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Introduction: Statin discontinuation has been investigated in a wide range of diseases and injuries, but there is a paucity of data in the older adult population with traumatic brain injury (TBI). The purpose of this study was to re-examine the extent to which early discontinuation of pre-injury statin (PIS) therapy increases the risk of poor patient outcomes in older adult patients suffering a TBI., Methods: This was a retrospective observational cohort study of adult trauma patients with a blunt TBI across three trauma centres over four years. Patients were excluded because of no PIS use, age <55years, or a hospital length of stay (LOS) less than three days. Patients found to be intentionally discontinued from statin therapy within 48h of hospital admission for injury-related reasons were excluded. The primary and secondary outcomes were in-hospital mortality and a hospital LOS ≥1 week. Outcomes were analysed using logistic regression., Results: There were 266 patients in the continuation group, and 131 in the discontinuation group. The statin discontinuation group had a significantly higher proportion of patients with a moderate or severe head injury, intubation in emergency department (ED), and disposition to the intensive care unit or operating room. Overall, 23 (6%) patients died while in the hospital. After adjusting for ED Glasgow coma scale, the odds of dying in the hospital were not significantly larger for patients having been discontinued from PIS, compared to those who were continued (OR=1.75, 95%CI=0.71-4.31, p=0.22). Among patients who received an in-hospital statin, the median (interquartile range) time between hospital admission and first administration of statin medication did not differ between patients who died and those who survived (22.8h [10.96-28.91] vs. 22.9h [11.67-39.80], p=0.94). There were no significant differences between study groups in the proportion of patients with a hospital length of stay >1 week (continuation=29% vs. discontinuation=36%, p=0.19)., Conclusion: We did not observe a significantly increased odds of in-hospital mortality following PIS discontinuation, compared to PIS continuation, in an older adult population with TBI. It remains to be seen whether statin discontinuation is a proxy variable for injury severity, or whether it exerts deleterious effects after injury., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Prognosis in patients with traumatic brain injury (TBI) and Glasgow Coma Scale (GCS) score of 3 is poor, raising concern regarding the utility of aggressive operative neurosurgical management. Our purpose was to describe outcomes in a propensity matched population with TBI and GCS3 treated with operative neurosurgical procedures of craniotomy or craniectomy (CRANI)., Methods: We conducted a five-year, multicenter retrospective cohort study of patients with an ED GCS 3 and a positive head CT identified by ICD-9CM diagnosis codes. Two populations were examined: (1) patients with extra-axial mass lesion (subdural or epidural haematoma), (2) patients without mass lesion (subarachnoid and intraparenchymal haemorrhage including contusion, other intracerebral haemorrhage or intracranial injury including diffuse axonal injury). In patients with extra-axial mass lesion, propensity score techniques were used to match patients 1:1 by CRANI, and the following outcomes were analysed with conditional logistic regression: survival, favourable hospital disposition to home or rehabilitation, and development of complications., Results: There were 541 patients with TBI and GCS3; 19% had a CRANI, 83% were initiated within 4h. In those with mass lesion, 27% (91/338) had a CRANI; after matching, a significant survival benefit was observed with CRANI vs. without CRANI (65% vs. 34% survival, OR: 3.9 (1.6-10.5) p<0.001). There was borderline increased odds of favourable disposition (43% vs. 26%, OR: 2.4 (0.99-6.3, p=0.052) with CRANI vs. without CRANI, and no difference in developing a complication (58% vs. 48%, OR: 1.5 (0.7-3.4), p=0.30)., Conclusions: Survival was achieved in 65% of patients that underwent surgical intervention for subdural and epidural haematoma, despite a presenting GCS of 3. These results demonstrate prompt operative neurosurgical management of mass lesion is warranted for selected patients with a GCS of 3, contributing to a significant 4-fold survival benefit. In the absence of mass lesion the effect of immediate neurosurgery on outcomes is inconclusive., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To synthesise published and unpublished findings examining the relationship between institutional trauma centre volume or trauma patient volume per surgeon and mortality., Background: Evidence on the relationship between patient volume and survival in trauma patients is inconclusive in the literature and remains controversial., Methods: A literature search was performed to identify studies published between 1976 and 2013 via MEDLINE (Pubmed) and the Cumulative Index to Nursing and Allied Health Literature (EbscoHost) as well as footnote chasing. Abstracts from appropriate conferences and ProQuest Dissertations and Theses were also searched. Inclusion criteria required studies to be original research published in English that examined the relationship between mortality and either institutional or per surgeon volume in American trauma centres. We employed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement checklist and flowchart. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was employed to rate the quality of the evidence., Results: Of 1392 studies reviewed, 19 studies met defined inclusion criteria; all studies were retrospective. The definition of volume was heterogeneous across the studies. Patient population and analysis methods also varied across the studies. Sixteen studies (84%) examined the relationship between institutional trauma centre volume and mortality. Of the 16 studies, 12 examined the volume of severely injured patients and eight examined overall trauma patient volume. High institutional volume was associated with at least somewhat improved mortality in ten of 16 studies (63%); however, nearly half of these studies found only some subpopulations experienced benefits. In the remaining six studies, volume was not associated with any benefits. Four studies (25%) analysed the impact of surgeon volume on mortality. High volume per surgeon was associated with improved mortality in only one of four studies (25%)., Conclusions: The studies were extremely heterogeneous, thus definitive conclusions cannot be drawn regarding optimal volume before a clear advantage in survival is observed. A prospective study defining volume as a continuous variable is warranted to support current admission criteria for American trauma patients., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Due to the heterogeneous nature of commercial human serum albumin (cHSA), other components, such as the protease dipeptidyl peptidase IV (DPP-IV), possibly contribute to the therapeutic effect of cHSA. Here, we provide evidence for the first time that DPP-IV activity contributes to the formation of aspartate-alanine diketopiperazine (DA-DKP), a known immunomodulatory molecule from the N terminus of human albumin. cHSA was assayed for DPP-IV activity using a specific DPP-IV substrate and inhibitor. DPP-IV activity was assayed at 37 and 60°C because cHSA solutions are pasteurized at 60°C. DPP-IV activity in cHSA was compared with other sources of albumin such as a recombinant albumin (rHSA). In addition, the production of DA-DKP was measured by negative electrospray ionization/liquid chromatography mass spectrometry (ESI(-)/LCMS). Significant levels of DPP-IV activity were present in cHSA. This activity was abolished using a specific DPP-IV inhibitor. Fully 70 to 80% DPP-IV activity remained at 60°C compared with the 37°C incubate. No DPP-IV activity was present in rHSA, suggesting that DPP-IV activity is present only in HSA produced using the Cohn fractionation process. The formation of DA-DKP at 60°C was observed with the DPP-IV inhibitor significantly decreasing this formation. DPP-IV activity in cHSA results in the production of DA-DKP, which could account for some of the clinical effects of cHSA., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Breakdown of endothelial barrier function is a hallmark event across a variety of pathologies such as inflammation, cancer, and diabetes. It has also been appreciated that steroid hormones impart direct biological activity on endothelial cells at many levels. The purpose of this investigation was to explore the effect of the androgen-like steroid, danazol, on endothelial cell barrier function in vitro. Primary human endothelial cells exposed to 0.01-50 μM danazol were evaluated for changes in permeability. We found that danazol altered endothelial permeability in a biphasic manner in which nanomolar concentrations enhance barrier function while micromolar concentrations are detrimental. Monitoring of trans-endothelial electrical resistance demonstrated that these barrier enhancing effects were rapid (within 5 min) and lasted for over 24h. Analysis of intracellular f-actin organization showed that barrier enhancement also correlated with the formation of a submembranous cortical actin ring. Conversely, at higher danazol concentrations, contractile cell phenotypes were observed, represented by stress fiber formation. Competitive binding studies performed using steroid hormone receptor antagonists proved that this activity is the result of androgen and estrogen receptor ligation. These findings suggest that low dose danazol may provide a therapeutic window for diseases involving vascular leakage., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The abbreviated injury scale (AIS) was updated in 2005 from the AIS 1998 version. The purpose of this study is to describe the effects of this change on injury severity scoring and outcome measures., Materials and Methods: Analyses were performed on all trauma patients consecutively admitted over a 6-month period at two geographically separate Level I trauma centers. Injuries were manually double-coded according to the AIS 05 and the AIS 98. Changes in AIS, ISS, and new ISS (NISS) were analysed using paired t-tests. Apparent differences in outcome by ISS strata (<16, 16-24, >24) were compared for AIS 05 versus AIS 98 using the Wald-type statistic. Lastly, the percent of patients with a change in ISS strata are reported., Results: There were 2250 patients included in the study. Nearly half (46.4%) of AIS codes changed, resulting in a different AIS score for 18.9% of all codes. The mean ISS was significantly lower using the AIS 05 (11.7) versus the AIS 98 (13.3, p<0.001). Similarly, the mean NISS was significantly lower (16.3 versus 18.7, p<0.001). In the ISS strata 16-24 an apparent increase in mortality, length of stay, and percent of patients not discharged home was observed for the AIS 05 versus AIS 98. Changes in outcome measures for this stratum were as follows (AIS 98 versus AIS 05): mortality, 4.3% versus 7.7% (p=0.002); hospital length of stay, 5.2 days versus 7.3 days (p<0.001); percent of patients not discharged home, 39.2% versus 49.3% (p<0.001). Finally, there was a 20.5% reduction in patients with an ISS>or=16 and a 26.2% reduction in patients with an ISS>or=25 using the AIS 05., Conclusions: The AIS revision had a significant impact on overall injury severity measures, clinical outcome measures, and percent of patients in each ISS strata. Therefore, the AIS revision affects the ability to directly compare data generated using AIS 05 and AIS 98 which has implications in trauma research, reimbursement and ACS accreditation.

Background: We previously hypothesized that the N-terminus of human serum albumin (HSA) is altered during ischemic events, thus establishing the foundation for the cobalt-HSA binding assay phenomenon. In this investigation, we attempt to clarify the mode of action of the cobalt-HSA binding assay by direct observations of cobalt binding to HSA., Methods: High pressure liquid chromatography coupled to positive electrospray ionization mass spectrometry (HPLC/MS) was used to study cobalt binding to HSA in the plasma of patients with and without evidence of myocardial ischemia., Results: Strong binding of cobalt to the N-terminus of HSA occurs at pH>7.0. No differences in cobalt binding to the N-terminus of HSA are observed in ischemic versus non-ischemic patients' plasma despite differences in the cobalt-HSA binding assay. Plasma free cysteine/cystine ratio appears to play a role in the quantitative response of the cobalt-HSA binding assay., Conclusions: The main determinants of the cobalt-HSA binding assay mechanism of action include but are not limited to: the proportion of intact N-terminus of HSA, HSA concentration, plasma cysteine/cystine ratio, plasma pH, and the state of oxidation of cys34 of HSA. Assay improvements that consider and take these factors into account could lead to an improved cobalt-HSA binding assay with greater clinical utility.

The amount of oxidative stress in severely traumatized patients is usually based on various individual parameters such as total antioxidants and lipid peroxidation. Serial measurements of plasma oxidation-reduction potential (ORP) in severely traumatized patients as a simple mean of assessing overall oxidative stress is described. Serial whole blood samples were obtained from multi-trauma patients (N=39) and healthy individuals (N=10). Plasma ORP in multi-trauma patients increased during the first few days of hospitalization and approached normal ORP levels upon discharge. On the ORP maxima day (5.8 days+/-0.5 SEM), a statistically significant decrease (p<0.05) was observed for negative acute phase reactants such as plasma paraoxonase-arylesterase (PON-AE) activity and total plasma protein in comparison with admission plasma levels. Monitoring ORP could be a useful tool for assessing the degree of oxidative stress, inflammation, severity of injury, and potential efficacy of treatment.

Introduction: Gaucher's disease (GD) is an inborn error, autosomal recessive lysosomal lipid storage disorder characterized by the lack of the enzyme glucocerebrosidase. We observed some abnormalities in the plasma of a traumatized patient with GD., Case Report: We report of a traumatized patient with GD that developed a severe systemic immune response during the course of an extended hospital stay. Plasma paraoxonase (PON) activity was assayed and found to be extremely low possibly due to the existence of GD in this particular patient. Also, a potentially novel post-translational modification (PTM) of albumin was noticed in the patient's plasma that coincided with enzyme replacement therapy (ERT) with Cerezyme., Conclusions: The decreased plasma PON activity measured might be a contributive factor in the development of an accentuated systemic immune response in a traumatized patient with GD. A modified albumin species could serve as a biomarker for ERT in Gaucher patients.

Introduction: Hypoalbuminemia is known to occur in critically ill patients and is associated with increased mortality. We observed a potentially novel, partial explanation for the hypoalbuminemia noticed in a severely traumatized patient., Case Report: We report of a severely, multi-system traumatized patient in whom hypoalbuminemia was present (1-2 g/dl). The plasma albumin (HSA) was analyzed by liquid chromatography/positive electrospray ionization mass spectrometry. A high percentage of a truncated albumin that lost its carboxy terminal amino acid leucine (HSA-L) associated with a 10-fold increase in plasma carboxypeptidase A (CPA) activity (R(2)=0.994) were found. We estimated the half life of this truncated albumin species to be <80 h., Conclusions: The increased CPA activity encountered following a traumatic event and subsequent rapid clearance of the resulting HSA-L from plasma might be a contributing factor to the hypoalbuminemia observed in the critically ill patients.