Classification of patients with COVID-19 by blood RNA endotype: a prospective cohort study.

IMPORTANCE: In this study, whole-blood RNAs (prolactin and toll-like receptor 3) involved in the prognosis of patients with COVID-19 were identified. The RNA endotypes classified by these important RNAs highlight the possibility of stratifying the COVID-19 patient population and the need for targeted therapy based on these phenotypes.

Complement factor D targeting protects endotheliopathy in organoid and monkey models of COVID-19.

COVID-19 is linked to endotheliopathy and coagulopathy, which can result in multi-organ failure. The mechanisms causing endothelial damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain elusive. Here, we developed an infection-competent human vascular organoid from pluripotent stem cells for modeling endotheliopathy. Longitudinal serum proteome analysis identified aberrant complement signature in critically ill patients driven by the amplification cycle regulated by complement factor B and D (CFD). This deviant complement pattern initiates endothelial damage, neutrophil activation, and thrombosis specific to organoid-derived human blood vessels, as verified through intravital imaging. We examined a new long-acting, pH-sensitive (acid-switched) antibody targeting CFD. In both human and macaque COVID-19 models, this long-acting anti-CFD monoclonal antibody mitigated abnormal complement activation, protected endothelial cells, and curtailed the innate immune response post-viral exposure. Collectively, our findings suggest that the complement alternative pathway exacerbates endothelial injury and inflammation. This underscores the potential of CFD-targeted therapeutics against severe viral-induced inflammathrombotic outcomes.

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.

Association between high cardiac output at altitude and acute mountain sickness: preliminary study on Mt. Fuji.

BACKGROUND: Acute mountain sickness (AMS) affects around 30% of people climbing Mt. Fuji, but its pathogenesis is incompletely understood. The influence of a rapid ascent to high altitude by climbing and summiting Mt. Fuji on cardiac function in the general population is unknown, and its association with altitude sickness has not been clarified. METHODS: Subjects climbing Mt. Fuji were included. Heart rate, oxygen saturation, systolic blood pressure, cardiac index (CI) and stroke volume index were measured multiple times at 120 m as baseline values and at Mt. Fuji Research Station (MFRS) at 3,775 m. Each value and its difference from the baseline value (Δ) of subjects with AMS (defined as Lake Louise Score [LLS] ≥ 3 with headache after sleeping at 3,775 m) were compared with those of non-AMS subjects. RESULTS: Eleven volunteers who climbed from 2,380 m to MFRS within 8 h and stayed overnight at MFRS were included. Four suffered AMS. Compared with the non-AMS subjects, CI in the AMS subjects was significantly higher than that before sleeping (median [interquartile range]: 4.9 [4.5, 5.0] vs. 3.8 [3.4, 3.9] mL/min/m2; p = 0.04), and their ΔCI was significantly higher before sleeping (1.6 [1.4, 2.1] vs. 0.2 [0.0, 0.7] mL/min/m2; p < 0.01) and after sleeping (0.7 [0.3, 1.7] vs. -0.2 [-0.5, 0.0] mL/min/m2; p < 0.01). ΔCI in the AMS subjects dropped significantly after sleeping versus before sleeping (3.8 [3.6, 4.5] vs. 4.9 [4.5, 5.0] mL/min/m2; p = 0.04). CONCLUSIONS: Higher values of CI and ΔCI were observed at high altitude in the AMS subjects. A high cardiac output might be associated with the development of AMS.

Combination of WFDC2, CHI3L1, and KRT19 in Plasma Defines a Clinically Useful Molecular Phenotype Associated with Prognosis in Critically Ill COVID-19 Patients.

BACKGROUND: COVID-19 is now a common disease, but its pathogenesis remains unknown. Blood circulating proteins reflect host defenses against COVID-19. We investigated whether evaluation of longitudinal blood proteomics for COVID-19 and merging with clinical information would allow elucidation of its pathogenesis and develop a useful clinical phenotype. METHODS: To achieve the first goal (determining key proteins), we derived plasma proteins related to disease severity by using a first discovery cohort. We then assessed the association of the derived proteins with clinical outcome in a second discovery cohort. Finally, the candidates were validated by enzyme-linked immunosorbent assay in a validation cohort to determine key proteins. For the second goal (understanding the associations of the clinical phenotypes with 28-day mortality and clinical outcome), we assessed the associations between clinical phenotypes derived by latent cluster analysis with the key proteins and 28-day mortality and clinical outcome. RESULTS: We identified four key proteins (WFDC2, GDF15, CHI3L1, and KRT19) involved in critical pathogenesis from the three different cohorts. These key proteins were related to the function of cell adhesion and not immune response. Considering the multicollinearity, three clinical phenotypes based on WFDC2, CHI3L1, and KRT19 were identified that were associated with mortality and clinical outcome. CONCLUSION: The use of these easily measured key proteins offered new insight into the pathogenesis of COVID-19 and could be useful in a potential clinical application.

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.

Significance of interferon signaling based on mRNA-microRNA integration and plasma protein analyses in critically ill COVID-19 patients.

We evaluated mRNA and miRNA in COVID-19 patients and elucidated the pathogenesis of COVID-19, including protein profiles, following mRNA and miRNA integration analysis. mRNA and miRNA sequencing was done on admission with whole blood of 5 and 16 healthy controls (HCs) and 10 and 31 critically ill COVID-19 patients (derivation and validation cohorts, respectively). Interferon (IFN)-α2, IFN-ß, IFN-γ, interleukin-27, and IFN-λ1 were measured in COVID-19 patients on admission (day 1, 181 critical/22 non-critical patients) and days 6-8 (168 critical patients) and in 19 HCs. In the derivation cohort, 3,488 mRNA and 31 miRNA expressions were identified among differentially expressed RNA expressions in the patients versus those in HCs, and 2,945 mRNA and 32 miRNA expressions in the validation cohort. Canonical pathway analysis showed the IFN signaling pathway to be most activated. The IFN-ß plasma level was elevated in line with increased severity compared with HCs, as were IFN-ß downstream proteins, such as interleukin-27. IFN-λ1 was higher in non-critically ill patients versus HCs but lower in critical than non-critical patients. Integration of mRNA and miRNA analysis showed activated IFN signaling. Plasma IFN protein profile revealed that IFN-ß (type I) and IFN-λ1 (type III) played important roles in COVID-19 disease progression.

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.

Sepsis-associated hypoglycemia on admission is associated with increased mortality in intensive care unit patients.

AIM: Hyperglycemia is a common response to acute illness, but it is not often seen in critical conditions. The frequency and cause of hypoglycemia in septic patients have not been well elucidated. In this study, we focused on sepsis-associated hypoglycemia in the early phase and evaluated the impact of hypoglycemia on mortality. METHODS: We performed a retrospective review of 265 patients with sepsis admitted to a tertiary medical center. Blood glucose levels on admission were evaluated and analyzed by a Cox proportional hazard model. RESULTS: We categorized patients with sepsis into five groups according to blood glucose levels. Seven patients (2.6%) were admitted with severe hypoglycemia (≤40 mg/dL), 19 (7.2%) with mild hypoglycemia (41-70 mg/dL), 103 (38.9%) with euglycemia (71-140 mg/dL), 58 (21.9%) with mild hyperglycemia (141-180 mg/dL), and 78 (29.4%) with hyperglycemia (>180 mg/dL). There was a significant difference in 28-day mortality between those with severe hypoglycemia and euglycemia (71.4% versus 8.7%; P < 0.05). We analyzed the hazard ratios for the groups (relative to the reference of euglycemia) adjusted for sex, age, and Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores on admission. The hazard ratios for 28-day mortality in patients with severe hypoglycemia and mild hypoglycemia compared with that in patients with euglycemia were 8.18 (95% confidence interval [CI], 2.39-27.96; P = 0.001) and 7.56 (95% CI, 2.96-19.35; P < 0.001), respectively. CONCLUSION: Septic patients with severe hypoglycemia had significantly higher mortality compared with patients with euglycemia.

Energy expenditure and oxygen uptake kinetics in critically ill elderly patients.

BACKGROUND: Resting energy expenditure (REE) measurement of critically ill patients is essential for better nutrition management. Younger people increase their oxygen delivery ( ḊO2${\dot{{\rm{D}}}}{{\rm{O}}_2}$ ) to meet energy demands, but few reports have investigated oxygen uptake kinetics in elderly patients, which are the main target population in today's intensive care units (ICUs). In this study, we evaluated REE, ḊO2${\dot{{\rm{D}}}}{{\rm{O}}_2}$ , and oxygen extraction ratio (O2 Ext: oxygen consumption [ V̇O2${\dot{{\rm{V}}}}{{\rm{O}}_2}$ ]/ ḊO2${\dot{{\rm{D}}}}{{\rm{O}}_2}$ ) to clarify appropriate energy needs and consumption in elderly ICU patients. METHODS: This retrospective observational study included ventilated ICU patients who were divided into elderly participants (age ≥ 65 years) and nonelderly participants (age ≤64 years). V̇O2${\dot{{\rm{V}}}}{{\rm{O}}_2}$ , CO2 production, and cardiac output were measured by indirect calorimetry and noninvasive hemodynamic monitoring for up to 5 days. The initial values of REE, ḊO2${\dot{{\rm{D}}}}{{\rm{O}}_2}$ , and O2 Ext were compared between elderly and nonelderly patients. RESULTS: This study included 102 patients, of whom 52% (n = 53) were elderly. The absolute deviation of measured REE per ideal body weight (IBW) was significantly higher in elderly than in nonelderly patients (9.3 ± 6.9 vs 6.3 ± 6.6 kcal/kg; P < .01). ḊO2${\dot{{\rm{D}}}}{{\rm{O}}_2}$ had a strong negative correlation with age (P < .01). The O2 Ext value was significantly higher in elderly than in nonelderly patients (37 ± 19% vs 29 ± 13%; P = .03). CONCLUSIONS: Elderly critically ill patients were characterized by higher deviations in REE, lower ḊO2${\dot{{\rm{D}}}}{{\rm{O}}_2}$ , and higher O2 Ext. In elderly patients, O2 Ext rather than ḊO2${\dot{{\rm{D}}}}{{\rm{O}}_2}$ could be increased to meet energy consumption demands.

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.

Hydrogen Gas Therapy Attenuates Inflammatory Pathway Signaling in Septic Mice.

BACKGROUND: Molecular hydrogen (H2) has been used in clinical cases. However, there are few studies of H2 therapy to treat sepsis, and anti-inflammatory mechanisms of H2 are mostly unknown. We aimed to confirm effects of H2 therapy on sepsis and reveal its therapeutic mechanism via RNA sequencing in multiple organs in septic mice. METHODS: Nine-week-old C57BL/6 male mice underwent cecal ligation and puncture (CLP) or sham procedure. Subsequently, the CLP model received immediate ± continuous inhalation of 7% H2. Mice were observed for a week to assess survival rates. Serum inflammatory cytokines were evaluated at 24 h after CLP procedure. Liver, intestine, and lungs in CLP mice receiving 24-h ± H2 therapy were assessed by RNA sequencing. Data were analyzed with Ingenuity Pathways Analysis (QIAGEN Inc). RESULTS: Seven-day survival rate in septic mice was significantly improved in the H2 inhalation group compared with that in the control group (75% versus 40%, P < 0.05). H2 treatment attenuated serum interleukin-6 and tumor necrosis factor-α levels at 24 h after CLP, and blood glucose levels were maintained in the H2-treated group. In RNA sequencing, canonical pathway analysis revealed inactivity of various inflammatory signaling pathways, for example, acute phase response signaling and STAT3 pathways, in the liver and intestine in the CLP model after 24-h H2 inhalation. We detected significantly decreased expressions of upstream regulator genes such as the CD14 antigen gene in the liver and various cytokine receptor genes in the intestine and lungs in the H2-treated group. CONCLUSIONS: These findings may contribute to clarifying the mechanism of action of H2 therapy in sepsis.

Adipocytokine Profile Reveals Resistin Forming a Prognostic-Related Cytokine Network in the Acute Phase of Sepsis.

INTRODUCTION: Cytokines compose a network and play crucial roles in the pathogenesis and prognosis of sepsis. Adipose tissue is an important immune endocrine organ that releases adipocytokines. This study aimed to evaluate adipocytokines in sepsis from a network perspective. MATERIALS AND METHODS: This retrospective study of 37 patients with sepsis and 12 healthy controls was conducted from February 2014 to July 2015. Blood samples were collected from patients on days 1 (within 24 h of diagnosis), 2, 4, 6, 8, 11, and 15 and from healthy controls. Adipocytokines (adiponectin, leptin, resistin, chemerin, visfatin, vaspin, CXCL-12/SDF-1, angiotensinogen), inflammatory cytokines (IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-12/IL-23p40, TNF-α, monocyte chemotactic protein [MCP-1]), and plasminogen activator inhibitor-1 were measured. Acute Physiology and Chronic Health Evaluation II score was evaluated on day 1, and Sequential Organ Failure Assessment (SOFA) score and Japanese Association for Acute Medicine (JAAM) and International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation (DIC) scores were assessed at the times of blood sampling. RESULTS: Hierarchical clustering analysis showed the cluster formed by resistin, IL-6, IL-8, MCP-1, and IL-10 on days 1, 2, and 4 represented the cytokine network throughout the acute phase of sepsis. Each cytokine in this network was significantly associated with SOFA and JAAM DIC scores over the acute phase. A Cox proportional hazards model focusing on the acute phase showed a significant relation of these five cytokines with patient prognosis. CONCLUSIONS: Adipocytokines and an inflammatory cytokine profile assessed over time in sepsis patients showed that resistin was involved in an inflammatory cytokine network including IL-6, IL-8, IL-10, and MCP-1 in the acute phase of sepsis, and this network was associated with severity and prognosis of sepsis.

Original experimental rat model of blast-induced mild traumatic brain injury: a pilot study.

OBJECTIVE: Diagnosing blast-induced mild traumatic brain injury (mTBI) is difficult due to minimal imaging findings. This study aimed to establish a rat model of behavioral abnormality caused by blast-induced mTBI and detect new findings for therapeutic intervention. METHODS: We used a bench-top blast wave generator with the blast wave exiting through a 20-mm I.D. nozzle aimed at the focused target. The blast wave was directed at the head of male Wistar rats under general anesthesia positioned prone 2.5 cm below the nozzle. Peak shock wave pressure was 646.2 ± 70.3 kPa. RESULTS: After blast injury, mTBI rats did not show the findings of brain hemorrhage or contusion macroscopically and on hematoxylin-eosin-stained frozen sections but did show anorexia and weight loss in the early post-injury phase. Behavioral experiments revealed short-term memory impairment at 2 weeks and depression-like behavior at 2 and 6 weeks. Diffusion-weighted ex vivo MRI showed high-intensity areas in layers of the bilateral hippocampus. Immunohistochemical analysis revealed accumulation of reactive microglia and GFAP-positive astrocytes in the same region and loss of NeuN-positive neurons in the hippocampal pyramidal cell layer. CONCLUSIONS: This model can reflect the pathophysiology of blast-induced mTBI and could potentially be used to develop therapeutic interventions in the future.

Cytokine Elevation in Severe COVID-19 From Longitudinal Proteomics Analysis: Comparison With Sepsis.

Introduction: Coronavirus disease 2019 (COVID-19) is a new viral disease. Uncontrolled inflammation called "cytokine storm" is reported to contribute to disease pathogenesis as well as sepsis. We aimed to identify cytokines related to the pathogenesis of COVID-19 through a proteomics analysis of 1463 plasma proteins, validate these cytokines, and compare them with sepsis. Materials and Methods: In a derivation cohort of 306 patients with COVID-19, 1463 unique plasma proteins were measured on days 1, 4, and 8. Cytokines associated with disease severity and prognosis were derived. In a validation cohort of 62 COVID-19 patients and 38 sepsis patients treated in the intensive care unit [ICU], these derived cytokines were measured on days 1 (day of ICU admission), 2-3, and 6-8 (maximum: 3 time points/patient). Derived cytokines were compared with healthy controls and between COVID-19 and sepsis patients, and the associations with prognosis were evaluated. The time to wean off mechanical ventilation (MV) was evaluated only for COVID-19. Results: IL-6, amphiregulin, and growth differentiation factor (GDF)-15 were associated with disease severity and prognosis in the derivation cohort. In the validation cohort, IL-6 and GDF-15 were elevated in COVID-19 and sepsis on day 1, and the levels of these cytokines were higher in sepsis than in COVID-19. IL-6 and GDF-15 were associated with prognosis in sepsis. Cox proportional hazards model with time as a dependent covariate showed a significant relationship between plasma GDF-15 level and time to wean off MV (hazard ratio, 0.549 [95% confidence level, 0.382-0.789]). The GDF-15 level at ICU admission predicted late recovery. Conclusion: GDF-15 and IL-6 derived from proteomics analysis were related with disease severity of COVID-19. Their values were higher in sepsis than in COVID-19 and were associated with prognosis in sepsis. In COVID-19 patients treated in the ICU, GDF-15 was associated with the time to wean off MV and better predicted late recovery.

Bone Marrow-Derived Mononuclear Cell Transplantation Can Reduce Systemic Inflammation and Endothelial Glycocalyx Damage in Sepsis.

ABSTRACT: Bone marrow-derived mononuclear cells (BMMNCs) secrete anti-inflammatory mediators that protect against acute inflammation. Current evidence suggests that BMMNC transplantation can reduce acute tissue injury caused by systemic inflammation and lung dysfunction. This study evaluated the role of BMMNCs in reducing systemic inflammatory responses to vascular endothelial injury in sepsis. Bone marrow cells were harvested from the tibias and femurs of 12-week-old male Wistar rats; BMMNCs were separated by density centrifugation. Additional rats underwent cecal ligation and puncture (CLP) or similar sham surgery. BMMNCs were injected intravenously 30 min after CLP. The Sham and CLP Control groups were administered PBS. The 7-day survival rate improved markedly in the CLP-BMMNC group compared with that in the Control group. BMMNCs markedly suppressed the serum levels of pro-inflammatory mediators such as tumor necrosis factor-alpha, interleukin-6, and histone H3 at 3, 6, and 12 h after CLP. In the CLP-BMMNC group, the serum levels of syndecan-1, the main component of the vascular endothelial glycocalyx layer, were notably lower than those in the Control group 6 h after CLP. Histological analysis revealed improvement of morphological damages in the CLP-BMMNC group. Ultrastructural analysis revealed that the glycocalyx structure was maintained and the continuity of the vascular endothelial glycocalyx layer was preserved in the BMMNC group, compared with the case for the Control group at 6 and 12 h. Therefore, BMMNC transplantation may provide reduced systemic inflammation and endothelial glycocalyx damage, dramatically improving the survival of rats. These findings provide insights into formulating potential therapeutic strategies against sepsis.

Bone marrow-derived mononuclear cell therapy can attenuate systemic inflammation in rat heatstroke.

BACKGROUND: This study was performed to gain insights into novel therapeutic approaches for acute systemic inflammation in heatstroke. Bone marrow-derived mononuclear cells (BMMNCs) secrete anti-inflammatory proteins and have protective effects against acute inflammation. Recent evidence suggested that transplantation of BMMNCs can reduce the acute tissue injury caused by regional myocardial reperfusion and the lung dysfunction induced by lipopolysaccharides. We evaluated whether BMMNCs attenuate systemic inflammatory response induced by severe heatstroke. MATERIAL AND METHODS: Anesthetized 12-week-old male Wistar rats were subjected to heat stress (41.8 °C for 30 min) with/without transplantation of BMMNCs. Bone marrow cells were harvested from the femur and tibia of other Wistar rats. BMMNCs were separated by density centrifugation, dissolved in phosphate-buffered saline (PBS), and injected intravenously immediately after heat stress (HS-BMMNCs group). The control group was administered an equal volume of PBS, and the sham group underwent the same procedure without heat stress. RESULTS: Seven-day survival improved significantly in the HS-BMMNCs group versus control group (83.3% vs 41.7%). Transplantation of BMMNCs significantly suppressed serum levels of pro-inflammatory mediators, such as tumor necrosis factor-alpha, interleukin-6 and histone H3 at 3, 6, and 12 h after heat stress. Besides, the elevation of serum syndecan-1, a main component of the vascular endothelial glycocalyx layer, in the BMMNCs group was significantly suppressed compared to that in the control group at 6 and 12 h after heat stress. Histological analysis revealed that edema of the alveolar septum and vascular endothelial injury in the lung were evident in the control group 6 h after heat stress, whereas the morphological alteration was ameliorated in the HS-BMMNCs group. Also, histological analysis using BMMNCs derived from green fluorescent protein transgenic rats showed that the transplanted BMMNCs migrated into lung, kidney, and spleen at 24 h after heat stress but did not engraft to host tissues. CONCLUSION: Transplantation of BMMNCs attenuated acute systemic inflammation and vascular endothelial injury, reduced organ dysfunction, and improved survival in a rat heatstroke model. These findings provide a possible therapeutic strategy against critical heatstroke.

Delay of computed tomography is associated with poor outcome in patients with blunt traumatic aortic injury: A nationwide observational study in Japan.

According to guidelines from the Eastern Association for the Surgery of Trauma, computed tomography (CT) with intravenous contrast is strongly recommended to diagnose clinically significant blunt traumatic aortic injury (BTAI). However, it remains unclear whether the timing of CT scanning is associated with the prognosis of BTAI patients.We extracted data on emergency patients who suffered a BTAI in the chest and/or the abdomen from 2004 to 2015 from the Japanese Trauma Data Bank, a nationwide trauma registry. The primary outcome was death in the emergency department (ED) and secondary outcome was discharge to death. In addition, we assessed the relationship between death in the ED and the timing of CT scanning by shock status in subgroup analysis. We divided these patients into the tertile groups of early (≤26 minutes), middle (27-40 minutes), and late (≥41 minutes) phases based on the time interval from hospital arrival to start of first CT scanning, and assessed death of BTAI patients in the ED by CT scanning time with the use of a multivariable logistic regression model.In total, 421 patients who suffered BTAI in the chest and/or the abdomen were eligible for our analysis. The proportion of patients dying at hospital admission was 7.7% (11/142) in the early group, 11.1% (15/135) in the middle group, and 17.6% (25/144) in the late group. In a multivariable logistic regression adjusted for confounding factors, the adjusted odds ratio (AOR) of death in the ED was 1.833 (95% confidence interval [CI]: 0.601-5.590, P = .287) in the middle group and 2.832 (95% CI: 1.007-7.960, P = .048) in the late group compared with the early group. Compared with the early group, the late group tended to have a higher rate of discharge to death (AOR: 1.438, 95% CI: 0.735-2.813). In the patients with shock, the AOR was 3.292 (95% CI: 0.495-21.902) in the middle group and 6.039 (95% CI: 0.990-36.837) in the late group compared with the early group.This study revealed that a longer time interval from hospital arrival to CT scanning was associated with higher mortality in the ED in patients with BTAI.

Surveillance on The Safety and Efficacy of Ambrisentan (Volibris Tablet 2.5 mg) in Patients with Pulmonary Arterial Hypertension in Real Clinical Practice: Post-marketing Surveillance (Interim Analysis Report).

BACKGROUND AND OBJECTIVE: Pulmonary arterial hypertension (PAH) is an intractable and rare disease and the accumulation of clinical evidence under real-world setting is needed. A post-marketing surveillance for the endothelin receptor antagonist ambrisentan (Volibris tablet) has been conducted by all-case investigation since September 2010. This paper is an interim report on the safety and efficacy of ambrisentan in 702 patients with PAH. METHODS: PAH patients aged 15 years or older were subjected to the analysis. The safety analysis by overall cases or stratification of patient backgrounds and the efficacy analysis were investigated. RESULTS: Regarding patient characteristics, the 702 patients subjected to safety analysis included 543 (77.4%) women and 546 (77.8%) patients at WHO functional class II/III. The mean observational time was 392.7 days. A total of 324 adverse drug reaction (ADR) occurred in 204 (29.1%) patients. Common ADRs (≥ 2%) included anemia (4.6%), peripheral edema (4.1%), headache (3.6%), edema and face edema (2.6% each), abnormal hepatic function (2.3%), and epistaxis (2.1%). There were 82 serious ADRs occurring in 44 (6.3%) patients (385 serious adverse events in 184 (26.2%) patients). Although 11 (1.6%) interstitial lung disease (ILD) cases were reported, all were observed in patients with disease that may contribute to ILD and therefore it is difficult to assess if ambrisentan was associated with these events. There was no difference in safety in relation to the presence/absence of connective tissue disease-related PAH (CTD-PAH) or combination therapy. Among 677 patients subjected to efficacy analysis, those in whom hemodynamic status was determined before and after treatment showed improvement in the mean pulmonary arterial pressure and pulmonary vascular resistance after treatment. CONCLUSION: The interim results showed safety consistent with the known profile of ambrisentan in terms of the types and frequencies of ADRs in patients with PAH in real clinical practice, in comparison with previous clinical trials in Japan and the rest of the world. Thus, these results provided another corroboration of the tolerability of ambrisentan and we continue to monitor proper use information via the post-marketing surveillance to ensure any new safety signals are identified in a timely manner (ClinTrial.gov: NCT01406327).