Outcomes of truncal vascular injuries in children.

BACKGROUND: Pediatric truncal vascular injuries occur infrequently and have a reported mortality rate of 30% to 50%. This report examines the demographics, mechanisms of injury, associated trauma, and outcome of patients presenting for the past 10 years at a single institution with truncal vascular injuries. METHODS: A retrospective review (1997-2006) of a pediatric trauma registry at a single institution was undertaken. RESULTS: Seventy-five truncal vascular injuries occurred in 57 patients (age, 12 +/- 3 years); the injury mechanisms were penetrating in 37%. Concomitant injuries occurred with 76%, 62%, and 43% of abdominal, thoracic, and neck vascular injuries, respectively. Nonvascular complications occurred more frequently in patients with abdominal vascular injuries who were hemodynamically unstable on presentation. All patients with thoracic vascular injuries presenting with hemodynamic instability died. In patients with neck vascular injuries, 1 of 2 patients who were hemodynamically unstable died, compared to 1 of 12 patients who died in those who presented hemodynamically stable. Overall survival was 75%. CONCLUSIONS: Survival and complications of pediatric truncal vascular injury are related to hemodynamic status at the time of presentation. Associated injuries are higher with trauma involving the abdomen.

Trends in utilization of computer tomography (CT) scans for victims of motor vehicle collision (MVCs) in a level I trauma center from 1996 to 2006

Purpose. To evaluate trends in the utilization of head, abdominal, thoracic and other body regions CTs in the management of victims of MVC at a level I trauma center from 1996 to 2006.^ Method. From the trauma registry, I identified patients involved in MVC's in a level I trauma center and categorized them into three age groups of 13-18, 19-55 and ≥56. I used International Classification of Disease (ICD-9-CM) codes to find the type and number of CTs examinations performed for each patient. I plotted the mean number of CTs per patient against year of admission to find the crude estimate of change in utilization pattern for each type of CT. I used logistic regression to assess whether repetitive CTs (≥ 2) for head, abdomen, thorax and other body regions were associated with age group and year of admission for MVC patients. I adjusted the estimates for gender, ethnicity, insurance status, mechanism and severity of injury, intensive care unit admission status, patient disposition (dead or alive) and year of admission.^ Results. Utilization of head, abdominal, thoracic and other body regions CTs significantly increased over 11-year period. Utilization of head CT was greatest in the 13-18 age group, and increased from 0.58 CT/patient in 1996 to 1.37 CT/patient in 2006. Abdominal CTs were more common in the ≥56+ age group, and increased from 0.33 CT/patient in 1996 to 0.72 CT/patient in 2006. Utilization of thoracic CTs was higher in the 56+ age group, and increased from 0.01 CT/patient in 1996 to 0.42 CT/patient in 2006. Utilization of other CTs did not change materially during the study period for adolescents, adults or older adults. In the multivariable analysis, after adjustment for potential confounders, repetitive head CTs significantly increased in the 13-18 age group (95% CI: 1.29-1.87, p=<0.001) relative to the 19-55 age group. Repetitive thoracic CT use was lower in adolescents (95% CI: 0.22-0.70, p=<0.001) relative to the 19-55 age group.^ Conclusion. There has been a substantial increase in the utilization of head, abdominal, thoracic and other CTs in the management of MVC patients. Future studies need to identify if increased utilization of CTs have resulted in better health outcome for these patients. ^

Penetrating injuries of the thorax and abdomen: Type of medical-care institution and case fatality

The purpose of this study was to determine, for penetrating injuries (gunshot, stab) of the chest/abdomen, the impact on fatality of treatment in trauma centers and shock trauma units compared with general hospitals. Medical records of all cases of penetrating injury limited to chest/abdomen and admitted to and discharged from 7 study facilities in Baltimore city 1979-1980 (n = 581) were studied: 4 general hospitals (n = 241), 2 area-wide trauma centers (n = 298), and a shock trauma unit (n = 42). Emergency center and transferred cases were not studied. Anatomical injury severity, measured by modified Injury Severity Score (mISS), was a significant prognostic factor for death, as were cardiovascular shock (SBP $\le$ 70), injury type (gunshot vs stab), and ambulance/helicopter (vs other) transport. All deaths occurred in cases with two or more prognostic factors. Unadjusted relative risks of death compared with general hospitals were 4.3 (95% confidence interval = 2.2, 8.4) for shock trauma and 0.8 (0.4, 1.7) for trauma centers. Controlling for prognostic factors by logistic regression resulted in these relative risks: shock trauma 4.0 (0.7, 22.2), and trauma centers 0.8 (0.2, 3.2). Factors significantly associated with increased risk had the following relative risks by multiple logistic regression: SBP $\le$ 70 (RR = 40.7 (11.0, 148.7)), highest mISS (42 (7.7, 227)), gunshot (8.4 (2.1, 32.6)), and ambulance/helicopter transport (17.2 (1.3, 228.1)). Controlling for age, race, and gender did not alter results significantly. Actual deaths compared with deaths predicted from a multivariable model of general-hospital cases showed 3.7 more than predicted deaths in shock trauma (SMR = 1.6 (0.8, 2.9)) and 0.7 more than predicted deaths in area-wide trauma centers (SMR = 1.05 (0.6, 1.7)). Selection bias due to exclusion of transfers and emergency center cases, and residual confounding due to insufficient injury information, may account for persistence of adjusted high case fatality in shock trauma. Studying all cases prospectively, including emergency center and transferred cases, is needed. ^

Thoracic radiotherapy treatment planning with cine PET/CT

Purpose: Respiratory motion causes substantial uncertainty in radiotherapy treatment planning. Four-dimensional computed tomography (4D-CT) is a useful tool to image tumor motion during normal respiration. Treatment margins can be reduced by targeting the motion path of the tumor. The expense and complexity of 4D-CT, however, may be cost-prohibitive at some facilities. We developed an image processing technique to produce images from cine CT that contain significant motion information without 4D-CT. The purpose of this work was to compare cine CT and 4D-CT for the purposes of target delineation and dose calculation, and to explore the role of PET in target delineation of lung cancer. Methods: To determine whether cine CT could substitute 4D-CT for small mobile lung tumors, we compared target volumes delineated by a physician on cine CT and 4D-CT for 27 tumors with intrafractional motion greater than 1 cm. We assessed dose calculation by comparing dose distributions calculated on respiratory-averaged cine CT and respiratory-averaged 4D-CT using the gamma index. A threshold-based PET segmentation model of size, motion, and source-to-background was developed from phantom scans and validated with 24 lung tumors. Finally, feasibility of integrating cine CT and PET for contouring was assessed on a small group of larger tumors. Results: Cine CT to 4D-CT target volume ratios were (1.05±0.14) and (0.97±0.13) for high-contrast and low-contrast tumors respectively which was within intraobserver variation. Dose distributions on cine CT produced good agreement (< 2%/1 mm) with 4D-CT for 71 of 73 patients. The segmentation model fit the phantom data with R2 = 0.96 and produced PET target volumes that matched CT better than 6 published methods (-5.15%). Application of the model to more complex tumors produced mixed results and further research is necessary to adequately integrate PET and cine CT for delineation. Conclusions: Cine CT can be used for target delineation of small mobile lesions with minimal differences to 4D-CT. PET, utilizing the segmentation model, can provide additional contrast. Additional research is required to assess the efficacy of complex tumor delineation with cine CT and PET. Respiratory-averaged cine CT can substitute respiratory-averaged 4D-CT for dose calculation with negligible differences.

Interruptions in Workflow for RNs in a Level One Trauma Center

An understanding of interruptions in healthcare is important for the design, implementation, and evaluation of health information systems and for the management of clinical workflow and medical errors. The purpose of this study is to identify and classify the types of interruptions experienced by Emergency Department(ED) nurses working in a Level One Trauma Center. This was an observational field study of Registered Nurses (RNs) employed in a Level One Trauma Center using the shadowing method. Results of the study indicate that nurses were both recipients and initiators of interruptions. Telephones, pagers, and face-to-face conversations were the most common sources of interruptions. Unlike other industries, the healthcare community has not systematically studied interruptions in clinical settings to determine and weigh the necessity of the interruption against their sometimes negative results such as medical errors, decreased efficiency, and increased costs. Our study presented here is an initial step to understand the nature, causes, and effects of interruptions, thereby improving both the quality of healthcare and patient safety. We developed an ethnographic data collection technique and a data coding method for the capturing and analysis of interruptions. The interruption data we collected are systematic, comprehensive, and close to exhaustive. They confirmed the findings from earlier studies by other researchers that interruptions are frequent events in critical care and other healthcare settings. We are currently using these data to analyze the workflow dynamics of ED clinicians, to identify the bottlenecks of information flow, and to develop interventions to improve the efficiency of emergency care through the management of interruptions.

Interruptions in workflow for RNs in a Level One Trauma Center.

An understanding of interruptions in healthcare is important for the design, implementation, and evaluation of health information systems and for the management of clinical workflow and medical errors. The purpose of this study is to identify and classify the types of interruptions experienced by ED nurses working in a Level One Trauma Center. This was an observational field study of Registered Nurses employed in a Level One Trauma Center using the shadowing method. Results of the study indicate that nurses were both recipients and initiators of interruptions. Telephone, pagers, and face-to-face conversations were the most common sources of interruptions. Unlike other industries, the outcomes caused by interruptions resulting in medical errors, decreased efficiency and increased cost have not been systematically studied in healthcare. Our study presented here is an initial step to understand the nature, causes, and effects of interruptions, and to develop interventions to manage interruptions to improve healthcare quality and patient safety. We developed an ethnographic data collection technique and a data coding method for the capturing and analysis of interruptions. The interruption data we collected are systematic, comprehensive, and close to exhaustive. They confirmed the findings from early studies by other researchers that interruptions are frequent events in critical care and other healthcare settings. We are currently using these data to analyze the workflow dynamics of ED clinicians, identify the bottlenecks of information flow, and develop interventions to improve the efficiency of emergency care through the management of interruptions.

Thoracic target volume delineation using various maximum-intensity projection computed tomography image sets for stereotactic body radiation therapy

The motion of lung tumors during respiration makes the accurate delivery of radiation therapy to the thorax difficult because it increases the uncertainty of target position. The adoption of four-dimensional computed tomography (4D-CT) has allowed us to determine how a tumor moves with respiration for each individual patient. Using information acquired during a 4D-CT scan, we can define the target, visualize motion, and calculate dose during the planning phase of the radiotherapy process. One image data set that can be created from the 4D-CT acquisition is the maximum-intensity projection (MIP). The MIP can be used as a starting point to define the volume that encompasses the motion envelope of the moving gross target volume (GTV). Because of the close relationship that exists between the MIP and the final target volume, we investigated four MIP data sets created with different methodologies (3 using various 4D-CT sorting implementations, and one using all available cine CT images) to compare target delineation. It has been observed that changing the 4D-CT sorting method will lead to the selection of a different collection of images; however, the clinical implications of changing the constituent images on the resultant MIP data set are not clear. There has not been a comprehensive study that compares target delineation based on different 4D-CT sorting methodologies in a patient population. We selected a collection of patients who had previously undergone thoracic 4D-CT scans at our institution, and who had lung tumors that moved at least 1 cm. We then generated the four MIP data sets and automatically contoured the target volumes. In doing so, we identified cases in which the MIP generated from a 4D-CT sorting process under-represented the motion envelope of the target volume by more than 10% than when measured on the MIP generated from all of the cine CT images. The 4D-CT methods suffered from duplicate image selection and might not choose maximum extent images. Based on our results, we suggest utilization of a MIP generated from the full cine CT data set to ensure a representative inclusive tumor extent, and to avoid geometric miss.

CHARACTERIZING A NOVEL GENETIC LOCUS ASSOCIATED WITH FAMILIAL CO-OCCURRENCE OF THORACIC AORTIC ANEURYSMS AND INTRACRANIAL ANEURYSMS

The Mendelian inheritance of genetic mutations can lead to adult-onset cardiovascular disease. Several genetic loci have been mapped for the familial form of Thoracic Aortic Aneurysms (TAA), and many causal mutations have been identified for this disease. Intracranial Aneurysms (ICA) also show linkage heterogeneity, but no mutations have been identified causing familial ICA alone. Here, we characterized a large family (TAA288) with an autosomal dominant pattern of inherited aneurysms. It is intriguing that female patients predominantly present with ICA and male patients predominantly with TAA in this family. To identify a causal mutation in this family, a genome-wide linkage analysis was previously performed on nine members of this family using the 50k GenChips Hind array from Affymetrix. This analysis eventually identified a single disease-segregating locus, on chromosome 5p15. We build upon this previous analysis in this study, hypothesizing that a genetic mutation inherited in this locus leads to the sex-specific phenotype of TAA and ICA in this family First we refined the boundaries of the 5p15 disease linked locus down to the genomic coordinates 5p15: 3,424,465- 6,312,925 (GRCh37/hg19 Assembly). This locus was named the TAA288 critical interval. Next, we sequenced candidate genes within the TAA288 critical interval. The selection of genes was simplified by the relatively small number of well-characterized genetic elements within the region. Seeking novel or rare disease-segregating variants, we initially observed a single point alteration in the metalloproteinase gene ADAMTS16 fulfilling this criteria. This variant was later classified as a low-frequency population polymorphism (rs72647757), but we continued to explore the potential role of the ADAMTS16 as the cause of disease in TAA288. We observed that fibroblasts cultured from TAA288 patients consistently upregulated the expression of this gene more strongly compared to matched control fibroblasts when treated with the cytokine TGF-β1, though there was some variation in the exact nature of this expression. We also observed evidence that this protein is expressed at elevated levels in aortic aneurysm tissue from patients with mutations in the gene TGFBR2 and Marfan syndrome, shown by immunohistochemical detection of this protein.

Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms.

OBJECTIVE: This study sought to characterize the inflammatory infiltrate in ascending thoracic aortic aneurysm in patients with Marfan syndrome, familial thoracic aortic aneurysm, or nonfamilial thoracic aortic aneurysm. BACKGROUND: Thoracic aortic aneurysms are associated with a pathologic lesion termed "medial degeneration," which is described as a noninflammatory lesion. Thoracic aortic aneurysms are a complication of Marfan syndrome and can be inherited in an autosomal dominant manner of familial thoracic aortic aneurysm. METHODS: Full aortic segments were collected from patients undergoing elective repair with Marfan syndrome (n = 5), familial thoracic aortic aneurysm (n = 6), and thoracic aortic aneurysms (n = 9), along with control aortas (n = 5). Immunohistochemistry staining was performed using antibodies directed against markers of lymphocytes and macrophages. Real-time polymerase chain reaction analysis was performed to quantify the expression level of the T-cell receptor beta-chain variable region gene. RESULTS: Immunohistochemistry of thoracic aortic aneurysm aortas demonstrated that the media and adventitia from Marfan syndrome, familial thoracic aortic aneurysm, and sporadic cases had increased numbers of T lymphocytes and macrophages when compared with control aortas. The number of T cells and macrophages in the aortic media of the aneurysm correlated inversely with the patient's age at the time of prophylactic surgical repair of the aorta. T-cell receptor profiling indicated a similar clonal nature of the T cells in the aortic wall in a majority of aneurysms, whether the patient had Marfan syndrome, familial thoracic aortic aneurysm, or sporadic disease. CONCLUSION: These results indicate that the infiltration of inflammatory cells contributes to the pathogenesis of thoracic aortic aneurysms. Superantigen-driven stimulation of T lymphocytes in the aortic tissues of patients with thoracic aortic aneurysms may contribute to the initial immune response.

Thoracic aortic disease in tuberous sclerosis complex: molecular pathogenesis and potential therapies in Tsc2+/- mice.

Tuberous sclerosis complex (TSC) is a genetic disorder with pleiotropic manifestations caused by heterozygous mutations in either TSC1 or TSC2. One of the less investigated complications of TSC is the formation of aneurysms of the descending aorta, which are characterized on pathologic examination by smooth muscle cell (SMC) proliferation in the aortic media. SMCs were explanted from Tsc2(+/-) mice to investigate the pathogenesis of aortic aneurysms caused by TSC2 mutations. Tsc2(+/-) SMCs demonstrated increased phosphorylation of mammalian target of rapamycin (mTOR), S6 and p70S6K and increased proliferation rates compared with wild-type (WT) SMCs. Tsc2(+/-) SMCs also had reduced expression of SMC contractile proteins compared with WT SMCs. An inhibitor of mTOR signaling, rapamycin, decreased SMC proliferation and increased contractile protein expression in the Tsc2(+/-) SMCs to levels similar to WT SMCs. Exposure to alpha-elastin fragments also decreased proliferation of Tsc2(+/-) SMCs and increased levels of p27(kip1), but failed to increase expression of contractile proteins. In response to artery injury using a carotid artery ligation model, Tsc2(+/-) mice significantly increased neointima formation compared with the control mice, and the neointima formation was inhibited by treatment with rapamycin. These results demonstrate that Tsc2 haploinsufficiency in SMCs increases proliferation and decreases contractile protein expression and suggest that the increased proliferative potential of the mutant cells may be suppressed in vivo by interaction with elastin. These findings provide insights into the molecular pathogenesis of aortic disease in TSC patients and identify a potential therapeutic target for treatment of this complication of the disease.

The genetic basis of thoracic aortic aneurysms and dissections: Genetic heterogeneity and mapping of TAAD1 and TAAD2 loci

Thoracic aortic aneurysms leading to aortic dissections (TAAD) are a major cause of morbidity and mortality in the United States. TAAD is a complication of some known genetic disorders, such as Marfan syndrome and Turner syndrome, but the majority of familial cases are not due to a known genetic syndrome. Previous studies by our group have established that nonsyndromic, familial TAAD is inherited in an autosomal dominant manner with decreased penetrance and variable expression. Using one large family with multiple members with TAAD for the genome wide scan, a major locus for familial TAAD was mapped to 5q13–14 (TAAD1). Nine out of 15 families studied were linked to this locus, establishing that TAAD1 was a major locus, and that there was genetic heterogeneity for the condition. Mapping of TAAD2 locus was accomplished using a single large family with multiple members with TAAD not linked to known loci of aneurysm formation. This established a second novel locus for familial TAAD on 3p24–25 (LOD score of 4.3), termed the TAAD2 locus. Two putative loci with suggestive LOD scores were mapped on 4q and 12q through a genome scan carried out using three families. TAAD phenotype in 12 families did not segregate with known loci, indicating further genetic heterogeneity. An STS-tagged BAC based contig was constructed for 7.8Mb and 25Mb critical interval of TAAD1 and TAAD2 respectively and characterized to identify the defective gene. The hypothesis that the defective genes responsible for the TAAD1 and TAAD2 encoded extracellular matrix (ECM) proteins, the major components of the elastic fiber system in the aortic media was tested. Four genes encoding ECM proteins, versican, thrombospondin-3, CRTL1, on TAAD1 and FBLN2 at TAAD2 were sequenced, but no disease-causing mutations were identified. Studies to identify the defective gene are initiated through the positional candidate gene approach using combination of bioinformatics and expression studies. The identification of the TAAD susceptibility genes will allow for presymptomatic diagnosis of individuals at risk for this life threatening disease. The identification of the molecular defects that contribute to TAAD will also further our understanding of the proteins that provide structural integrity to the aortic wall. ^

Assessing the need and options available for trauma physician funding in Texas

Efforts have been made to provide supplemental funding to emergency departments to offset the costs of uncompensated medical care. But a problem exists within the trauma system in Texas that has largely been overlooked by the state. This project will focus on the lack of funding available to physicians and on-call specialists who contract with hospitals to provide emergency care. ^ A lack of funding and reimbursement for emergency care is directly influencing the number of medical specialists willing to provide emergency treatment in hospitals on a contractual basis. A shortage of emergency physicians has an impact on the public health of all Texans who may need trauma care in a hospital. Specifically, a shortage of emergency physicians can lead to a complete denial of specialty emergency health care, a delay in patient treatment, and increased ambulance diversions. Quality and access barriers to emergency services undoubtedly threaten the stability of the trauma care system in Texas and the health status of its citizens. ^ In 2003, Texas took a significant step towards addressing the issue of uncompensated care provided by the trauma system and passed House Bill 3588, creating the Trauma Facilities and Emergency Medical Services Fund (“the Trauma Fund”). However, the primary shortfall to this legislation is that the Trauma Fund is only available to emergency medical service providers and hospitals. The Trauma Fund does little to help offset the cost incurred by contracting physicians and on-call specialists who provide emergency services to the uninsured. ^ This paper addresses how funding shortages for emergency department physicians negatively impact the trauma care system in Texas and the policy options available to create physician funding to offset the cost of uncompensated trauma care. Ultimately this paper concludes that although creating a new funding stream similar to the actions taken in other states would be a dramatic step towards addressing the problem, the political process in Texas may slow implementation of this option. Consequently, modifying existing legislation, although the weaker of the options, may be more attractive to those looking for immediate action. ^

The Texas driver responsibility program: A preliminary analysis of the impact on impaired driving and trauma system funding

Objective. In 2003, the State of Texas instituted the Driver Responsibility Program (TDRP), a program consisting of a driving infraction point system coupled with a series of graded fines and annual surcharges for specific traffic violations such as driving while intoxicated (DWI). Approximately half of the revenues generated are earmarked to be disbursed to the state's trauma system to cover uncompensated trauma care costs. This study examined initial program implementation, the impact of trauma system funding, and initial impact on impaired driving knowledge, attitudes and behaviors. A model for targeted media campaigns to improve the program's deterrence effects was developed. ^ Methods. Data from two independent driver survey samples (conducted in 1999 and 2005), department of public safety records, state health department data and a state auditor's report were used to evaluate the program's initial implementation, impact and outcome with respect to drivers' impaired driving knowledge, attitudes and behavior (based on constructs of social cognitive theory) and hospital uncompensated trauma care funding. Survey results were used to develop a regression model of high risk drivers who should be targeted to improve program outcome with respect to deterring impaired driving. ^ Results. Low driver compliance with fee payment (28%) and program implementation problems were associated with lower surcharge revenues in the first two years ($59.5 million versus $525 million predicted). Program revenue distribution to trauma hospitals was associated with a 16% increase in designated trauma centers. Survey data demonstrated that only 28% of drivers are aware of the TDRP and that there has been no initial impact on impaired driving behavior. Logistical regression modeling suggested that target media campaigns highlighting the likelihood of DWI detection by law enforcement and the increased surcharges associated with the TDRP are required to deter impaired driving. ^ Conclusions. Although the TDRP raised nearly $60 million in surcharge revenue for the Texas trauma system over the first two years, this study did not find evidence of a change in impaired driving knowledge, attitudes or behaviors from 1999 to 2005. Further research is required to measure whether the program is associated with decreased alcohol-related traffic fatalities. ^

Trauma care capacity and performance in Texas: Regional comparisons

Objective. The study reviewed one year of Texas hospital discharge data and Trauma Registry data for the 22 trauma services regions in Texas to identify regional variations in capacity, process of care and clinical outcomes for trauma patients, and analyze the statistical associations among capacity, process of care, and outcomes. ^ Methods. Cross sectional study design covering one year of state-wide Texas data. Indicators of trauma capacity, trauma care processes, and clinical outcomes were defined and data were collected on each indicator. Descriptive analyses were conducted of regional variations in trauma capacity, process of care, and clinical outcomes at all trauma centers, at Level I and II trauma centers and at Level III and IV trauma centers. Multilevel regression models were performed to test the relations among trauma capacity, process of care, and outcome measures at all trauma centers, at Level I and II trauma centers and at Level III and IV trauma centers while controlling for confounders such as age, gender, race/ethnicity, injury severity, level of trauma centers and urbanization. ^ Results. Significant regional variation was found among the 22 trauma services regions across Texas in trauma capacity, process of care, and clinical outcomes. The regional trauma bed rate, the average staffed bed per 100,000 varied significantly by trauma service region. Pre-hospital trauma care processes were significantly variable by region---EMS time, transfer time, and triage. Clinical outcomes including mortality, hospital and intensive care unit length of stay, and hospital charges also varied significantly by region. In multilevel regression analysis, the average trauma bed rate was significantly related to trauma care processes including ambulance delivery time, transfer time, and triage after controlling for age, gender, race/ethnicity, injury severity, level of trauma centers, and urbanization at all trauma centers. Transfer time only among processes of care was significant with the average trauma bed rate by region at Level III and IV. Also trauma mortality only among outcomes measures was significantly associated with the average trauma bed rate by region at all trauma centers. Hospital charges only among outcomes measures were statistically related to trauma bed rate at Level I and II trauma centers. The effect of confounders on processes and outcomes such as age, gender, race/ethnicity, injury severity, and urbanization was found significantly variable by level of trauma centers. ^ Conclusions. Regional variation in trauma capacity, process, and outcomes in Texas was extensive. Trauma capacity, age, gender, race/ethnicity, injury severity, level of trauma centers and urbanization were significantly associated with trauma process and clinical outcomes depending on level of trauma centers. ^ Key words: regionalized trauma systems, trauma capacity, pre-hospital trauma care, process, trauma outcomes, trauma performance, evaluation measures, regional variations ^

Mechanotransduction pathway activation in familial thoracic aortic aneurysms and dissections

Thoracic aortic aneurysms and dissections (TAAD) are autosomal dominantly inherited in 19% of patients. Mapping studies determined that the disease is genetically heterogeneous with multiple loci and genetic mutations accounting for familial TAAD. However, regardless of the specific mutation, resulting pathology is consistently medial degeneration, characterized by increased proteoglycans and loss of elastic fibers. We tested the hypothesis that genetic mutations leading to familial TAAD alter common pathways in aortic smooth muscle cells (SMCs). Identification of mutations at R460 in TGFBR2 reveals a 5% contribution to TAAD, however downstream analysis of Smad2 phosphorylation in the TGF-β pathway is not commonly altered in familial or sporadic disease when compared to controls. Expression profiling using Illumina's Sentrix HumanRef 8 Expression Beadchip array was done on RNA isolated from SMCs explanted from 6 patients with inherited TAAD with no identified mutation and 3 healthy controls obtained from the International Institute for the Advancement of Medicine. Significant increases in expression of proteoglycan genes in patients' SMCs, specifically lumican, podocan, and decorin were confirmed using Q-PCR and tissue immunofluorescence. NCI's Ingenuity Pathway Analysis predicted alterations in the ERK, insulin receptor and SAPK/JNK pathways (p<0.001), which SMCs activate in response to cyclic stretch. Immunoblotting indicated increased phosphorylation of ERK and GSK-3β, a protein from the insulin receptor pathway, in explanted patient SMCs, also confirmed by increased immunoreactivity against phosphorylated ERK and GSK-3β in the sub-intimal SMCs from patient tissue compared to controls. To determine if mechanotransduction pathway activation was responsible for the medial degeneration a specific inhibitor of GSK-3β, SB216763 was incubated with control cells and significantly increased the expression levels of proteoglycans. Mechanical strain was also applied to control SMCs confirming pathways stimulation with stretch. Incubation with pathway inhibitors against insulin receptor and ERK pathways identify, for the first time that stretch induced GSK-3β phosphorylation may increase proteoglycan expression, and ERK phosphorylation may regulate the expression of MMP2, a protein known to degrade elastic fibers. Furthermore, specific mutations in SMC-specific β-myosin heavy chain and α-actin, in addition to upregulation of pathways activated by cyclic stretch suggest that SMC response to hemodynamic factors, play a role in this disease. ^