T cell dysfunction in elderly ARDS patients based on miRNA and mRNA integration analysis.

Background: Acute respiratory distress syndrome (ARDS) is respiratory failure that commonly occurs in critically ill patients, and the molecular mechanisms underlying its pathogenesis and severity are poorly understood. We evaluated mRNA and miRNA in patients with ARDS and elucidated the pathogenesis of ARDS after performing mRNA and miRNA integration analysis. Methods: In this single-center, prospective, observational clinical study of patients with ARDS, peripheral blood of each patient was collected within 24 hours of admission. Sequencing of mRNA and miRNA was performed using whole blood from the ARDS patients and healthy donors. Results: Thirty-four ARDS patients were compared with 15 healthy donors. Compared with the healthy donors, 1233 mRNAs and 6 miRNAs were upregulated and 1580 mRNAs and 13 miRNAs were downregulated in the ARDS patients. For both mRNA and miRNA-targeted mRNA, canonical pathway analysis showed that programmed death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) cancer immunotherapy pathway was most activated and the Th2 pathway was most suppressed. For mRNA, the Th1 pathway was most suppressed. miR-149-3p and several miRNAs were identified as upstream regulators. Conclusion: miRNAs regulated the PD-1 and PD-L1 cancer immunotherapy pathway and Th2 pathway through miRNA interference action of mRNA. Integrated analysis of mRNAs and miRNAs showed that T cells were dysfunctional in ARDS patients.

Relationship between extravascular leakage and clinical outcome on computed tomography of isolated traumatic brain injury.

Aim: This study investigated whether contrast extravasation on computed tomography (CT) angiography in patients with traumatic brain injury (TBI) is associated with death or surgical procedures. Methods: Patients over 18 years old, directly brought in by ambulance with an isolated head injury and confirmed to have acute intracranial hemorrhage on a CT scan upon admission between 2010 and 2020, were included. The primary outcome was mortality, and the secondary outcome was neurosurgical procedures performed from admission to discharge from the intensive care unit. Multivariable logistic regression analyses were performed to evaluate the association between these outcomes and contrast extravasation. Results: The analysis included 188 patients with a median age of 65 years, 123 men (65.4%), 34 deaths (18.1%), and 91 surgeries (48.4%). Among the 66 patients with contrast extravasation, 22 (33.3%) died and 47 (71.2%) required surgery. Among the 122 patients with no contrast extravasation, 12 (9.8%) died, and 44 (36.1%) required surgery. The presence or absence of extravascular leakage was associated with death (odds ratio, 3.6 [95% CI: 1.2-12.2]) and surgery (odds ratio, 7.6 [95% CI: 2.5-22.7]). Conclusion: Contrast extravasation was associated with mortality and performance of surgery in patients with an isolated head injury.

Gp130-HIF1α axis-induced vascular damage is prevented by the short-term inhibition of IL-6 receptor signaling.

Protection against endothelial damage is recognized as a frontline approach to preventing the progression of cytokine release syndrome (CRS). Accumulating evidence has demonstrated that interleukin-6 (IL-6) promotes vascular endothelial damage during CRS, although the molecular mechanisms remain to be fully elucidated. Targeting IL-6 receptor signaling delays CRS progression; however, current options are limited by persistent inhibition of the immune system. Here, we show that endothelial IL-6 trans-signaling promoted vascular damage and inflammatory responses via hypoxia-inducible factor-1α (HIF1α)-induced glycolysis. Using pharmacological inhibitors targeting HIF1α activity or mice with the genetic ablation of gp130 in the endothelium, we found that inhibition of IL-6R (IL-6 receptor)-HIF1α signaling in endothelial cells protected against vascular injury caused by septic damage and provided survival benefit in a mouse model of sepsis. In addition, we developed a short half-life anti-IL-6R antibody (silent anti-IL-6R antibody) and found that it was highly effective at augmenting survival for sepsis and severe burn by strengthening the endothelial glycocalyx and reducing cytokine storm, and vascular leakage. Together, our data advance the role of endothelial IL-6 trans-signaling in the progression of CRS and indicate a potential therapeutic approach for burns and sepsis.

Combination of HBA1, TTR, and SERPINF2 in plasma defines phenotype correlated with severe burn outcome.

Recent advancements in proteomics allow for the concurrent identification and quantification of multiple proteins. This study aimed to identify proteins associated with severe burn pathology and establish a clinically useful molecular pathology classification. In a retrospective observational study, blood samples were collected from severe burn patients. Proteins were measured using mass spectrometry, and prognosis-related proteins were extracted by comparing survivors and non-survivors. Enrichment and ROC analyses evaluated the extracted proteins, followed by latent class analysis. Measurements were performed on 83 burn patients. In the non-survivor group, ten proteins significantly changing on the day of injury were associated with metabolic processes and toxin responses. ROC analysis identified HBA1, TTR, and SERPINF2 with AUCs > 0.8 as predictors of 28-day mortality. Latent class analysis classified three molecular pathotypes, and plasma mass spectrometry revealed ten proteins associated with severe burn prognosis. Molecular pathotypes based on HBA1, TTR, and SERPINF2 significantly correlated with outcomes.

Resistin Associated With Cytokines and Endothelial Cell Adhesion Molecules Is Related to Worse Outcome in COVID-19.

Introduction: Resistin is reported to form a cytokine network and cause endothelial damage. The pathogenesis of coronavirus disease 2019 (COVID-19) remains unknown, but the association between cytokine storm and endothelial damage is crucial. This study aimed to evaluate resistin in COVID-19 pathogenesis compared with sepsis. Materials and Methods: First, we evaluated the association of plasma resistin levels and disease severity and clinical outcome in two large cohorts: a publicly available cohort including 306 COVID-19 patients in the United States (MGH cohort) and our original cohort including only intubated 113 patients in Japan (Osaka cohort 1). Second, to understand pathogenesis, we evaluate resistin, cytokines and endothelial cell adhesion molecules in COVID-19 compared with sepsis. Blood samples were collected from 62 ICU-treated COVID-19 patients and 38 sepsis patients on day 1 (day of ICU admission), days 2-3, days 6-8, and from 18 healthy controls (Osaka cohort 2). The plasma resistin, inflammatory cytokines (IL-6, IL-8, MCP-1 and IL-10) and endothelial cell adhesion molecules (ICAM-1 and VCAM-1) were compared between patients and control. Correlations among resistin, inflammatory cytokines and endothelial cell adhesion molecules were evaluated in COVID-19 and sepsis. Results: In the MGH cohort, the day 1 resistin levels were associated with disease severity score. The non-survivors showed significantly greater resistin levels than survivors on days 1, 4 and 8. In the Osaka cohort 1, 28-day non-survivors showed significantly higher resistin levels than 28-day survivors on days 6-8. Patients with late recovery (defined as the day of weaning off mechanical ventilation >12 or death) had significantly higher resistin levels than those with early recovery on day 1 and days 6-8. In the Osaka cohort 2, plasma resistin levels were elevated in COVID-19 and sepsis patients compared to controls at all measurement points and were associated with inflammatory cytokines and endothelial cell adhesion molecules. Conclusion: Resistin was elevated in COVID-19 patients and was associated with cytokines and endothelial cell adhesion molecules. Higher resistin levels were related to worse outcome.

Growth Differentiation Factor-15 Correlates with Mortality and Severity in Severe Burns.

BACKGROUND: Growth differentiation factor-15 (GDF-15) is expressed in almost all tissues of the body and is necessary for the body's defense response to stress such as inflammation. It has been reported to be associated with incidence and mortality in many diseases, including systemic inflammatory response syndromes. There are no reports on GDF-15 in burns. The purpose of this study was to investigate the trend of GDF-15 in blood in patients with severe burns and to determine its relationship with severity and mortality. METHODS: This was a retrospective, observational, single-center study. The level of GDF-15 in the blood was measured and compared with clinical parameters, including prognosis. Time points for sample collection were the day of injury, 4 days after injury, and 1 week after injury. RESULTS: Eighty-three patients were enrolled in the study. At all time points, GDF-15 levels in the nonsurvivor group were significantly higher than those in the survivor group. In the analysis using the ROC curve for 28-day survival, the AUC of the GDF-15 value on the day of injury was 0.798, which was higher than those of % total body surface area, burn index, and Sequential Organ Failure Assessment (SOFA) score. GDF-15 levels correlated positively with SOFA score, and the relationship became stronger along with the time course of severe burn. CONCLUSIONS: In the acute phase of severe burn, GDF-15 levels were associated with mortality and SOFA scores.

Resistin forms a network with inflammatory cytokines and is associated with prognosis in major burns.

BACKGROUND: In current intensive care treatment, some patients with severe burns cannot be saved due to progressive organ failure. Further investigation of the pathogenesis of severe burns is needed to improve the mortality rate. In burns, inflammatory cytokines form a network that leads to an inflammatory response. Adipocytes secrete physiologically active substances (adipokines). The roles of adipokines have not been completely clarified in burn patients. This study aimed to determine the relation between serial changes of adipokines and clinical course in severely burned patients. METHODS: This was a single-center, retrospective, observational study. Patients' blood samples were collected on the day of injury and around 1 week later. Adipokines (adiponectin, angiotensinogen, chemerin, CXCL-12/SDF-1, leptin, resistin, vaspin, visfatin), various inflammatory cytokines, syndecan-1 and C1 esterase inhibitor were measured. RESULTS: Thirty-eight patients were included. Resistin levels were significantly higher in the non-survivors versus survivors on Day 1 after burn injury. Hierarchical clustering analysis showed common clusters on Day 1 and at 1 Week after burn injury (resistin, IL-6, IL-8, IL10 and MCP-1). The correlation coefficient of resistin to SOFA score at 1 Week was significant. Logistic regression analysis showed a significant relation of resistin levels on Day 1 with prognosis; the area under the ROC curve for resistin was 0.801. CONCLUSIONS: In the acute phase of burns, resistin was associated with other pro-inflammatory cytokines and was related to the severity and prognosis of major burns.

Association of Extravascular Leakage on Computed Tomography Angiography with Fibrinogen Levels at Admission in Patients with Traumatic Brain Injury.

Extravascular leakage on computed tomography (CT) angiography in patients with traumatic brain injury (TBI) is associated with hematoma expansion, functional prognosis, subsequent surgery, and death. Fresh frozen plasma (FFP) administration is often necessary to treat coagulation disorders associated with TBI. This study aimed to determine the relationship between the presence of extravascular leakage on contrast-enhanced head CT, fibrinogen level at admission, and FFP administration in patients with TBI. The medical records of patients with TBI ≥18 years of age referred to our hospital between January 2010 and December 2020 were examined retrospectively. Patients who underwent contrast-enhanced CT immediately after admission were selected, and the presence or absence of extravascular leakage, fibrinogen level at admission, and percentage of patients who required FFP administration within 24 h of admission were examined; 172 patients were included. Multi-variable linear regression analysis was performed to determine the effects of contrast extravasation on fibrinogen levels at admission and was adjusted for age, sex, systolic blood pressure, time from injury to admission, Marshall CT score, Glasgow Coma Scale score at admission, Injury Severity Score, and need for emergency surgery; the regression coefficient was -19.8. The effect of extravasation on FFP administration within 24 h of admission was analyzed using logistic regression while adjusting for age, systolic blood pressure, Marshall CT score, need for emergency surgery, and fibrinogen level at admission. The odds ratio of contrast extravasation was 7.08 after adjustment. Extravascular leakage is associated with fibrinogen levels at admission and FFP administration within 24 h of admission.

Indications of early intubation for patients with inhalation injury.

Aim: For patients with inhalation injury, the indications for early intubation are diverse. The purpose of this study was to identify the most reliable symptoms, physical findings, and medical examinations with which to determine the indications for early intubation in patients with inhalation injury. Methods: We retrospectively collected patient data from medical records. Collected data included age, sex, burn size, symptoms, physical findings, carboxyhemoglobin levels (COHb), and bronchial wall thickness (BWT) determined from chest computed tomography images. We analyzed the relationships between these findings and the early intubation. We performed fiberoptic bronchoscopy in all patients, and analyzed the relationships between bronchoscopic severity and other findings. Results: Of the 205 patients, 80 patients were diagnosed as having inhalation injury, and 34 patients were intubated. Burn size, facial burns, neck burns, use of accessory respiratory muscles, and COHb seemed to be related with intubation, whereas singed nasal hair was not. If the patients suffered ≥27% total body surface area burn and BWT ≥3.5 mm, the positive predictive value for early intubation was 1.00. If the patients suffered smaller cutaneous burn without neck burn, and their COHb <4.0%, the negative predictive value for early intubation was 0.97. Fiberoptic bronchoscopy findings from above the glottis were mainly related with patients' symptoms. Findings from below the glottis were mainly related with BWT and COHb. Conclusions: Patients' symptoms, especially use of accessory respiratory muscles, are reliable, and BWT and COHb are also useful tools, for determining the indication for early intubation.

Acute pancreatitis and necrotizing colitis following extensive burn injury.

Case: We describe a patient with severe pancreatitis and ischemic colitis after extensive burn injury. An 81-year-old man presented with a 55% total body surface area burn with inhalation injury. A low-density area was detected in the pancreas on the abdominal computed tomography scan on admission. The clinical course of the patient was good until 28 days after injury when he complained of abdominal pain and distension. Abdominal computed tomography revealed acute pancreatitis and ischemic colitis. Outcome: The patient died 59 days after burn injury. Conclusions: Extensive burn injury can cause acute pancreatitis. Further work-up is necessary to identify pancreatic complications after severe burn injury.