The why and how our trauma patients die: A prospective Multicenter Western Trauma Association study.

BACKGROUND: Historically, hemorrhage has been attributed as the leading cause (40%) of early death. However, a rigorous, real-time classification of the cause of death (COD) has not been performed. This study sought to prospectively adjudicate and classify COD to determine the epidemiology of trauma mortality. METHODS: Eighteen trauma centers prospectively enrolled all adult trauma patients at the time of death during December 2015 to August 2017. Immediately following death, attending providers adjudicated the primary and contributing secondary COD using standardized definitions. Data were confirmed by autopsies, if performed. RESULTS: One thousand five hundred thirty-six patients were enrolled with a median age of 55 years (interquartile range, 32-75 years), 74.5% were male. Penetrating mechanism (n = 412) patients were younger (32 vs. 64, p < 0.0001) and more likely to be male (86.7% vs. 69.9%, p < 0.0001). Falls were the most common mechanism of injury (26.6%), with gunshot wounds second (24.3%). The most common overall primary COD was traumatic brain injury (TBI) (45%), followed by exsanguination (23%). Traumatic brain injury was nonsurvivable in 82.2% of cases. Blunt patients were more likely to have TBI (47.8% vs. 37.4%, p < 0.0001) and penetrating patients exsanguination (51.7% vs. 12.5%, p < 0.0001) as the primary COD. Exsanguination was the predominant prehospital (44.7%) and early COD (39.1%) with TBI as the most common later. Penetrating mechanism patients died earlier with 80.1% on day 0 (vs. 38.5%, p < 0.0001). Most deaths were deemed disease-related (69.3%), rather than by limitation of further aggressive care (30.7%). Hemorrhage was a contributing cause to 38.8% of deaths that occurred due to withdrawal of care. CONCLUSION: Exsanguination remains the predominant early primary COD with TBI accounting for most deaths at later time points. Timing and primary COD vary significantly by mechanism. Contemporaneous adjudication of COD is essential to elucidate the true understanding of patient outcome, center performance, and future research. LEVEL OF EVIDENCE: Epidemiologic, level II.

Serendipitous discovery of novel bacterial methionine aminopeptidase inhibitors.

In this article we describe the application of structural biology methods to the discovery of novel potent inhibitors of methionine aminopeptidases. These enzymes are employed by the cells to cleave the N-terminal methionine from nascent peptides and proteins. As this is one of the critical steps in protein maturation, it is very likely that inhibitors of these enzymes may prove useful as novel antibacterial agents. Involvement of crystallography at the very early stages of the inhibitor design process resulted in serendipitous discovery of a new inhibitor class, the pyrazole-diamines. Atomic-resolution structures of several inhibitors bound to the enzyme illuminate a new mode of inhibitor binding.

Instillation of coarse ash particulate matter and lipopolysaccharide produces a systemic inflammatory response in mice.

Coronary ischemic events increase significantly following a "bad air" day. Ambient particulate matter (PM10) is the pollutant most strongly associated with these events. PM10 produces inflammatory injury to the lower airways. It is not clear, however, whether pulmonary inflammation translates to a systemic response. Lipopolysaccharide (LPS) is a proinflammatory molecule often associated with the coarse fraction of PM. It was hypothesized that PM>2.5 from coal plus LPS induce pulmonary inflammation leading to a systemic inflammatory response. Mice were intratracheally instilled with saline, PM (200 microg), PM + LPS10 (PM + 10 microg LPS), or PM + LPS100 (PM + 100 microg LPS). Eighteen hours later, histologic analysis was performed on lungs from each group. Pulmonary and systemic inflammation were assessed by measuring the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in the pulmonary supernatant and plasma. In a follow-up study, the effects of LPS alone were assessed. Histologic analysis revealed a dose-dependent elevation in pulmonary inflammation with all treatments. Pulmonary TNF-alpha and IL-6 both increased significantly with PM + LPS100 treatment. Regarding plasma, TNF-alpha significantly increased in both PM + LPS10 and PM + LPS100 treatments. For plasma IL-6, all groups tended to rise with a significant increase in the PM + LPS100 group. The results of the follow-up study indicate that the responses to PM + LPS were not due to LPS alone. These results suggest that coarse coal fly ash PM>2.5 combined with LPS produced pulmonary and systemic inflammatory responses. The resulting low-level systemic inflammation may contribute to the increased severity of ischemic heart disease observed immediately following a bad air day.

Racial/Ethnic Disparities in Rates of Traumatic Injury in Arizona, 2011-2012.

OBJECTIVE: The purpose of this study was to compare the rates of traumatic injury among five racial/ethnic groups in Arizona and to identify which mechanisms and intents of traumatic injury were predominant in each group. METHODS: We obtained 2011 and 2012 data on traumatic injury from Arizona's trauma registry and data on mortality from Arizona's death registry. We calculated location- and age-adjusted rates (aRs) of traumatic injury and rates of mortality per 100,000 Arizona residents and rate ratios (RRs) for each racial/ethnic group. We also calculated race/ethnicity specific aRs and RRs by mechanism of injury, intent of injury, and alcohol use. RESULTS: We analyzed data on 58,034 cases of traumatic injury. After adjusting for age and location, American Indians/Alaska Natives (AI/ANs) had the highest overall rate of traumatic injury (n = 6,287; aR = 729) and Asian Americans/Pacific Islanders had the lowest overall rate of traumatic injury (n = 553; aR = 141). By intent, AI/ANs had the highest rate of homicide/assault-related traumatic injury (n = 2,170; aR = 221) and by mechanism, non-Hispanic black/African American people had the highest rate of firearm-related traumatic injury (n = 265; aR = 40). In 2011-2012, 8,868 deaths in Arizona were related to traumatic injury. AI/ANs had the highest adjusted mortality rate (n = 716; aR = 95). CONCLUSION: Racial/ethnic disparities in traumatic injuries persisted after adjusting for age and injury location. Understanding how these disparities differ by mechanism, intent, and alcohol use may lead to the development of more effective initiatives to prevent traumatic injury.

The elimination of anastomosis in open trauma vascular reconstruction: A novel technique using an animal model.

BACKGROUND: The standard approach to vascular trauma involves arterial exposure and reconstruction using either a vein or polytetrafluoroethylene graft. We have developed a novel technique to repairing arterial injuries by deploying commercially available vascular stents through an open approach, thus eliminating the need for suture anastomosis. The objective of this study was to evaluate the feasibility, stent deployment time (SDT), and stent patency of this technique in a ewe vascular injury model. METHODS: After proximal and distal control, a 2-cm superficial femoral arterial segment was resected in 8 Dorper ewes to simulate an arterial injury. Two stay sutures were placed in the 3- and 9-o'clock positions of the transected arterial ends to prevent further retraction. Ten milliliters of 10-IU/mL heparinized saline was flushed proximally and distally. An arteriotomy was then created 2.5 cm from the transected distal end through which we deployed Gore Viabahn stents with a 20% oversize and at least 1-cm overlap with the native vessel on either end. The arteriotomy was then closed with 3 (1) interrupted 6-0 Prolene sutures. The ewes were fed acetylsalicylic acid 325 mg daily. Duplex was performed at 2 months postoperatively to evaluate stent patency. SDT was defined as time from stay suture placement to arteriotomy closure. RESULTS: The 8 ewes weighed a mean (SD) of 34.4 (4.3) kg. The mean (SD) superficial femoral arterial was 4.3 (0.6) mm. Six 5 mm × 5 cm and two 6 mm × 5 cm Gore Viabahn stents were deployed. The mean (SD) SDT was 34 (19) minutes, with a trend toward less time with increasing experience (SDTmax, 60 minutes; SDTmin, 10 minutes). Duplex performed at 2 months postoperatively showed stent patency in five of eight stents. There was an association between increasing SDT and stent thrombosis. CONCLUSION: Open deployment of commercially available vascular stents to treat vascular injuries is a conceptually sound and technically feasible alternative to standard open repair. Larger studies are needed to refine this technique and minimize stent complications, which are likely technical in nature.

Mechanism of insulin sensitization by BMOV (bis maltolato oxo vanadium); unliganded vanadium (VO4) as the active component.

Organovanadium compounds have been shown to be insulin sensitizers in vitro and in vivo. One potential biochemical mechanism for insulin sensitization by these compounds is that they inhibit protein tyrosine phosphatases (PTPs) that negatively regulate insulin receptor activation and signaling. In this study, bismaltolato oxovanadium (BMOV), a potent insulin sensitizer, was shown to be a reversible, competitive phosphatase inhibitor that inhibited phosphatase activity in cultured cells and enhanced insulin receptor activation in vivo. NMR and X-ray crystallographic studies of the interaction of BMOV with two different phosphatases, HCPTPA (human low molecular weight cytoplasmic protein tyrosine phosphatase) and PTP1B (protein tyrosine phosphatase 1B), demonstrated uncomplexed vanadium (VO(4)) in the active site. Taken together, these findings support phosphatase inhibition as a mechanism for insulin sensitization by BMOV and other organovanadium compounds and strongly suggest that uncomplexed vanadium is the active component of these compounds.

Cost savings with interventions to reduce aerosolized bronchodilator use in mechanically ventilated patients.

PURPOSE: The purpose of this evaluation is to describe the cost savings associated with multimodal interventions aimed at reducing aerosolized bronchodilator use in mechanically ventilated patients without adversely affecting costs associated with length of stay (LOS). MATERIALS AND METHODS: Subjects were included in the analysis if they were aged more than 18 years, on mechanical ventilation in the intensive care unit, and received aerosolized bronchodilators. Patients were excluded if they had reversible airway disease, an indication needing bronchodilator therapy. Patient data were obtained using the University Health System Consortium Clinical Data Base/Resource Manager (Chicago, IL) to compare outcomes during two 6-month periods separated by a 4-month intervention phase aimed to reduce bronchodilator use. RESULTS: There were no significant differences in age, sex, and LOS (observed and expected) between the preintervention and postintervention phases. Based on whole acquisition costs, the total cost of bronchodilators dispensed to the adult intensive care units over the 6-month postintervention phase was reduced by $56960 compared with the 6-month preintervention phase ($120562 vs $63602, respectively). CONCLUSIONS: Multimodal efforts to restrict aerosolized bronchodilator therapy in mechanically ventilated patients were successful and led to sustained reductions in use that was associated with substantial reductions in cost, without affecting LOS.

Engineering the catalytic domain of human protein tyrosine phosphatase beta for structure-based drug discovery.

Protein tyrosine phosphatases (PTPs) play roles in many biological processes and are considered to be important targets for drug discovery. As inhibitor development has proven challenging, crystal structure-based design will be very helpful to advance inhibitor potency and selectivity. Successful application of protein crystallography to drug discovery heavily relies on high-quality crystal structures of the protein of interest complexed with pharmaceutically interesting ligands. It is very important to be able to produce protein-ligand crystals rapidly and reproducibly for as many ligands as necessary. This study details our efforts to engineer the catalytic domain of human protein tyrosine phosphatase beta (HPTPbeta-CD) with properties suitable for rapid-turnaround crystallography. Structures of apo HPTPbeta-CD and its complexes with several novel small-molecule inhibitors are presented here for the first time.

Evaluation of [Co(gly)3]- as a 35Cl- NMR shift reagent for cellular studies.

We studied the efficacy of the tris-glycinatocobaltate(II) complex ([Co(gly)(3)](-)) as a shift reagent (SR) for chloride by (35)Cl NMR spectroscopy and compared to that of Co(2+)((aq)). Due to the relatively low thermodynamic stability of [Co(gly)(3)](-), a 1:3 Co(II)/gly stoichiometric solution at physiological pH is approximately a 2:1 mixture of [Co(gly)(2)(H(2)O)(2)] and [Co(gly)(H(2)O)(4)](+). This SR was found to be stable up to higher pH values than Co(2+)((aq)), better preventing Co(OH)(2) formation at alkaline pH. No significant differences in the (35)Cl(-) NMR chemical shift induced by Co(II)/gly or Co(2+)((aq)) were observed in the presence of physiological concentrations of either Ca(2+) or Mg(2+), or of either Na(+) or K(+). Although Co(2+)((aq)) was almost twice as effective as Co(II)/gly in shifting the (35)Cl(-) NMR resonance at the same high rho ([SR]/[Cl(-)]) value and low ionic strength, Co(2+)((aq)) showed a significant decrease (p < 0.05) in the (35)Cl(-) chemical shift at higher ionic strength. Line widths at half-height were significantly (p < 0.05) less for Co(II)/gly than for Co(2+)((aq)) at rho values in the range 0.066-0.40. Intracellular chloride was clearly detectable by (35)Cl NMR spectroscopy in human skin fibroblast cells suspended in medium containing 40 mM Co(II)/gly SR. We determined that, although Co(2+)((aq)) provides a larger shift than Co(II)/gly at the same rho value, there are significant advantages for using Co(II)/gly, such as pH stability, ionic strength independent chemical shifts, narrow (35)Cl(-) NMR resonances, and reduced cellular toxicity, as a SR in biological systems.

Solid-supported synthesis of putative peptide beta-turn mimetics via Ugi reaction for diketopiperazine formation.

The scope and limitations of the solid-supported synthesis of a bicyclic diketopiperazine, an internal, putative peptide beta-turn mimetic, are presented. The 4CC multicomponent Ugi reaction of alpha-N-Boc-diaminopropionic acid resin ester (an amine input), optically active alpha-bromoacid, aldehyde, and isocyanide is the key step in the proposed synthetic protocol. Application of cyclitive cleavage as the final step led to desired products in high purity.