ATF3 is a neuron-specific biomarker for spinal cord injury and ischaemic stroke.

BACKGROUND: Although many molecules have been investigated as biomarkers for spinal cord injury (SCI) or ischemic stroke, none of them are specifically induced in central nervous system (CNS) neurons following injuries with low baseline expression. However, neuronal injury constitutes a major pathology associated with SCI or stroke and strongly correlates with neurological outcomes. Biomarkers characterized by low baseline expression and specific induction in neurons post-injury are likely to better correlate with injury severity and recovery, demonstrating higher sensitivity and specificity for CNS injuries compared to non-neuronal markers or pan-neuronal markers with constitutive expressions. METHODS: In animal studies, young adult wildtype and global Atf3 knockout mice underwent unilateral cervical 5 (C5) SCI or permanent distal middle cerebral artery occlusion (pMCAO). Gene expression was assessed using RNA-sequencing and qRT-PCR, while protein expression was detected through immunostaining. Serum ATF3 levels in animal models and clinical human samples were measured using commercially available enzyme-linked immune-sorbent assay (ELISA) kits. RESULTS: Activating transcription factor 3 (ATF3), a molecular marker for injured dorsal root ganglion sensory neurons in the peripheral nervous system, was not expressed in spinal cord or cortex of naïve mice but was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Additionally, ATF3 protein levels in mouse blood significantly increased 1 day after SCI or ischemic stroke. Importantly, ATF3 protein levels in human serum were elevated in clinical patients within 24 hours after SCI or ischemic stroke. Moreover, Atf3 knockout mice, compared to the wildtype mice, exhibited worse neurological outcomes and larger damage regions after SCI or ischemic stroke, indicating that ATF3 has a neuroprotective function. CONCLUSIONS: ATF3 is an easily measurable, neuron-specific biomarker for clinical SCI and ischemic stroke, with neuroprotective properties. HIGHLIGHTS: ATF3 was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Serum ATF3 protein levels are elevated in clinical patients within 24 hours after SCI or ischemic stroke. ATF3 exhibits neuroprotective properties, as evidenced by the worse neurological outcomes and larger damage regions observed in Atf3 knockout mice compared to wildtype mice following SCI or ischemic stroke.

Designer Receptor Exclusively Activated by Designer Drug (DREADD)-Mediated Activation of the Periaqueductal Gray Restores Nociceptive Descending Inhibition After Traumatic Brain Injury in Rats.

Traumatic brain injury (TBI) patients frequently experience chronic pain that can enhance their suffering and significantly impair rehabilitative efforts. Clinical studies suggest that damage to the periaqueductal gray matter (PAG) following TBI, a principal center involved in endogenous pain control, may underlie the development of chronic pain. We hypothesized that TBI would diminish the usual pain control functions of the PAG, but that directly stimulating this center using a chemogenetic approach would restore descending pain modulation. We used a well-characterized lateral fluid percussion model (1.3 ± 0.1 atm) of TBI in male rats (n = 271) and measured hindpaw mechanical nociceptive withdrawal thresholds using von Frey filaments. To investigate the role of the PAG in pain both before and after TBI, we activated the neurons of the PAG using a Designer Receptor Exclusively Activated by Designer Drug (DREADD) viral construct. Immunohistochemical analysis of brain tissue was used to assess the location and confirm the appropriate expression of the viral constructs in the PAG. Activation of the PAG DREADD using clozapine N-oxide (CNO) caused hindpaw analgesia that could be blocked using opioid receptor antagonist, naloxone, in uninjured but not TBI rats. Due to the importance of descending serotonergic signaling in modulating nociception, we ablated spinal serotonin signaling using 5,7-DHT. This treatment strongly reduced CNO-mediated anti-nociceptive effects in TBI but not uninjured rats. To define the serotonergic receptor(s) required for the CNO-stimulated effects in TBI rats, we administered 5-HT7 (SB-269970) and 5-HT1A (WAY-100635) receptor antagonists but observed no effects. The selective 5-HT2A receptor antagonist ketanserin, however, blocked CNO's effects in the DREADD expressing TBI but not DREADD expressing sham TBI animals. Blockade of alpha-1 adrenergic receptors with prazosin also had no effect after TBI. Descending pain control originating in the PAG is mediated through opioid receptors in uninjured rats. TBI, however, fundamentally alters the descending nociceptive control circuitry such that serotonergic influences predominate, and those are mediated by the 5-HT2A receptor. These results provide further evidence that the PAG is a key target for anti-nociception after TBI.

Predicting Progression of Intracranial Hemorrhage in the Prehospital TXA for TBI Trial.

Progression of intracranial hemorrhage is a common, potentially devastating complication after moderate/severe traumatic brain injury (TBI). Clinicians have few tools to predict which patients with traumatic intracranial hemorrhage on their initial head computed tomography (hCT) scan will progress. The objective of this investigation was to identify clinical, imaging, and/or protein biomarkers associated with progression of intracranial hemorrhage (PICH) after moderate/severe TBI and to create an accurate predictive model of PICH based on clinical features available at presentation. We analyzed a subset of subjects from the phase II double-blind, multi-center, randomized "Prehospital Tranexamic Acid Use for TBI" trial. This subset was limited to the placebo arm of the parent trial with evidence of hemorrhage on the initial hCT and a follow-up hCT 6 h after. PICH was defined as an increase in hemorrhage size by 30% or more, or the development of new hemorrhage in the intra- and extra-axial intracranial vault between the initial and the follow-up hCT. Two independent radiologists evaluated each hCT, and conflicts were adjudicated by a third. Clinical and radiographic characteristics were collected, along with plasma protein biomarkers at admission. Principal component analysis (PCA) was performed, and each principal component (PC) was interrogated for its association with PICH. Finally, expert opinion and recursive feature extraction (RFE) were used to select input features for the construction of several supervised classification models. Their ability to predict PICH was quantified and compared. In this subset of subjects (n = 104), 46% (n = 48) demonstrated PICH. Univariate analyses showed no association between PICH and age, sex, admission Glasgow Coma Scale (GCS), GCS motor subscore, presence of midline shift, admission platelet count or admission INR. Radiographic severity scores (Marshall score [p = 0.007], Rotterdam score [p = 0.004]), and initial hematoma volume [p = 0.005] were associated with PICH. Higher levels of admission glial fibrillary acidic protein (p < 0.001) and MAP (p = 0.011) were also associated with PICH. Of the PCs, PC1 was significantly associated with PICH (p = 0.0125). Using multimodal data input, machine learning classifiers successfully discriminated patients with or without PICH. Models composed of machine-selected features performed better than models composed of expert-selected variables (reaching an average of 77% accuracy, AUC = 0.78 versus AUC = 0.68 for the expert-selected variables). Predictive models utilizing variables measured at admission can accurately predict PICH, confirmed by the 6-hour follow-up hCT. Our best-performing models must now be externally validated in a separate cohort of TBI patients with low GCS and initial hCT positive for hemorrhage.

Enlarged perivascular spaces are associated with white matter injury, cognition and inflammation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Enlarged perivascular spaces have been previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, but their significance and pathophysiology remains unclear. We investigated associations of white matter enlarged perivascular spaces with classical imaging measures, cognitive measures and plasma proteins to better understand what enlarged perivascular spaces represent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and whether radiographic measures of enlarged perivascular spaces would be of value in future therapeutic discovery studies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Twenty-four individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 24 age- and sex-matched controls were included. Disease status was determined based on the presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity, brain parenchymal fraction, white matter enlarged perivascular space volumes, clinical and cognitive measures as well as plasma proteomics were used in models. White matter enlarged perivascular space volumes were calculated via a novel, semiautomated pipeline, and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of enlarged perivascular spaces with global burden of white matter hyperintensity, brain atrophy, functional status, neurocognitive measures and plasma proteins was modelled with linear regression models. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and control groups did not exhibit differences in mean enlarged perivascular space volumes. However, increased enlarged perivascular space volumes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were associated with increased white matter hyperintensity volume (ß = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (ß = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (ß = -0.03, P = 0.10). In interaction term models, the interaction term between cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease status and enlarged perivascular space volume was associated with increased white matter hyperintensity volume (ß = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (ß = 0.52, P = 0.02), Mini-Mental State Examination score (ß = -1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (ß = -0.03, P = 0.07). Proteins positively associated with enlarged perivascular space volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with enlarged perivascular space volumes: CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. The levels of CXC motif chemokine ligand 8/interleukin-8 were also associated with increased white matter hyperintensity volume (ß = 42.86, P = 0.03), and levels of C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 were further associated with decreased brain parenchymal fraction (ß = -0.0007, P < 0.01) and Mini-Mental State Examination score (ß = -0.02, P < 0.01) and increased Trail Making Test B completion time (ß = 0.76, P < 0.01). No proteins were associated with all three studied imaging measures of pathology (brain parenchymal fraction, enlarged perivascular spaces, white matter hyperintensity). Based on associations uncovered between enlarged perivascular space volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter enlarged perivascular space volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Diagnostic Utility of Glial Fibrillary Acidic Protein Beyond 12 Hours After Traumatic Brain Injury: A TRACK-TBI Study.

Blood levels of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) within 12h of suspected traumatic brain injury (TBI) have been approved by the Food and Drug administration to aid in determining the need for a brain computed tomography (CT) scan. The current study aimed to determine whether this context of use can be expanded beyond 12h post-TBI in patients presenting with Glasgow Coma Scale (GCS) 13-15. The prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled TBI participants aged ≥17 years who presented to a United States Level 1 trauma center and received a clinically indicated brain CT scan within 24h post-injury, a blood draw within 24h and at 14 days for biomarker analysis. Data from participants with emergency department arrival GCS 13-15 and biomarker values at days 1 and 14 were extracted for the primary analysis. A subgroup of hospitalized participants with serial biomarkers at days 1, 3, 5, and 14 were analyzed, including plasma GFAP and UCH-L1, and serum neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B). The primary analysis compared biomarker values dichotomized by head CT results (CT+/CT-). Area under receiver-operating characteristic curve (AUC) was used to determine diagnostic accuracy. The overall cohort included 1142 participants with initial GCS 13-15, with mean age 39.8 years, 65% male, and 73% Caucasian. The GFAP provided good discrimination in the overall cohort at days 1 (AUC = 0.82) and 14 (AUC = 0.72), and in the hospitalized subgroup at days 1 (AUC = 0.84), 3 (AUC = 0.88), 5 (AUC = 0.82), and 14 (AUC = 0.74). The UCH-L1, NSE, and S100B did not perform well (AUC = 0.51-0.57 across time points). This study demonstrates the utility of GFAP to aid in decision-making for diagnostic brain CT imaging beyond the 12h time frame in patients with TBI who have a GCS 13-15.

Data-driven distillation and precision prognosis in traumatic brain injury with interpretable machine learning.

Traumatic brain injury (TBI) affects how the brain functions in the short and long term. Resulting patient outcomes across physical, cognitive, and psychological domains are complex and often difficult to predict. Major challenges to developing personalized treatment for TBI include distilling large quantities of complex data and increasing the precision with which patient outcome prediction (prognoses) can be rendered. We developed and applied interpretable machine learning methods to TBI patient data. We show that complex data describing TBI patients' intake characteristics and outcome phenotypes can be distilled to smaller sets of clinically interpretable latent factors. We demonstrate that 19 clusters of TBI outcomes can be predicted from intake data, a ~ 6× improvement in precision over clinical standards. Finally, we show that 36% of the outcome variance across patients can be predicted. These results demonstrate the importance of interpretable machine learning applied to deeply characterized patients for data-driven distillation and precision prognosis.

Correction: Expert-augmented automated machine learning optimizes hemodynamic predictors of spinal cord injury outcome.

[This corrects the article DOI: 10.1371/journal.pone.0265254.].

Safety and comparative efficacy of initiating low-molecular-weight heparin within 24 hours of injury or surgery for venous thromboembolism prophylaxis in patients with spinal cord injury: a prospective TRACK-SCI registry study.

OBJECTIVE: Venous thromboembolism (VTE) following traumatic spinal cord injury (SCI) is a significant clinical concern. This study sought to determine the incidence of VTE and hemorrhagic complications among patients with SCI who received low-molecular-weight heparin (LMWH) within 24 hours of injury or surgery and identify variables that predict VTE using the prospective Transforming Research and Clinical Knowledge in SCI (TRACK-SCI) database. METHODS: The TRACK-SCI database was queried for individuals with traumatic SCI from 2015 to 2022. Primary outcomes of interest included rates of VTE (including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and in-hospital hemorrhagic complications that occurred after LWMH administration. Secondary outcomes included intensive care unit and hospital length of stay, discharge location type, and in-hospital mortality. RESULTS: The study cohort consisted of 162 patients with SCI. Fifteen of the 162 patients withdrew from the study, leading to loss of data for certain variables for these patients. One hundred thirty patients (87.8%) underwent decompression and/or fusion surgery for SCI. DVT occurred in 11 (7.4%) of 148 patients, PE in 9 (6.1%) of 148, and any VTE in 18 (12.2%) of 148 patients. The analysis showed that admission lower-extremity motor score (p = 0.0408), injury at the thoracic level (p = 0.0086), admission American Spinal Injury Association grade (p = 0.0070), and younger age (p = 0.0372) were significantly associated with VTE. There were 3 instances of postoperative spine surgery-related bleeding (2.4%) in the 127 patients who had spine surgery with bleeding complication data available, with one requiring return to surgery (0.8%). Thirteen (8.8%) of 147 patients had a bleeding complication not related to spine surgery. There were 2 gastrointestinal bleeds associated with nasogastric tube placement, 3 cases of postoperative non-spine-related surgery bleeding, and 8 cases of other bleeding complications (5.4%) not related to any surgery. CONCLUSIONS: Initiation of LMWH within 24 hours was associated with a low rate of spine surgery-related bleeding. Bleeding complications unrelated to SCI surgery still occur with LMWH administration. Because neurosurgical intervention is typically the limiting factor in initializing chemical DVT prophylaxis, many of these bleeding complications would have likely occurred regardless of the protocol.

Longitudinal Recovery Following Repetitive Traumatic Brain Injury.

Importance: One traumatic brain injury (TBI) increases the risk of subsequent TBIs. Research on longitudinal outcomes of civilian repetitive TBIs is limited. Objective: To investigate associations between sustaining 1 or more TBIs (ie, postindex TBIs) after study enrollment (ie, index TBIs) and multidimensional outcomes at 1 year and 3 to 7 years. Design, Setting, and Participants: This cohort study included participants presenting to emergency departments enrolled within 24 hours of TBI in the prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study (enrollment years, February 2014 to July 2020). Participants who completed outcome assessments at 1 year and 3 to 7 years were included. Data were analyzed from September 2022 to August 2023. Exposures: Postindex TBI(s). Main Outcomes and Measures: Demographic and clinical factors, prior TBI (ie, preindex TBI), and functional (Glasgow Outcome Scale-Extended [GOSE]), postconcussive (Rivermead Post-Concussion Symptoms Questionnaire [RPQ]), psychological distress (Brief Symptom Inventory-18 [BSI-18]), depressive (Patient Health Questionnaire-9 [PHQ-9]), posttraumatic stress disorder (PTSD; PTSD Checklist for DSM-5 [PCL-5]), and health-related quality-of-life (Quality of Life After Brain Injury-Overall Scale [QOLIBRI-OS]) outcomes were assessed. Adjusted mean differences (aMDs) and adjusted relative risks are reported with 95% CIs. Results: Of 2417 TRACK-TBI participants, 1572 completed the outcomes assessment at 1 year (1049 [66.7%] male; mean [SD] age, 41.6 [17.5] years) and 1084 completed the outcomes assessment at 3 to 7 years (714 [65.9%] male; mean [SD] age, 40.6 [17.0] years). At 1 year, a total of 60 participants (4%) were Asian, 255 (16%) were Black, 1213 (77%) were White, 39 (2%) were another race, and 5 (0.3%) had unknown race. At 3 to 7 years, 39 (4%) were Asian, 149 (14%) were Black, 868 (80%) were White, 26 (2%) had another race, and 2 (0.2%) had unknown race. A total of 50 (3.2%) and 132 (12.2%) reported 1 or more postindex TBIs at 1 year and 3 to 7 years, respectively. Risk factors for postindex TBI were psychiatric history, preindex TBI, and extracranial injury severity. At 1 year, compared with those without postindex TBI, participants with postindex TBI had worse functional recovery (GOSE score of 8: adjusted relative risk, 0.57; 95% CI, 0.34-0.96) and health-related quality of life (QOLIBRI-OS: aMD, -15.9; 95% CI, -22.6 to -9.1), and greater postconcussive symptoms (RPQ: aMD, 8.1; 95% CI, 4.2-11.9), psychological distress symptoms (BSI-18: aMD, 5.3; 95% CI, 2.1-8.6), depression symptoms (PHQ-9: aMD, 3.0; 95% CI, 1.5-4.4), and PTSD symptoms (PCL-5: aMD, 7.8; 95% CI, 3.2-12.4). At 3 to 7 years, these associations remained statistically significant. Multiple (2 or more) postindex TBIs were associated with poorer outcomes across all domains. Conclusions and Relevance: In this cohort study of patients with acute TBI, postindex TBI was associated with worse symptomatology across outcome domains at 1 year and 3 to 7 years postinjury, and there was a dose-dependent response with multiple postindex TBIs. These results underscore the critical need to provide TBI prevention, education, counseling, and follow-up care to at-risk patients.

Improving rigor and reproducibility in western blot experiments with the blotRig analysis software.

Western blot is a popular biomolecular analysis method for measuring the relative quantities of independent proteins in complex biological samples. However, variability in quantitative western blot data analysis poses a challenge in designing reproducible experiments. The lack of rigorous quantitative approaches in current western blot statistical methodology may result in irreproducible inferences. Here we describe best practices for the design and analysis of western blot experiments, with examples and demonstrations of how different analytical approaches can lead to widely varying outcomes. To facilitate best practices, we have developed the blotRig tool for designing and analyzing western blot experiments to improve their rigor and reproducibility. The blotRig application includes functions for counterbalancing experimental design by lane position, batch management across gels, and analytics with covariates and random effects.

Increasing Rigor of Preclinical Research to Maximize Opportunities for Translation.

The use of animal models in pre-clinical research has significantly broadened our understanding of the pathologies that underlie traumatic brain injury (TBI)-induced damage and deficits. However, despite numerous pre-clinical studies reporting the identification of promising neurotherapeutics, translation of these therapies to clinical application has so far eluded the TBI research field. A concerted effort to address this lack of translatability is long overdue. Given the inherent heterogeneity of TBI and the replication crisis that continues to plague biomedical research, this is a complex task that will require a multifaceted approach centered around rigor and reproducibility. Here, we discuss the role of three primary focus areas for better aligning pre-clinical research with clinical TBI management. These focus areas are (1) reporting and standardization of protocols, (2) replication of prior knowledge including the confirmation of expected pharmacodynamics, and (3) the broad application of open science through inter-center collaboration and data sharing. We further discuss current efforts that are establishing the core framework needed for successfully addressing the translatability crisis of TBI.

Emergence of functionally aberrant and subsequent reduction of neuromuscular connectivity and improved motor performance after cervical spinal cord injury in Rhesus.

Introduction: The paralysis that occurs after a spinal cord injury, particularly during the early stages of post-lesion recovery (∼6 weeks), appears to be attributable to the inability to activate motor pools well beyond their motor threshold. In the later stages of recovery, however, the inability to perform a motor task effectively can be attributed to abnormal activation patterns among motor pools, resulting in poor coordination. Method: We have tested this hypothesis on four adult male Rhesus monkeys (Macaca mulatta), ages 6-10 years, by recording the EMG activity levels and patterns of multiple proximal and distal muscles controlling the upper limb of the Rhesus when performing three tasks requiring different levels of skill before and up to 24 weeks after a lateral hemisection at C7. During the recovery period the animals were provided routine daily care, including access to a large exercise cage (5' × 7' × 10') and tested every 3-4 weeks for each of the three motor tasks. Results: At approximately 6-8 weeks the animals were able to begin to step on a treadmill, perform a spring-loaded task with the upper limb, and reaching, grasping, and eating a grape placed on a vertical stick. The predominant changes that occurred, beginning at ∼6-8 weeks of the recovery of these tasks was an elevated level of activation of most motor pools well beyond the pre-lesion level. Discussion: As the chronic phase progressed there was a slight reduction in the EMG burst amplitudes of some muscles and less incidence of co-contraction of agonists and antagonists, probably contributing to an improved ability to selectively activate motor pools in a more effective temporal pattern. Relative to pre-lesion, however, the EMG patterns even at the initial stages of recovery of successfully performing the different motor tasks, the level of activity of most muscle remained higher. Perhaps the most important concept that emerges from these data is the large combinations of adaptive strategies in the relative level of recruitment and the timing of the peak levels of activation of different motor pools can progressively provide different stages to regain a motor skill.

Integrating, Harmonizing, and Curating Studies With High-Frequency and Hourly Physiological Data: Proof of Concept from Seven Traumatic Brain Injury Data Sets.

Research in severe traumatic brain injury (TBI) has historically been limited by studies with relatively small sample sizes that result in low power to detect small, yet clinically meaningful outcomes. Data sharing and integration from existing sources hold promise to yield larger more robust sample sizes that improve the potential signal and generalizability of important research questions. However, curation and harmonization of data of different types and of disparate provenance is challenging. We report our approach and experience integrating multiple TBI data sets containing collected physiological data, including both expected and unexpected challenges encountered in the integration process. Our harmonized data set included data on 1536 patients from the Citicoline Brain Injury Treatment Trial (COBRIT), Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial (EPO Severe TBI), BEST-TRIP, Progesterone for the Treatment of Traumatic Brain Injury III Clinical Trial (ProTECT III), Transforming Research and Clinical Knowledge in Traumatic brain Injury (TRACK-TBI), Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II (BOOST-2), and Ben Taub General Hospital (BTGH) Research Database studies. We conclude with process recommendations for data acquisition for future prospective studies to aid integration of these data with existing studies. These recommendations include using common data elements whenever possible, a standardized recording system for labeling and timing of high-frequency physiological data, and secondary use of studies in systems such as Federal Interagency Traumatic Brain Injury Research Informatics System (FITBIR), to engage investigators who collected the original data.

Pharmacological management of acute spinal cord injury: a longitudinal multi-cohort observational study.

Multiple types and classes of medications are administered in the acute management of traumatic spinal cord injury. Prior clinical studies and evidence from animal models suggest that several of these medications could modify (i.e., enhance or impede) neurological recovery. We aimed to systematically determine the types of medications commonly administered, alone or in combination, in the transition from acute to subacute spinal cord injury. For that purpose, type, class, dosage, timing, and reason for administration were extracted from two large spinal cord injury datasets. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury. Across 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in a clinical trial were administered 9.9 ± 4.9 (range 0-34), 14.3 ± 6.3 (range 1-40), 18.6 ± 8.2 (range 0-58), and 21.5 ± 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Those enrolled in an observational study were administered on average 1.7 ± 1.7 (range 0-11), 3.7 ± 3.7 (range 0-24), 8.5 ± 6.3 (range 0-42), and 13.5 ± 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections). To our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, raising the potential to impact neurological recovery. All results can be interactively explored on the RXSCI web site ( https://jutzelec.shinyapps.io/RxSCI/ ) and GitHub repository ( https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/ ).

Associations of Microvascular Injury-Related Biomarkers With Traumatic Brain Injury Severity and Outcomes: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot Study.

Traumatic brain injury (TBI) is characterized by heterogeneity in terms of injury severity, mechanism, outcome, and pathophysiology. A single biomarker alone is unlikely to capture the heterogeneity of even one injury subtype, necessitating the use of panels of biomarkers. Herein, we focus on traumatic cerebrovascular injury and investigate associations of a panel of 16 vascular injury-related biomarkers with indices of TBI severity and outcomes using data from 159 participants in the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot Study. Associations of individual biomarkers and clusters of biomarkers identified using non-linear principal components analysis with TBI severity and outcomes were assessed using logistic regression models and Spearman's correlations. As individual biomarkers, higher levels of thrombomodulin, angiopoietin (Ang)-2, von Willebrand factor, and P-selectin were associated with more severe injury; higher levels of Ang-1, Tie2, vascular endothelial growth factor (VEGF)-C, and basic fibroblast growth factor (bFGF) were associated with less severe injury (all p < 0.05 in age-adjusted models). After false discovery rate correction for multiple comparisons, higher levels of Ang-2 remained associated with more severe injury and higher levels of Ang-1, Tie2, and bFGF remained associated with less severe injury at a p < 0.05 level. In principal components analysis, principal component (PC)1, comprised of Ang1, bFGF, P-selectin, VEGF-C, VEGF-A, and Tie2, was associated with less severe injury (age-adjusted odds ratio [OR]: 0.63, 95% confidence interval [CI]: 0.44-0.88 for head computer tomography [CT] positive vs. negative) and PC2 (Ang-2, E-selectin, Flt-1, placental growth factor, thrombomodulin, and vascular cell adhesion protein 1) was associated with greater injury severity (age-adjusted OR: 2.29, 95% CI: 1.49-3.69 for Glasgow Coma Scale [GCS] 3-12 vs. 13-15 and age-adjusted OR 1.59, 95% CI: 1.11-2.32 for head CT positive vs. negative). Neither individual biomarkers nor PCs were associated with outcomes in adjusted models (all p > 0.05). In conclusion, in this trauma-center based population of acute TBI patients, biomarkers of microvascular injury were associated with TBI severity.

Neuroinflammatory Biomarkers for Traumatic Brain Injury Diagnosis and Prognosis: A TRACK-TBI Pilot Study.

The relationship between systemic inflammation and secondary injury in traumatic brain injury (TBI) is complex. We investigated associations between inflammatory markers and clinical confirmation of TBI diagnosis and prognosis. The prospective TRACK-TBI Pilot (Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot) study enrolled TBI patients triaged to head computed tomography (CT) and received blood draw within 24 h of injury. Healthy controls (HCs) and orthopedic controls (OCs) were included. Thirty-one inflammatory markers were analyzed from plasma. Area under the receiver operating characteristic curve (AUC) was used to evaluate discriminatory ability. AUC >0.7 was considered acceptable. Criteria included: TBI diagnosis (vs. OC/HC); moderate/severe vs. mild TBI (Glasgow Coma Scale; GCS); radiographic TBI (CT positive vs. CT negative); 3- and 6-month Glasgow Outcome Scale-Extended (GOSE) dichotomized to death/greater relative disability versus less relative disability (GOSE 1-4/5-8); and incomplete versus full recovery (GOSE <8/ = 8). One-hundred sixty TBI subjects, 28 OCs, and 18 HCs were included. Markers discriminating TBI/OC: HMGB-1 (AUC = 0.835), IL-1b (0.795), IL-16 (0.784), IL-7 (0.742), and TARC (0.731). Markers discriminating GCS 3-12/13-15: IL-6 (AUC = 0.747), CRP (0.726), IL-15 (0.720), and SAA (0.716). Markers discriminating CT positive/CT negative: SAA (AUC = 0.767), IL-6 (0.757), CRP (0.733), and IL-15 (0.724). At 3 months, IL-15 (AUC = 0.738) and IL-2 (0.705) discriminated GOSE 5-8/1-4. At 6 months, IL-15 discriminated GOSE 1-4/5-8 (AUC = 0.704) and GOSE <8/ = 8 (0.711); SAA discriminated GOSE 1-4/5-8 (0.704). We identified a profile of acute circulating inflammatory proteins with potential relevance for TBI diagnosis, severity differentiation, and prognosis. IL-15 and serum amyloid A are priority markers with acceptable discrimination across multiple diagnostic and outcome categories. Validation in larger prospective cohorts is needed. ClinicalTrials.gov Registration: NCT01565551.

Hypotension requiring vasopressor treatment and increased cardiac complications in elderly spinal cord injury patients: a prospective TRACK-SCI registry study.

OBJECTIVE: Increasing life expectancy has led to an older population. In this study, the authors analyzed complications and outcomes in elderly patients following spinal cord injury (SCI) using the established multi-institutional prospective study Transforming Research and Clinical Knowledge in SCI (TRACK-SCI) database collected in the Department of Neurosurgical Surgery at the University of California, San Francisco. METHODS: TRACK-SCI was queried for elderly individuals (≥ 65 years of age) with traumatic SCI from 2015 to 2019. Primary outcomes of interest included total hospital length of stay, perioperative complications, postoperative complications, and in-hospital mortality. Secondary outcomes included disposition location, and neurological improvement based on the American Spinal Injury Association Impairment Scale (AIS) grade at discharge. Descriptive analysis, Fisher's exact test, univariate analysis, and multivariable regression analysis were performed. RESULTS: The study cohort consisted of 40 elderly patients. The in-hospital mortality rate was 10%. Every patient in this cohort experienced at least 1 complication, with a mean of 6.6 separate complications (median 6, mode 4). The most common complication categories were cardiovascular, with a mean of 1.6 complications (median 1, mode 1), and pulmonary, with a mean of 1.3 (median 1, mode 0) complications, with 35 patients (87.5%) having at least 1 cardiovascular complication and 25 (62.5%) having at least 1 pulmonary complication. Overall, 32 patients (80%) required vasopressor treatment for mean arterial pressure (MAP) maintenance goals. The use of norepinephrine correlated with increased cardiovascular complications. Only 3 patients (7.5%) of the total cohort had an improved AIS grade compared with their acute level at admission. CONCLUSIONS: Given the increased frequency of cardiovascular complications associated with vasopressor use in elderly SCI patients, caution is warranted when targeting MAP goals in these patients. A downward adjustment of blood pressure maintenance goals and prophylactic cardiology consultation to select the most appropriate vasopressor agent may be advisable for SCI patients ≥ 65 years of age.

Combined space stressors induce independent behavioral deficits predicted by early peripheral blood monocytes.

Interplanetary space travel poses many hazards to the human body. To protect astronaut health and performance on critical missions, there is first a need to understand the effects of deep space hazards, including ionizing radiation, confinement, and altered gravity. Previous studies of rodents exposed to a single such stressor document significant deficits, but our study is the first to investigate possible cumulative and synergistic impacts of simultaneous ionizing radiation, confinement, and altered gravity on behavior and cognition. Our cohort was divided between 6-month-old female and male mice in group, social isolation, or hindlimb unloading housing, exposed to 0 or 50 cGy of 5 ion simplified simulated galactic cosmic radiation (GCRsim). We report interactions and independent effects of GCRsim exposure and housing conditions on behavioral and cognitive performance. Exposure to GCRsim drove changes in immune cell populations in peripheral blood collected early after irradiation, while housing conditions drove changes in blood collected at a later point. Female mice were largely resilient to deficits observed in male mice. Finally, we used principal component analysis to represent total deficits as principal component scores, which were predicted by general linear models using GCR exposure, housing condition, and early blood biomarkers.

Harmonization-Information Trade-Offs for Sharing Individual Participant Data in Biomedicine.

Biomedical practice is evidence-based. Peer-reviewed papers are the primary medium to present evidence and data-supported results to drive clinical practice. However, it could be argued that scientific literature does not contain data, but rather narratives about and summaries of data. Meta-analyses of published literature may produce biased conclusions due to the lack of transparency in data collection, publication bias, and inaccessibility to the data underlying a publication ('dark data'). Co-analysis of pooled data at the level of individual research participants can offer higher levels of evidence, but this requires that researchers share raw individual participant data (IPD). FAIR (findable, accessible, interoperable, and reusable) data governance principles aim to guide data lifecycle management by providing a framework for actionable data sharing. Here we discuss the implications of FAIR for data harmonization, an essential step for pooling data for IPD analysis. We describe the harmonization-information trade-off, which states that the level of granularity in harmonizing data determines the amount of information lost. Finally, we discuss a framework for managing the trade-off and the levels of harmonization. In the coming era of funder mandates for data sharing, research communities that effectively manage data harmonization will be empowered to harness big data and advanced analytics such as machine learning and artificial intelligence tools, leading to stunning new discoveries that augment our understanding of diseases and their treatments. By elevating scientific data to the status of a first-class citizen of the scientific enterprise, there is strong potential for biomedicine to transition from a narrative publication product orientation to a modern data-driven enterprise where data itself is viewed as a primary work product of biomedical research.