Trauma is the leading cause of death and disability in patients aged 1-46 y. Severely injured patients experience considerable blood loss and hemorrhagic shock requiring treatment with massive ...transfusion of red blood cells (RBCs). Preclinical and retrospective human studies in trauma patients have suggested that poorer therapeutic efficacy, increased severity of organ injury, and increased bacterial infection are associated with transfusion of large volumes of stored RBCs, although the mechanisms are not fully understood.
We developed a murine model of trauma hemorrhage (TH) followed by resuscitation with plasma and leukoreduced RBCs (in a 1:1 ratio) that were banked for 0 (fresh) or 14 (stored) days. Two days later, lungs were infected with Pseudomonas aeruginosa K-strain (PAK). Resuscitation with stored RBCs significantly increased the severity of lung injury caused by P. aeruginosa, as demonstrated by higher mortality (median survival 35 h for fresh RBC group and 8 h for stored RBC group; p < 0.001), increased pulmonary edema (mean 95% CI 106.4 μl 88.5-124.3 for fresh RBCs and 192.5 μl 140.9-244.0 for stored RBCs; p = 0.003), and higher bacterial numbers in the lung (mean 95% CI 1.2 × 10(7) -1.0 × 10(7) to 2.5 × 10(7) for fresh RBCs and 3.6 × 10(7) 2.5 × 10(7) to 4.7 × 10(7) for stored RBCs; p = 0.014). The mechanism underlying this increased infection susceptibility and severity was free-heme-dependent, as recombinant hemopexin or pharmacological inhibition or genetic deletion of toll-like receptor 4 (TLR4) during TH and resuscitation completely prevented P. aeruginosa-induced mortality after stored RBC transfusion (p < 0.001 for all groups relative to stored RBC group). Evidence from studies transfusing fresh and stored RBCs mixed with stored and fresh RBC supernatants, respectively, indicated that heme arising both during storage and from RBC hemolysis post-resuscitation plays a role in increased mortality after PAK (p < 0.001). Heme also increased endothelial permeability and inhibited macrophage-dependent phagocytosis in cultured cells. Stored RBCs also increased circulating high mobility group box 1 (HMGB1; mean 95% CI 15.4 ng/ml 6.7-24.0 for fresh RBCs and 50.3 ng/ml 12.3-88.2 for stored RBCs), and anti-HMGB1 blocking antibody protected against PAK-induced mortality in vivo (p = 0.001) and restored macrophage-dependent phagocytosis of P. aeruginosa in vitro. Finally, we showed that TH patients, admitted to the University of Alabama at Birmingham ER between 1 January 2015 and 30 April 2016 (n = 50), received high micromolar-millimolar levels of heme proportional to the number of units transfused, sufficient to overwhelm endogenous hemopexin levels early after TH and resuscitation. Limitations of the study include lack of assessment of temporal changes in different products of hemolysis after resuscitation and the small sample size precluding testing of associations between heme levels and adverse outcomes in resuscitated TH patients.
We provide evidence that large volume resuscitation with stored blood, compared to fresh blood, in mice increases mortality from subsequent pneumonia, which occurs via mechanisms sensitive to hemopexin and TLR4 and HMGB1 inhibition.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC).
Gene expression and clinical-pathological ...data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated.
Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival.
The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Even when patients survive the initial insult, there is significant morbidity and mortality secondary to subsequent ...pulmonary edema, acute lung injury (ALI), and nosocomial pneumonia. Whereas the relationship between TBI and secondary pulmonary complications is recognized, little is known about the mechanistic interplay of the two phenomena. Changes in mental status secondary to acute brain injury certainly impair airway- and lung-protective mechanisms. However, clinical and translational evidence suggests that more specific neuronal and cellular mechanisms contribute to impaired systemic and lung immunity that increases the risk of TBI-mediated lung injury and infection. To better understand the cellular mechanisms of that immune impairment, we review here the current clinical data that support TBI-induced impairment of systemic and lung immunity. Furthermore, we also review the animal models that attempt to reproduce human TBI. Additionally, we examine the possible role of damage-associated molecular patterns, the chlolinergic anti-inflammatory pathway, and sex dimorphism in post-TBI ALI. In the last part of the review, we discuss current treatments and future pharmacological therapies, including fever control, tracheostomy, and corticosteroids, aimed to prevent and treat pulmonary edema, ALI, and nosocomial pneumonia after TBI.
Traumatic brain injury (TBI) is the leading cause of injury-related death and disability in patients under the age of 46 years. Survivors of the initial injury often endure systemic complications ...such as pulmonary infection, and
is one of the most common causes of nosocomial pneumonia in intensive care units. Female patients are less likely to develop secondary pneumonia after TBI, and pre-clinical studies have revealed a salutary role for estrogen after trauma. Therefore, we hypothesized that female mice would experience less mortality after post-TBI pneumonia with
. We employed a mouse model of TBI followed by
pneumonia. Male mice had greater mortality and impaired lung bacterial clearance after post-TBI pneumonia compared with female mice. This was confirmed as a difference in sex hormones, as oophorectomized wild-type mice had mortality and lung bacterial clearance similar to male mice. There were differences in tumor necrosis factor-α secretion in male and female alveolar macrophages after
infection. Finally, injection of male or oophorectomized wild-type female mice with estrogen restored lung bacterial clearance and prevented mortality. Our model of TBI followed by
pneumonia is among the first to reveal sex dimorphism in secondary, long-term TBI complications.
Blunt cerebrovascular injury (BCVI) can result in thromboembolic stroke. Many trauma centers selectively screen patients with cervical computed tomographic angiography (CTA) based on clinical ...criteria. In 2016, our institution adopted universal screening for BCVI for all blunt trauma patients. The aim of this study was to accurately determine the incidence of BCVI and to evaluate the diagnostic performance of the Denver criteria (DC), expanded Denver criteria (eDC), and Memphis criteria (MC) in selecting patients for screening.
Retrospective cohort study of adult (≥16 years) blunt trauma patients who presented to the Level I trauma center at University of Alabama at Birmingham. We reviewed all CTA reports and selected CTA images to obtain the true incidence rate of BCVI. We then evaluated the diagnostic performance of the DC, eDC, and MC.
A total of 6,800 patients who had suffered blunt trauma were evaluated, of whom 6,287 (92.5%) had a neck CTA. Of these, 480 (7.6%) patients had CTA evidence of BCVI. The eDC identified the most BCVI cases (sensitivity 74.7%) but had the lowest positive predictive value (14.6%). The DC and MC had slightly greater positive predictive values (19.6% and 20.6%, respectively) and had the highest diagnostic ability in terms of likelihood ratio (2.8 and 2.9) but had low sensitivity (57.5% and 47.3%). Consequently, if relying on the traditional screening criteria, the DC, eDC, and MC would have respectively resulted in 42.5%, 25.3%, and 52.7% of patients with BCVI identified by universal screening not receiving a neck CTA to screen for BCVI.
Blunt cerebrovascular injury is even more common than previously thought. The diagnostic performance of selective clinical screening criteria is poor. Consideration should be given to the implementation of universal screening for BCVI using neck CTA in all blunt trauma patients.
Diagnostic, level III.
The use of the extremity tourniquet in military environments has reduced preventable deaths due to exsanguinating hemorrhage, leading to increased use in civilian settings. However, the outcomes of ...contemporary prehospital tourniquet use in civilian settings are not well-described nationally. The objective of this study was to describe the characteristics and outcomes following prehospital tourniquet use by emergency medical services (EMS) in the United States.
All trauma activations reported to the National EMS Information System 2019 (NEMSIS) were included. Patients who had ≥1 tourniquet applied were identified. Descriptive analyses were used to compare characteristics between tourniquet and no-tourniquet cohorts. Coarsened exact matching was performed to generate a k2k match (on age, sex, lowest-systolic blood pressure, initial patient acuity, provider's initial impression, injury mechanism, and presence of upper/lower extremity injuries) and used to compare outcomes. Trauma patients who may have potentially benefited from tourniquet application (extremity injury, shock index ≥1 and no documented tourniquet application) were identified.
A total of 7,161 tourniquets were applied among 4,571,379 trauma activations (1.6/1000 activations). Patients in the tourniquet cohort were younger (40 ± 18 vs 52 ± 26 mean ± SD years), more hypotensive (16.1% vs. 2.5%) and had higher initial acuity (65.0% critical/emergent vs. 20.6%) p < 0.01 for all. A total of 7,074 patients in the tourniquet cohort were matched with 7,074 patients in the non-tourniquet cohort. Post-match analysis revealed that the patients in tourniquet cohort had a higher final acuity (80.8% vs. 75.0%, p < 0.01), lower scene-time (15.4 ± 13.6 vs. 17.0 ± 14.2 mean ± SD minutes, p < 0.01), and higher survival-to-hospital (83.6% vs. 75.1%, p < 0.01). A total of 141,471 trauma patients who may have potentially benefited from tourniquet application were identified.
Prehospital tourniquet use by EMS in the United States is associated with lower scene-time and improved survivability to hospital. Results indicate that patients might benefit from wider tourniquet use in the civilian prehospital setting.
Slope was significantly non-zero for number of units (r2 = 0.91, p<0.001). https://doi.org/10.1371/journal.pmed.1002991.g001 In the Results, in the subsection “Heme levels in patients after TH and ...resuscitation”, there is an error in the fifth sentence of the first paragraph. While the absolute concentration of these mediators is important, the relative concentrations of hemoglobin and free heme, compared to Hp and Hpx respectively is likely of greater clinical significance; Hp and Hpx are the endogenous primary defense mechanisms protecting against hemolysis-dependent injury. (2018) Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACTTraumatic injury and hemorrhagic shock result in endothelial cell activation and vascular dysfunction that, if not corrected, can propagate multiorgan failure. Angiopoietin-1 and ...angiopoietin-2 are important regulators of endothelial cell function, and the ratio of plasma angiopoietin-2-to-1 is a useful indicator of overall vascular health. We therefore characterized plasma angiopoietin-2/-1 ratios over time after trauma in adults in an effort to gain insight into the pathophysiology that may drive post-traumatic vasculopathy and organ injury. We performed a single-center prospective observational study to measure plasma angiopoietin-1 and -2 levels and determine angiopoietin-2/-1 ratios in adult trauma patients upon hospital arrival and after 12, 24, and 48 h. Compared with levels in healthy adults, angiopoietin-1 levels were significantly elevated at hospital arrival, and angiopoietin-2 levels were significantly elevated at 12, 24, and 48 h. These kinetics translated in angiopoietin-2/-1 ratios that were significantly greater than controls at 24 and 48 h. After regression analysis, elevated angiopoietin-2 levels were independently associated with blunt injuries at admission, with coagulopathy at admission and 12 h, and with hemorrhagic shock at 24 and 48 h. Significant correlations were observed between both angiopoietins and 24-h transfusion requirements. Angiopoietin-2/-1 ratios correlated with mechanical ventilation duration and intensive care unit and hospital lengths of stay. In this study, we demonstrate novel temporal associations between angiopoietin dysregulation and blunt injuries, acute coagulopathy, and hemorrhagic shock. Moreover, our findings highlight the presence of endothelial activation following traumatic insults in adults that may contribute to worse clinical outcomes.
BACKGROUND:Angiopoietin-1 (Agpt-1) and Agpt-2 are cytokine regulators of vascular endothelial integrity. Elevated plasma Agpt-2 levels and ratios of Agpt-2:Agpt-1 are associated with adverse outcomes ...in adult trauma and pediatric sepsis populations. However, the behavior of the angiopoietins after pediatric trauma has not been characterized, and their relationship to endothelial glycocalyx damage, indicated by plasma syndecan-1 (Syn-1) levels, has not been established.
METHODS:We performed a secondary analysis of prospectively collected data from 52 pediatric trauma patients and 12 control patients at a level one pediatric trauma center from 2013 to 2016. We measured Agpt-1, Agpt-2, and Syn-1 levels from plasma taken upon hospital arrival and 24 h after admission. Angiopoietin levels were compared to controls, and the correlation between Agpt-2 and Syn-1 was assessed.
RESULTS:Plasma Agpt-1 and Agpt-2 levels are elevated immediately after pediatric trauma compared with controls. At 24 h, trauma patients demonstrated significantly elevated plasma Agpt-2:Agpt-1 ratios relative to controls due to decline of Agpt-1 levels to near that of controls. Higher 24-h Agpt-2 levels are associated with more hypoperfusion, and elevated 24-h Agpt-2:Agpt-1 ratios are associated with adverse clinical outcomes. Significant positive correlations between Agpt-2 and Syn-1 upon admission and at 24 h after injury were identified.
CONCLUSION:Our findings suggest dysregulation of circulating angiopoietins after pediatric trauma that may be linked to endothelial glycocalyx injury. Larger prospective studies are needed to validate these findings and determine the relationship of Agpt-2 with other markers of endotheliopathy.
(1) Background: Spinal cord injuries and diseases necessitate sophisticated tools for accurate diagnosis and treatment planning. However, the lack of reliable phantoms mimicking the complex structure ...of the spinal cord hinders the development and validation of advanced imaging techniques. This study aims to address this critical unmet need by exploring the application of electrospinning to create polymeric fibers resembling the human spinal cord; (2) Methods: Direct jet coaxial electrospinning (DJ-co-ES) is a specialized electrospinning process characterized by the presence of solely the straight segment of a fluid jet. The research firstly investigates the effects of various solution properties and process parameters on the formation and characteristics of core/shell fibers with polycaprolactone (PCL) as the shell and polyethylene oxide (PEO) as the core. Furthermore, the study explores the potential of these DJ-co-ES fibers as phantoms by measuring various diffusion MRI parameters; (3) Results: Scanning electron microscopy (SEM) revealed the successful production of hollow PCL microfibers (2–12 μm diameter) with smooth, cylindrical morphology and high orientation. The DJ-co-ES process demonstrated optimal stability when utilizing 10 w/v% PCL in DCM/DMF for the shell and 4 w/v% PEO in deionized water for the core. Additionally, the high miscibility between core and shell solvents in other core and shell solutions cases facilitated the production of fibers with smaller diameters. The findings demonstrate that the measured values fall within the range observed in both healthy and diseased spinal cord tissues; (4) Conclusions: This research paves the way for utilizing DJ-co-ES technology to develop reliable phantoms for spinal cord applications, ultimately fostering advancements in diagnosis, treatment, and research related to spinal cord conditions.
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