Faculty publications - Department of Surgery

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    AutoImplant 2020-First MICCAI Challenge on Automatic Cranial Implant Design
    (2021-09) Li, Jianning; Pimentel, Pedro; Szengel, Angelika; Ehlke, Moritz; Lamecker, Hans; Zachow, Stefan; Estacio, Laura; Doenitz, Christian; Ramm, Heiko; Shi, Haochen; Chen, Xiaojun; Matzkin, Franco; Newcombe, Virginia; Ferrante, Enzo; Jin, Yuan; Ellis, David G; Aizenberg, Michele R; Kodym, Oldrich; Spanel, Michal; Herout, Adam; Mainprize, James G; Fishman, Zachary; Hardisty, Michael R; Bayat, Amirhossein; Shit, Suprosanna; Wang, Bomin; Liu, Zhi; Eder, Matthias; Pepe, Antonio; Gsaxner, Christina; Alves, Victor; Zefferer, Ulrike; von Campe, Gord; Pistracher, Karin; Schafer, Ute; Schmalstieg, Dieter; Menze, Bjoern H; Glocker, Ben; Egger, Jan
    The aim of this paper is to provide a comprehensive overview of the MICCAI 2020 AutoImplant Challenge. The approaches and publications submitted and accepted within the challenge will be summarized and reported, highlighting common algorithmic trends and algorithmic diversity. Furthermore, the evaluation results will be presented, compared and discussed in regard to the challenge aim: seeking for low cost, fast and fully automated solutions for cranial implant design. Based on feedback from collaborating neurosurgeons, this paper concludes by stating open issues and post-challenge requirements for intra-operative use. The codes can be found at https://github.com/Jianningli/tmi.
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    A U-Net Based System for Cranial Implant Design with Pre-processing and Learned Implant Filtering
    (2021) Mahdi, Hamza; Clement, Allison; Kim, Evan; Fishman, Zachary; Whyne, Cari M.; Mainprize, James G.; Hardisty, Michael R.
    Craniomaxillofacial skeletal (CMFS) reconstructive surgeries require patient specific implants that reproduce pre-injury 3D geometries, often pre-injury geometry is not available and the implant design must be estimated from the remaining skull that contains defects. A pipeline was created to automate patient specific implant design geometries suitable for post-injury segmentations. This investigation was done as part of the MICCAI AutoImplant Grand Challenge 2021. The challenge included two datasets; SkullBreak (clinically representative synthetic defects) and SkullFix (uniform synthetic defects). The developed pipeline consisted of: cropping the skull geometry, prediction of intact skull geometry using a U-Net style encoder/decoder, binary subtraction of the predicted intact skull and defect skull to create a candidate implant, and post processing filtering. Changes in performance of the algorithm were investigated by varying 3 stages within the workflow: pre-processing, the dataset used to train the U-Net, and the post-processing filtering (spherical topological, or a U-Net trained filtering network). The dataset used for training had the largest effect on the performance of the algorithm, with the SkullBreak trained networks generalizing better than the SkullFix trained algorithms. The spherical topological post process filtering was comparable to a network trained to filter the implant directly. The image cropping method also influenced the final predictive results. Our best performing model for the Task 3 test sets had a DSC = 0.88±0.14 . The trained algorithms present a useful step towards an automated pipeline for generating implants, suitable for integration into a clinical pipeline that could increase reconstruction fidelity and dramatically decrease the cost of design
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    Shape Completion by U-Net: An Approach to the AutoImplant MICCAI Cranial Implant Design Challenge
    (2020) Mainprize, James G.; Fishman, Zachary; Hardisty, Michael R.
    Reconstruction of the craniomaxillofacial (CMF) skeleton requires patient specific implants that restore cosmesis and protect the neural structures. Designing 3D patient specific geometries is challenging and labor intensive because of the lack of pre-injury information. We present an automated shape completion framework for the MICCAI AutoImplant Challenge 2020. The automated workflow selected standardized segmented skull volumes from the skull base to the apex. A U-Net style encoder/decoder framework was used to create the predictive model. The training data consisted of defective skulls with matched intact skulls. The challenge training set (100 cases) was augmented by randomly placed cubic and spherical defects on the same 100 cases for a total of 300 samples split 75/25% by case into a training and validation set. Probability volumes of the predicted skulls were generated by the U-Net and segmented to create an intact skull. Subtraction with defect skulls was used to isolate the implant geometry and were denoised with a connected region extraction of the single largest object, followed by a spherical topological filter. Dice Score (DSC) was 0.86 and Hausdorff distance (HD) was 14.2 mm for the validation set of 25 skulls (×3 defect types). Filtering improved the predicted implants with DSC of 0.87 and HD of 6.72. The automated pipeline for generating implants, produced geometries suitable for integration into a clinical pipeline that could dramatically decrease design time, cost, and increase reconstruction accuracy.
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    Expression of VEGF gene isoforms in a rat segmental bone defect model treated with EPCs
    (Lippincott, Williams & Wilkins, 2012-12-26) Li, Ru; Nauth, Aaron; Li, Claire; Qamirani, Erion; Atesok, Kivanc; Schemitsch, Emil H
    Angiogenesis and osteogenesis are essential for bone growth, fracture repair, and bone remodeling. Vascular endothelial growth factor (VEGF) has an important role in bone repair by promoting angiogenesis and osteogenesis. In our previous study, endothelial progenitor cells (EPCs) promoted bone healing in a rat segmental bone defect as confirmed by radiological, histological, biomechanical and microCT evaluations. While EPCs have demonstrated effectiveness in animal models of fracture healing, the mechanism by which EPCs enhance fracture healing remains unclear. We hypothesized a possible paracrine mechanism of action, where the secretion of growth factors critical to the processes of fracture healing (such as VEGF), is responsible for the positive effects of EPC therapy. The purpose of this study was to evaluate VEGF gene expression after local EPC therapy for a rat segmental bone defect. Methods: Rat bone marrow-derived EPCs were isolated by the Ficoll-paque gradient centrifuge technique. The EPCs were cultured for 7 to 10 days in endothelial cell growth medium with supplements and collected for treatment of the rat segmental bone defect. EPCs were identified by immunocytochemistry staining with primary antibodies for CD34, CD133, FLK-1, and vWF. A total of fifty six rats were studied. A five millimeter segmental bone defect was created in the middle 1/3 of each femur followed by mini plate fixation. The treatment group received 1x106 EPCs locally at the bone defect on a gelfoam scaffold and control animals received the gelfoam scaffold only. Seven control and seven EPC treated rats were included in each group at 1, 2, 3 and 10 weeks. Animals were sacrificed at the end of the treatment period, and specimens from the fracture gap 4 area were collected and immediately frozen. Rat VEGF mRNA was measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and quantified by VisionWorksLS. All measurements were performed in triplicate. Results: Cultured EPCs at 1 week showed positive staining for CD34, CD133, Flk-1 and vWf markers. The EPC group had a greater VEGF expression than the control group at weeks 1, 2 and 3, but not at week 10. Three VEGF isoforms were detected in this rat model: VEGF120, VEGF164 and VEGF188. VEGF120 and VEGF164 levels peaked at two weeks, while VEGF188 levels peaked at three weeks. All three VEGF isoform levels were low at ten weeks. Discussion and Conclusion: EPC-based therapy for a segmental bone defect results in increased VEGF expression during the early period of fracture repair. In addition, the specific VEGF isoform may be a key regulator of the bone healing process. These findings demonstrate that EPCs may promote fracture healing by increasing VEGF levels and thus stimulating angiogenesis, a process that is essential for early callus formation and bone regeneration.
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    Associations between a History of Traumatic Brain Injuries and Current Cigarette Smoking, Substance Use, and Elevated Psychological Distress in a Population Sample of Canadian Adults
    (Mary Ann Liebert, 2015-07-15) Ilie, Gabriela; Adlaf, Edward M.; Mann, Robert E.; Ialomiteanu, Anca; Hamilton, Hayley; Rehm, Jürgen; Asbridge, Mark; Cusimano, Michael D.
    This study describes the prevalence of reported history of traumatic brain injury (TBI) and its association with reports of current substance use, cigarette smoking, and psychological distress among Canadian adults in a population sample. A cross-sectional sample of 1999 Ontario adults 18–93 years of age were surveyed by telephone in 2011 as part of the Center for Addiction and Mental Health's ongoing representative survey of adult mental health and substance use in Ontario, Canada. Loss of consciousness for at least 5 min or at least one overnight hospitalization resulting from symptoms associated with the TBI injury represented minimum criteria for TBI. An estimated 16.8% (95% confidence interval, 14.8, 19.0) of adults reported a TBI in their lifetime. Men had higher prevalence of TBI than women. Adults who reported a history of TBI had higher odds of reported past-year daily smoking (adjusted odds ratio [AOR]=2.15), using cannabis (AOR=2.80) and nonmedical opioids (AOR=2.90), as well as screened significantly for recent elevated psychological distress (AOR=1.97) in the past few weeks, compared to adults without a history of TBI. Co-occurrence of a history of TBI with current elevated psychological distress and substance use warrants vigilance among medical practitioners to assess the possibility of a history of TBI during reviews of the history leading to the occurrence of these conditions.
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    Traumatic brain injury, driver aggression and motor vehicle collisions in Canadian adults
    (Elsevier, 2015-05-02) Ilie, Gabriela; Mann, Robert E.; Ialomiteanu, Anca; Adlaf, Edward M.; Hamilton, Hayley; Wickens, Christine M.; Asbridge, Mark; Rehm, Jürgen; Cusimano, Michael D.
    Objective: This study examines the associations between lifetime traumatic brain injury (TBI), driver aggression, and motor vehicle collisions among a population sample of adults who reside in the province of Ontario, Canada. Method: A cross-sectional sample of 3993 Ontario adults, aged 18–97 were surveyed by telephone in 2011 and 2012 as part of Center for Addiction and Mental Health’s ongoing representative survey of adult mental health and substance use in Canada. TBI was defined as trauma to the head that resulted in loss of consciousness for at least five minutes or overnight hospitalization. Results: An estimated 91% (95% CI: 90.0, 91.9) of individuals in this sample held a valid Ontario driver’s license at the time of testing. Among those,16.7% reported a history of lifetime TBI and 83.3% reported no TBI. The prevalence of TBI was higher among men than women. Relative to licensed adults without TBI, adults with a history of TBI had significantly higher odds of engaging in serious driver aggression in the past 12 months, such as making threats to hurt another driver, passenger or their vehicle (AOR = 4.39). These individuals also reported significantly higher odds (AOR = 1.74) of being involved in a motor vehicle collision that resulted in hurting themselves, their passenger(s) or their vehicle. Conclusion: This is the first population-based study to demonstrate a relationship between a history of TBI and higher rates of serious driver aggression and collision involvement. Given the large proportion of adult drivers with a history of TBI, these individuals may account for a disproportion burden of all traffic safety problems. Whether the increased road safety risk of adults with a history of TBI is reflective of neurocognitive deficits or is merely evidence of a cluster of unsafe activities produced by a higher risk lifestyles requires further research attention. 2015 Elsevier Ltd. All rights reserved.
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    The association between traumatic brain injury and ADHD in a Canadian adult sample
    (Elsevier, 2015-08-08) Ilie, Gabriela; Vingilis, Evelyn R; Mann, Robert E; Hamilton, Hayley; Toplak, Maggie; Adlaf, Edward M; Kolla, Nathan; Ialomiteanu, Anca; van der Mass, Mark; Vingilis-Jaremko, Larissa; Rehm, Jürgen; Cusimano, Michael D
    Objective: This study describes the association between lifetime traumatic brain injury (TBI) and attention deficit and hyperactivity disorder (ADHD) among Canadian adults. Method: A cross-sectional sample of 3993 Ontario adults aged 18 or older were surveyed by Computer Assisted Telephone Interviewing (CATI) throughout 2011 and 2012 as part of the CAMH Monitor, a rolling survey assessing the health, mental health and substance use of Ontario adults. TBI was defined as trauma to the head that resulted in loss of consciousness for at least five minutes or overnight hospitalization. ADHD was measured by the 6-item ASRS screener for adult ADHD, and self-reported history of diagnosed ADHD. Results: Among adults with a history of TBI, 6.6% (95% CI: 4.7, 9.4) screened ADHD positive, and 5.9% (95% CI: 3.6, 9.5) reported having been diagnosed with ADHD in their lifetime. Adults with lifetime TBI had significantly greater odds of scoring positive on the ADHD/ASRS screen (OR ¼ 2.49, 95% CI: 1.54, 4.04), and of reporting a history of diagnosed ADHD (OR ¼ 2.64, 95% CI: 1.40, 4.98) than without TBI, when holding values of sex, age, and education constant. Conclusion: Significant positive associations between lifetime TBI and both current and past ADHD were observed among adults in this population. More research to understand these associations, and their significance for the etiology and management of TBI and ADHD, is needed. © 2015 Elsevier Ltd. All rights reserved.
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    Can legislation aimed at preventing sports-related concussions in youth succeed?
    (BMJ, 2014-04) Sharma, Bhanu; Cusimano, Michael D.
    ABSTRACT: The importance of preventing sports-related traumatic head and brain injuries such as concussion is underscored by their clinical severity and prevalence. Legislation to prevent injury has been successful in many settings, including cycling. Recently, legislation designed to reduce rates of sports-related concussion has been introduced in North America. The Zackery Lystedt Law (ZLL) was drafted and enacted by Washington State in 2009, and Bill 39, legislation with a similar intent, was introduced in Ontario, Canada, in 2012. In this study, we compare the ZLL and Bill 39 and contrast them with legislation to prevent cycling head injuries. We found important similarities and differences between the ZLL and Bill 39 and helmet laws for cyclists. Both the ZLL and Bill 39 have a strong bias in favour of education, but no means of enforcement. In contrast to cycling legislation, the ZLL and Bill 39 are revenue-neutral for the participant. Although our findings suggest that the ZLL and Bill 39 are promising means of preventing sports-related concussions, their effectiveness needs to be empirically evaluated.
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    Cycling-related crash risk and the role of cannabis and alcohol: a case-crossover study
    (Elsevier, 2014-09) Asbridge, Mark; Mann, Robert; Cusimano, Michael D.; Tallon, John M.; Pauley, Chris; Rehm, Jürgen
    OBJECTIVE: To examine whether alcohol and cannabis consumption increase crash risk among non-fatally injured bicyclists (N=393) seen in three Canadian emergency departments, between April 2009 and July 2011. METHOD: Employing a case-crossover design, cannabis and alcohol were identified through blood sample or by self-report. All cyclists involved in a crash and exposure status (cannabis and alcohol) were compared between case period (current crash) and two control periods: prior to the last time the victim cycled around the same time of day; and the typical use prior to bicycling. Crash risk was assessed through conditional fixed effects logistic regression models. RESULTS: Approximately 15% of cyclists reported using cannabis just prior to the crash, and 14.5% reported using alcohol. Cannabis use identified by blood testing or self-report in the case period and by self-report in the control period yielded a crash risk of 2.38 (1.04-5.43); however, when self-report was used for both the case and control periods the estimate was 0.40 (0.12-1.27). Alcohol use, as measure either in blood or self-report, was associated with an odds ratio of 4.00 (95% CI: 1.64-9.78); results were similar when alcohol was measured by self-report only. CONCLUSION: Cannabis and alcohol use each appear to increase the risk of a non-fatal injury-related crash among bicyclists, and point to the need for improved efforts to deter substance use prior to cycling, with the help of regulation, increased education, and greater public awareness. However, cannabis results should be interpreted with caution, as the observed association with crash risk was contingent on how consumption was measured.
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    The influence of acceleration loading curve characteristics on traumatic brain injury
    (Elsevier, 2014-03-21) Post, Andrew; Hoshizaki, Blaine T.; Gilchrist, Michael D.; Brien, Susan; Cusimano, Michael D.; Marshall, Shawn
    To prevent brain trauma, understanding the mechanism of injury is essential. Once the mechanism of brain injury has been identified, prevention technologies could then be developed to aid in their prevention. The incidence of brain injury is linked to how the kinematics of a brain injury event affects the internal structures of the brain. As a result it is essential that an attempt be made to describe how the characteristics of the linear and rotational acceleration influence specific traumatic brain injury lesions. As a result, the purpose of this study was to examine the influence of the characteristics of linear and rotational acceleration pulses and how they account for the variance in predicting the outcome of TBI lesions, namely contusion, subdural hematoma (SDH), subarachnoid hemorrhage (SAH), and epidural hematoma (EDH) using a principal components analysis (PCA). Monorail impacts were conducted which simulated falls which caused the TBI lesions. From these reconstructions, the characteristics of the linear and rotational acceleration were determined and used for a PCA analysis. The results indicated that peak resultant acceleration variables did not account for any of the variance in predicting TBI lesions. The majority of the variance was accounted for by duration of the resultant and component linear and rotational acceleration. In addition, the components of linear and rotational acceleration characteristics on the x, y, and z axes accounted for the majority of the remainder of the variance after duration.
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    Cannabis and traffic collision risk: findings from a case-crossover study of injured drivers presenting to emergency departments
    (Springer International Publishing, 2014-04) Asbridge, Mark; Mann, Robert; Cusimano, Michael D.; Trayling, Cynthia; Roerecke, Michael; Tallon, John M.; Whipp, Alyce; Rehm, Jürgen
    OBJECTIVES: This study examined whether acute cannabis use leads to an increased collision risk. METHODS: Participants were 860 drivers presenting to emergency departments in Toronto and Halifax, Canada, with an injury from a traffic collision, between April 2009 and July 2011. Cannabis and other drug use were identified either through blood sample or self-report. A case-crossover design was employed with two control conditions: a fixed condition measuring substance use during last time driving, and whether the driver typically uses cannabis prior to driving. Collision risk was assessed through conditional fixed-effects logistic regression models. RESULTS: Results revealed that 98 (11 %; 95 % CI: 9.0-13.1) drivers reported using cannabis prior to the collision. Regression results measuring exposure with blood and self-report data indicated that cannabis use alone was associated with a fourfold increased (OR 4.11; 95 % CI: 1.98-8.52) odds of a collision; a regression relying on self-report measures only found no significant association. CONCLUSIONS: Main findings confirmed that cannabis use increases collision risk and reinforces existing policy and educational efforts, in many high-income countries, aimed at reducing driving under the influence of cannabis.
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    Economic burden of time lost due to injury in NHL hockey players
    (BMJ, 2014-10) Donaldson, Laura; Li, Bing; Cusimano, Michael D.
    OBJECTIVE: To determine the economic burden of salary costs lost due to injury in the National Hockey League (NHL). METHODS: All NHL players who engaged in at least one regular season game during the 2009-2010 to 2011-2012 seasons comprised the study population. We performed a retrospective cross-sectional analysis of publically available media sources to collect injury and salary data. Outcome measurements were games missed during regular season play due to hockey-related injury and lost salary. RESULTS: A total of 50.9% of all NHL players missed at least one game within a season of play, and injuries represented a total salary cost of approximately US$218 million per year. Concussions alone amounted to a salary loss of US$42.8 million a year. Head/neck injuries and leg/foot injuries were the most expensive in terms of overall cost, while head/neck and shoulder injuries had the highest mean cost. CONCLUSIONS: NHL players commonly miss time due to injury, which creates a substantial burden in lost salary costs.
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    Substance Use and Related Harms Among Adolescents With and Without Traumatic Brain Injury
    (Lippincott Williams & Wilkins, 2015-09) Ilie, Gabriela; Mann, Robert E.; Hamilton, Hayley; Adlaf, Edward M.; Boak, Angela; Asbridge, Mark; Rehm, Jürgen; Cusimano, Michael D.
    OBJECTIVE: The relationship between self-reported lifetime traumatic brain injury (TBI) and drug and alcohol use and associated harms was examined using an epidemiological sample of Canadian adolescents. SETTINGS AND DESIGN: Data were derived from a 2011 population-based cross-sectional school survey, which included 6383 Ontario 9th-12th graders who self-completed anonymous self-administered questionnaires in classrooms. Traumatic brain injury was defined as loss of consciousness for at least 5 minutes or a minimum 1-night hospital stay due to symptoms. RESULTS: Relative to high schoolers without a history of TBI, those who acknowledged having a TBI in their lifetime had odds 2 times greater for binge drinking (5+ drinks per occasion in the past 4 weeks), 2.5 times greater for daily cigarette smoking, 2.9 times greater for non-medical use of prescription drugs, and 2.7 times greater for consuming illegal drug in the past 12 months. Adolescents with a history of TBI had greater odds for experiencing hazardous/harmful drinking (adjusted odds ratio [aOR] = 2.3), cannabis problems (aOR = 2.4), and drug problems (aOR = 2.1), compared with adolescents who were never injured. CONCLUSION: There are strong and demographically stable associations between TBI and substance use. These associations may not only increase the odds of injury but impair the quality of post-injury recovery.
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    Recent trends in hospitalization and in-hospital mortality associated with traumatic brain injury in Canada: A nationwide, population-based study.
    (Lippincott, Williams & Wilkins, 2015-09) Fu, Terence S.; Jing, Rowan; McFaull, Steven R.; Cusimano, Michael D.
    BACKGROUND: Traumatic brain injury (TBI) is the leading cause of traumatic death and disability worldwide.We examined nationwide trends in TBI-related hospitalizations and in-hospital mortality between April 2006 and March 2011 using a nationwide, population based database that is mandatory for all hospitals in Canada. METHODS: Trends in hospitalization rates for all acute hospital separations in Canada were analyzed using linear regression. Independent predictors of in-hospital mortality were evaluated using logistic regression. RESULTS: Hospitalization rates remained stable for children and young adults but increased considerably among elderly adults (age Q65 years). Falls and motor vehicle collisions (MVCs) were the most common causes of TBI hospitalizations. TBIs caused by falls increased by 24% (p = 0.01), while MVC-related hospitalization rates decreased by 18% (p = 0.03). Elderly adults were most vulnerable to falls and experienced the greatest increase (29%) in fall-related hospitalization rates. Young adults (ages, 15Y24 years) were most at risk for MVCs but experienced the greatest decline (28%) in MVC-related admissions. There were significant trends toward increasing age, injury severity, comorbidity, hospital length of stay, and rate of in-hospital mortality.However, multivariate regression showed that odds of death decreased over time after controlling for relevant factors. Injury severity, comorbidity, and advanced age were the most important predictors of in-hospital mortality for TBI inpatients. CONCLUSION: Hospitalizations for TBI are increasing in severity and involve older populations with more complex comorbidities. Although preventive strategies for MVC-related TBI are likely having some effects, there is a critical need for effective fall prevention strategies, especially among elderly adults.
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    Traumatic Brain Injuries: The influence of the direction of impact
    (Lippincott Williams & Wilkins, 2015-01) Post, Andew; Hoshizaki, T.Blaine; Gilchrist, Michael D.; Brien, Susan; Cusimano, Michael; Marshall, Shawn
    BACKGROUND: Head impact direction has been identified as an influential risk factor in the risk of traumatic brain injury (TBI) from animal and anatomic research; however, to date, there has been little investigation into this relationship in human subjects. If a susceptibility to certain types of TBI based on impact direction was found to exist in humans, it would aid in clinical diagnoses as well as prevention methods for these types of injuries. OBJECTIVE: To examine the influence of impact direction on the presence of TBI lesions, specifically, subdural hematomas, subarachnoid hemorrhage, and parenchymal contusions. METHODS: Twenty reconstructions of falls that resulted in a TBI were conducted in a laboratory based on eyewitness, interview, and medical reports. The reconstructions involved impacts to a Hybrid III anthropometric dummy and finite element modeling of the human head to evaluate the brain stresses and strains for each TBI event. RESULTS: The results showed that it is likely that increased risk of incurring a subdural hematoma exists from impacts to the frontal or occipital regions, and parenchymal contusions from impacts to the side of the head. There was no definitive link between impact direction and subarachnoid hemorrhage. In addition, the results indicate that there is a continuum of stresses and strain magnitudes between lesion types when impact location is isolated, with subdural hematoma occurring at lower magnitudes for frontal and occipital region impacts, and contusions lower for impacts to the side. CONCLUSION: This hospital data set suggests that there is an effect that impact direction has on TBI depending on the anatomy involved for each particular lesion.
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    Influence of lung volume reduction surgery (LVRS) on health related quality of life in patients with chronic obstructive pulmonary disease
    (BMJ Publishing Group, 2003) Goldstein, R. S.; Todd, T. R. J.; Guyatt, G.; Keshavjee, S.; Dolmage, T. E.; Rooy, S. Van; Krip, B.; Maltais, F.; LeBlanc, P.; Pakhale, S.; Waddell, T. K.
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    Regression of aortic aneurysms through pharmacologic therapy?
    (Massachusetts Medical Society, 2006) Verma, S.; Lindsay, T. F.
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    Feline immunodeficiency virus vectors persistently transduce nondividing airway epithelia and correct the cystic fibrosis defect
    (American Society of Clinical Investigation, 1999) Wang, G.; Slepushkin, V.; Zabner, J.; Keshavjee, S.; Johnston, J. C.; Sauter, S. L.; Jolly, D. J.; Dubensky, Thomas; Davidson, B. L.; McCray Jr., Paul B