Rank normalization empowers a t-test for microbiome differential abundance analysis while controlling for false discoveries.

A major task in the analysis of microbiome data is to identify microbes associated with differing biological conditions. Before conducting analysis, raw data must first be adjusted so that counts from different samples are comparable. A typical approach is to estimate normalization factors by which all counts in a sample are multiplied or divided. However, the inherent variation associated with estimation of normalization factors are often not accounted for in subsequent analysis, leading to a loss of precision. Rank normalization is a nonparametric alternative to the estimation of normalization factors in which each count for a microbial feature is replaced by its intrasample rank. Although rank normalization has been successfully applied to microarray analysis in the past, it has yet to be explored for microbiome data, which is characterized by high frequencies of 0s, strongly correlated features and compositionality. We propose to use rank normalization as an alternative to the estimation of normalization factors and examine its performance when paired with a two-sample t-test. On a rigorous 3rd-party benchmarking simulation, it is shown to offer strong control over the false discovery rate, and at sample sizes greater than 50 per treatment group, to offer an improvement in performance over commonly used normalization factors paired with t-tests, Wilcoxon rank-sum tests and methodologies implemented by R packages. On two real datasets, it yielded valid and reproducible results that were strongly in agreement with the original findings and the existing literature, further demonstrating its robustness and future potential. Availability: The data underlying this article are available online along with R code and supplementary materials at https://github.com/matthewlouisdavisBioStat/Rank-Normalization-Empowers-a-T-Test.

Finite Element-Based Pelvic Injury Metric Creation and Validation in Lateral Impact for a Human Body Model.

Pelvic fractures are serious injuries resulting in high mortality and morbidity. The objective of this study is to develop and validate local pelvic anatomical, cross section-based injury risk metrics for a finite element (FE) model of the human body. Cross-sectional instrumentation was implemented in the pelvic region of the Global Human Body Models Consortium (GHBMC M50-O) 50th percentile detailed male FE model (v4.3). In total, 25 lateral impact FE simulations were performed using input data from cadaveric lateral impact tests performed by Bouquet et al. The experimental force-time data were scaled using five normalization techniques, which were evaluated using log rank, Wilcoxon rank sum, and correlation and analysis (CORA) testing. Survival analyses with Weibull distribution were performed on the experimental peak force (scaled and unscaled) and the simulation test data to generate injury risk curves (IRCs) for total pelvic injury. Additionally, IRCs were developed for regional injury using cross-sectional forces from the simulation results and injuries documented in the experimental autopsies. These regional IRCs were also evaluated using the receiver operator characteristic (ROC) curve analysis. Based on the results of all the evaluation methods, the equal stress equal velocity (ESEV) and ESEV using effective mass (ESEV-EM) scaling techniques performed best. The simulation IRC shows slight under prediction of injury in comparison to these scaled experimental data curves. However, this difference was determined not to be statistically significant. Additionally, the ROC curve analysis showed moderate predictive power for all regional IRCs.

An Objective Evaluation of Mass Scaling Techniques Utilizing Computational Human Body Finite Element Models.

Biofidelity response corridors developed from post-mortem human subjects are commonly used in the design and validation of anthropomorphic test devices and computational human body models (HBMs). Typically, corridors are derived from a diverse pool of biomechanical data and later normalized to a target body habitus. The objective of this study was to use morphed computational HBMs to compare the ability of various scaling techniques to scale response data from a reference to a target anthropometry. HBMs are ideally suited for this type of study since they uphold the assumptions of equal density and modulus that are implicit in scaling method development. In total, six scaling procedures were evaluated, four from the literature (equal-stress equal-velocity, ESEV, and three variations of impulse momentum) and two which are introduced in the paper (ESEV using a ratio of effective masses, ESEV-EffMass, and a kinetic energy approach). In total, 24 simulations were performed, representing both pendulum and full body impacts for three representative HBMs. These simulations were quantitatively compared using the International Organization for Standardization (ISO) ISO-TS18571 standard. Based on these results, ESEV-EffMass achieved the highest overall similarity score (indicating that it is most proficient at scaling a reference response to a target). Additionally, ESEV was found to perform poorly for two degree-of-freedom (DOF) systems. However, the results also indicated that no single technique was clearly the most appropriate for all scenarios.

Risk Factors for Open Malleolar Fractures: An Analysis of the National Trauma Data Bank (2007 to 2011).

A limited number of studies have described the epidemiology of open fractures, and the epidemiology of open ankle fractures is not an exception. Therefore, the risk factors associated with open ankle fractures have not been extensively evaluated. The frequencies and proportions of open ankle fractures among all the recorded malleolar fractures in the US National Trauma Data Bank data set from January 2007 to December 2011 were analyzed. Clinically relevant variables captured in the data set were also used to evaluate the risk factors associated with open ankle fractures, adjusting for other covariates. The entire cohort was further subdivided into "lower" and "higher" energy trauma groups and the same analysis performed for each group separately. We found that a body mass index of >40 kg/m(2) and farm location were risk factors for open ankle fractures and impaired sensorium was protective against open ankle fractures. In the "lower energy" group, male gender, alcohol use, peripheral vascular disease, other injuries, and injury occurring at a farm location were risk factors for open fractures. In the "higher energy" group, female gender, work-related injury, and injury at a farm or industry location demonstrated statistically significantly associations with open fractures.

The Trauma Center Organizational Culture Survey: development and conduction.

BACKGROUND: The Trauma Center Organizational Culture Survey (TRACCS) instrument was developed to assess organizational culture of trauma centers enrolled in the American College of Surgeons Trauma Quality Program (ACS TQIP). The objective is to provide evidence on the psychometric properties of the factors of TRACCS and describe the current organizational culture of TQIP-enrolled trauma centers. METHODS: A cross-sectional study was conducted by surveying a sampling of employees at 174 TQIP-enrolled trauma centers. Data collection was preceded by multistep survey development. Psychometric properties were assessed by an exploratory factor analysis (construct validity) and the item-total correlations and Cronbach alpha were calculated (internal reliability). Statistical outcomes of the survey responses were measured by descriptive statistics and mixed effect models. RESULTS: The response rate for trauma center participation in the study was 78.7% (n = 137). The factor analysis resulted in 16 items clustered into three factors as described: opportunity, pride, and diversity, trauma center leadership, and employee respect and recognition. TRACCS was found to be highly reliable with a Cronbach alpha of 0.90 in addition to the three factors (0.91, 0.90, and 0.85). Considerable variability of TRACCS overall and factor score among hospitals was measured, with the largest interhospital deviations among trauma center leadership. More than 80% of the variability in the responses occurred within rather than between hospitals. CONCLUSIONS: TRACCS was developed as a reliable tool for measuring trauma center organizational culture. Relationships between TQIP outcomes and measured organizational culture are under investigation. Trauma centers could apply TRACCS to better understand current organizational culture and how change tools can impact culture and subsequent patient and process outcomes.

Blood-brain barrier dysfunction following traumatic brain injury.

Traumatic brain injury is a serious cause of morbidity and mortality worldwide. After traumatic brain injury, the blood-brain barrier, the protective barrier between the brain and the intravascular compartment, becomes dysfunctional, leading to leakage of proteins, fluid, and transmigration of immune cells. As this leakage has profound clinical implications, including edema formation, elevated intracranial pressure and decreased perfusion pressure, much interest has been paid to better understanding the mechanisms responsible for these events. Various molecular pathways and numerous mediators have been found to be involved in the intricate process of regulating blood-brain barrier permeability following traumatic brain injury. This review provides an update to the existing knowledge about the various pathophysiological pathways and advancements in the field of blood-brain barrier dysfunction and hyperpermeability following traumatic brain injury, including the role of various tight junction proteins involved in blood-brain barrier integrity and regulation. We also address pitfalls of existing systems and propose strategies to improve the various debilitating functional deficits caused by this progressive epidemic.

Reactive oxygen species-caspase-3 relationship in mediating blood-brain barrier endothelial cell hyperpermeability following oxygen-glucose deprivation and reoxygenation.

OBJECTIVE: Microvascular hyperpermeability that occurs due to breakdown of the BBB is a major contributor of brain vasogenic edema, following IR injury. In microvascular endothelial cells, increased ROS formation leads to caspase-3 activation following IR injury. The specific mechanisms, by which ROS mediates microvascular hyperpermeability following IR, are not clearly known. We utilized an OGD-R in vitro model of IR injury to study this. METHODS: RBMEC were subjected to OGD-R in presence of a caspase-3 inhibitor Z-DEVD, caspase-3 siRNA or an ROS inhibitor L-AA. Cytochrome c levels were measured by ELISA and caspase-3 activity was measured fluorometrically. TJ integrity and cytoskeletal assembly were studied using ZO-1 immunofluorescence and rhodamine phalloidin staining for f-actin, respectively. RESULTS: OGD-R significantly increased monolayer permeability, ROS formation, cytochrome c levels, and caspase-3 activity (p < 0.05) and induced TJ disruption and actin stress fiber formation. Z-DEVD, L-AA and caspase-3 siRNA significantly attenuated OGD-R-induced hyperpermeability (p < 0.05) while only L-AA decreased cytochrome c levels. Z-DEVD and L-AA protected TJ integrity and actin cytoskeletal assembly. CONCLUSIONS: These results suggest that OGD-R-induced hyperpermeability is ROS and caspase-3 dependent and can be regulated by their inhibitors.

Association of a modified frailty index with mortality after femoral neck fracture in patients aged 60 years and older.

BACKGROUND: Frailty, a multidimensional syndrome entailing loss of energy, physical ability, cognition, and health, plays a significant role in elderly morbidity and mortality. No study has examined frailty in relation to mortality after femoral neck fractures in elderly patients. QUESTIONS/PURPOSES: We examined the association of a modified frailty index abbreviated from the Canadian Study of Health and Aging Frailty Index to 1- and 2-year mortality rates after a femoral neck fracture. Specifically we examined: (1) Is there an association of a modified frailty index with 1- and 2-year mortality rates in patients aged 60 years and older who sustain a low-energy femoral neck fracture? (2) Do the receiver operating characteristic (ROC) curves indicate that the modified frailty index can be a potential tool predictive of mortality and does a specific modified frailty index value demonstrate increased odds ratio for mortality? (3) Do any of the individual clinical deficits comprising the modified frailty index independently associate with mortality? METHODS: We retrospectively reviewed 697 low-energy femoral neck fractures in patients aged 60 years and older at our Level I trauma center from 2005 to 2009. A total of 218 (31%) patients with high-energy or pathologic fracture, postoperative complication including infection or revision surgery, fracture of the contralateral hip, or missing documented mobility status were excluded. The remaining 481 patients, with a mean age of 81.2 years, were included. Mortality data were obtained from a state vital statistics department using date of birth and Social Security numbers. Statistical analysis included unequal variance t-test, Pearson correlation of age and frailty, ROC curves and area under the curve, Hosmer-Lemeshow statistics, and logistic regression models. RESULTS: One-year mortality analysis found the mean modified frailty index was higher in patients who died (4.6 ± 1.8) than in those who lived (3.0 ± 2; p < 0.001), which was maintained in a 2-year mortality analysis (4.4 ± 1.8 versus 3.0 ± 2; p < 0.001). In ROC analysis, the area under the curve was 0.74 and 0.72 for 1- and 2-year mortality, respectively. Patients with a modified frailty index of 4 or greater had an odds ratio of 4.97 for 1-year mortality and an odds ratio of 4.01 for 2-year mortality as compared with patients with less than 4. Logistic regression models demonstrated that the clinical deficits of mobility, respiratory, renal, malignancy, thyroid, and impaired cognition were independently associated with 1- and 2-year mortality. CONCLUSIONS: Patients aged 60 years and older sustaining a femoral neck fracture, with a higher modified frailty index, had increased 1- and 2-year mortality rates, and the ROC analysis suggests that this tool may be predictive of mortality. Patients with a modified frailty index of 4 or greater have increased risk for mortality at 1 and 2 years. Clinical deficits of mobility, respiratory, renal, malignancy, thyroid, and impaired cognition also may be independently associated with mortality. The modified frailty index may be a useful tool in predicting mortality, guiding patient and family expectations and elucidating implant/surgery choices. Further prospective studies are necessary to strengthen the predictive power of the index. LEVEL OF EVIDENCE: Level IV, prognostic study. See Instructions for Authors for a complete description of levels of evidence.

High-energy femur fractures increase morbidity but not mortality in elderly patients.

BACKGROUND: Trauma centers are projected to have an increase in the number of elderly patients with high-energy femur fractures. Greater morbidity and mortality have been observed in these patients. Further clarification regarding the impact of high-energy femur fractures is necessary in this population. QUESTIONS/PURPOSES: Our purpose was to assess the influence of high-energy femur fractures on mortality and morbidity in patients 60 years and older. Specifically, we asked (1) if the presence of a high-energy femur fracture increases in-hospital, 6-month, and 1-year mortality in patients 60 years and older, and (2) if there is a difference in morbidity (number of complications, intensive care unit [ICU] and total hospital length of stay, discharge disposition, accompanying fractures, and surgical intervention) between patients 60 years and older with and without high-energy femur fractures. METHODS: A retrospective review of 242 patients was performed. Patients with traumatic brain injury or spine injury with a neurologic deficit were excluded. A control group, including patients admitted secondary to high-energy trauma without femur fractures, was matched by gender and Injury Severity Score (ISS). In-hospital mortality, 6-month and 1-year mortality, complications, ICU and total hospital length of stay, discharge disposition, accompanying fractures, surgical intervention, and covariates were recorded. Statistical analyses using Fisher's exact test, ANOVA, Kaplan-Meier estimates, and Cox regression models were performed to show differences in mortality (in-hospital, 6-month, 1-year), complications, length of ICU and total hospital stay, discharge disposition, surgical intervention, and accompanying fractures between elderly patients with and without femur fractures. The average ages of the patients were 72.8 years (± 9 years) in the femur fracture group and 71.8 years (± 9 years) in the control group. Sex, age, ISS, and comorbidities were homogenous between groups. RESULTS: In-hospital (p = 0.45), 6-month (p = 0.79), and 1-year mortality (p = 0.55) did not differ in patients with and without high-energy femur fractures. Elderly patients with high-energy femur fractures had an increased number of complications (p = 0.029), longer total hospital length of stay (p = 0.039), were discharged more commonly to rehabilitation centers (p < 0.005), had more accompanying long bone fractures (p = 0.002), and were more likely to have surgery (p < 0.001). Average ICU length of stay was similar between the two groups (p = 0.17). CONCLUSIONS: High-energy femur fractures increased morbidity in patients 60 years and older; however, no increase in mortality was observed in our patients. Concomitant injuries may play a more critical role in this population. Additional studies are necessary to clarify the role of high-energy femur fracture mortality in this age group. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

Imaging chronic traumatic brain injury as a risk factor for neurodegeneration.

Population-based studies have supported the hypothesis that a positive history of traumatic brain injury (TBI) is associated with an increased incidence of neurological disease and psychiatric comorbidities, including chronic traumatic encephalopathy, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These epidemiologic studies, however, do not offer a clear definition of that risk, and leave unanswered the bounding criteria for greater lifetime risk of neurodegeneration. Key factors that likely mediate the degree of risk of neurodegeneration include genetic factors, significant premorbid and comorbid medical history (e.g. depression, multiple head injuries and repetitive subconcussive impact to the brain, occupational risk, age at injury, and severity of brain injury). However, given the often-described concerns in self-report accuracy as it relates to history of multiple TBIs, low frequency of patient presentation to a physician in the case of mild brain injuries, and challenges with creating clear distinctions between injury severities, disentangling the true risk for neurodegeneration based solely on population-based studies will likely remain elusive. Given this reality, multiple modalities and approaches must be combined to characterize who are at risk so that appropriate interventions to alter progression of neurodegeneration can be evaluated. This article presents data from a study that highlights uses of neuroimaging and areas of needed research in the link between TBI and neurodegenerative disease.

Epidemiology of foot and ankle fractures in the United States: an analysis of the National Trauma Data Bank (2007 to 2011).

Understanding the epidemiology of foot and ankle trauma could be useful in health services research and for policy makers. It can also define practice patterns. Using the National Trauma Data Bank data set from 2007 to 2011, we analyzed the frequency and proportion of each fracture in the foot and ankle in major trauma hospitals in the United States. A total of 280,933 foot and/or ankle fractures or dislocations were identified. Although oversampling of more severe trauma in younger patients might have occurred owing to the nature of the data set, we found that the most common fractures in the foot and ankle were ankle fractures. Midfoot fractures were the least common among all the foot and ankle fractures when categorized by anatomic location. Approximately 20% of all foot and ankle fractures were open.

The I-PREDICT 50th Percentile Male Warfighter Finite Element Model: Development and Validation of the Thoracolumbar Spine.

Military personnel are commonly at risk of lower back pain and thoracolumbar spine injury. Human volunteers and postmortem human subjects have been used to understand the scenarios where injury can occur and the tolerance of the warfighter to these loading regimes. Finite element human body models (HBMs) can accurately simulate the mechanics of the human body and are a useful tool for understanding injury. In this study, a HBM thoracolumbar spine was developed and hierarchically ï»¿validated as part of the Incapacitation Prediction for Readiness in Expeditionary Domains: an Integrated Computational Tool (I-PREDICT) program. Constitutive material models were sourced from literature and the vertebrae and intervertebral discs were hexahedrally meshed from a 50th percentile male CAD dataset. Ligaments were modeled through attaching beam elements at the appropriate anatomical insertion sites. 94 simulations were replicated from experimental PMHS tests at the vertebral body, functional spinal unit (FSU), and regional lumbar spine levels. The BioRank (BRS) biofidelity ranking system was used to assess the response of the I-PREDICT model. At the vertebral body level, the I-PREDICT model showed good agreement with experimental results. The I-PREDICT FSUs showed good agreement in tension and compression and had comparable stiffness values in flexion, extension, and axial rotation. The regional lumbar spine exhibited "good" biofidelity when tested in tension, compression, extension, flexion, posterior shear, and anterior shear (BRS regional average = 1.05). The validated thoracolumbar spine of the I-PREDICT model can be used to better understand and mitigate injury risk to the warfighter.

Probabilistic Finite Element Analysis of Human Rib Biomechanics: A Framework for Improved Generalizability.

In dynamic impact events, thoracic injuries often involve rib fractures, which are closely related to injury severity. Previous studies have investigated the behavior of isolated ribs under impact loading conditions, but often neglected the variability in anatomical shape and tissue material properties. In this study, we used probabilistic finite element analysis and statistical shape modeling to investigate the effect of population-wide variability in rib cortical bone tissue mechanical properties and rib shape on the biomechanical response of the rib to impact loading. Using the probabilistic finite element analysis results, a response surface model was generated to rapidly investigate the biomechanical response of an isolated rib under dynamic anterior-posterior load given the variability in rib morphometry and tissue material properties. The response surface was used to generate pre-fracture force-displacement computational corridors for the overall population and a population sub-group of older mid-sized males. When compared to the experimental data, the computational mean response had a RMSE of 4.28N (peak force 94N) and 6.11N (peak force 116N) for the overall population and sub-group respectively, whereas the normalized area metric when comparing the experimental and computational corridors ranged from 3.32% to 22.65% for the population and 10.90% to 32.81% for the sub-group. Furthermore, probabilistic sensitivities were computed in which the contribution of uncertainty and variability of the parameters of interest was quantified. The study found that rib cortical bone elastic modulus, rib morphometry and cortical thickness are the random variables that produce the largest variability in the predicted force-displacement response. The proposed framework offers a novel approach for accounting biological variability in a representative population and has the potential to improve the generalizability of findings in biomechanical studies.

Incidence and risk factors for amputation in foot and ankle trauma.

Mobility, especially in elderly patients, is often a proxy for overall health. It is thus of interest to understand the rates of lower extremity amputation and the risk factors for these procedures in the trauma population. We compared the rates of lower extremity amputation in low- versus high-level trauma by analyzing the National Trauma Data Bank. We also attempted to identify the risk factors in the low-level trauma population with foot and ankle trauma that predispose to lower extremity amputation. The factors associated with lower extremity amputation in foot and ankle trauma differed slightly from those in other multi-trauma patients. The factors associated with lower extremity amputation in the low-level foot and ankle trauma population that were statistically and clinically significant in this study included male gender, confounding injury, other trauma type versus blunt trauma, penetrating versus blunt trauma, occurrence of fracture, and occurrence of crush injury or wound. Understanding these risk factors will assist in educating patients and their family about their prognosis. Also, understanding these risk factors will assist surgeons with patient selection when considering salvage procedures.

Incidence of acute deep vein thrombosis and pulmonary embolism in foot and ankle trauma: analysis of the National Trauma Data Bank.

The incidence of deep vein thrombosis (DVT) after foot and ankle surgery is generally believed to be low. However, little information is available regarding DVT as it specifically relates to foot and ankle trauma. The National Trauma Data Bank data set (2007 to 2009) was used to evaluate the incidence of thromboembolism in foot and ankle trauma. Also, the risk factors associated with the thromboembolic events were identified. Data regarding the demographics, comorbidities, procedures, trauma types, and complications, including DVT and pulmonary embolism (PE), were collected from the data set for analysis. The incidence of DVT and PE was 0.28% and 0.21%, respectively. The risk factors statistically significantly associated and clinically relevant for both DVT and PE in foot and ankle trauma were older age (DVT, odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01 to 1.03; PE, OR 1.02, 95% CI 1.01 to 1.03), obesity (DVT, OR 2.35, 95% CI 1.33 to 4.14; PE, OR 3.06, 95% CI 1.68 to 5.59), and higher injury severity score (DVT, OR 1.22, 95% CI 1.16 to 1.28; PE, OR 1.21, 95% CI 1.14 to 1.29). Owing to the low incidence, routine pharmacologic thromboprophylaxis might be contraindicated in foot and ankle trauma. Instead, careful, individualized assessment of the risk factors associated with DVT/PE is important.

Effect of body size and enhanced helmet systems on risk for motorsport drivers.

OBJECTIVE: Computational modeling has been shown to be a useful tool for simulating representative motorsport impacts and analyzing data for relative injury risk assessment. Previous studies have used computational modeling to analyze the probability of injury in specific regions of a 50th percentile male driver. However, NASCAR drivers can represent a large range in terms of size and female drivers are becoming increasingly more common in the sport. Additionally, motorsport helmets can be outfitted with external attachments, or enhanced helmet systems (EHS), whose effect is unknown relative to head and neck kinematics. The current study expands on this previous work by incorporating the F05-OS and M95-OS into the motorsport environment in order to determine correlations between metrics and factors such as PDOF, resultant ΔV occupant size, and EHS. METHODS: A multi-step computational process was used to integrate the Global Human Body Models Consortium family of simplified occupant models into a motorsport environment. This family included the 5th percentile female (F05-OS), 50th percentile male (M50-OS), and 95th percentile male (M95-OS), which provide a representative range for the size and sex of drivers seen in NASCAR's racing series'. A series of 45 representative impacts, developed from real-world crash data, and set of observed on-track severe impacts were conducted with these models. These impacts were run in triplicate for three helmet configurations: bare helmet, helmet with visor, helmet with visor and camera. This resulted in 450 total simulations. A paired t-test was initially performed as an exploratory analysis to study the effect of helmet configuration on 10 head and neck injury metrics. A mixed-effects model with unstructured covariance matrix was then utilized to correlate the effect between five independent variables (resultant ΔV, body size, helmet configuration, impact quadrant, and steering wheel position) and a selection of 25 metrics. All simulations were conducted in LS-Dyna R. 9.1. RESULTS: Risk estimates from the M50-OS with bare helmet were used as reference values to determine the effect of body size and helmet configuration. The paired t-test found significance for helmet configuration in select head-neck metrics, but the relative increase in these metrics was low and not likely to increase injury risk. The mixed-effects model analyzed statistical relationships across multiple types of variables. Within the mixed-effects model, no significance was found between helmet configuration and metrics. The greatest effect was found from resultant ΔV, body size, and impact quadrant. CONCLUSIONS: Overall, smaller drivers showed statistically significant reductions in injury metrics, while larger drivers showed statistically significant increases. Lateral impacts showed the greatest effect on neck metrics and, on average, showed decreases for head metrics related to linear acceleration and increases for head metrics related to angular velocity. HBM parametric studies such as this may provide an avenue to assist injury detection for motorsport incidents, improve triage effectiveness, and assist in the development of safety standards.

Simulation-based assessment of injury risk for an average male motorsport driver.

OBJECTIVE: While well-protected through a variety of safety countermeasures, motorsports drivers can be exposed to a large variety of crash modes and severities. Computational human body models (HBMs) are currently used to assess occupant safety for the general driving public in production vehicles. The purpose of this study was to incorporate a HBM into a motorsport environment using a simulation-based approach and provide quantitative data on relative risk for on-track motorsport crashes. METHODS: Unlike a traditional automotive seat, the NASCAR driver environment is driver-customized and form-fitting. A multi-step process was developed to integrate the Global Human Body Models Consortium (GHBMC) 50th percentile male simplified occupant into a representative motorsport environment which includes a donned helmet, a 7-point safety belt system, head and neck restraint (HNR), poured-foam seat, steering wheel, and leg enclosure. A series of 45 representative impacts, developed from real-world crash data, of varying severity (10 kph ≤ ΔV ≤ 100 kph) and impact direction (∼290° ≤ PDOF ≤ 20°) were conducted with the GHBMC 50th percentile male simplified occupant (M50-OS v2.2). Kinematic and kinetic data, and a variety of injury criteria, were output from each of the simulations and used to calculate AIS 1+, 2+, and 3+ injury risk. All simulations were conducted in LS-Dyna R. 9.1. RESULTS: Injury risk of the occupant using the previously mentioned injury criteria was calculated for the head, neck, thorax, and lower extremity, and the probability of injury for each region was plotted. Of the simulated impacts, five had a maximum AIS 1+ injury risk >20%, six had a maximum AIS 2+ injury risk >10%, and no cases had a maximum AIS 3+ injury >1%. Overall, injury risk estimates were reasonable compared to on-track data reported from Patalak et al. (2020). CONCLUSIONS: Beyond injury risk, the study is the first of its kind to provide mechanical loading values likely experienced during motorsports crash incidents with crash pulses developed from real-world data. Given the severity of the crash pulses, the simulated environments reinforce the need for the robust safety environment implemented by NASCAR.

Injury risk curves in far-side lateral motor vehicle crashes by AIS level, body region and injury code.

OBJECTIVE: The objective of this study was to develop injury risk curves as a function of change in vehicle velocity for occupants in far-side lateral motor vehicle crashes (MVCs) by AIS level, body region, and specific AIS codes that commonly occur in this crash mode. METHODS: The National Automotive Sampling System-Crashworthiness Data System (NASS-CDS) years 2000-2015 database was queried, resulting in 4,495 non-weighted far-side crashes. For each case, occupant age, sex, and the following metadata were collected: vehicle model year, vehicle body type, lateral delta-v, normalized PDOF, multiple impacts, belt use, seat position, object contacted, striking vehicle body type, maximum crush extent and side airbag deployment. Multivariable logistic regression was used to develop risk curves for AIS 2+ through 5+ injuries, AIS 2+ injuries by body region (head, thorax, lower extremity), and for each of the 10 most frequent far-side AIS 2+ injuries. Significant covariates were determined by backwards elimination (p < 0.05). The full dataset and a subsampled dataset of only cases with side airbag deployment were used to develop risk curves. RESULTS: For AIS 2+ through 5+ injury, greater delta-V was associated with greater injury risk (OR's: 2.48-3.66 per 11.9 kph increase) and belt use was associated with lower risk (OR's: 0.04-0.36 compared to unbelted). Multiple impacts were significant predictors of increased AIS 3+, 4+ and 5+ injury risk (OR's: 2.56, 2.27 and 2.83 compared to single impact). For AIS 2+ body region injuries, lateral delta-V and maximum CDC extent were positively associated with increased head, thorax and lower extremity injury risk while belt use was associated with lower risk. Increased lateral delta-v, unbelted status, and greater maximum CDC extent frequently increased injury risk for the most common far-side injuries. Side airbag deployment was not a significant covariate for the injury risk models. CONCLUSIONS: The resulting risk models expand upon previous literature gaps to provide a more comprehensive view of contributors to injury risk for occupants in far-side MVCs. This study yields risk curves based on the latest available NASS-CDS data.

The Tri-phasic Role of Hydrogen Peroxide in Blood-Brain Barrier Endothelial cells.

Hydrogen peroxide (H2O2) plays an important role physiologically as the second messenger and pathologically as an inducer of oxidative stress in injury, ischemia and other conditions. However, it is unclear how H2O2 influences various cellular functions in health and disease differentially, particularly in the blood-brain barrier (BBB). We hypothesized that the change in cellular concentrations of H2O2 is a major contributor in regulation of angiogenesis, barrier integrity/permeability and cell death/apoptosis in BBB endothelial cells. Rat brain microvascular endothelial cells were exposed to various concentrations of H2O2 (1 nM to 25 mM). BBB tight junction protein (zonula ocludens-1; ZO-1) localization and expression, cytoskeletal organization, monolayer permeability, angiogenesis, cell viability and apoptosis were evaluated. H2O2 at low concentrations (0.001 µM to 1 µM) increased endothelial cell tube formation indicating enhanced angiogenesis. H2O2 at 100 µM and above induced monolayer hyperpermeability significantly (p < 0.05). H2O2 at 10 mM and above decreased cell viability and induced apoptosis (p < 0.05). There was a decrease of ZO-1 tight junction localization with 100 µm H2O2, but had no effect on protein expression. Cytoskeletal disorganizations were observed starting at 1 µm. In conclusion H2O2 influences angiogenesis, permeability, and cell death/apoptosis in a tri-phasic and concentration-dependent manner in microvascular endothelial cells of the blood-brain barrier.

A Mouse Controlled Cortical Impact Model of Traumatic Brain Injury for Studying Blood-Brain Barrier Dysfunctions.

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. It is a silently growing epidemic with multifaceted pathogenesis, and current standards of treatments aim to target only the symptoms of the primary injury, while there is a tremendous need to explore interventions that can halt the progression of the secondary injuries. The use of a reliable animal model to study and understand the various aspects the pathobiology of TBI is extremely important in therapeutic drug development against TBI-associated complications. The controlled cortical impact (CCI) model of TBI described here, uses a mechanical impactor to inflict a mechanical injury into the mouse brain. This method is a reliable and reproducible approach to inflict mild, moderate or severe injuries to the animal for studying TBI-associated blood-brain barrier (BBB) dysfunctions, neuronal injuries, brain edema, neurobehavioral changes, etc. The present method describes how the CCI model could be utilized for determining the BBB dysfunction and hyperpermeability associated with TBI. Blood-brain barrier disruption is a hallmark feature of the secondary injury that occur following TBI, frequently associated with leakage of fluid and proteins into the extravascular space leading to vasogenic edema and elevation of intracranial pressure. The method described here focuses on the development of a CCI-based mouse model of TBI followed by the evaluation of BBB integrity and permeability by intravital microscopy as well as Evans Blue extravasation assay.