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Abstract: Introduction: The prehospital environment is fraught with operational constraints, making it difficult to assess the need for resources such as lifesaving interventions (LSI) for adults with traumatic injuries. While invasive methods such as lactate have been found to be highly predictive for estimating injury severity and resource requirements, noninvasive methods, to include continuous vital signs ( VS ), have the potential to provide prognostic information that can be quickly acquired, interpreted, and incorporated into decision making. In this work, we hypothesized that an analysis of continuous VS would have predictive capacity comparable to lactate and other laboratory tests for the prediction of injury severity, need for LSIs and intensive care unit admission. Methods: In this preplanned secondary analysis of 300 prospectively enrolled patients, venous blood samples were collected in the prehospital environment aboard a helicopter and analyzed with a portable lab device. Patients were transported to the primary adult resource center for trauma in the state of Maryland. Continuous VS were simultaneously collected. Descriptive statistics were used to describe the cohort and predictive models were constructed using a regularized gradient boosting framework with 10-fold cross-validation with additional analyses using Shapley additive explanations (SHAP). Results: Complete VS and laboratory data from 166 patients were available for analysis. The continuous VS models had better performance for prediction of receiving LSIs and intensive care unit length of stay compared to single (initial) VS measurements. The continuous VS models had comparable performance to models using only laboratory tests in predicting discharge within 24 h (continuous VS model: area under the receiver operating curve [AUROC] 0.71; 95% CI, 0.68-0.75 vs. lactate model: AUROC, 0.65; 95% CI, 0.68; 95% CI, 0.66-0.71). The model using all laboratory data yielded the highest sensitivity and sensitivity (AUROC, 0.77; 95% CI, 0.74-0.81). Discussion: The results from this study suggest that continuous VS obtained from autonomous monitors in an aeromedical environment may be helpful for predicting LSIs and the critical care requirements for traumatically injured adults. The collection and use of noninvasively obtained physiological data during the early stages of prehospital care may be useful for in developing user-friendly early warning systems for identifying potentially unstable trauma patients.

Abstract: Background : New strategies are needed to mitigate further tissue injury during traumatic limb ischemia in cases requiring damage control resuscitation (DCR). Little is known about the pathophysiology and injury course in acute limb ischemia (ALI) with DCR in polytraumatized casualties. We therefore investigated the effects of therapeutic limb hypothermia in a swine model of ALI and DCR. Methods : Fifteen swine underwent a published 6-h DCR protocol of hemorrhage and then resuscitation. After hemorrhage, animals were randomized to 5°C or 15°C cooling of one hindlimb; the contralateral limb serving as an uncooled control. Physiologic variables, limb temperature, and limb tissue metabolites (glucose, lactate, and pyruvate) were measured throughout the DCR protocol. Muscle and nerve biopsies were obtained after the 6-h protocol. Results : Lactate and pyruvate levels were significantly lower in the cooled limbs than in the uncooled control limbs but did not differ between the 5°C and 15°C groups. Tissue glucose levels did not differ between the 5°C group, the 15°C group, and controls. Mean histologic muscle score was significantly higher in the 5°C group than in controls ( P = 0.03). Mean nerve histology scores did not differ between the 5°C and paired control limbs, or between the mean muscle and nerve histology scores of the 15°C and paired control limbs. Conclusion : Cooling to 15°C significantly reduced local tissue metabolites compared to paired controls, while producing no significant increase in histologic damage, whereas cooling to 5°C increased histologic muscle damage. These results suggest an approach to prevention of ischemic injury through local hypothermia but warrant further functional testing.

Abstract: Background: Growing evidence has found the critical role of circular RNAs (circRNAs) in sepsis-induced acute kidney injury (S-AKI). CircTMCO3 has been found to be involved in tumor microenvironment changes of ovarian cancer. This study aimed to explore whether circTMCO3 functions in S-AKI, and if so, to elucidate the molecular mechanism. Methods: CircTMCO3 expression was analyzed in lipopolysaccharide (LPS)-induced HK-2 cells and in the kidney tissues of mice treated with cecal ligation and puncture (CLP), respectively. Furthermore, the effects of circTMCO3 on S-AKI and the related mechanisms were evaluated in both models through gain- and/or loss-of-function strategies. Results: CircTMCO3 expression was suppressed in both S-AKI models. Upregulation of circTMCO3 mitigated LPS-induced apoptosis, oxidative stress, and inflammation in HK-2 cells. In contrast, circTMCO3 downregulation exacerbated LPS-induced injuries in HK-2 cells. Intravenous injection of circTMCO3 lentivirus to increase circTMCO3 expression improved renal function and attenuated kidney injury in S-AKI mice, as evidenced by the decrease in serum creatinine and blood urea nitrogen concentrations, amelioration of tubular pathological injury, reduction of renal cell apoptosis, and mitigation of oxidative stress and proinflammatory cytokines (TNF-α, IL-1β, and IL-6). Moreover, circTMCO3 directly targeted miR-218-5p, and the mimic of which abolished the protective effect of circTMCO3 in cell models. ZEB2 was identified to be a target of miR-218-5p; its downregulation not only reversed the impacts of miR-218-5p inhibitor on S-AKI, but also mitigated the effects mediated by circTMCO3 upregulation in vitro . Conclusions: CircTMCO3 protects against S-AKI by regulating miR-218-5p/ZEB2 axis, thereby mediating antiapoptotic, antioxidant, and anti-inflammatory activities. This indicates that increasing circTMCO3 expression might be a future therapeutic method for S-AKI.

Abstract: Mice used in biomedical research are typically housed at ambient temperatures (22°C-24°C) below thermoneutrality (26°C-31°C). This chronic cold stress triggers a hypermetabolic response that may limit the utility of mice in modeling hypermetabolism in response to burns. To evaluate the effect of housing temperature on burn-induced hypermetabolism, mice were randomly assigned to receive sham, small, or large scald burns. Mice recovered for 21 days in metabolic phenotyping cages at 24°C or 30°C. Regardless of sex or sham/burn treatment, mice housed at 24°C had greater total energy expenditure ( P < 0.001), which was largely attributable to greater basal energy expenditure when compared to mice housed at 30°C ( P < 0.001). Thermoneutral housing (30°C) altered adipose tissue mass in a sex-dependent manner. Compared to sham and small burn groups, large burns resulted in greater water vapor loss, regardless of housing temperature ( P < 0.01). Compared to sham, large burns resulted in greater basal energy expenditure and total energy expenditure in mice housed at 24°C; however, this hypermetabolic response to large burns was blunted in female mice housed at 30°C, and absent in male mice housed at 30°C. Locomotion was significantly reduced in mice with large burns compared to sham and small burn groups, irrespective of sex or housing temperature ( P < 0.05). Housing at 30°C revealed sexual dimorphism in terms of the impact of burns on body mass and composition, where males with large burns displayed marked cachexia, whereas females did not. Collectively, this study demonstrates a sex-dependent role for housing temperature in influencing energetics and body composition in a rodent model of burn trauma.

Abstract: Background: Acute respiratory distress syndrome (ARDS) is a serious pathological process with high mortality. Ferroptosis is pivotal in sepsis, whose regulatory mechanisms in sepsis-induced ARDS remains unknown. We aimed to determine key ferroptosis-related genes in septic ARDS and investigate therapeutic traditional Chinese medicine. Method: Sepsis-induced ARDS dataset obtained from Gene Expression Omnibus was analyzed to identify ferroptosis-related differentially expressed genes. Enrichment analysis and protein-protein interaction network construction were performed to identify hub genes. Immune cells infiltration was analyzed and competitive endogenous RNA network was constructed. The diagnostic value of hub genes in septic ARDS was analyzed and the occurrence of ferroptosis and the expression of hub genes were detected. Traditional Chinese medicine targeting hub genes was predicted via SymMap database and was verified. Results: Sixteen ferroptosis-related differentially expressed genes were obtained, among which the top four genes ( IL1B , TXN , MAPK3 , HSPB1 ) were selected as hub genes, which may be potential diagnostic markers of septic ARDS. Immunoassay showed that sepsis-induced ARDS and hub genes were closely related to immune cells. The competitive endogenous RNA network showed 26 microRNAs and 38 long noncoding RNA. Ferroptosis occurred and the expressions of IL1B , MAPK3 , and TXN were increased in septic ARDS mice and LPS-challenged human pulmonary alveolar epithelial cells. Sea buckthorn alleviated septic lung injury and affected hub genes expression. Conclusions: Ferroptosis-related genes of IL1B , MAPK 3, and TXN serve as potential diagnostic genes for sepsis-induced ARDS. Sea buckthorn may be therapeutic medication for ARDS. This study provides a new direction for septic ARDS treatment.

Abstract: Objective: The combination of catecholamine-resistant vasodilatory shock and acute kidney injury (AKI) is associated with high morbidity and mortality. The role of angiotensin II (ANGII) in this setting is unclear. Methods: We conducted a post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS) 3 trial which assessed the effect of Intravenous ANG II or placebo in patients with refractory vasodilatory shock in 75 intensive care units across nine countries in North America, Australasia, and Europe. We included patients with all stages AKI at initiation of ANG II or placebo and assessed 28-day mortality as primary outcome. We studied mean arterial pressure (MAP) response and days alive and free from renal replacement therapy (RRT) up to day 7 as secondary outcome. Results: Of 321 ATHOS-3 patients, 203 (63%) had AKI at randomization, with stage 3 AKI being dominant (67%). Median age was 63 years and median APACHE II score was 30. By day 28, overall, 118 (58%) of patients had died (53% with ANGII vs. 63% with placebo, hazard ratio = 0.75, 95% CI [0.52-1.08], P = 0.121). Among AKI stage 3 patients, however, ANGII was associated with significantly lower mortality (48% vs. 67%, hazard ratio = 0.57, 95% CI [0.36-0.91], P = 0.024). Additionally, in this subgroup, compared with placebo, patients receiving ANGII were more likely to achieve a MAP response (P < 0.001) and had more days alive and free from RRT (P < 0.001). Conclusions: Compared with placebo, in patients with catecholamine-resistant vasodilatory shock and stage 3 AKI, ANGII is associated with lower 28-day, greater likelihood of MAP response, and more days alive and free from RRT. These findings support the conduct of future ANGII trials in patients with stage 3 AKI.

Abstract: Background: Acute lung injury (ALI) is a severe condition characterized by a high mortality rate, driven by an uncontrolled inflammatory response. Emerging evidence has underscored the crucial role of the ubiquitin system in ALI. However, because of their vast number, the specific functions of individual ubiquitination regulators remain unclear. Materials and methods: In this study, we established human lung organoids (HLOs) derived from human embryonic stem cells and subjected them to lipopolysaccharide (LPS) treatment to induce an inflammatory response, mimicking ALI. Subsequently, we detected the expression of inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin 6, interleukin 18 (IL-18), and interleukin-1β (IL-1β), by quantitative polymerase chain reaction experiments. We also detected changes in the mRNA expression of several USPs before and after HLOs treatment and thus screened for USPs that had significant changes in HLOs after LPS stimulation. After screening for USP, we silenced the USP in HLOs and then subjected them to LPS treatment, and TNF-α, IL-6, IL-18, and IL-1β expressions were detected using quantitative polymerase chain reaction assays. Meanwhile, western blot was used to detect changes in NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) and apoptosis-associated Speck-like protein containing a CARD (ASC) protein level in HLOs. Results: Through screening the expression of 40 ubiquitin-specific proteases (USPs), which are responsible for removing ubiquitination, we identified several USPs that exhibited differential expression in LPS-treated HLOs compared to untreated HLOs. Notably, USP31 emerged as the most significantly upregulated USP, and the knockdown of USP31 markedly attenuated the inflammatory response of HLOs to LPS treatment. Conclusions: USP31 may play a facilitating role in the inflammatory response during ALI.

Abstract: Background: Acute infections and sepsis are a leading cause of death. These patients are primarily encountered at the emergency department (ED), where early assessment for sepsis is necessary to improve outcome. In sepsis, the inflammatory response causes several characteristic pathophysiological changes, including a dysregulated and generalized activation of the endothelium. This study aimed to analyze endothelial markers released to the blood as diagnostic biomarkers for acute infection and sepsis in the ED, as smaller studies have previously shown promising results in other settings. Methods : Serum samples from n = 312 adult patients with suspected acute infections at presentation to the ED were utilized. Patients' courses of disease and outcomes were assessed by clinical adjudication. E-selectin, P-selectin, ICAM-1, and VCAM-1 were measured by ELISAs. The accuracy of each marker for predicting bacterial infection, sepsis, and in-hospital mortality was evaluated. Results : For sepsis, E-selectin and ICAM-1 both showed an area under the receiver operating characteristic (AUROC) of 0.62, lower than procalcitonin with 0.77 (both P < 0.01) and lactate with 0.73 ( P = 0.030 and 0.046, respectively), but similar to CRP with 0.60 ( P = 0.758 and 0.876, respectively). For 28-day in-hospital mortality among patients with infection, ICAM-1 performed best with an AUROC of 0.75. Conclusions : Despite promising results in small studies and specific cohorts, particularly in intensive care units, this large-scale evaluation of four endothelial biomarkers highlights their limited diagnostic utility in a broader inclusion setup design at the earliest possible time point of evaluation.