Mild traumatic brain injury (mTBI) refers to the clinical condition of transient alteration of co... more Mild traumatic brain injury (mTBI) refers to the clinical condition of transient alteration of consciousness as a result of traumatic injury to the brain. The priority of emergency care is to identify and facilitate the treatment of rare but potentially life-threatening intracranial injuries associated with mTBI through the judicious application of appropriate imaging studies and neurosurgical consultation. Although post-mTBI symptoms quickly and completely resolve in the vast majority of cases, a significant number of patients will complain of lasting problems that may cause significant disability. Simple and early interventions such as patient education and appropriate referral can reduce the likelihood of chronic symptoms. Although definitive evidence is lacking, mTBI is likely to be related to significant long-term sequelae such as Alzheimer disease and other neurodegenerative processes.
Current approaches to diffusion tensor imaging (DTI) analysis do not permit identification of ind... more Current approaches to diffusion tensor imaging (DTI) analysis do not permit identification of individual-level changes in DTI indices. We investigated the ability of wild bootstrapping analysis to detect subject-specific changes in brain white matter (WM) before and after sports-related concussion. A prospective cohort study was performed in nine high school athletes engaged in hockey or football and six controls. Subjects underwent DTI pre- and postseason within a 3-month interval. One athlete was diagnosed with concussion (scanned within 72 h), and eight suffered between 26 and 399 subconcussive head blows. Fractional anisotropy (FA) and mean diffusivity (MD) were measured in each WM voxel. Bootstrap samples were generated, and a permuted t test was used to compare voxel-wise FA/MD changes in each subject pre- vs. postseason. The percentage of WM voxels with significant (p<.05) pre-post FA changes was highest for the concussion subject (3.2%), intermediary for those with subconcussive head blows (mean 1.05%±.15%) and lowest for controls (mean 0.28%±.01%). Similarly, the percentage of WM voxels with significant MD changes was highest for the concussion subject (3.44%), intermediary for those with subconcussive head blows (mean 1.48%±.17%) and lowest for controls (mean 0.48%±.05%). Significantly changed FA and MD voxels colocalized in the concussion subject to the right corona radiata and right inferior longitudinal fasciculus. Wild bootstrap analysis detected significantly changed WM in a single concussed athlete. Athletes with multiple subconcussive head blows had significant changes in a percentage of their WM that was over three times higher than controls. Efforts to understand the significance of these WM changes and their relationship to head impact forces appear warranted.
The objective of this study was to estimate the independent association of sex with outcome after... more The objective of this study was to estimate the independent association of sex with outcome after mild traumatic brain injury (mTBI). We performed an analysis of a subset of an established cohort involving 1425 mTBI patients presenting to an academic emergency department (ED). The associations between sex and three outcomes determined 3 months after the initial ED visit were examined: post-concussive symptom (PCS) score (0, 1-5, 6-16, and >16), the number of days to return of normal activities (0, 1-7, and >7), and the number of days of work missed (0, 1-7,and >7). Logistic regression analyses were used to determine the relationship between sex and each outcome after controlling for 12 relevant subject-level variables. Of the 1425 subjects, 643 (45.1%) were female and 782 (54.9%) were male. Three months after mTBI, males had significantly lower odds of being in a higher PCS score category (odds ratio [OR] 0.62, 95% confidence interval [CI]: 0.50, 0.78); this association appeared to be more prominent during child-bearing years for females. Males and females did not significantly differ with respect to the odds of poorer outcome as defined by the number of days to return of normal activities or the number of days of work missed. Female sex is associated with significantly higher odds of poor outcome after mTBI, as measured by PCS score, after control for appropriate confounders. The observed pattern of peak disability for females during the child-bearing years suggests disruption of endogenous estrogen or progesterone production. Attempts to better understand how mTBI affects production of these hormones acutely after injury and during the recovery period may shed light on the mechanism behind poorer outcome among females and putative therapeutic interventions.
The goal of the current investigation was to detect clinically important axonal damage in cerebra... more The goal of the current investigation was to detect clinically important axonal damage in cerebral white matter after mild traumatic brain injury (TBI) using diffusion tensor imaging (DTI). To this end, we evaluated a prospective, pilot study of six subjects with isolated mild TBI and six matched orthopedic controls. All subjects underwent DTI scanning, post-concussive symptom (PCS) assessment, and neurobehavioral testing within 72 h of injury. Fractional anisotropy (FA) and trace values in white matter voxels of whole brain and five preslected regions of interest (ROI) were compared in mild TBI and control subjects using a quantile approach. In addition, whole brain images were analyzed using voxel-based morphometry. All subjects underwent quality of life and repeat PCS assessment at 1 month. Whole brain images revealed significantly lower st percentile trace values (mean 0.465 vs. 0.488, p ؍ 0.049) among mild TBI subjects. These trace values correlated with PCS scores at both 72 h (r ؍ ؊0.57, p ؍ 0.05) and 1 month (r ؍ ؊0.61, p ؍ 0.04). Analysis of ROIs showed mild TBI subjects to have significantly lower mean trace in the left anterior internal capsule (0.536 vs. 0.574, p ؍ 0.007) and higher maximum ROI-specific median FA values (mean 0.801 vs. 0.756, p ؍ 0.035) in the posterior corpus callosum. These FA values correlated with 72-h PCS score (r ؍ 0.63, p ؍ 0.03), and two neurobehavioral tests (visual motor speed [r ؍ ؊0.63, p ؍ 0.03] and impulse control [r ؍ 0.59, p ؍ 0.04])
The objective of the current study was to determine the classification accuracy of serum S100B an... more The objective of the current study was to determine the classification accuracy of serum S100B and apolipoprotein (apoA-I) for mild traumatic brain injury (mTBI) and abnormal initial head computed tomography (CT) scan, and to identify ethnic, racial, age, and sex variation in classification accuracy. We performed a prospective, multi-centered study of 787 patients with mTBI who presented to the emergency department within 6 h of injury and 467 controls who presented to the outpatient laboratory for routine blood work. Serum was analyzed for S100B and apoA-I. The outcomes were disease status (mTBI or control) and initial head CT scan. At cutoff values defined by 90% of controls, the specificity for mTBI using S100B (0.899 [95% confidence interval (CI): 0.78-0.92]) was similar to that using apoA-I (0.902 [0.87-0.93]), and the sensitivity using S100B (0.252 [0.22-0.28]) was similar to that using apoA-I (0.249 [0.22-0.28]). The area under the receiver operating characteristic curve (AUC) for the combination of S100B and apoA-I (0.738, 95% CI: 0.71, 0.77), however, was significantly higher than the AUC for S100B alone (0.709, 95% CI: 0.68, 0.74, p = 0.001) and higher than the AUC for apoA-I alone (0.645, 95% CI: 0.61, 0.68, p < 0.0001). The AUC for prediction of abnormal initial head CT scan using S100B was 0.694 (95%CI: 0.62, 0.77) and not significant for apoA-I. At a S100B cutoff of < 0.060 lg/L, the sensitivity for abnormal head CT was 98%, and 22.9% of CT scans could have been avoided. There was significant age and race-related variation in the accuracy of S100B for the diagnosis of mTBI. The combined use of serum S100B and apoA-I maximizes classification accuracy for mTBI, but only S100B is needed to classify abnormal head CT scan. Because of significant subgroup variation in classification accuracy, age and race need to be considered when using S100B to classify subjects for mTBI.
The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of ... more The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of most watersoluble molecules over 500 Da, is often disrupted after trauma. Post-traumatic BBB disruption may have important implications for prognosis and therapy. Assessment of BBB status is not routine in clinical practice because available techniques are invasive. The gold-standard measure, the cerebrospinal fluide (CSF)-serum albumin quotient (Q A ), requires the measurement of albumin in CSF and serum collected contemporaneously. Accurate, less invasive techniques are necessary. The objective of this study was to evaluate the relationship between Q A and serum concentrations of monomeric transthyretin (TTR) or S100B. Nine subjects with severe traumatic brain injury (TBI; Glasgow Coma Scale [GCS] score 8) and 11 subjects with non-traumatic headache who had CSF collected by ventriculostomy or lumbar puncture (LP) were enrolled. Serum and CSF were collected at the time of LP for headache subjects and at 12, 24, and 48 h after ventriculostomy for TBI subjects. The Q A was calculated for all time points at which paired CSF and serum samples were available. Serum S100B and TTR levels were also measured. Pearson's correlation coefficient and area under the receiver operating characteristic (ROC) curve were used to determine the relationship between the serum proteins and Q A . Seven TBI subjects had abnormal Q A 's indicating BBB dysfunction. The remaining TBI and control subjects had normal BBB function. No significant relationship between TTR and Q A was found. A statistically significant linear correlation between serum S100B and Q A was present (r ¼ 0.432, p ¼ 0.02). ROC analysis demonstrated a significant relationship between Q A and serum S100B concentrations at 12 h after TBI (AUC ¼ 0.800; SE 0.147, 95% CI 0.511-1.089). Using an S100B concentration cutoff of 0.027 ng=ml, specificity for abnormal Q A was 90% or higher at each time point. We conclude that serum S100B concentrations accurately indicate BBB dysfunction at 12 h after TBI.
The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of ... more The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of most watersoluble molecules over 500 Da, is often disrupted after trauma. Post-traumatic BBB disruption may have important implications for prognosis and therapy. Assessment of BBB status is not routine in clinical practice because available techniques are invasive. The gold-standard measure, the cerebrospinal fluide (CSF)-serum albumin quotient (Q A ), requires the measurement of albumin in CSF and serum collected contemporaneously. Accurate, less invasive techniques are necessary. The objective of this study was to evaluate the relationship between Q A and serum concentrations of monomeric transthyretin (TTR) or S100B. Nine subjects with severe traumatic brain injury (TBI; Glasgow Coma Scale [GCS] score 8) and 11 subjects with non-traumatic headache who had CSF collected by ventriculostomy or lumbar puncture (LP) were enrolled. Serum and CSF were collected at the time of LP for headache subjects and at 12, 24, and 48 h after ventriculostomy for TBI subjects. The Q A was calculated for all time points at which paired CSF and serum samples were available. Serum S100B and TTR levels were also measured. Pearson's correlation coefficient and area under the receiver operating characteristic (ROC) curve were used to determine the relationship between the serum proteins and Q A . Seven TBI subjects had abnormal Q A 's indicating BBB dysfunction. The remaining TBI and control subjects had normal BBB function. No significant relationship between TTR and Q A was found. A statistically significant linear correlation between serum S100B and Q A was present (r ¼ 0.432, p ¼ 0.02). ROC analysis demonstrated a significant relationship between Q A and serum S100B concentrations at 12 h after TBI (AUC ¼ 0.800; SE 0.147, 95% CI 0.511-1.089). Using an S100B concentration cutoff of 0.027 ng=ml, specificity for abnormal Q A was 90% or higher at each time point. We conclude that serum S100B concentrations accurately indicate BBB dysfunction at 12 h after TBI.
The emergency management of cerebral concussion typically centers on the decision to perform a he... more The emergency management of cerebral concussion typically centers on the decision to perform a head computed tomography (CT) scan, which only rarely detects hemorrhagic lesions requiring neurosurgery. The absence of hemorrhage on CT scan often is equated with a lack of brain injury. However, observational studies revealing poor long-term cognitive outcome after concussion suggest that brain injury may be present despite a normal CT scan. To explore this idea further, the authors reviewed the evidence for objective neurologic injury in humans after concussion, with particular emphasis on those with a normal brain CT. This evidence comes from studies involving brain tissue pathology, CT scanning, magnetic resonance image (MRI) scanning, serum biomarkers, formal cognitive and balance tests, functional MRI, positron emission tomography, and single-photon emission computed tomography scanning. Each section is accompanied by technical information to help the reader understand what these tests are, not to endorse their use clinically. The authors discuss the strengths and weaknesses of the evidence in each case. These reports make a compelling case for the existence of concussion as a clinically relevant disease with demonstrable neurologic pathology. Areas for future emergency medicine research are suggested.
Background: The on-field diagnosis of sports-related concussion (SRC) is complicated by the lack ... more Background: The on-field diagnosis of sports-related concussion (SRC) is complicated by the lack of an accurate and objective marker of brain injury.
Mild traumatic brain injury (mTBI) refers to the clinical condition of transient alteration of co... more Mild traumatic brain injury (mTBI) refers to the clinical condition of transient alteration of consciousness as a result of traumatic injury to the brain. The priority of emergency care is to identify and facilitate the treatment of rare but potentially life-threatening intracranial injuries associated with mTBI through the judicious application of appropriate imaging studies and neurosurgical consultation. Although post-mTBI symptoms quickly and completely resolve in the vast majority of cases, a significant number of patients will complain of lasting problems that may cause significant disability. Simple and early interventions such as patient education and appropriate referral can reduce the likelihood of chronic symptoms. Although definitive evidence is lacking, mTBI is likely to be related to significant long-term sequelae such as Alzheimer disease and other neurodegenerative processes.
Current approaches to diffusion tensor imaging (DTI) analysis do not permit identification of ind... more Current approaches to diffusion tensor imaging (DTI) analysis do not permit identification of individual-level changes in DTI indices. We investigated the ability of wild bootstrapping analysis to detect subject-specific changes in brain white matter (WM) before and after sports-related concussion. A prospective cohort study was performed in nine high school athletes engaged in hockey or football and six controls. Subjects underwent DTI pre- and postseason within a 3-month interval. One athlete was diagnosed with concussion (scanned within 72 h), and eight suffered between 26 and 399 subconcussive head blows. Fractional anisotropy (FA) and mean diffusivity (MD) were measured in each WM voxel. Bootstrap samples were generated, and a permuted t test was used to compare voxel-wise FA/MD changes in each subject pre- vs. postseason. The percentage of WM voxels with significant (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.05) pre-post FA changes was highest for the concussion subject (3.2%), intermediary for those with subconcussive head blows (mean 1.05%±.15%) and lowest for controls (mean 0.28%±.01%). Similarly, the percentage of WM voxels with significant MD changes was highest for the concussion subject (3.44%), intermediary for those with subconcussive head blows (mean 1.48%±.17%) and lowest for controls (mean 0.48%±.05%). Significantly changed FA and MD voxels colocalized in the concussion subject to the right corona radiata and right inferior longitudinal fasciculus. Wild bootstrap analysis detected significantly changed WM in a single concussed athlete. Athletes with multiple subconcussive head blows had significant changes in a percentage of their WM that was over three times higher than controls. Efforts to understand the significance of these WM changes and their relationship to head impact forces appear warranted.
The objective of this study was to estimate the independent association of sex with outcome after... more The objective of this study was to estimate the independent association of sex with outcome after mild traumatic brain injury (mTBI). We performed an analysis of a subset of an established cohort involving 1425 mTBI patients presenting to an academic emergency department (ED). The associations between sex and three outcomes determined 3 months after the initial ED visit were examined: post-concussive symptom (PCS) score (0, 1-5, 6-16, and >16), the number of days to return of normal activities (0, 1-7, and >7), and the number of days of work missed (0, 1-7,and >7). Logistic regression analyses were used to determine the relationship between sex and each outcome after controlling for 12 relevant subject-level variables. Of the 1425 subjects, 643 (45.1%) were female and 782 (54.9%) were male. Three months after mTBI, males had significantly lower odds of being in a higher PCS score category (odds ratio [OR] 0.62, 95% confidence interval [CI]: 0.50, 0.78); this association appeared to be more prominent during child-bearing years for females. Males and females did not significantly differ with respect to the odds of poorer outcome as defined by the number of days to return of normal activities or the number of days of work missed. Female sex is associated with significantly higher odds of poor outcome after mTBI, as measured by PCS score, after control for appropriate confounders. The observed pattern of peak disability for females during the child-bearing years suggests disruption of endogenous estrogen or progesterone production. Attempts to better understand how mTBI affects production of these hormones acutely after injury and during the recovery period may shed light on the mechanism behind poorer outcome among females and putative therapeutic interventions.
The goal of the current investigation was to detect clinically important axonal damage in cerebra... more The goal of the current investigation was to detect clinically important axonal damage in cerebral white matter after mild traumatic brain injury (TBI) using diffusion tensor imaging (DTI). To this end, we evaluated a prospective, pilot study of six subjects with isolated mild TBI and six matched orthopedic controls. All subjects underwent DTI scanning, post-concussive symptom (PCS) assessment, and neurobehavioral testing within 72 h of injury. Fractional anisotropy (FA) and trace values in white matter voxels of whole brain and five preslected regions of interest (ROI) were compared in mild TBI and control subjects using a quantile approach. In addition, whole brain images were analyzed using voxel-based morphometry. All subjects underwent quality of life and repeat PCS assessment at 1 month. Whole brain images revealed significantly lower st percentile trace values (mean 0.465 vs. 0.488, p ؍ 0.049) among mild TBI subjects. These trace values correlated with PCS scores at both 72 h (r ؍ ؊0.57, p ؍ 0.05) and 1 month (r ؍ ؊0.61, p ؍ 0.04). Analysis of ROIs showed mild TBI subjects to have significantly lower mean trace in the left anterior internal capsule (0.536 vs. 0.574, p ؍ 0.007) and higher maximum ROI-specific median FA values (mean 0.801 vs. 0.756, p ؍ 0.035) in the posterior corpus callosum. These FA values correlated with 72-h PCS score (r ؍ 0.63, p ؍ 0.03), and two neurobehavioral tests (visual motor speed [r ؍ ؊0.63, p ؍ 0.03] and impulse control [r ؍ 0.59, p ؍ 0.04])
The objective of the current study was to determine the classification accuracy of serum S100B an... more The objective of the current study was to determine the classification accuracy of serum S100B and apolipoprotein (apoA-I) for mild traumatic brain injury (mTBI) and abnormal initial head computed tomography (CT) scan, and to identify ethnic, racial, age, and sex variation in classification accuracy. We performed a prospective, multi-centered study of 787 patients with mTBI who presented to the emergency department within 6 h of injury and 467 controls who presented to the outpatient laboratory for routine blood work. Serum was analyzed for S100B and apoA-I. The outcomes were disease status (mTBI or control) and initial head CT scan. At cutoff values defined by 90% of controls, the specificity for mTBI using S100B (0.899 [95% confidence interval (CI): 0.78-0.92]) was similar to that using apoA-I (0.902 [0.87-0.93]), and the sensitivity using S100B (0.252 [0.22-0.28]) was similar to that using apoA-I (0.249 [0.22-0.28]). The area under the receiver operating characteristic curve (AUC) for the combination of S100B and apoA-I (0.738, 95% CI: 0.71, 0.77), however, was significantly higher than the AUC for S100B alone (0.709, 95% CI: 0.68, 0.74, p = 0.001) and higher than the AUC for apoA-I alone (0.645, 95% CI: 0.61, 0.68, p < 0.0001). The AUC for prediction of abnormal initial head CT scan using S100B was 0.694 (95%CI: 0.62, 0.77) and not significant for apoA-I. At a S100B cutoff of < 0.060 lg/L, the sensitivity for abnormal head CT was 98%, and 22.9% of CT scans could have been avoided. There was significant age and race-related variation in the accuracy of S100B for the diagnosis of mTBI. The combined use of serum S100B and apoA-I maximizes classification accuracy for mTBI, but only S100B is needed to classify abnormal head CT scan. Because of significant subgroup variation in classification accuracy, age and race need to be considered when using S100B to classify subjects for mTBI.
The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of ... more The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of most watersoluble molecules over 500 Da, is often disrupted after trauma. Post-traumatic BBB disruption may have important implications for prognosis and therapy. Assessment of BBB status is not routine in clinical practice because available techniques are invasive. The gold-standard measure, the cerebrospinal fluide (CSF)-serum albumin quotient (Q A ), requires the measurement of albumin in CSF and serum collected contemporaneously. Accurate, less invasive techniques are necessary. The objective of this study was to evaluate the relationship between Q A and serum concentrations of monomeric transthyretin (TTR) or S100B. Nine subjects with severe traumatic brain injury (TBI; Glasgow Coma Scale [GCS] score 8) and 11 subjects with non-traumatic headache who had CSF collected by ventriculostomy or lumbar puncture (LP) were enrolled. Serum and CSF were collected at the time of LP for headache subjects and at 12, 24, and 48 h after ventriculostomy for TBI subjects. The Q A was calculated for all time points at which paired CSF and serum samples were available. Serum S100B and TTR levels were also measured. Pearson's correlation coefficient and area under the receiver operating characteristic (ROC) curve were used to determine the relationship between the serum proteins and Q A . Seven TBI subjects had abnormal Q A 's indicating BBB dysfunction. The remaining TBI and control subjects had normal BBB function. No significant relationship between TTR and Q A was found. A statistically significant linear correlation between serum S100B and Q A was present (r ¼ 0.432, p ¼ 0.02). ROC analysis demonstrated a significant relationship between Q A and serum S100B concentrations at 12 h after TBI (AUC ¼ 0.800; SE 0.147, 95% CI 0.511-1.089). Using an S100B concentration cutoff of 0.027 ng=ml, specificity for abnormal Q A was 90% or higher at each time point. We conclude that serum S100B concentrations accurately indicate BBB dysfunction at 12 h after TBI.
The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of ... more The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of most watersoluble molecules over 500 Da, is often disrupted after trauma. Post-traumatic BBB disruption may have important implications for prognosis and therapy. Assessment of BBB status is not routine in clinical practice because available techniques are invasive. The gold-standard measure, the cerebrospinal fluide (CSF)-serum albumin quotient (Q A ), requires the measurement of albumin in CSF and serum collected contemporaneously. Accurate, less invasive techniques are necessary. The objective of this study was to evaluate the relationship between Q A and serum concentrations of monomeric transthyretin (TTR) or S100B. Nine subjects with severe traumatic brain injury (TBI; Glasgow Coma Scale [GCS] score 8) and 11 subjects with non-traumatic headache who had CSF collected by ventriculostomy or lumbar puncture (LP) were enrolled. Serum and CSF were collected at the time of LP for headache subjects and at 12, 24, and 48 h after ventriculostomy for TBI subjects. The Q A was calculated for all time points at which paired CSF and serum samples were available. Serum S100B and TTR levels were also measured. Pearson's correlation coefficient and area under the receiver operating characteristic (ROC) curve were used to determine the relationship between the serum proteins and Q A . Seven TBI subjects had abnormal Q A 's indicating BBB dysfunction. The remaining TBI and control subjects had normal BBB function. No significant relationship between TTR and Q A was found. A statistically significant linear correlation between serum S100B and Q A was present (r ¼ 0.432, p ¼ 0.02). ROC analysis demonstrated a significant relationship between Q A and serum S100B concentrations at 12 h after TBI (AUC ¼ 0.800; SE 0.147, 95% CI 0.511-1.089). Using an S100B concentration cutoff of 0.027 ng=ml, specificity for abnormal Q A was 90% or higher at each time point. We conclude that serum S100B concentrations accurately indicate BBB dysfunction at 12 h after TBI.
The emergency management of cerebral concussion typically centers on the decision to perform a he... more The emergency management of cerebral concussion typically centers on the decision to perform a head computed tomography (CT) scan, which only rarely detects hemorrhagic lesions requiring neurosurgery. The absence of hemorrhage on CT scan often is equated with a lack of brain injury. However, observational studies revealing poor long-term cognitive outcome after concussion suggest that brain injury may be present despite a normal CT scan. To explore this idea further, the authors reviewed the evidence for objective neurologic injury in humans after concussion, with particular emphasis on those with a normal brain CT. This evidence comes from studies involving brain tissue pathology, CT scanning, magnetic resonance image (MRI) scanning, serum biomarkers, formal cognitive and balance tests, functional MRI, positron emission tomography, and single-photon emission computed tomography scanning. Each section is accompanied by technical information to help the reader understand what these tests are, not to endorse their use clinically. The authors discuss the strengths and weaknesses of the evidence in each case. These reports make a compelling case for the existence of concussion as a clinically relevant disease with demonstrable neurologic pathology. Areas for future emergency medicine research are suggested.
Background: The on-field diagnosis of sports-related concussion (SRC) is complicated by the lack ... more Background: The on-field diagnosis of sports-related concussion (SRC) is complicated by the lack of an accurate and objective marker of brain injury.
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