% CI 0.550-0.746, p=0.003) for predicting adverse outcome and an optimal cut-off of 300 ng/mL, increased the risk significantly (OR 3.73, 95% CI 1.822-7.638, p<0.001). C-reactive protein (CRP) was also associated with adverse outcome (AUC 0.619, 95% CI: 0.512-0.726, p: 0.03), with an optimal cut-off ≥90 mg/l. Combined elevation of PSP and CRP conferred stronger prognostic value (OR 7.04, 95% CI: 2.78-17.85, p<0.001). In multivariate analysis, PSP ≥300 ng/ml (p: 0.006) and CRP ≥90 mg/l (p:0.04) remained independently associated with unfavorable outcome.

Conclusions: This is the first study evaluating PSP in CDI. PSP, especially combined with CRP, may serve as complementary biomarkers for early risk stratification.

Background: Sepsis and its associated microcirculatory and endothelial dysfunction leading to organ failure remained the primary causes of morbidity and mortality in intensive care units. Fluid resuscitation served as the cornerstone of early supportive therapy. This study aimed to evaluate the impact of human albumin (HA) versus crystalloid-based resuscitation on microcirculation, capillary leakage, and endothelial function in sepsis patients with hypoalbuminemia who are not severely ill.

Methods: This retrospective cohort study included sepsis patients admitted to the same hospital between January 2022 and December 2024. Patients were divided into two groups based on the type of fluid resuscitation received: HA or crystalloids. Key parameters assessed included microcirculatory parameters, markers of capillary leakage, endothelial function, inflammatory markers, and albumin function within 72 hours, with organ support outcomes and clinical indicators evaluated at four weeks.

Results: The study included 223 patients (crystalloid group: n=108; HA group: n=115). The HA group showed superior microcirculatory perfusion at 72 hours [Microvascular Flow Index: 2.87 vs. 2.73, P=0.003; Tissue Oxygen Saturation: 80.14% vs. 78.32%, P=0.002], reduced capillary leakage (albumin leakage: 30.35% vs. 33.16%, P=0.006), and improved endothelial function at 72 hours (Nitric Oxide: 25.83 vs. 24.56 μmol/L, P=0.003). The incidence of acute kidney injury was lower (14.78% vs. 25.93%, P=0.038), and ICU stay duration was shorter (7.57 vs. 8.31 days, P=0.006). Albumin treatment independently reduced the risk of microcirculatory deterioration (P<0.001).

Conclusion: In hypoalbuminemic sepsis patients who are not severely ill, human albumin resuscitation provided multi-target benefits by improving microcirculation, endothelial integrity, and organ outcomes.

Preclinical models using animals are crucial for medical advancements despite their limitations and criticisms. Critical illnesses like sepsis, trauma, and burns remain huge causes of morbidity and mortality despite medical advances, and human studies may not always be feasible. In this part 1 of 2 reviews about animal models for critical illness, we discuss sepsis and the considerations one should take to optimize the rodent sepsis model. There are multiple models of sepsis used, each with advantages and disadvantages and they can be modified to reflect how patients are treated in the hospital, including intensive care unit care. Patient factors like age, sex, and comorbidities are important considerations given the different responses to sepsis. Aspects of sepsis that our patients encounter including muscle and neurocognitive dysfunction can be modeled to try and improve those aspects of outcomes. Choosing the right models for the question one is asking and optimizing that model is key to recapitulate the human condition to make animal models more translatable to humans. In other words, we suggest that, in lieu of abandoning animal models of sepsis, we seek to enhance translatability to the human condition.

Traumatic brain injury (TBI) is a significant cause of death and disability, affecting nearly 300,000 Americans annually. Beyond the immediate physical damage, TBI induces chronic neuroinflammation and long-term neurodegeneration, leading to various neurologic and psychiatric disorders. This review examines the cerebrovascular unit (CVU), particularly the cerebral endothelial cells, and their critical role in the aftermath of TBI. Following TBI, the CVU undergoes functional changes to counteract inflammation, repair endothelial damage, and promote angiogenesis. However, dysregulation of these protective mechanisms can lead to chronic neuroinflammation, increased cerebrovascular permeability, and systemic endothelial dysfunction. The review explores the molecular and cellular responses of the CVU following TBI, highlighting the roles of inflammatory cytokines, oxidative stress, and various endothelial transport mechanisms. Moreover, TBI-related endothelial dysfunction may extend beyond the brain, potentially contributing to systemic complications such as acute respiratory distress syndrome (ARDS) and multisystem organ failure. Despite the gravity of these conditions, clinical breakthroughs remain limited. This review underscores the necessity for targeted therapeutic strategies to mitigate endothelial dysfunction and improve long-term outcomes for TBI patients. Future research is essential to elucidate the precise mechanisms driving CVU dysfunction and to develop interventions that can alleviate the chronic effects of TBI.

Nearly half of the burn patients in the United States are under the influence of alcohol at the time of injury and alcohol intoxication is associated with poor clinical outcomes. Ethanol has been shown to worsen burn-induced intestinal dysfunction and inflammation, facilitating bacterial translocation from the intestine to the mesenteric lymph nodes and systemic circulation. Regenerating islet-derived protein 3-gamma (REG3G), an antimicrobial peptide crucial for maintaining intestinal homeostasis, protects mice from ethanol-induced bacterial translocation. In this study, we utilized a murine model to determine whether REG3G protects against the combined effects of acute ethanol exposure and burn injury. Mice with intestinal epithelial cell-specific overexpression of REG3G (Reg3g-Tg) were evaluated for gut barrier function, intestinal and hepatic inflammatory cytokines, and antimicrobial peptide expression after ethanol and burn injury. Additionally, we performed 16S rRNA gene sequencing of fecal microbiota. Our results demonstrate that ethanol exposure before burn injury downregulates the antimicrobial peptide REG3G in the ileum, when compared to burn alone. Intestine-specific overexpression of REG3G reversed several gastrointestinal effects of the combined injury, reducing intestinal inflammation and preventing bacterial translocation to the lymph nodes. Moreover, Reg3g-Tg mice exhibited reduced liver inflammation after combined injury, suggesting that improving intestinal function can also influence extra-intestinal organs. These findings highlight the therapeutic potential of REG3G in mitigating the effects of burn injury and alcohol intoxication.