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Item Association of Sex and Age With Mild Traumatic Brain Injury-Related Symptoms: A TRACK-TBI Study(American Medical Association, 2021-04-01) Levin, Harvey S.; Temkin, Nancy R.; Barber, Jason; Nelson, Lindsay D.; Robertson, Claudia; Brennan, Jeffrey; Stein, Murray B.; Yue, John K.; Giacino, Joseph T.; McCrea, Michael A.; Diaz-Arrastia, Ramon; Mukherjee, Pratik; Okonkwo, David O.; Boase, Kim; Markowitz, Amy J.; Bodien, Yelena; Taylor, Sabrina; Vassar, Mary J.; Manley, Geoffrey T.; TRACK-TBI Investigators; Adeoye, Opeolu; Badjatia, Neeraj; Bullock, M. Ross; Chesnut, Randall; Corrigan, John D.; Crawford, Karen; Dikmen, Sureyya; Duhaime, Ann-Christine; Ellenbogen, Richard; Feeser, V. Ramana; Ferguson, Adam R.; Foreman, Brandon; Gardner, Raquel; Gaudette, Etienne; Gonzalez, Luis; Gopinath, Shankar; Gullapalli, Rao; Hemphill, J. Claude; Hotz, Gillian; Jain, Sonia; Keene, C. Dirk; Korley, Frederick K.; Kramer, Joel; Kreitzer, Natalie; Lindsell, Chris; Machamer, Joan; Madden, Christopher; Martin, Alastair; McAllister, Thomas; Merchant, Randall; Nolan, Amber; Ngwenya, Laura B.; Noel, Florence; Palacios, Eva; Puccio, Ava; Rabinowitz, Miri; Rosand, Jonathan; Sander, Angelle; Satris, Gabriella; Schnyer, David; Seabury, Seth; Sun, Xiaoying; Toga, Arthur; Valadka, Alex; Wang, Kevin; Yuh, Esther; Zafonte, Ross; Psychiatry, School of MedicineImportance: 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.Item COMT Val 158 Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury(Elsevier, 2017-01) Winkler, Ethan A.; Yue, John K.; Ferguson, Adam R.; Temkin, Nancy R.; Stein, Murray B.; Barber, Jason; Yuh, Esther L.; Sharma, Sourabh; Satris, Gabriela G.; McAllister, Thomas W.; Rosand, Jonathan; Sorani, Marco D.; Lingsma, Hester F.; Tarapore, Phiroz E.; Burchard, Esteban G.; Hu, Donglei; Eng, Celeste; Wang, Kevin K.W.; Mukherjee, Pratik; Okonkwo, David O.; Diaz-Arrastia, Ramon; Manley, Geoffrey T.; TRACK-TBI Investigators; Psychiatry, School of MedicineMild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o-methyltransferase (COMT) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val158Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist - Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively. Results in 93 predominately Caucasian subjects with mTBI show that the COMT Met158 allele is associated with lower incidence of PTSD (univariate odds ratio (OR) of 0.25, 95% CI [0.09-0.69]) and higher GOSE scores (univariate OR 2.87, 95% CI [1.20-6.86]) 6-months following injury. The COMT Val158Met genotype and PTSD association persists after controlling for race (multivariable OR of 0.29, 95% CI [0.10-0.83]) and pre-existing psychiatric disorders/substance abuse (multivariable OR of 0.32, 95% CI [0.11-0.97]). PTSD emerged as a strong predictor of poorer outcome on GOSE (multivariable OR 0.09, 95% CI [0.03-0.26]), which persists after controlling for age, GCS, and race. When accounting for PTSD in multivariable analysis, the association of COMT genotype and GOSE did not remain significant (multivariable OR 1.73, 95% CI [0.69-4.35]). Whether COMT genotype indirectly influences global functional outcome through PTSD remains to be determined and larger studies in more diverse populations are needed to confirm these findings.Item COMT Val 158 Met polymorphism is associated with nonverbal cognition following mild traumatic brain injury(Springer, 2016-01) Winker, Ethan A.; Yue, John K.; McAllister, Thomas W.; Temkin, Nancy R.; Oh, Sam S.; Burchard, Esteban G.; Hu, Donglei; Ferguson, Adam R.; Lingsma, Hester F.; Burke, John F.; Sorani, Marco D.; Rosand, Jonathan; Yuh, Esther L.; Barber, Jason; Tarapore, Phiroz E.; Gardner, Raquel C.; Sharma, Sourabh; Satris, Gabriela G.; Eng, Celeste; Puccio, Ava M.; Wang, Kevin K.W.; Mukherjee, Pratik; Valadka, Alex B.; Okonkwo, David O.; Diaz-Arrastia, Ramon; Manley, Geoffrey T.; Department of Psychiatry, IU School of MedicineMild traumatic brain injury (mTBI) results in variable clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism in catechol-o-methyltransferase (COMT), an enzyme which degrades catecholamine neurotransmitters, may influence cognitive deficits following moderate and/or severe head trauma. However, this has been disputed, and its role in mTBI has not been studied. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val (158) Met polymorphism influences outcome on a cognitive battery 6 months following mTBI--Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), Trail Making Test (TMT) Trail B minus Trail A time, and California Verbal Learning Test, Second Edition Trial 1-5 Standard Score (CVLT-II). All patients had an emergency department Glasgow Coma Scale (GCS) of 13-15, no acute intracranial pathology on head CT, and no polytrauma as defined by an Abbreviated Injury Scale (AIS) score of ≥3 in any extracranial region. Results in 100 subjects aged 40.9 (SD 15.2) years (COMT Met (158) /Met (158) 29 %, Met (158) /Val (158) 47 %, Val (158) /Val (158) 24 %) show that the COMT Met (158) allele (mean 101.6 ± SE 2.1) associates with higher nonverbal processing speed on the WAIS-PSI when compared to Val (158) /Val (158) homozygotes (93.8 ± SE 3.0) after controlling for demographics and injury severity (mean increase 7.9 points, 95 % CI [1.4 to 14.3], p = 0.017). The COMT Val (158) Met polymorphism did not associate with mental flexibility on the TMT or with verbal learning on the CVLT-II. Hence, COMT Val (158) Met may preferentially modulate nonverbal cognition following uncomplicated mTBI.Registry: ClinicalTrials.gov Identifier NCT01565551.Item DRD2 C957T polymorphism is associated with improved 6-month verbal learning following traumatic brain injury(Springer, 2017-01) Yue, John K.; Winkler, Ethan A.; Rick, Jonathan W.; Burke, John F.; McAllister, Thomas W.; Oh, Sam S.; Burchard, Esteban G.; Hu, Donglei; Rosand, Jonathan; Temkin, Nancy R.; Korley, Frederick K.; Sorani, Marco D.; Ferguson, Adam R.; Lingsma, Hester F.; Sharma, Sourabh; Robinson, Caitlin K.; Yuh, Esther L.; Tarapore, Phiroz E.; Wang, Kevin K.W.; Puccio, Ava M.; Mukherjee, Pratik; Diaz-Arrastia, Ramon; Gordon, Wayne A.; Valadka, Alex B.; Okonkwo, David O.; Manley, Geoffrey T.; TRACK-TBI Investigators; Psychiatry, School of MedicineTraumatic brain injury (TBI) often leads to heterogeneous clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism (SNP) in the dopamine D2 receptor (DRD2) may influence cognitive deficits following TBI. However, part of the association with DRD2 has been attributed to genetic variability within the adjacent ankyrin repeat and kinase domain containing 1 protein (ANKK1). Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether a novel DRD2 C957T polymorphism (rs6277) influences outcome on a cognitive battery at 6 months following TBI-California Verbal Learning Test (CVLT-II), Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), and Trail Making Test (TMT). Results in 128 Caucasian subjects show that the rs6277 T-allele associates with better verbal learning and recall on CVLT-II Trials 1-5 (T-allele carrier 52.8 ± 1.3 points, C/C 47.9 ± 1.7 points; mean increase 4.9 points, 95% confidence interval [0.9 to 8.8]; p = 0.018), Short-Delay Free Recall (T-carrier 10.9 ± 0.4 points, C/C 9.7 ± 0.5 points; mean increase 1.2 points [0.1 to 2.5]; p = 0.046), and Long-Delay Free Recall (T-carrier 11.5 ± 0.4 points, C/C 10.2 ± 0.5 points; mean increase 1.3 points [0.1 to 2.5]; p = 0.041) after adjusting for age, education years, Glasgow Coma Scale, presence of acute intracranial pathology on head computed tomography scan, and genotype of the ANKK1 SNP rs1800497 using multivariable regression. No association was found between DRD2 C947T and non-verbal processing speed (WAIS-PSI) or mental flexibility (TMT) at 6 months. Hence, DRD2 C947T (rs6277) may be associated with better performance on select cognitive domains independent of ANKK1 following TBI.Item Functional Outcomes Over the First Year After Moderate to Severe Traumatic Brain Injury in the Prospective, Longitudinal TRACK-TBI Study(American Medical Association, 2021) McCrea, Michael A.; Giacino, Joseph T.; Barber, Jason; Temkin, Nancy R.; Nelson, Lindsay D.; Levin, Harvey S.; Dikmen, Sureyya; Stein, Murray; Bodien, Yelena G.; Boase, Kim; Taylor, Sabrina R.; Vassar, Mary; Mukherjee, Pratik; Robertson, Claudia; Diaz-Arrastia, Ramon; Okonkwo, David O.; Markowitz, Amy J.; Manley, Geoffrey T.; TRACK-TBI Investigators; Adeoye, Opeolu; Badjatia, Neeraj; Bullock, M. Ross; Chesnut, Randall; Corrigan, John D.; Crawford, Karen; Duhaime, Ann-Christine; Ellenbogen, Richard; Feeser, V. Ramana; Ferguson, Adam R.; Foreman, Brandon; Gardner, Raquel; Gaudette, Etienne; Goldman, Dana; Gonzalez, Luis; Gopinath, Shankar; Gullapalli, Rao; Hemphill, J. Claude; Hotz, Gillian; Jain, Sonia; Keene, C. Dirk; Korley, Frederick K.; Kramer, Joel; Kreitzer, Natalie; Lindsell, Chris; Machamer, Joan; Madden, Christopher; Martin, Alastair; McAllister, Thomas; Merchant, Randall; Ngwenya, Laura B.; Noel, Florence; Nolan, Amber; Palacios, Eva; Perl, Daniel; Puccio, Ava; Rabinowitz, Miri; Rosand, Jonathan; Sander, Angelle; Satris, Gabriella; Schnyer, David; Seabury, Seth; Sherer, Mark; Toga, Arthur; Valadka, Alex; Wang, Kevin; Yue, John K.; Yuh, Esther; Zafonte, Ross; Psychiatry, School of MedicineImportance: 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.Item High-Sensitivity C-Reactive Protein is a Prognostic Biomarker of Six-Month Disability after Traumatic Brain Injury: Results from the TRACK-TBI Study(Mary Ann Liebert, 2021) Xu, Linda B.; Yue, John K.; Korley, Frederick; Puccio, Ava M.; Yuh, Esther L.; Sun, Xiaoying; Rabinowitz, Miri; Vassar, Mary J.; Taylor, Sabrina R.; Winkler, Ethan A.; Puffer, Ross C.; Deng, Hansen; McCrea, Michael; Stein, Murray B.; Robertson, Claudia S.; Levin, Harvey S.; Dikmen, Sureyya; Temkin, Nancy R.; Giacino, Joseph T.; Mukherjee, Pratik; Wang, Kevin K. W.; Okonkwo, David O.; Markowitz, Amy J.; Jain, Sonia; Manley, Geoffrey T.; Diaz-Arrastia, Ramon; TRACK-TBI Investigators; Psychiatry, School of MedicineSystemic 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 < 0.001). Longitudinally, hsCRP was significantly higher in the first 2 weeks for subjects with death/severe disability (GOSE <5) compared with those with moderate disability/good recovery (GOSE ≥5); AUC was highest at 2 weeks (AUC = 0.892). Combining hsCRP and GFAP at 2 weeks produced AUC = 0.939 for prediction of disability. Serum hsCRP measured within 2 weeks of TBI is a prognostic biomarker for disability 6 months later. hsCRP may have utility as a biomarker of target engagement for anti-inflammatory therapies.Item Latent Profile Analysis of Neuropsychiatric Symptoms and Cognitive Function of Adults 2 Weeks After Traumatic Brain Injury: Findings From the TRACK-TBI Study(American Medical Association, 2021-03-01) Brett, Benjamin L.; Kramer, Mark D.; Whyte, John; McCrea, Michael A.; Stein, Murray B.; Giacino, Joseph T.; Sherer, Mark; Markowitz, Amy J.; Manley, Geoffrey T.; Nelson, Lindsay D.; TRACK-TBI Investigators; Adeoye, Opeolu; Badjatia, Neeraj; Boase, Kim; Barber, Jason; Bodien, Yelena; Bullock, M. Ross; Chesnut, Randall; Corrigan, John D.; Crawford, Karen; Diaz-Arrastia, Ramon; Dikmen, Sureyya; Duhaime, Ann-Christine; Ellenbogen, Richard; Feeser, V. Ramana; Ferguson, Adam R.; Foreman, Brandon; Gardner, Raquel; Gaudette, Etienne; Gonzalez, Luis; Gopinath, Shankar; Gullapalli, Rao; Hemphill, J. Claude; Hotz, Gillian; Jain, Sonia; Keene, C. Dirk; Korley, Frederick K.; Kramer, Joel; Kreitzer, Natalie; Levin, Harvey; Lindsell, Chris; Machamer, Joan; Madden, Christopher; Martin, Alastair; McAllister, Thomas; Merchant, Randall; Mukherjee, Pratik; Ngwenya, Laura B.; Noel, Florence; Okonkwo, David; Palacios, Eva; Puccio, Ava; Rabinowitz, Miri; Robertson, Claudia; Rosand, Jonathan; Sander, Angelle; Satris, Gabriella; Schnyer, David; Seabury, Seth; Taylor, Sabrina; Temkin, Nancy; Toga, Arthur; Valadka, Alex; Vassar, Mary; Wang, Kevin; Yue, John K.; Yuh, Esther; Zafonte, Ross; Psychiatry, School of MedicineImportance: 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.Item Traumatic brain injury: progress and challenges in prevention, clinical care, and research(Elsevier, 2022) Maas, Andrew I. R.; Menon, David K.; Manley, Geoffrey T.; Abrams, Mathew; Åkerlund, Cecilia; Andelic, Nada; Aries, Marcel; Bashford, Tom; Bell, Michael J.; Bodien, Yelena G.; Brett, Benjamin L.; Büki, András; Chesnut, Randall M.; Citerio, Giuseppe; Clark, David; Clasby, Betony; Cooper, D. Jamie; Czeiter, Endre; Czosnyka, Marek; Dams-O'Connor, Kristen; De Keyser, Véronique; Diaz-Arrastia, Ramon; Ercole, Ari; van Essen, Thomas A.; Falvey, Éanna; Ferguson, Adam R.; Figaji, Anthony; Fitzgerald, Melinda; Foreman, Brandon; Gantner, Dashiell; Gao, Guoyi; Giacino, Joseph; Gravesteijn, Benjamin; Guiza, Fabian; Gupta, Deepak; Gurnell, Mark; Haagsma, Juanita A.; Hammond, Flora M.; Hawryluk, Gregory; Hutchinson, Peter; van der Jagt, Mathieu; Jain, Sonia; Jain, Swati; Jiang, Ji-Yao; Kent, Hope; Kolias, Angelos; Kompanje, Erwin J. O.; Lecky, Fiona; Lingsma, Hester F.; Maegele, Marc; Majdan, Marek; Markowitz, Amy; McCrea, Michael; Meyfroidt, Geert; Mikolić, Ana; Mondello, Stefania; Mukherjee, Pratik; Nelson, David; Nelson, Lindsay D.; Newcombe, Virginia; Okonkwo, David; Orešič, Matej; Peul, Wilco; Pisică, Dana; Polinder, Suzanne; Ponsford, Jennie; Puybasset, Louis; Raj, Rahul; Robba, Chiara; Røe, Cecilie; Rosand, Jonathan; Schueler, Peter; Sharp, David J.; Smielewski, Peter; Stein, Murray B.; von Steinbüchel, Nicole; Stewart, William; Steyerberg, Ewout W.; Stocchetti, Nino; Temkin, Nancy; Tenovuo, Olli; Theadom, Alice; Thomas, Ilias; Torres Espin, Abel; Turgeon, Alexis F.; Unterberg, Andreas; Van Praag, Dominique; van Veen, Ernest; Verheyden, Jan; Vande Vyvere, Thijs; Wang, Kevin K. W.; Wiegers, Eveline J. A.; Williams, W. Huw; Wilson, Lindsay; Wisniewski, Stephen R.; Younsi, Alexander; Yue, John K.; Yuh, Esther L.; Zeiler, Frederick A.; Zeldovich, Marina; Zemek, Roger; InTBIR Participants and Investigators; Physical Medicine and Rehabilitation, School of MedicineTraumatic brain injury (TBI) has the highest incidence of all common neurological disorders, and poses a substantial public health burden. TBI is increasingly documented not only as an acute condition but also as a chronic disease with long-term consequences, including an increased risk of late-onset neurodegeneration. The first Lancet Neurology Commission on TBI, published in 2017, called for a concerted effort to tackle the global health problem posed by TBI. Since then, funding agencies have supported research both in high-income countries (HICs) and in low-income and middle-income countries (LMICs). In November 2020, the World Health Assembly, the decision-making body of WHO, passed resolution WHA73.10 for global actions on epilepsy and other neurological disorders, and WHO launched the Decade for Action on Road Safety plan in 2021. New knowledge has been generated by large observational studies, including those conducted under the umbrella of the International Traumatic Brain Injury Research (InTBIR) initiative, established as a collaboration of funding agencies in 2011. InTBIR has also provided a huge stimulus to collaborative research in TBI and has facilitated participation of global partners. The return on investment has been high, but many needs of patients with TBI remain unaddressed. This update to the 2017 Commission presents advances and discusses persisting and new challenges in prevention, clinical care, and research. In LMICs, the occurrence of TBI is driven by road traffic incidents, often involving vulnerable road users such as motorcyclists and pedestrians. In HICs, most TBI is caused by falls, particularly in older people (aged ≥65 years), who often have comorbidities. Risk factors such as frailty and alcohol misuse provide opportunities for targeted prevention actions. Little evidence exists to inform treatment of older patients, who have been commonly excluded from past clinical trials—consequently, appropriate evidence is urgently required. Although increasing age is associated with worse outcomes from TBI, age should not dictate limitations in therapy. However, patients injured by low-energy falls (who are mostly older people) are about 50% less likely to receive critical care or emergency interventions, compared with those injured by high-energy mechanisms, such as road traffic incidents. Mild TBI, defined as a Glasgow Coma sum score of 13–15, comprises most of the TBI cases (over 90%) presenting to hospital. Around 50% of adult patients with mild TBI presenting to hospital do not recover to pre-TBI levels of health by 6 months after their injury. Fewer than 10% of patients discharged after presenting to an emergency department for TBI in Europe currently receive follow-up. Structured follow-up after mild TBI should be considered good practice, and urgent research is needed to identify which patients with mild TBI are at risk for incomplete recovery. The selection of patients for CT is an important triage decision in mild TBI since it allows early identification of lesions that can trigger hospital admission or life-saving surgery. Current decision making for deciding on CT is inefficient, with 90–95% of scanned patients showing no intracranial injury but being subjected to radiation risks. InTBIR studies have shown that measurement of blood-based biomarkers adds value to previously proposed clinical decision rules, holding the potential to improve efficiency while reducing radiation exposure. Increased concentrations of biomarkers in the blood of patients with a normal presentation CT scan suggest structural brain damage, which is seen on MR scanning in up to 30% of patients with mild TBI. Advanced MRI, including diffusion tensor imaging and volumetric analyses, can identify additional injuries not detectable by visual inspection of standard clinical MR images. Thus, the absence of CT abnormalities does not exclude structural damage—an observation relevant to litigation procedures, to management of mild TBI, and when CT scans are insufficient to explain the severity of the clinical condition. Although blood-based protein biomarkers have been shown to have important roles in the evaluation of TBI, most available assays are for research use only. To date, there is only one vendor of such assays with regulatory clearance in Europe and the USA with an indication to rule out the need for CT imaging for patients with suspected TBI. Regulatory clearance is provided for a combination of biomarkers, although evidence is accumulating that a single biomarker can perform as well as a combination. Additional biomarkers and more clinical-use platforms are on the horizon, but cross-platform harmonisation of results is needed. Health-care efficiency would benefit from diversity in providers. In the intensive care setting, automated analysis of blood pressure and intracranial pressure with calculation of derived parameters can help individualise management of TBI. Interest in the identification of subgroups of patients who might benefit more from some specific therapeutic approaches than others represents a welcome shift towards precision medicine. Comparative-effectiveness research to identify best practice has delivered on expectations for providing evidence in support of best practices, both in adult and paediatric patients with TBI. Progress has also been made in improving outcome assessment after TBI. Key instruments have been translated into up to 20 languages and linguistically validated, and are now internationally available for clinical and research use. TBI affects multiple domains of functioning, and outcomes are affected by personal characteristics and life-course events, consistent with a multifactorial bio-psycho-socio-ecological model of TBI, as presented in the US National Academies of Sciences, Engineering, and Medicine (NASEM) 2022 report. Multidimensional assessment is desirable and might be best based on measurement of global functional impairment. More work is required to develop and implement recommendations for multidimensional assessment. Prediction of outcome is relevant to patients and their families, and can facilitate the benchmarking of quality of care. InTBIR studies have identified new building blocks (eg, blood biomarkers and quantitative CT analysis) to refine existing prognostic models. Further improvement in prognostication could come from MRI, genetics, and the integration of dynamic changes in patient status after presentation. Neurotrauma researchers traditionally seek translation of their research findings through publications, clinical guidelines, and industry collaborations. However, to effectively impact clinical care and outcome, interactions are also needed with research funders, regulators, and policy makers, and partnership with patient organisations. Such interactions are increasingly taking place, with exemplars including interactions with the All Party Parliamentary Group on Acquired Brain Injury in the UK, the production of the NASEM report in the USA, and interactions with the US Food and Drug Administration. More interactions should be encouraged, and future discussions with regulators should include debates around consent from patients with acute mental incapacity and data sharing. Data sharing is strongly advocated by funding agencies. From January 2023, the US National Institutes of Health will require upload of research data into public repositories, but the EU requires data controllers to safeguard data security and privacy regulation. The tension between open data-sharing and adherence to privacy regulation could be resolved by cross-dataset analyses on federated platforms, with the data remaining at their original safe location. Tools already exist for conventional statistical analyses on federated platforms, however federated machine learning requires further development. Support for further development of federated platforms, and neuroinformatics more generally, should be a priority. This update to the 2017 Commission presents new insights and challenges across a range of topics around TBI: epidemiology and prevention (section 1); system of care (section 2); clinical management (section 3); characterisation of TBI (section 4); outcome assessment (section 5); prognosis (Section 6); and new directions for acquiring and implementing evidence (section 7). Table 1 summarises key messages from this Commission and proposes recommendations for the way forward to advance research and clinical management of TBI.Item Validity of the Brief Test of Adult Cognition by Telephone in Level 1 Trauma Center Patients Six Months Post-Traumatic Brain Injury: A TRACK-TBI Study(Mary Ann Liebert, 2021) Nelson, Lindsay D.; Barber, Jason K.; Temkin, Nancy R.; Dams-O’Connor, Kristen; Dikmen, Sureyya; Giacino, Joseph T.; Kramer, Mark D.; Levin, Harvey S.; McCrea, Michael A.; Whyte, John; Bodien, Yelena G.; Yue, John K.; Manley, Geoffrey T.; TRACK-TBI Investigators; Psychiatry, School of MedicineOur objective was to examine the construct validity of the Brief Test of Adult Cognition by Telephone (BTACT) and its relationship to traumatic brain injury (TBI) of differing severities. Data were analyzed on 1422 patients with TBI and 170 orthopedic trauma controls (OTC) from the multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Participants were assessed at 6 months post-injury with the BTACT and an in-person neuropsychological battery. We examined the BTACT's factor structure, factorial group invariance, convergent and discriminant validity, and relationship to TBI and TBI severity. Confirmatory factor analysis supported both a 1-factor model and a 2-factor model comprising correlated Episodic Memory and Executive Function (EF) factors. Both models demonstrated strict invariance across TBI severity and OTC groups. Correlations between BTACT and criterion measures suggested that the BTACT memory indices predominantly reflect verbal episodic memory, whereas the BTACT EF factor correlated with a diverse range of cognitive tests. Although the EF factor and other BTACT indices showed significant relationships with TBI and TBI severity, some group effect sizes were larger for more comprehensive in-person cognitive tests than the BTACT. The BTACT is a promising, brief, phone-based cognitive screening tool for patients with TBI. Although the BTACT's memory items appear to index verbal Episodic Memory, items that purport to assess EFs may reflect a broader array of cognitive domains. The sensitivity of the BTACT to TBI severity is lower than domain-specific neuropsychological measures, suggesting it should not be used as a substitute for comprehensive, in-person cognitive testing at 6 months post-TBI.