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Diffusion tensor imaging (DTI) literature on single-center studies contains conflicting results regarding acute effects of mild traumatic brain injury (mTBI) on white matter (WM) microstructure and the prognostic significance. This larger-scale multi-center DTI study aimed to determine how acute mTBI affects WM microstructure over time and how early WM changes affect long-term outcome. From Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI), a cohort study at 11 United States level 1 trauma centers, a total of 391 patients with acute mTBI ages 17 to 60 years were included and studied at two weeks and six months post-injury. Demographically matched friends or family of the participants were the control group (in/i = 148). Axial diffusivity (AD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were the measures of WM microstructure. The primary outcome was the Glasgow Outcome Scale Extended (GOSE) score of injury-related functional limitations across broad life domains at six months post-injury. The AD, MD, and RD were higher and FA was lower in mTBI versus friend control (FC) at both two weeks and six months post-injury throughout most major WM tracts of the cerebral hemispheres. In the mTBI group, AD and, to a lesser extent, MD decreased in WM from two weeks to six months post-injury. At two weeks post-injury, global WM AD and MD were both independently associated with six-month incomplete recovery (GOSElt;8 vs = 8) even after accounting for demographic, clinical, and other imaging factors. DTI provides reliable imaging biomarkers of dynamic WM microstructural changes after mTBI that have utility for patient selection and treatment response in clinical trials. Continued technological advances in the sensitivity, specificity, and precision of diffusion magnetic resonance imaging hold promise for routine clinical application in mTBI.

Polytrauma and traumatic brain injury (TBI) frequently co-occur and outcomes are routinely measured by the Glasgow Outcome Scale-Extended (GOSE). Polytrauma may confound GOSE measurement of TBI-specific outcomes. Adult patients with TBI from the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study had presented to a Level 1 trauma center after injury, received head computed tomography (CT) within 24 h, and completed the GOSE at 3 months and 6 months post-injury. Polytrauma was defined as an Abbreviated Injury Score (AIS) ≥3 in any extracranial region. Univariate regressions were performed using known GOSE clinical cutoffs. Multi-variable regressions were performed for the 3- and 6-month GOSE, controlling for known demographic and injury predictors. Of 361 subjects (age 44.9 ± 18.9 years, 69.8% male), 69 (19.1%) suffered polytrauma. By Glasgow Coma Scale (GCS) assessment, 80.1% had mild, 5.8% moderate, and 14.1% severe TBI. On univariate logistic regression, polytrauma was associated with increased odds of moderate disability or worse (GOSE ≤6; 3 month odds ratio [OR] = 2.57 [95% confidence interval (CI): 1.50-4.41; 6 month OR = 1.70 [95% CI: 1.01-2.88]) and death/severe disability (GOSE ≤4; 3 month OR = 3.80 [95% CI: 2.03-7.11]; 6 month OR = 3.33 [95% CI: 1.71-6.46]). Compared with patients with isolated TBI, more polytrauma patients experienced a decline in GOSE from 3 to 6 months (37.7 vs. 24.7%), and fewer improved (11.6 vs. 22.6%). Polytrauma was associated with greater univariate ordinal odds for poorer GOSE (3 month OR = 2.79 [95% CI: 1.73-4.49]; 6 month OR = 1.73 [95% CI: 1.07-2.79]), which was conserved on multi-variable ordinal regression (3 month OR = 3.05 [95% CI: 1.76-5.26]; 6 month OR = 2.04 [95% CI: 1.18-3.42]). Patients with TBI with polytrauma are at greater risk for 3- and 6-month disability compared with those with isolated TBI. Methodological improvements in assessing TBI-specific disability, versus disability attributable to all systemic injuries, will generate better TBI outcomes assessment tools.

Background:High-quality data are critical to the entire scientific enterprise, yet the complexity and effort involved in data curation are vastly under-appreciated. This is especially true for large observational, clinical studies because of the amount of multimodal data that is captured and the opportunity for addressing numerous research questions through analysis, either alone or in combination with other data sets. However, a lack of details concerning data curation methods can result in unresolved questions about the robustness of the data, its utility for addressing specific research questions or hypotheses and how to interpret the results. We aimed to develop a framework for the design, documentation and reporting of data curation methods in order to advance the scientific rigour, reproducibility and analysis of the data.Methods:Forty-six experts participated in a modified Delphi process to reach consensus on indicators of data curation that could be used in the design and reporting of studies.Results:We identified 46 indicators that are applicable to the design, training/testing, run time and post-collection phases of studies.Conclusion:The Data Acquisition, Quality and Curation for Observational Research Designs (DAQCORD) Guidelines are the first comprehensive set of data quality indicators for large observational studies. They were developed around the needs of neuroscience projects, but we believe they are relevant and generalisable, in whole or in part, to other fields of health research, and also to smaller observational studies and preclinical research. The DAQCORD Guidelines provide a framework for achieving high-quality data; a cornerstone of health research.

Key Points Question Is posttraumatic epilepsy (PTE) associated with unfavorable functional outcomes after traumatic brain injury (TBI)? Findings In this cohort study that included 3296 individuals, the incidence of self-reported diagnosis of PTE at 1 year after injury among individuals who had experienced TBI was 2.8%. Patients with PTE had worse outcome scores at 1 year after injury compared with those without PTE, even after accounting for injury severity and neuroimaging findings on cranial computed tomography. Meaning These findings suggest that PTE is a significant sequela of TBI with adverse associations with recovery., This cohort study assesses the incidence, risk factors, and functional outcomes associated with self-reported posttraumatic epilepsy in patients with traumatic brain injury., Importance Posttraumatic epilepsy (PTE) is a recognized sequela of traumatic brain injury (TBI), but the long-term outcomes associated with PTE independent of injury severity are not precisely known. Objective To determine the incidence, risk factors, and association with functional outcomes and self-reported somatic, cognitive, and psychological concerns of self-reported PTE in a large, prospectively collected TBI cohort. Design, Setting, and Participants This multicenter, prospective cohort study was conducted as part of the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study and identified patients presenting with TBI to 1 of 18 participating level 1 US trauma centers from February 2014 to July 2018. Patients with TBI, extracranial orthopedic injuries (orthopedic controls), and individuals without reported injuries (eg, friends and family of participants; hereafter friend controls) were prospectively followed for 12 months. Data were analyzed from January 2020 to April 2021. Exposure Demographic, imaging, and clinical information was collected according to TBI Common Data Elements. Incidence of self-reported PTE was assessed using the National Institute of Neurological Disorders and Stroke Epilepsy Screening Questionnaire (NINDS-ESQ). Main Outcomes and Measures Primary outcomes included Glasgow Outcome Scale Extended, Rivermead Cognitive Metric (RCM; derived from the Rivermead Post Concussion Symptoms Questionnaire), and the Brief Symptom Inventory-18 (BSI). Results Of 3296 participants identified as part of the study, 3044 met inclusion criteria, and 1885 participants (mean [SD] age, 41.3 [17.1] years; 1241 [65.8%] men and 644 [34.2%] women) had follow-up information at 12 months, including 1493 patients with TBI; 182 orthopedic controls, 210 uninjured friend controls; 41 patients with TBI (2.8%) and no controls had positive screening results for PTE. Compared with a negative screening result for PTE, having a positive screening result for PTE was associated with presenting Glasgow Coma Scale score (8.1 [4.8] vs.13.5 [3.3]; P

In nearly all clinical and research contexts, the initial severity of a traumatic brain injury (TBI) is measured using the Glasgow Coma Scale (GCS) total score. However, the GCS total score may not accurately reflect level of consciousness, a critical indicator of injury severity. We investigated the relationship between GCS total scores and level of consciousness in a consecutive sample of 2,455 adult subjects assessed with the GCS 69,487 times as part of the multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. We assigned each GCS subscale score combination a level of consciousness rating based upon published criteria for the following disorders of consciousness (DoC) diagnoses: coma, vegetative state/unresponsive wakefulness syndrome, minimally conscious state, and post-traumatic confusional state, and present our findings using summary statistics and four illustrative cases. Participants had the following characteristics: mean (standard deviation) age 41.9 (17.6) years, 69% male, initial GCS 3-8=13%; 9-12=5%; 13-15=82%. All GCS total scores between 4-14 were associated with more than one DoC diagnosis; the greatest variability was observed for scores of 7-11. Furthermore, a wide range of total scores were associated with identical DoC diagnoses. Importantly, a diagnosis of coma was only possible with GCS total scores of 3-6. The GCS total score does not accurately reflect level of consciousness based on published DoC diagnostic criteria. To improve the classification of patients with TBI and to inform the design of future clinical trials, clinicians and investigators should consider individual subscale behaviors and more comprehensive assessments when evaluating TBI severity.

Key Points Question Are different patterns of intracranial injury on head computed tomography associated with prognosis after mild traumatic brain injury (mTBI)? Findings In this cohort study, subarachnoid hemorrhage, subdural hematoma, and contusion often co-occurred and were associated with both incomplete recovery and more severe impairment out to 12 months after injury, while intraventricular and/or petechial hemorrhage co-occurred and were associated with more severe impairment up to 12 months after injury; epidural hematoma was associated with incomplete recovery at some points but not with more severe impairment. Some intracranial hemorrhage patterns were more strongly associated with outcomes than previously validated demographic and clinical variables. Meaning In this study, different pathological features on head computed tomography carried different implications for mild traumatic brain injury prognosis to 1 year., The longitudinal, observational study aims to identify pathological computed tomography features associated with adverse outcomes after mild traumatic brain injury., Importance A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood. Objective To identify pathological CT features associated with adverse outcomes after mTBI. Design, Setting, and Participants The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale–Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021. Exposures Acute nonpenetrating head trauma. Main Outcomes and Measures Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores

Importance Moderate to severe traumatic brain injury (msTBI) is a major cause of death and disability in the US and worldwide. Few studies have enabled prospective, longitudinal outcome data collection from the acute to chronic phases of recovery after msTBI. Objective To prospectively assess outcomes in major areas of life function at 2 weeks and 3, 6, and 12 months after msTBI. Design, Setting, and Participants This cohort study, as part of the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, was conducted at 18 level 1 trauma centers in the US from February 2014 to August 2018 and prospectively assessed longitudinal outcomes, with follow-up to 12 months postinjury. Participants were patients with msTBI (Glasgow Coma Scale scores 3-12) extracted from a larger group of patients with mild, moderate, or severe TBI who were enrolled in TRACK-TBI. Data analysis took place from October 2019 to April 2021. Exposures Moderate or severe TBI. Main Outcomes and Measures The Glasgow Outcome Scale–Extended (GOSE) and Disability Rating Scale (DRS) were used to assess global functional status 2 weeks and 3, 6, and 12 months postinjury. Scores on the GOSE were dichotomized to determine favorable (scores 4-8) vs unfavorable (scores 1-3) outcomes. Neurocognitive testing and patient reported outcomes at 12 months postinjury were analyzed. Results A total of 484 eligible patients were included from the 2679 individuals in the TRACK-TBI study. Participants with severe TBI (n = 362; 283 men [78.2%]; median [interquartile range] age, 35.5 [25-53] years) and moderate TBI (n = 122; 98 men [80.3%]; median [interquartile range] age, 38 [25-53] years) were comparable on demographic and premorbid variables. At 2 weeks postinjury, 36 of 290 participants with severe TBI (12.4%) and 38 of 93 participants with moderate TBI (41%) had favorable outcomes (GOSE scores 4-8); 301 of 322 in the severe TBI group (93.5%) and 81 of 103 in the moderate TBI group (78.6%) had moderate disability or worse on the DRS (total score ≥4). By 12 months postinjury, 142 of 271 with severe TBI (52.4%) and 54 of 72 with moderate TBI (75%) achieved favorable outcomes. Nearly 1 in 5 participants with severe TBI (52 of 270 [19.3%]) and 1 in 3 with moderate TBI (23 of 71 [32%]) reported no disability (DRS score 0) at 12 months. Among participants in a vegetative state at 2 weeks, 62 of 79 (78%) regained consciousness and 14 of 56 with available data (25%) regained orientation by 12 months. Conclusions and Relevance In this study, patients with msTBI frequently demonstrated major functional gains, including recovery of independence, between 2 weeks and 12 months postinjury. Severe impairment in the short term did not portend poor outcomes in a substantial minority of patients with msTBI. When discussing prognosis during the first 2 weeks after injury, clinicians should be particularly cautious about making early, definitive prognostic statements suggesting poor outcomes and withdrawal of life-sustaining treatment in patients with msTBI.

Introduction: Risk factors for young adults with mTBI are not well understood. Improved understanding of age and sex as risk factors for impaired six-month outcomes in young adults is needed.Methods: Young adult mTBI subjects aged 18-39 years (18-29y; 30-39y) with six-month outcomes were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study. Multivariable regressions were performed for outcomes with age, sex, and the interaction factor age-group*sex as variables of interest, controlling for demographic and injury variables. Mean-differences (B) and 95% CIs are reported.Results: One hundred mTBI subjects (18-29y, 70%; 30-39y, 30%; male, 71%; female, 29%) met inclusion criteria. On multivariable analysis, age-group*sex was associated with six-month post-traumatic stress disorder (PTSD; PTSD Checklist-Civilian version); compared with female 30-39y, female 18-29y (B= -19.55 [-26.54, -4.45]), male 18-29y (B= -19.70 [-30.07, -9.33]), and male 30-39y (B= -15.49 [-26.54, -4.45]) were associated with decreased PTSD symptomatology. Female sex was associated with decreased six-month functional outcome (Glasgow Outcome Scale-Extended (GOSE): B= -0.6 [1.0, -0.1]). Comparatively, 30-39y scored higher on six-month nonverbal processing speed (Wechsler Adult Intelligence Scale-Processing Speed Index (WAIS-PSI); B= 11.88, 95% CI [1.66, 22.09]).Conclusions: Following mTBI, young adults aged 18-29y and 30-39y may have different risks for impairment. Sex may interact with age for PTSD symptomatology, with females 30-39y at highest risk. These results may be attributable to cortical maturation, biological response, social modifiers, and/or differential self-report. Confirmation in larger samples is needed; however, prevention and rehabilitation/counseling strategies after mTBI should likely be tailored for age and sex.

Introduction Return to work (RTW) is an important milestone of mild traumatic brain injury (mTBI) recovery. The objective of this study was to evaluate whether baseline clinical variables, three-month RTW, and three-month postconcussional symptoms (PCS) were associated with six-month RTW after mTBI. Methods Adult subjects from the prospective multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot study with mTBI (Glasgow Coma Scale 13–15) who were employed at baseline, with completed three- and six-month RTW status, and three-month Acute Concussion Evaluation (ACE), were extracted. Univariate and multivariable analyses were performed for six-month RTW, with focus on baseline employment, three-month RTW, and three-month ACE domains (physical, cognitive, sleep, and/or emotional postconcussional symptoms (PCS)). Odds ratios (OR) and 95% confidence intervals [CI] were reported. Significance was assessed at p Results In 152 patients aged 40.7 ± 15.0 years, 72% were employed full-time at baseline. Three- and six-month RTW were 77.6% and 78.9%, respectively. At three months, 59.2%, 47.4%, 46.1% and 31.6% scored positive for ACE physical, cognitive, sleep, and emotional PCS domains, respectively. Three-month RTW predicted six-month RTW (OR = 19.80, 95% CI [7.61–51.52]). On univariate analysis, scoring positive in any three-month ACE domain predicted inability for six-month RTW (OR = 0.10–0.11). On multivariable analysis, emotional symptoms predicted inability to six-month RTW (OR = 0.19 [0.04–0.85]). Subjects who scored positive in all four ACE domains were more likely to be unable to RTW at six months (4 domains: 58.3%, vs. 0-to-3 domains: 9.5%; multivariable OR = 0.09 [0.02–0.33]). Conclusions Three-month post-injury is an important time point at which RTW status and PCS should be assessed, as both are prognostic markers for six-month RTW. Clinicians should be particularly vigilant of patients who present with emotional symptoms, and patients with symptoms across multiple PCS categories, as these patients are at further risk of inability to RTW and may benefit from targeted evaluation and support.

Systemic inflammation impacts outcome after traumatic brain injury (TBI), but most TBI biomarker studies have focused on brain-specific proteins. C-reactive protein (CRP) is a widely used biomarker of inflammation with potential as a prognostic biomarker after TBI. The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study prospectively enrolled TBI patients within 24 h of injury, as well as orthopedic injury and uninjured controls; biospecimens were collected at enrollment. A subset of hospitalized participants had blood collected on day 3, day 5, and 2 weeks. High-sensitivity CRP (hsCRP) and glial fibrillary acidic protein (GFAP) were measured. Receiver operating characteristic analysis was used to evaluate the prognostic ability of hsCRP for 6-month outcome, using the Glasgow Outcome Scale-Extended (GOSE). We included 1206 TBI subjects, 122 orthopedic trauma controls (OTCs), and 209 healthy controls (HCs). Longitudinal biomarker sampling was performed in 254 hospitalized TBI subjects and 19 OTCs. hsCRP rose between days 1 and 5 for TBI and OTC subjects, and fell by 2 weeks, but remained elevated compared with HCs (p

Background Brain volumes in regions such as the hippocampus and amygdala have been associated with risk for the development of posttraumatic stress disorder (PTSD). The objective of this study was to determine whether a set of regional brain volumes, measured by magnetic resonance imaging at 2 weeks following mild traumatic brain injury, were predictive of PTSD at 3 and 6 months after injury. Methods Using data from TRACK-TBI (Transforming Research and Clinical Knowledge in TBI), we included patients (N = 421) with Glasgow Coma Scale scores 13–15 assessed after evaluation in the emergency department and at 2 weeks, 3 months, and 6 months after injury. Probable PTSD diagnosis (PTSD Checklist for DSM-5 score, ≥33) was the outcome. FreeSurfer 6.0 was used to perform volumetric analysis of three-dimensional T1-weighted magnetic resonance images at 3T obtained 2 weeks post injury. Brain regions selected a priori for volumetric analyses were insula, hippocampus, amygdala, superior frontal cortex, rostral and caudal anterior cingulate, and lateral and medial orbitofrontal cortices. Results Overall, 77 (18.3%) and 70 (16.6%) patients had probable PTSD at 3 and 6 months. A composite volume derived as the first principal component incorporating 73.8% of the variance in insula, superior frontal cortex, and rostral and caudal cingulate contributed to the prediction of 3-month (but not 6-month) PTSD in multivariable models incorporating other established risk factors. Conclusions Results, while needing replication, provide support for a brain reserve hypothesis of PTSD and proof of principle for how prediction of at-risk individuals might be accomplished to enhance prognostic accuracy and enrich clinical prevention trials for individuals at the highest risk of PTSD following mild traumatic brain injury.

We report white matter changes after mild traumatic brain injury and their relationship with self-reported and cognitive symptoms., Neuroimaging biomarkers that can detect white matter (WM) pathology after mild traumatic brain injury (mTBI) and predict long-term outcome are needed to improve care and develop therapies. We used diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to investigate WM microstructure cross-sectionally and longitudinally after mTBI and correlate these with neuropsychological performance. Cross-sectionally, early decreases of fractional anisotropy and increases of mean diffusivity corresponded to WM regions with elevated free water fraction on NODDI. This elevated free water was more extensive in the patient subgroup reporting more early postconcussive symptoms. The longer-term longitudinal WM changes consisted of declining neurite density on NODDI, suggesting axonal degeneration from diffuse axonal injury for which NODDI is more sensitive than DTI. Therefore, NODDI is a more sensitive and specific biomarker than DTI for WM microstructural changes due to mTBI that merits further study for mTBI diagnosis, prognosis, and treatment monitoring.

Substance use is commonly associated with traumatic brain injury (TBI). We investigate associations between active substance use, peri-injury factors, and outcome after TBI across three U.S. Level I trauma centers. TBI subjects from the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) with Marshall computed tomography (CT) score 1-3, no neurosurgical procedure/operation, and admission urine toxicology screen (tox+/-) were extracted. Associations between tox+/-, comorbidities, hospital variables, and six-month functional (GOSE) and neuropsychiatric (PCL-C, BSI18, RPQ-13, SWLS) outcomes were analyzed. Multivariable regression was performed for associations significant on univariate analysis with odds ratios (mOR) presented. Significance assessed at p 0.05. In 133 subjects, tox+/tox- were 29.1%/72.9%. Tox+ was younger (35.5/43.6-years, p = 0.018), trended toward male sex (80.6%/63.9%, p = 0.067), was associated with history of seizures (27.8%/10.3%, p = 0.012), self-reported substance use (44.4%/17.5%, p = 0.001), prior TBI (58.8%/34.1%, p = 0.009), GCS 15 (69.4%/48.4%, p = 0.031) and blood alcohol level0.08-mg/dl (55.6%/30.8%, p = 0.022). In CT-negative subjects, tox+ was associated with increased hospital admission (95.7%/66.7%, p = 0.034). At six-months, tox+ was associated with screening positive for post-traumatic stress disorder (PCL-C: 40.0%/15.9%; mOR = 8.24, p = 0.022) and psychiatric symptoms (BSI18: 40.0%/14.3%, mOR = 11.06, p = 0.023). Active substance use in TBI may confound GCS assessment, triage to higher level of care, and be associated with increased six-month neuropsychiatric symptoms. Substance use screening should be integrated into standard emergency/acute care TBI protocols to optimize management and resource utilization. Clinicians should be vigilant in providing education, counselling, and follow-up for TBI patients with substance use.

INTRODUCTION: Mild traumatic brain injury (MTBI) can cause persistent functional deficits and healthcare burden. Intracerebral contusions cause permanent parenchymal injury, and understanding their association with outcomes may aid in treatment and prognosis. METHODS: Adult MTBI patients with arrival GCS 13–15 and six-month outcomes [Glasgow Outcome Scale Extended (GOSE)], without polytrauma or operative neurosurgery from the prospective TRACK-TBI Pilot study were analyzed. Intracranial contusions detected by computed tomography (CT) were coded by location. Multivariable regression evaluated associations between intracranial injury type (temporal contusion (TC), frontal contusion, extraaxial [epidural/subdural/subarachnoid], other-intraaxial [intracerebral/intraventricular hemorrhage, axonal injury]) and GOSE. Odds ratios (OR) are reported. RESULTS: Overall, 260 MTBI subjects were aged 44.4±18.1-years and 67.7%-male. Ninety-seven subjects were CT-positive, of which 46 had contusions (41.3%-frontal, 30.4%-temporal, 21.7%-frontal+temporal, 2.2%-parietal, 2.2%-occipital, 2.2%-brainstem); 95.7% had concurrent extraaxial hemorrhage. Mortality was 0% at discharge and 2.3% by six months. Six-month GOSE was distributed with 2.3%-death, 1.5%-severe disability, 27.7%-moderate disability, 68.5%-good recovery. Nearly 46% of TC-positive subjects suffered moderate disability or worse (GOSE≤6) and 41.7% were unable to return to baseline work capacity (RTBWC), compared to 29.1%/20.4% for CT-negative and 26.1%/20.9% for CT-positive subjects without TC. On multivariable regression, TC associated with OR=3.33 (95% CI [1.16–9.60], p=0.026) for GOSE≤6, and OR=4.48 ([1.49–13.51], p=0.008) for inability to RTBWC. CONCLUSIONS: Parenchymal contusions in MTBI are often accompanied by extraaxial hemorrhage. TCs may be associated with six-month functional impairment. Their presence on imaging should alert the clinician to the need for heightened surveillance of sequelae complicating RTBWC, with low threshold for referral to services.

The relationship between blood alcohol level (BAL) and mild traumatic brain injury (mTBI) remains in need of improved characterization. Adult patients suffering mTBI without intracranial pathology on computed tomography (CT) from the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot study with emergency department (ED) Glasgow Coma Scale (GCS) 13-15 and recorded blood alcohol level (BAL) were extracted. BAL≥80-mg/dl was set as proxy for excessive use. Multivariable regression was performed for patients with six-month Glasgow Outcome Scale-Extended (GOSE; functional recovery) and Wechsler Adult Intelligence Scale Processing Speed Index Composite Score (WAIS-PSI; nonverbal processing speed), using BAL≥80-mg/dl and80-mg/dl cohorts, adjusting for demographic/injury factors. Overall, 107 patients were aged 42.7±16.8-years, 67.3%-male, and 80.4%-Caucasian; 65.4% had BAL=0-mg/dl, 4.6% BAL80-mg/dl, and 30.0% BAL≥80-mg/dl (range 100-440-mg/dl). BAL differed across loss of consciousness (LOC; none: median 0-mg/dl [interquartile range (IQR) 0-0],30-min: 0-mg/dl [0-43], ≥30-min: 224-mg/dl [50-269], unknown: 108-mg/dl [0-232]; p=0.002). GCS15 associated with higher BAL (19-mg/dl [0-204] vs. 0-mg/dl [0-20]; p=0.013). On univariate analysis, BAL≥80-mg/dl associated with less-than-full functional recovery (GOSE≤7; 38.1% vs. 11.5%; p=0.025) and lower WAIS-PSI (92.4±12.7, 30th-percentile vs. 105.1±11.7, 63rd-percentile; p0.001). On multivariable regression BAL≥80-mg/dl demonstrated an odds ratio of 8.05 (95% CI [1.35-47.92]; p=0.022) for GOSE≤7 and an adjusted mean decrease of 8.88-points (95% CI [0.67-17.09]; p=0.035) on WAIS-PSI. Day-of-injury BAL80-mg/dl after uncomplicated mTBI was associated with decreased GCS score and prolongation of reported LOC. BAL may be a biomarker for impaired return to baseline function and decreased nonverbal processing speed at six-months postinjury. Future confirmatory studies are needed.

Most traumatic brain injuries (TBIs) are classified as mild (mTBI) based on admission Glasgow Coma Scale (GCS) scores of 13 to 15. The prevalence of persistent functional limitations for these patients is unclear.To characterize the natural history of recovery of daily function following mTBI vs peripheral orthopedic traumatic injury in the first 12 months postinjury using data from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study, and, using clinical computed tomographic (CT) scans, examine whether the presence (CT+) or absence (CT-) of acute intracranial findings in the mTBI group was associated with outcomes.TRACK-TBI, a cohort study of patients with mTBI presenting to US level I trauma centers, enrolled patients from February 26, 2014, to August 8, 2018, and followed up for 12 months. A total of 1453 patients at 11 level I trauma center emergency departments or inpatient units met inclusion criteria (ie, mTBI [n = 1154] or peripheral orthopedic traumatic injury [n = 299]) and were enrolled within 24 hours of injury; mTBI participants had admission GCS scores of 13 to 15 and clinical head CT scans. Patients with peripheral orthopedic trauma injury served as the control (OTC) group.Participants with mTBI or OTC.The Glasgow Outcome Scale Extended (GOSE) scale score, reflecting injury-related functional limitations across broad life domains at 2 weeks and 3, 6, and 12 months postinjury was the primary outcome. The possible score range of the GOSE score is 1 (dead) to 8 (upper good recovery), with a score less than 8 indicating some degree of functional impairment.Of the 1453 participants, 953 (65.6%) were men; mean (SD) age was 40.9 (17.1) years in the mTBI group and 40.9 (15.4) years in the OTC group. Most participants (mTBI, 87%; OTC, 93%) reported functional limitations (GOSE8) at 2 weeks postinjury. At 12 months, the percentage of mTBI participants reporting functional limitations was 53% (95% CI, 49%-56%) vs 38% (95% CI, 30%-45%) for OTCs. A higher percentage of CT+ patients reported impairment (61%) compared with the mTBI CT- group (49%; relative risk [RR], 1.24; 95% CI, 1.08-1.43) and a higher percentage in the mTBI CT-group compared with the OTC group (RR, 1.28; 95% CI, 1.02-1.60).Most patients with mTBI presenting to US level I trauma centers report persistent, injury-related life difficulties at 1 year postinjury, suggesting the need for more systematic follow-up of patients with mTBI to provide treatments and reduce the risk of chronic problems after mTBI.

IMPORTANCE: Traumatic brain injury (TBI) has been associated with adverse mental health outcomes, such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), but little is known about factors that modify risk for these psychiatric sequelae, particularly in the civilian sector. OBJECTIVE: To ascertain prevalence of and risk factors for PTSD and MDD among patients evaluated in the emergency department for mild TBI (mTBI). DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal cohort study (February 2014 to May 2018). Posttraumatic stress disorder and MDD symptoms were assessed using the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9 Item. Risk factors evaluated included preinjury and injury characteristics. Propensity score weights-adjusted multivariable logistic regression models were performed to assess associations with PTSD and MDD. A total of 1155 patients with mTBI (Glasgow Coma Scale score, 13-15) and 230 patients with nonhead orthopedic trauma injuries 17 years and older seen in 11 US hospitals with level 1 trauma centers were included in this study. MAIN OUTCOMES AND MEASURES: Probable PTSD (PTSD Checklist for DSM-5 score, ≥33) and MDD (Patient Health Questionnaire-9 Item score, ≥15) at 3, 6, and 12 months postinjury. RESULTS: Participants were 1155 patients (752 men [65.1%]; mean [SD] age, 40.5 [17.2] years) with mTBI and 230 patients (155 men [67.4%]; mean [SD] age, 40.4 [15.6] years) with nonhead orthopedic trauma injuries. Weights-adjusted prevalence of PTSD and/or MDD in the mTBI vs orthopedic trauma comparison groups at 3 months was 20.0% (SE, 1.4%) vs 8.7% (SE, 2.2%) (P

Key Points Question Do postacute mild traumatic brain injury (mTBI) symptoms differ between men and women? Findings In this cohort study of 2000 patients with mTBI, the severity of cognitive and somatic symptoms on the Rivermead Post Concussion Symptoms Questionnaire at 12 months after injury was significantly worse in women than in men, whereas this difference was not significant in an orthopedic trauma control group. The association between mTBI and somatic symptoms was greater in women aged 35 to 49 years than those aged 17 to 34 years or older than 50 years. Meaning Sex and age may be important factors in the individualized, postacute treatment of patients with mTBI., This cohort study uses data from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study to assess whether patient sex and age are associated with mild traumatic brain injury symptoms., Importance Knowledge of differences in mild traumatic brain injury (mTBI) recovery by sex and age may inform individualized treatment of these patients. Objective To identify sex-related differences in symptom recovery from mTBI; secondarily, to explore age differences within women, who demonstrate poorer outcomes after TBI. Design, Setting, and Participants The prospective cohort study Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) recruited 2000 patients with mTBI from February 26, 2014, to July 3, 2018, and 299 patients with orthopedic trauma (who served as controls) from January 26, 2016, to July 27, 2018. Patients were recruited from 18 level I trauma centers and followed up for 12 months. Data were analyzed from August 19, 2020, to March 3, 2021. Exposures Patients with mTBI (defined by a Glasgow Coma Scale score of 13-15) triaged to head computed tomography in 24 hours or less; patients with orthopedic trauma served as controls. Main Outcomes and Measures Measured outcomes included (1) the Rivermead Post Concussion Symptoms Questionnaire (RPQ), a 16-item self-report scale that assesses postconcussion symptom severity over the past 7 days relative to preinjury; (2) the Posttraumatic Stress Disorder Checklist for the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (PCL-5), a 20-item test that measures the severity of posttraumatic stress disorder symptoms; (3) the Patient Health Questionnaire-9 (PHQ-9), a 9-item scale that measures depression based on symptom frequency over the past 2 weeks; and (4) the Brief Symptom Inventory-18 (BSI-18), an 18-item scale of psychological distress (split into Depression and Anxiety subscales). Results A total of 2000 patients with mTBI (1331 men [67%; mean (SD) age, 41.0 (17.3) years; 1026 White (78%)] and 669 women [33%; mean (SD) age, 43.0 (18.5) years; 505 (76%) White]). After adjustment of multiple comparisons, significant TBI × sex interactions were observed for cognitive symptoms (B = 0.76; 5% false discovery rate–corrected P = .02) and somatic RPQ symptoms (B = 0.80; 5% false discovery rate–corrected P = .02), with worse symptoms in women with mTBI than men, but no sex difference in symptoms in control patients with orthopedic trauma. Within the female patients evaluated, there was a significant TBI × age interaction for somatic RPQ symptoms, which were worse in female patients with mTBI aged 35 to 49 years compared with those aged 17 to 34 years (B = 1.65; P = .02) or older than 50 years (B = 1.66; P = .02). Conclusions and Relevance This study found that women were more vulnerable than men to persistent mTBI-related cognitive and somatic symptoms, whereas no sex difference in symptom burden was seen after orthopedic injury. Postconcussion symptoms were also worse in women aged 35 to 49 years than in younger and older women, but further investigation is needed to corroborate these findings and to identify the mechanisms involved. Results suggest that individualized clinical management of mTBI should consider sex and age, as some women are especially predisposed to chronic postconcussion symptoms even 12 months after injury.

Importance Heterogeneity across patients with traumatic brain injury (TBI) presents challenges for clinical care and intervention design. Identifying distinct clinical phenotypes of TBI soon after injury may inform patient selection for precision medicine clinical trials. Objective To investigate whether distinct neurobehavioral phenotypes can be identified 2 weeks after TBI and to characterize the degree to which early neurobehavioral phenotypes are associated with 6-month outcomes. Design, setting, and participants This prospective cohort study included patients presenting to 18 US level 1 trauma centers within 24 hours of TBI from 2014 to 2019 as part of the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Data were analyzed from January 28, 2020, to January 11, 2021. Exposures TBI. Main outcomes and measures Latent profiles (LPs) were derived from common dimensions of neurobehavioral functioning at 2 weeks after injury, assessed through National Institutes of Health TBI Common Data Elements (ie, Brief Symptom Inventory-18, Patient Health Questionnaire-9 Depression checklist, Posttraumatic Stress Disorder Checklist for DSM-5, PROMIS Pain Intensity scale, Insomnia Severity Index, Rey Auditory Verbal Learning Test, Wechsler Adult Intelligence Scale-Fourth Edition Coding and Symbol Search subtests, Trail Making Test, and NIH Toolbox Cognitive Battery Pattern Comparison Processing Speed, Dimensional Change Card Sort, Flanker Inhibitory Control and Attention, and Picture Sequence Memory subtests). Six-month outcomes were the Satisfaction With Life Scale (SWLS), Quality of Life after Brain Injury-Overall Scale (QOLIBRI-OS), Glasgow Outcome Scale-Extended (GOSE), and Rivermead Post-Concussion Symptoms Questionnaire (RPQ). Results Among 1757 patients with TBI included, 1184 (67.4%) were men, and the mean (SD) age was 39.9 (17.0) years. LP analysis revealed 4 distinct neurobehavioral phenotypes at 2 weeks after injury: emotionally resilient (419 individuals [23.8%]), cognitively impaired (368 individuals [20.9%]), cognitively resilient (620 individuals [35.3%]), and neuropsychiatrically distressed (with cognitive weaknesses; 350 individuals [19.9%]). Adding LP group to models including demographic characteristics, medical history, Glasgow Coma Scale score, and other injury characteristics was associated with significantly improved estimation of association with 6-month outcome (GOSE R2 increase = 0.09-0.19; SWLS R2 increase = 0.12-0.22; QOLIBRI-OS R2 increase = 0.14-0.32; RPQ R2 = 0.13-0.34). Conclusions and relevance In this cohort study of patients with TBI presenting to US level-1 trauma centers, qualitatively distinct profiles of symptoms and cognitive functioning were identified at 2 weeks after TBI. These distinct phenotypes may help optimize clinical decision-making regarding prognosis, as well as selection and stratification for randomized clinical trials.

Summary Background After traumatic brain injury (TBI), plasma concentration of glial fibrillary acidic protein (GFAP) correlates with intracranial injury visible on CT scan. Some patients with suspected TBI with normal CT findings show pathology on MRI. We assessed the discriminative ability of GFAP to identify MRI abnormalities in patients with normal CT findings. Methods TRACK-TBI is a prospective cohort study that enrolled patients with TBI who had a clinically indicated head CT scan within 24 h of injury at 18 level 1 trauma centres in the USA. For this analysis, we included patients with normal CT findings (Glasgow Coma Scale score 13–15) who consented to venepuncture within 24 h post injury and who had an MRI scan 7–18 days post injury. We compared MRI findings in these patients with those of orthopaedic trauma controls and healthy controls recruited from the study sites. Plasma GFAP concentrations (pg/mL) were measured using a prototype assay on a point-of-care platform. We used receiver operating characteristic (ROC) analysis to evaluate the discriminative ability of GFAP for positive MRI scans in patients with negative CT scans over 24 h (time between injury and venepuncture). The primary outcome was the area under the ROC curve (AUC) for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings within 24 h of injury. The Dunn Kruskal–Wallis test was used to compare GFAP concentrations between MRI lesion types with Benjamini–Hochberg correction for multiple comparisons. This study is registered with ClinicalTrials.gov , number NCT02119182 . Findings Between Feb 26, 2014, and June 15, 2018, we recruited 450 patients with normal head CT scans (of whom 330 had negative MRI scans and 120 had positive MRI scans), 122 orthopaedic trauma controls, and 209 healthy controls. AUC for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings was 0·777 (95% CI 0·726–0·829) over 24 h. Median plasma GFAP concentration was highest in patients with CT-negative and MRI-positive findings (414·4 pg/mL, 25–75th percentile 139·3–813·4), followed by patients with CT-negative and MRI-negative findings (74·0 pg/mL, 17·5–214·4), orthopaedic trauma controls (13·1 pg/mL, 6·9–20·0), and healthy controls (8·0 pg/mL, 3·0–14·0; all comparisons between patients with CT-negative MRI-positive findings and other groups p Interpretation Analysis of blood GFAP concentrations using prototype assays on a point-of-care platform within 24 h of injury might improve detection of TBI and identify patients who might need subsequent MRI and follow-up. Funding National Institute of Neurological Disorders and Stroke and US Department of Defense.

BACKGROUND Preinjury employment status may contribute to disparity, injury risk, and recovery patterns following mild traumatic brain injury (MTBI). OBJECTIVE To characterize associations between preinjury unemployment, prior comorbidities, and outcomes following MTBI. METHODS MTBI patients from TRACK-TBI Pilot with complete six-month outcomes were extracted. Preinjury unemployment, comorbidities, injury factors, and intracranial pathology were considered. Multivariable regression was performed for employment and outcomes, correcting for demographic and injury factors. Mean-differences (B) and 95% CIs are reported. Statistical significance was assessed at p < 0.05. RESULTS 162 MTBI patients were aged 39.8±15.4-years and 24.6% -unemployed. Unemployed patients demonstrated increased psychiatric comorbidities (45.0% -vs.- 23.8%; p = 0.010), drug use (52.5% -vs.- 21.3%; p < 0.001), smoking (62.5% -vs.- 27.0%; p < 0.001), prior TBI (78.4% -vs.- 55.0%; p = 0.012), and lower education (15.0% -vs.- 45.1% college degree; p = 0.003). On multivariable analysis, unemployment associated with decreased six-month functional outcome (Glasgow Outcome Scale-Extended: B = - 0.50, 95% CI [- 0.88, - 0.11]), increased psychiatric disturbance (Brief Symptom Inventory-18: B = 6.22 [2.33, 10.10]), postconcussional symptoms (Rivermead Questionnaire: B = 4.91 [0.38, 9.44]), and post-traumatic stress disorder (PTSD Checklist-Civilian: B = 5.99 [0.76, 11.22]). No differences were observed for cognitive measures or satisfaction with life. CONCLUSIONS Unemployed patients are at risk for preinjury psychosocial comorbidities, poorer six-month functional recovery and increased psychiatric/postconcussional/PTSD symptoms. Resource allocation and return precautions should be implemented to mitigate and/or prevent the decline of at-risk patients.

Neuroimaging biomarkers show promise for improving precision diagnosis and prognosis after mild traumatic brain injury (mTBI), but none has yet been adopted in routine clinical practice. Biophysical modeling of multishell diffusion MRI, using the neurite orientation dispersion and density imaging (NODDI) framework, may improve upon conventional diffusion tensor imaging (DTI) in revealing subtle patterns of underlying white matter microstructural pathology, such as diffuse axonal injury (DAI) and neuroinflammation, that are important for detecting mTBI and determining patient outcome. With a cross-sectional and longitudinal design, we assessed structural MRI, DTI and NODDI in 40 mTBI patients at 2 weeks and 6 months after injury and 14 matched control participants with orthopedic trauma but not suffering from mTBI at 2 weeks. Self-reported and performance-based cognitive measures assessing postconcussive symptoms, memory, executive functions and processing speed were investigated in post-acute and chronic phase after injury for the mTBI subjects. Machine learning analysis was used to identify mTBI patients with the best neuropsychological improvement over time and relate this outcome to DTI and NODDI biomarkers. In the cross-sectional comparison with the trauma control group at 2 weeks post-injury, mTBI patients showed decreased fractional anisotropy (FA) and increased mean diffusivity (MD) on DTI mainly in anterior tracts that corresponded to white matter regions of elevated free water fraction (FISO) on NODDI, signifying vasogenic edema. Patients showed decreases from 2 weeks to 6 months in white matter neurite density on NODDI, predominantly in posterior tracts. No significant longitudinal changes in DTI metrics were observed. The machine learning analysis divided the mTBI patients into two groups based on their recovery. Voxel-wise group comparison revealed associations between white matter orientation dispersion index (ODI) and FISO with degree and trajectory of improvement within the mTBI group. In conclusion, white matter FA and MD alterations early after mTBI might reflect vasogenic edema, as shown by elevated free water on NODDI. Longer-term declines in neurite density on NODDI suggest progressive axonal degeneration due to DAI, especially in tracts known to be integral to the structural connectome. Overall, these results show that the NODDI parameters appear to be more sensitive to longitudinal changes than DTI metrics. Thus, NODDI merits further study in larger cohorts for mTBI diagnosis, prognosis and treatment monitoring.

Objective: To investigate the clinical management and medical follow-up of patients with mild traumatic brain injury (mTBI) presenting to emergency departments (EDs). Methods: Overall, 168 adult patients with mTBI from the prospective, multicentre Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot study with Glasgow Coma Scale (GCS) 13–15, no polytrauma and alive at six months were included. Predictors for hospital admission, three-month follow-up referral and six-month functional disability (Glasgow Outcome Scale-Extended (GOSE) ≤ 6) were analysed using multivariable regression. Results: Overall, 48% were admitted to hospital, 22% received three-month referral and 27% reported six-month functional disability. Intracranial pathology on ED head computed tomography (multivariable odds ratio (OR) = 81.08, 95% confidence interval (CI) [10.28–639.36]) and amnesia (>30-minutes: OR = 5.27 [1.75–15.87]; unknown duration: OR = 4.43 [1.26–15.62]) predicted hospital admission. Older age (per-year OR = 1.03 [1.01–1.05]) predicted three-month referral, while part-time/unemployment predicted lack of referral (OR = 0.17 [0.06–0.50]). GCS < 15 (OR = 2.46 [1.05–5.78]) and prior history of seizures (OR = 3.62 [1.21–10.89]) predicted six-month functional disability, while increased education (per-year OR = 0.86 [0.76–0.97]) was protective. Conclusions: Clinical factors modulate triage to admission, while demographic/socioeconomic elements modulate follow-up care acquisition; six-month functional disability associates with both clinical and demographic/socioeconomic variables. Improving triage to acute and outpatient care requires further investigation to optimize resource allocation and outcome after mTBI. ClinicalTrials.gov registration: NCT01565551

Background and purposePrecision medicine is an approach to disease diagnosis, treatment, and prevention that relies on quantitative biomarkers that minimize the variability of individual patient measurements. The aim of this study was to assess the intersite variability after harmonization of a high-angular-resolution 3T diffusion tensor imaging protocol across 13 scanners at the 11 academic medical centers participating in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury multisite study.Materials and methodsDiffusion MR imaging was acquired from a novel isotropic diffusion phantom developed at the National Institute of Standards and Technology and from the brain of a traveling volunteer on thirteen 3T MR imaging scanners representing 3 major vendors (GE Healthcare, Philips Healthcare, and Siemens). Means of the DTI parameters and their coefficients of variation across scanners were calculated for each DTI metric and white matter tract.ResultsFor the National Institute of Standards and Technology diffusion phantom, the coefficients of variation of the apparent diffusion coefficient across the 13 scanners was

Brain lesions are subtle or absent in most patients with mild traumatic brain injury (mTBI) and the standard clinical criteria are not reliable for predicting long-term outcome. This study investigates resting-state functional MRI (rsfMRI) to assess semiacute alterations in brain connectivity and its relationship with outcome measures assessed 6 months after injury. Seventy-five mTBI patients were recruited as part of the prospective multicenter Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) pilot study and compared with matched 47 healthy subjects. Patients were classified following radiological criteria: CT/MRI positive, evidence of lesions; CT/MRI negative, without evidence of brain lesions. rsfMRI data were acquired and then processed using probabilistic independent component analysis. We compared the functional connectivity of the resting-state networks (RSNs) between patients and controls, as well as group differences in the interactions between RSNs, and related both to cognitive and behavioral performance at 6 months post-injury. Alterations were found in the spatial maps of the RSNs between mTBI patients and healthy controls in networks involved in behavioral and cognition processes. These alterations were predictive of mTBI patients' outcomes at 6 months post-injury. Moreover, different patterns of reduced network interactions were found between the CT/MRI positive and CT/MRI negative patients and the control group. These rsfMRI results demonstrate that even mTBI patients not showing brain lesions on conventional CT/MRI scans can have alterations of functional connectivity at the semiacute stage that help explain their outcomes. These results suggest rsfMRI as a sensitive biomarker both for early diagnosis and for prediction of the cognitive and behavioral performance of these patients.

BACKGROUND:Traumatic brain injury (TBI) is a complex disorder that is traditionally stratified based on clinical signs and symptoms. Recent imaging and molecular biomarker innovations provide unprecedented opportunities for improved TBI precision medicine, incorporating patho-anatomical and molecular mechanisms. Complete integration of these diverse data for TBI diagnosis and patient stratification remains an unmet challenge. METHODS AND FINDINGS:The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot multicenter study enrolled 586 acute TBI patients and collected diverse common data elements (TBI-CDEs) across the study population, including imaging, genetics, and clinical outcomes. We then applied topology-based data-driven discovery to identify natural subgroups of patients, based on the TBI-CDEs collected. Our hypothesis was two-fold: 1) A machine learning tool known as topological data analysis (TDA) would reveal data-driven patterns in patient outcomes to identify candidate biomarkers of recovery, and 2) TDA-identified biomarkers would significantly predict patient outcome recovery after TBI using more traditional methods of univariate statistical tests. TDA algorithms organized and mapped the data of TBI patients in multidimensional space, identifying a subset of mild TBI patients with a specific multivariate phenotype associated with unfavorable outcome at 3 and 6 months after injury. Further analyses revealed that this patient subset had high rates of post-traumatic stress disorder (PTSD), and enrichment in several distinct genetic polymorphisms associated with cellular responses to stress and DNA damage (PARP1), and in striatal dopamine processing (ANKK1, COMT, DRD2). CONCLUSIONS:TDA identified a unique diagnostic subgroup of patients with unfavorable outcome after mild TBI that were significantly predicted by the presence of specific genetic polymorphisms. Machine learning methods such as TDA may provide a robust method for patient stratification and treatment planning targeting identified biomarkers in future clinical trials in TBI patients. TRIAL REGISTRATION:ClinicalTrials.gov Identifier NCT01565551.

**Background:** Traumatic brain injury (TBI) is an increasingly diagnosed condition, but the trends in TBI visits and the cost of which have not been quantified from the hospital perspective. **Objectives:** To quantify the costs of TBI stratified by inpatient and outpatient visits and to examine trends in TBI incidence over time. **Methods:** This descriptive study utilized data for 2007-2012 from the Premier hospital database, which includes clinical and utilization information from hospitals across the United States. TBI was identified through International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. Descriptive data were obtained to identify the TBI costs, visit costs, patient characteristics, and intertemporal trends in TBI rates. **Results:** TBI patients were treated on an outpatient basis 88% of the time. Nearly 45% (44.3%) of TBI patients requiring inpatient admissions were age 65 or over, and 20% of TBI patients treated as an outpatient were age 75 or over. Children aged 4 or younger accounted for nearly 14% of TBI cases treated on an outpatient basis. TBI patients treated in the inpatient setting incurred fairly long hospital visits (mean 4.8 days; median 3.0 days) and substantial hospital costs (mean $12,717; median $8,176). The rate of TBI visits have risen substantially over time, especially among children under age 18 years and patients in the Northeast US Census Region. **Conclusion:** TBI is a serious medical condition that appears to be on the rise. Large differences exist between the hospital costs associated with TBIs treated in the inpatient and outpatient settings. Further research to understand factors affecting the costs and clinical outcomes of TBI can help refine treatment strategies to enhance patient outcomes while providing cost effective care.

We evaluated 3T diffusion tensor imaging (DTI) for white matter injury in 76 adult mild traumatic brain injury (mTBI) patients at the semiacute stage (11.2 +/- 3.3 days), employing both whole-brain voxel-wise and region-of-interest (ROI) approaches. The subgroup of 32 patients with any traumatic intracranial lesion on either day-of-injury computed tomography (CT) or semiacute magnetic resonance imaging (MRI) demonstrated reduced fractional anisotropy (FA) in numerous white matter tracts, compared to 50 control subjects. In contrast, 44 CT/MRI-negative mTBI patients demonstrated no significant difference in any DTI parameter, compared to controls. To determine the clinical relevance of DTI, we evaluated correlations between 3- and 6-month outcome and imaging, demographic/socioeconomic, and clinical predictors. Statistically significant univariable predictors of 3-month Glasgow Outcome Scale-Extended (GOS-E) included MRI evidence for contusion (odds ratio [OR] 4.9 per unit decrease in GOS-E; p=0.01), >= 1 ROI with severely reduced FA (OR, 3.9; p=0.005), neuropsychiatric history (OR, 3.3; p=0.02), age (OR, 1.07/year; p=0.002), and years of education (OR, 0.79/year; p=0.01). Significant predictors of 6-month GOS-E included >= 1 ROI with severely reduced FA (OR, 2.7; p=0.048), neuropsychiatric history (OR, 3.7; p=0.01), and years of education (OR, 0.82/year; p=0.03). For the subset of 37 patients lacking neuropsychiatric and substance abuse history, MRI surpassed all other predictors for both 3- and 6-month outcome prediction. This is the first study to compare DTI in individual mTBI patients to conventional imaging, clinical, and demographic/socioeconomic characteristics for outcome prediction. DTI demonstrated utility in an inclusive group of patients with heterogeneous backgrounds, as well as in a subset of patients without neuropsychiatric or substance abuse history.

Biomarkers are important for accurate diagnosis of complex disorders such as traumatic brain injury (TBI). For a complex and multifaceted condition such as TBI, it is likely that a single biomarker will not reflect the full spectrum of the response of brain tissue to injury. Ubiquitin C-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) are among of the most widely studied biomarkers for TBI. Because UCH-L1 and GFAP measure distinct molecular events, we hypothesized that analysis of both biomarkers would be superior to analysis of each alone for the diagnosis and prognosis of TBI. Serum levels of UCH-L1 and GFAP were measured in a cohort of 206 patients with TBI enrolled in a multicenter observational study (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI]). Levels of the two biomarkers were weakly correlated to each other (r=0.364). Each biomarker in isolation had good sensitivity and sensitivity for discriminating between TBI patients and healthy controls (area under the curve [AUC] 0.87 and 0.91 for UCH-L1 and GFAP, respectively). When biomarkers were combined, superior sensitivity and specificity for diagnosing TBI was obtained (AUC 0.94). Both biomarkers discriminated between TBI patients with intracranial lesions on CT scan and those without such lesions, but GFAP measures were significantly more sensitive and specific (AUC 0.88 vs. 0.71 for UCH-L1). For association with outcome 3 months after injury, neither biomarker had adequate sensitivity and specificity (AUC 0.65-0.74, for GFAP, and 0.59-0.80 for UCH-L1, depending upon Glasgow Outcome Scale Extended [GOS-E] threshold used). Our results support a role for multiple biomarker measurements in TBI research. (ClinicalTrials.gov Identifier NCT01565551)

Reliable diagnosis of traumatic brain injury (TBI) is a major public health need. Glial fibrillary acidic protein (GFAP) is expressed in the central nervous system, and breakdown products (GFAP-BDP) are released following parenchymal brain injury. Here, we evaluate the diagnostic accuracy of elevated levels of plasma GFAP-BDP in TBI. Participants were identified as part of the prospective Transforming Research And Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study. Acute plasma samples (

The idea that multiple traumatic brain injury (TBI) can have a cumulative detrimental effect on functioning is widely accepted. Most research supporting this idea comes from athlete samples, and it is not known whether remote history of previous TBI affects functioning after subsequent TBI in community-based samples. This study investigates whether a previous history of TBI with loss of consciousness (LOC) is associated with worse health and functioning in a sample of individuals who require emergency department care for current TBI. Twenty-three percent of the 586 individuals with current TBI in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study reported having sustained a previous TBI with LOC. Individuals with previous TBI were more likely to be unemployed ((2)=17.86; p=0.000), report a variety of chronic medical and psychiatric conditions (4.75(2)24.16; p

We described recently a subacute serum autoantibody response toward glial fibrillary acidic protein (GFAP) and its breakdown products 5-10 days after severe traumatic brain injury (TBI). Here, we expanded our anti-GFAP autoantibody (AutoAb[GFAP]) investigation to the multicenter observational study Transforming Research and Clinical Knowledge in TBI Pilot (TRACK-TBI Pilot) to cover the full spectrum of TBI (Glasgow Coma Scale 3-15) by using acute (

Traumatic brain injury (TBI) is a widespread global disease, often with widely varying outcomes. Standardization of care and adherence to established guidelines are central to the effort to improve outcomes. At our level I urban trauma center, we developed and implemented a Joint Commission-certified TBI Program of Care in 2011 and compared our post-implementation patient data set with historical controls, using the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) prognostic model. Historical controls were drawn from the San Francisco General Hospital Traumatic Coma Data Bank (SFGH/TCDB) from 1987 to 1996. Recent era patients were drawn from the NeuroTracker database, a customized electronic medical record used in our clinical practice. Descriptive statistics were calculated. Adherence to four quality-of-care metrics on the clinical service was tracked for 2011-2013. The IMPACT prognostic model was used to calculate expected versus observed mortality for current and historical patient groups. In the historical control group, 832 patients were identified and 6-month mortality was available for 592. Observed 6-month mortality was 49%. In the recent era patient group, 211 patients were identified and 6-month mortality was 38%. The IMPACT prognostic model was applied to each patient group. Areas under the curve for each analysis were0.85 and goodness of fit was satisfactory, indicating good performance of the IMPACT model. Comparison of observed versus expected deaths in the recent versus the control patient sets revealed a drop of 59% in early mortality. The greatest reductions in mortality were observed in the group of patients with IMPACT-predicted mortality ≤50%. Significant progress has been made in reducing the percentage of unexpected deaths in TBI patients. It is likely that major factors include more aggressive management and tracking of compliance with the implementation of guidelines for the management of TBI patients.

Key Points Question Do patients with mild traumatic brain injury (mTBI) receive adequate levels of follow-up care? Findings In a cohort study using data on 831 patients with mTBI presenting to the emergency department at 1 of 11 level I trauma centers across the United States, 42% of patients reported receiving educational material at discharge and 44% reported seeing a physician or other medical practitioner within 3 months after injury. Among patients with 3 or more moderate to severe postconcussive symptoms, only 52% reported having seen a practitioner within 3 months following the injury. Meaning A large proportion of patients with mTBI do not receive follow-up care after injury even when they experience ongoing postconcussive symptoms., This cohort study describes follow-up care for patients within 3 months of receiving treatment for mild traumatic brain injury (TBI) or concussion at US emergency departments of level I trauma centers., Importance Mild traumatic brain injury (mTBI) affects millions of Americans each year. Lack of consistent clinical practice raises concern that many patients with mTBI may not receive adequate follow-up care. Objective To characterize the provision of follow-up care to patients with mTBI during the first 3 months after injury. Design, Setting, and Participants This cohort study used data on patients with mTBI enrolled in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study between February 26, 2014, and August 25, 2016. We examined site-specific variations in follow-up care, the types of clinicians seen by patients receiving follow-up care, and patient and injury characteristics associated with a higher likelihood of receiving follow-up care. The TRACK-TBI study is a prospective, multicenter, longitudinal observational study of patients with TBI presenting to the emergency department of 1 of 11 level I US trauma centers. Study data included patients with head trauma who underwent a computed tomography (CT) scan within 24 hours of injury, had a Glasgow Coma Scale score of 13 to 15, were aged 17 years or older, and completed follow-up care surveys at 2 weeks and 3 months after injury (N = 831). Main Outcomes and Measures Follow-up care was defined as hospitals providing TBI educational material at discharge, hospitals calling patients to follow up, and patients seeing a physician or other medical practitioner within 3 months after the injury. Unfavorable outcomes were assessed with the Rivermead Post Concussion Symptoms Questionnaire. Results Of 831 patients (289 [35%] female; 483 [58%] non-Hispanic white; mean [SD] age, 40.3 [16.9] years), less than half self-reported receiving TBI educational material at discharge (353 patients [42%]) or seeing a physician or other health care practitioner within 3 months after injury (367 patients [44%]). Follow-up care varied by study site; adjusting for patient characteristics, the provision of educational material varied from 19% to 72% across sites. Of 236 patients with a positive finding on a CT scan, 92 (39%) had not seen a medical practitioner 3 months after the injury. Adjusting for injury severity and demographics, patient admission to the hospital ward or intensive care unit, patient income, and insurance status were not associated with the probability of seeing a medical practitioner. Among the patients with 3 or more moderate to severe postconcussive symptoms, only 145 of 279 (52%) reported having seen a medical practitioner by 3 months. Conclusions and Relevance There are gaps in follow-up care for patients with mTBI after hospital discharge, even those with a positive finding on CT or who continue to experience postconcussive symptoms.

Glial fibrillary acidic protein and its breakdown products (GFAP-BDP) are brain-specific proteins released into serum as part of the pathophysiological response after traumatic brain injury (TBI). We performed a multi-center trial to validate and characterize the use of GFAP-BDP levels in the diagnosis of intracranial injury in a broad population of patients with a positive clinical screen for head injury. This multi-center, prospective, cohort study included patients 16-93 years of age presenting to three level 1 trauma centers with suspected TBI (loss of consciousness, post-trauma amnesia, and so on). Serum GFAP-BDP levels were drawn within 24 h and analyzed, in a blinded fashion, using sandwich enzyme-linked immunosorbent assay. The ability of GFAP-BDP to predict intracranial injury on admission computed tomography (CT) as well as delayed magnetic resonance imaging was analyzed by multiple regression and assessed by the area under the receiver operating characteristic curve (AUC). Utility of GFAP-BDP to predict injury and reduce unnecessary CT scans was assessed utilizing decision curve analysis. A total of 215 patients were included, of which 83% suffered mild TBI, 4% moderate, and 12% severe; mean age was 42.1 +/- 18 years. Evidence of intracranial injury was present in 51% of the sample (median Rotterdam Score, 2; interquartile range, 2). GFAP-BDP demonstrated very good predictive ability (AUC=0.87) and demonstrated significant discrimination of injury severity (odds ratio, 1.45; 95% confidence interval, 1.29-1.64). Use of GFAP-BDP yielded a net benefit above clinical screening alone and a net reduction in unnecessary scans by 12-30%. Used in conjunction with other clinical information, rapid measurement of GFAP-BDP is useful in establishing or excluding the diagnosis of radiographically apparent intracranial injury throughout the spectrum of TBI. As an adjunct to current screening practices, GFAP-BDP may help avoid unnecessary CT scans without sacrificing sensitivity (Registry: ClinicalTrials.gov Identifier: NCT01565551).

Although the majority of patients with mild traumatic brain injury (mTBI) recover completely, some still suffer from disabling ailments at 3 or 6 months. We validated existing prognostic models for mTBI and explored predictors of poor outcome after mTBI. We selected patients with mTBI from TRACK-TBI Pilot, an unselected observational cohort of TBI patients from three centers in the United States. We validated two prognostic models for the Glasgow Outcome Scale Extended (GOS-E) at 6 months after injury. One model was based on the CRASH study data and another from Nijmegen, The Netherlands. Possible predictors of 3- and 6-month GOS-E were analyzed with univariate and multi-variable proportional odds regression models. Of the 386 of 485 patients included in the study (median age, 44 years; interquartile range, 27-58), 75% (n=290) presented with a Glasgow Coma Score (GCS) of 15. In this mTBI population, both previously developed models had a poor performance (area under the receiver operating characteristic curve, 0.49-0.56). In multivariable analyses, the strongest predictors of lower 3- and 6-month GOS-E were older age, pre-existing psychiatric conditions, and lower education. Injury caused by assault, extracranial injuries, and lower GCS were also predictive of lower GOS-E. Existing models for mTBI performed unsatisfactorily. Our study shows that, for mTBI, different predictors are relevant as for moderate and severe TBI. These include age, pre-existing psychiatric conditions, and lower education. Development of a valid prediction model for mTBI patients requires further research efforts.

The goals of this study were to determine the incidence and duration of hypotension and hypoxia in the prehospital setting in patients with potentially survivable brain injuries, and to prospectively examine the association of these secondary insults with mortality and disability at hospital discharge.Trauma patients with suspected brain injuries underwent continuous blood pressure and pulse oximetry monitoring during helicopter transport. Postadmission inclusion criteria were (1) diagnosis of acute traumatic brain injury (TBI) confirmed by computed tomography (CT) scan, operative findings, or autopsy findings; and (2) Head Abbreviated Injury Scale (AIS) score ofor = 3 or Glasgow Coma Scale (GCS) score ofor = 12 within the first 24 hours of admission. Patients were excluded with (1) no abnormal intracranial findings on the patient's CT scan; (2) determination of a nonsurvivable injury (based on an AIS score of 6 for any body region; or, (3) death in less than 12 hours after injury. Primary outcome measures included mortality and Disability Rating Scale score at discharge.We enrolled 150 patients into the study. Fifty-seven patients had at least one secondary insult; 37 had only hypoxic episodes, 14 had only hypotensive episodes, and 6 patients had both. Demographics and injury characteristics did not differ between those with and those without secondary insults. The mortality for patients without secondary insults was 20%, compared with 37% for patients with hypoxic episodes, 8% for patients with hypotensive episodes, and 24% for patients with both. The Disability Rating Scale score at discharge was significantly higher in patients with secondary insults. Using multivariate analysis, the calculated odds ratio of mortality caused by prehospital hypoxia after head injury was 2.66 (p0.05).Secondary insults after TBI are common, and these insults are associated with disability. Hypoxia in the prehospital setting significantly increases the odds of mortality after brain injury controlled for multiple variables.

Annually in the United States, at least 3.5 million people seek medical attention for traumatic brain injury (TBI). The development of therapies for TBI is limited by the absence of diagnostic and prognostic biomarkers. Microtubule-associated protein tau is an axonal phosphoprotein. To date, the presence of the hypophosphorylated tau protein (P-tau) in plasma from patients with acute TBI and chronic TBI has not been investigated.To examine the associations between plasma P-tau and total-tau (T-tau) levels and injury presence, severity, type of pathoanatomic lesion (neuroimaging), and patient outcomes in acute and chronic TBI.In the TRACK-TBI Pilot study, plasma was collected at a single time point from 196 patients with acute TBI admitted to 3 level I trauma centers (24 hours after injury) and 21 patients with TBI admitted to inpatient rehabilitation units (mean [SD], 176.4 [44.5] days after injury). Control samples were purchased from a commercial vendor. The TRACK-TBI Pilot study was conducted from April 1, 2010, to June 30, 2012. Data analysis for the current investigation was performed from August 1, 2015, to March 13, 2017.Plasma samples were assayed for P-tau (using an antibody that specifically recognizes phosphothreonine-231) and T-tau using ultra-high sensitivity laser-based immunoassay multi-arrayed fiberoptics conjugated with rolling circle amplification.In the 217 patients with TBI, 161 (74.2%) were men; mean (SD) age was 42.5 (18.1) years. The P-tau and T-tau levels and P-tau-T-tau ratio in patients with acute TBI were higher than those in healthy controls. Receiver operating characteristic analysis for the 3 tau indices demonstrated accuracy with area under the curve (AUC) of 1.000, 0.916, and 1.000, respectively, for discriminating mild TBI (Glasgow Coma Scale [GCS] score, 13-15, n = 162) from healthy controls. The P-tau level and P-tau-T-tau ratio were higher in individuals with more severe TBI (GCS, ≤12 vs 13-15). The P-tau level and P-tau-T-tau ratio outperformed the T-tau level in distinguishing cranial computed tomography-positive from -negative cases (AUC = 0.921, 0.923, and 0.646, respectively). Acute P-tau levels and P-tau-T-tau ratio weakly distinguished patients with TBI who had good outcomes (Glasgow Outcome Scale-Extended GOS-E, 7-8) (AUC = 0.663 and 0.658, respectively) and identified those with poor outcomes (GOS-E, ≤4 vs4) (AUC = 0.771 and 0.777, respectively). Plasma samples from patients with chronic TBI also showed elevated P-tau levels and a P-tau-T-tau ratio significantly higher than that of healthy controls, with both P-tau indices strongly discriminating patients with chronic TBI from healthy controls (AUC = 1.000 and 0.963, respectively).Plasma P-tau levels and P-tau-T-tau ratio outperformed T-tau level as diagnostic and prognostic biomarkers for acute TBI. Compared with T-tau levels alone, P-tau levels and P-tau-T-tau ratios show more robust and sustained elevations among patients with chronic TBI.

Background: The most effective treatment for traumatic injuries is to prevent them from occurring. Currently, few surgeons receive any formal training in injury control and prevention. This study was designed to test the knowledge of injury prevention principles among practicing surgeons, in order to identify areas in need of intensified educational efforts. Study Design: Survey questions designed by members of the American College of Surgeons Committee on Trauma were programmed into a specialized touch-screen computer, which was displayed at four different surgery and trauma meetings, including the ACS Clinical Congress in 1999 and 2000. Participants were questioned about their knowledge of trauma epidemiology, bicycle helmet effectiveness, child safety seat usage, suicide, and domestic violence. Results: Seventy-nine surveys were completed by surgeons, including 33 specializing in trauma care, and by 106 nurses attending trauma courses. Overall, the percentage of correct answers was 50%. There were no significant differences in survey scores between trauma surgeons and general surgeons, although both scored higher than trauma nurses. Areas where knowledge deficits were the most apparent included proper use of child safety seats, the effectiveness of airbags, the prevalence of suicide, and the annual cost of injury in America. Conclusions: The majority of practicing surgeons and nurses, including those working at trauma centers, are unaware of the basic concepts of injury prevention. Advancements in the field of injury control will require efforts to educate medical professionals and the public.

To conduct a multicenter study to validate the accuracy of the Acute Physiology and Chronic Health Evaluation (APACHE) II system, APACHE III system, Trauma and Injury Severity Score (TRISS) methodology, and a 24-hour intensive care unit (ICU) point system for prediction of mortality in ICU trauma patient admissions.The study population consisted of retrospectively identified, consecutive ICU trauma admissions (n = 2,414) from six Level I trauma centers. Probabilities of death were calculated by using logistic regression analysis. The predictive power of each system was evaluated by using decision matrix analysis to compare observed and predicted outcomes with a decision criterion of 0.50 for risk of hospital death. The Youden Index (YI) was used to compare the proportion of patients correctly classified by each system. Measures of model calibration were based on goodness-of-fit testing (Hosmer-Lemeshow statistic less than 15.5) and model discrimination were based on the area under the receiver operating characteristic curve (AUC).Overall, APACHE II (sensitivity, 38%; specificity, 99%; YI, 37%; H-L statistic, 92.6; AUC, 0.87) and TRISS (sensitivity, 52%; specificity, 94%; YI, 46%; H-L statistic, 228.1; AUC, 0.82) were poor predictors of aggregate mortality, because they did not meet the acceptable thresholds for both model calibration and discrimination. APACHE III (sensitivity, 60%; specificity, 98%; YI, 58%; H-L statistic, 7.0; AUC, 0.89) was comparable to the 24-hour ICU point system (sensitivity, 51%; specificity, 98%; YI, 50%; H-L statistic, 14.7; AUC, 0.89) with both systems showing strong agreement between the observed and predicted outcomes based on acceptable thresholds for both model calibration and discrimination. The APACHE III system significantly improved upon APACHE II for estimating risk of death in ICU trauma patients (p0.001). Compared with the overall performance, for the subset of patients with nonoperative head trauma, the percentage correctly classified was decreased to 46% for APACHE II; increased to 71% for APACHE III (p0.001 vs. APACHE II); increased to 59% for TRISS; and increased to 62% for 24-hour ICU points. For operative head trauma, the percentage correctly classified was increased to 60% for APACHE II; increased to 61% for APACHE III; decreased to 43% for TRISS (p0.004 vs. APACHE III); and increased to 54% for 24-hour ICU points. For patients without head injuries, all of the systems were unreliable and considerably underestimated the risk of death. The percentage of nonoperative and operative patients without head trauma who were correctly classified was decreased, respectively, to 26% and 30% for APACHE II; 33% and 29% for APACHE III; 33% and 19% for TRISS; 20% and 23% for 24-hour ICU points.For the overall estimation of aggregate ICU mortality, the APACHE III system was the most reliable; however, performance was most accurate for subsets of patients with head trauma. The 24-hour ICU point system also demonstrated acceptable overall performance with improved performance for patients with head trauma. Overall, APACHE II and TRISS did not meet acceptable thresholds of performance. When estimating ICU mortality for subsets of patients without head trauma, none of these systems had an acceptable level of performance. Further multicenter studies aimed at developing better outcome prediction models for patients without head injuries are warranted, which would allow trauma care providers to set uniform standards for judging institutional performance.