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Introduction: Female sex may provide a survival benefit after trauma, possibly attributable to protective effects of estrogen. This study aimed to compare markers of coagulation between male and female trauma patients across different ages., Methods: Secondary analysis of a prospective cohort study that was conducted at six trauma centers. Trauma patients presenting with full trauma team activation were eligible for inclusion. Patients with a penetrating trauma or traumatic brain injury were excluded. Upon hospital arrival, blood was drawn for measurement of endothelial and coagulation markers and for rotational thromboelastometry measurement. Trauma patients were divided into four categories: males younger than 45 years, males 45 years or older, females younger than 45 years, and females 45 years or older. In a sensitivity analysis, patients between 45 and 55 years old were excluded to control for menopausal transitioning. Groups were compared with a Kruskal-Wallis test with Bonferroni correction. A logistic regression was performed to assess whether the independent effect of sex and age on mortality., Results: A total of 1,345 patients were available for analysis. Compared with the other groups, mortality was highest in females 45 years or older, albeit not independent from injury severity and shock. In the group of females 45 years or older, there was increased fibrinolysis, demonstrated by increased levels of plasmin-antiplasmin complexes with a concomitant decrease in α2-antiplasmin. Also, a modest decrease in coagulation factors II and X was observed. Fibrinogen levels were comparable between groups. The sensitivity analysis in 1,104 patients demonstrated an independent relationship between female sex, age 55 years or older, and mortality. Rotational thromboelastometry profiles did not reflect the changes in coagulation tests., Conclusion: Female trauma patients past their reproductive age have an increased risk of mortality compared with younger females and males, associated with augmented fibrinolysis and clotting factor consumption. Rotational thromboelastometry parameters did not reflect coagulation differences between groups., Level of Evidence: Prognostic and Epidemiological; Level III., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The endothelial angiopoietin/Tie2 system is an important regulator of endothelial permeability and targeting Tie2 reduces hemorrhagic shock-induced organ edema in males. However, sexual dimorphism of the endothelium has not been taken into account. This study investigated whether there are sex-related differences in the endothelial angiopoietin/Tie2 system and edema formation., Methods: Adult male and female heterozygous Tie2 knockout mice (Tie2+/-) and wild-type controls (Tie2+/+) were included (n = 9 per group). Renal and pulmonary injury were determined by wet/dry weight ratio and H&E staining of tissue sections. Protein levels were studied in plasma by ELISA and pulmonary and renal mRNA expression levels by RT-qPCR., Results: In Tie2+/+ mice, females had higher circulating angiopoietin-2 (138%, p<0.05) compared to males. Gene expression of angiopoietin-1 (204%, p<0.01), angiopoietin-2 (542%, p<0.001) were higher in females compared to males in kidneys, but not in lungs. Gene expression of Tie2, Tie1 and VE-PTP were similar between males and females in both organs. Renal and pulmonary wet/dry weight ratio did not differ between Tie2+/+ females and males. Tie2+/+ females had lower circulating NGAL (41%, p<0.01) compared to males, whereas renal NGAL and KIM1 gene expression was unaffected. Interestingly, male Tie2+/- mice had 28% higher renal wet/dry weight ratio (p<0.05) compared to Tie2+/+ males, which was not observed in females nor in lungs. Partial deletion of Tie2 did not affect circulating angiopoietin-1 or angiopoietin-2, but soluble Tie2 was 44% and 53% lower in males and females, respectively, compared to Tie2+/+ mice of the same sex. Renal and pulmonary gene expression of angiopoietin-1, angiopoietin-2, estrogen receptors and other endothelial barrier regulators was comparable between Tie2+/- and Tie2+/+ mice in both sexes., Conclusion: Female sex seems to protect against renal, but not pulmonary edema in heterozygous Tie2 knock-out mice. This could not be explained by sex dimorphism in the endothelial angiopoietin/Tie2 system., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 van Leeuwen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The objective of this study was to determine whether there is an association between sex and outcome in trauma patients presented with severe traumatic brain injury (TBI). A retrospective multicenter study was performed in trauma patients aged ≥ 16 years who presented with severe TBI (Head Abbreviated Injury Scale (AIS) ≥ 4) over a 4-year-period. Subgroup analyses were performed for ages 16-44 and ≥45 years. Also, patients with isolated severe TBI (other AIS ≤ 2) were assessed, likewise, with subgroup analysis for age. Sex differences in mortality, Glasgow Outcome Score (GOS), ICU admission/length of stay (LOS), hospital LOS, and mechanical ventilation (MV) were examined. A total of 1566 severe TBI patients were included (831 patients with isolated TBI). Crude analysis shows an association between female sex and lower ICU admission rates, shorter ICU/hospital LOS, and less frequent and shorter MV in severe TBI patients ≥ 45 years. After adjusting, female sex appears to be associated with shorter ICU/hospital LOS. Sex differences in mortality and GOS were not found. In conclusion, this study found sex differences in patient outcomes following severe TBI, potentially favoring (older) females, which appear to indicate shorter ICU/hospital LOS (adjusted analysis). Large prospective studies are warranted to help unravel sex differences in outcomes after severe TBI.

Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases ( p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis.