Search

Traumatic spinal cord injury (SCI) produces a complex syndrome that is expressed across multiple endpoints ranging from molecular and cellular changes to functional behavioral deficits. Effective therapeutic strategies for CNS injury are therefore likely to manifest multi-factorial effects across a broad range of biological and functional outcome measures. Thus, multivariate analytic approaches are needed to capture the linkage between biological and neurobehavioral outcomes. Injury-induced neuroinflammation (NI) presents a particularly challenging therapeutic target, since NI is involved in both degeneration and repair. Here, we used big-data integration and large-scale analytics to examine a large dataset of preclinical efficacy tests combining five different blinded, fully counter-balanced treatment trials for different acute anti-inflammatory treatments for cervical spinal cord injury in rats. Multi-dimensional discovery, using topological data analysis (TDA) and principal components analysis (PCA) revealed that only one showed consistent multidimensional syndromic benefit: intrathecal application of recombinant soluble TNFα receptor 1 (sTNFR1), which showed an inverse-U dose response efficacy. Using the optimal acute dose, we showed that clinically-relevant 90 min delayed treatment profoundly affected multiple biological indices of NI in the first 48 h after injury, including reduction in pro-inflammatory cytokines and gene expression of a coherent complex of acute inflammatory mediators and receptors. Further, a 90 min delayed bolus dose of sTNFR1 reduced the expression of NI markers in the chronic perilesional spinal cord, and consistently improved neurological function over 6 weeks post SCI. These results provide validation of a novel strategy for precision preclinical drug discovery that is likely to improve translation in the difficult landscape of CNS trauma, and confirm the importance of TNFα signaling as a therapeutic target.

BackgroundSystemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics.Patients and methodsMyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR).ResultsAs of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred.ConclusionsOverall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.

BACKGROUND AND PURPOSE:Our aim was to use 2D convolutional neural networks for automatic segmentation of the spinal cord and traumatic contusion injury from axial T2-weighted MR imaging in a cohort of patients with acute spinal cord injury. MATERIALS AND METHODS:Forty-seven patients who underwent 3T MR imaging within 24 hours of spinal cord injury were included. We developed an image-analysis pipeline integrating 2D convolutional neural networks for whole spinal cord and intramedullary spinal cord lesion segmentation. Linear mixed modeling was used to compare test segmentation results between our spinal cord injury convolutional neural network (Brain and Spinal Cord Injury Center segmentation) and current state-of-the-art methods. Volumes of segmented lesions were then used in a linear regression analysis to determine associations with motor scores. RESULTS:Compared with manual labeling, the average test set Dice coefficient for the Brain and Spinal Cord Injury Center segmentation model was 0.93 for spinal cord segmentation versus 0.80 for PropSeg and 0.90 for DeepSeg (both components of the Spinal Cord Toolbox). Linear mixed modeling showed a significant difference between Brain and Spinal Cord Injury Center segmentation compared with PropSeg (P < .001) and DeepSeg (P < .05). Brain and Spinal Cord Injury Center segmentation showed significantly better adaptability to damaged areas compared with PropSeg (P < .001) and DeepSeg (P < .02). The contusion injury volumes based on automated segmentation were significantly associated with motor scores at admission (P = .002) and discharge (P = .009). CONCLUSIONS:Brain and Spinal Cord Injury Center segmentation of the spinal cord compares favorably with available segmentation tools in a population with acute spinal cord injury. Volumes of injury derived from automated lesion segmentation with Brain and Spinal Cord Injury Center segmentation correlate with measures of motor impairment in the acute phase. Targeted convolutional neural network training in acute spinal cord injury enhances algorithm performance for this patient population and provides clinically relevant metrics of cord injury.

Background and purposeAcute markers of spinal cord injury are essential for both diagnostic and prognostic purposes. The goal of this study was to assess the relationship between early MR imaging biomarkers after acute cervical spinal cord injury and to evaluate their predictive validity of neurologic impairment.Materials and methodsWe performed a retrospective cohort study of 95 patients with acute spinal cord injury and preoperative MR imaging within 24 hours of injury. The American Spinal Injury Association Impairment Scale was used as our primary outcome measure to define neurologic impairment. We assessed several MR imaging features of injury, including axial grade (Brain and Spinal Injury Center score), sagittal grade, length of injury, maximum canal compromise, and maximum spinal cord compression. Data-driven nonlinear principal component analysis was followed by correlation and optimal-scaled multiple variable regression to predict neurologic impairment.ResultsNonlinear principal component analysis identified 2 clusters of MR imaging variables related to 1) measures of intrinsic cord signal abnormality and 2) measures of extrinsic cord compression. Neurologic impairment was best accounted for by MR imaging measures of intrinsic cord signal abnormality, with axial grade representing the most accurate predictor of short-term impairment, even when correcting for surgical decompression and degree of cord compression.ConclusionsThis study demonstrates the utility of applying nonlinear principal component analysis for defining the relationship between MR imaging biomarkers in a complex clinical syndrome of cervical spinal cord injury. Of the assessed imaging biomarkers, the intrinsic measures of cord signal abnormality were most predictive of neurologic impairment in acute spinal cord injury, highlighting the value of axial T2 MR imaging.

Mechanisms governing a neuron's regenerative ability are important but not well understood. We identify Rtca (RNA 3′-terminal phosphate cyclase) as an inhibitor of axon regeneration. Removal of Rtca cell-autonomously enhanced axon regrowth in the Drosophila CNS, whereas its overexpression reduced axon regeneration in the periphery. Rtca along with the RNA ligase Rtcb and its catalyst Archease operate in the RNA repair and splicing pathway important for stress-induced mRNA splicing, including that of Xbp1, a cellular stress sensor. Drosophila Rtca and Archease had opposing effects on Xbp1 splicing, and deficiency of Archease or Xbp1 impeded axon regeneration in Drosophila. Moreover, overexpressing mammalian Rtca in cultured rodent neurons reduced axonal complexity in vitro, whereas reducing its function promoted retinal ganglion cell axon regeneration after optic nerve crush in mice. Our study thus links axon regeneration to cellular stress and RNA metabolism, revealing new potential therapeutic targets for treating nervous system trauma.

Spinal cord injury (SCI) and other neurological disorders involve complex biological and functional changes. Well-characterized preclinical models provide a powerful tool for understanding mechanisms of disease; however managing information produced by exp

The proinflammatory cytokine TNFα contributes to cell death in central nervous system (CNS) disorders by altering synaptic neurotransmission. TNFα contributes to excitotoxicity by increasing GluA2-lacking AMPA receptor (AMPAR) trafficking to the neuronal p

Injury-induced overexpression of tumor necrosis factor alpha (TNFα) in the spinal cord can induce chronic neuroinflammation and excitotoxicity that ultimately undermines functional recovery. Here we investigate how TNFα might also act to upset spinal funct

Primates are an important and unique animal resource. We have developed a nonhuman primate model of spinal cord injury (SCI) to expand our knowledge of normal primate motor function, to assess the impact of disease and injury on sensory and motor function, and to test candidate therapies before they are applied to human patients. The lesion model consists of a lateral spinal cord hemisection at the C7 spinal level with subsequent examination of behavioral, electrophysiological, and anatomical outcomes. Results to date have revealed significant neuroanatomical and functional differences between rodents and primates that impact the development of candidate therapies. Moreover, these findings suggest the importance of testing some therapeutic approaches in nonhuman primates prior to the use of invasive approaches in human clinical trials. Our primate model is intended to: 1) lend greater positive predictive value to human translatable therapies, 2) develop appropriate methods for human translation, 3) lead to basic discoveries that might not be identified in rodent models and are relevant to human translation, and 4) identify new avenues of basic research to "reverse-translate" important questions back to rodent models. [ABSTRACT FROM AUTHOR]

The complex and heterogeneous nature of spinal cord injury has limited translational bench-to-bedside results. The wide variety of data, including injury parameters, biochemical, histological, and behavioral outcome measures represent a 'big data' problem, calling for modern data science solutions. There are some instances in which SCI researchers collect sensitive data that needs to remain private, such as datasets designed to meet regulatory approval, sensitive intellectual property, and non-human primate studies. For these types of data, we have developed a Private Data Commons for SCI (PDC-SCI). Our objective is to give an overview of this novel data commons, describing how this type of commons works, how it can benefit the research community, and the cases in which it would be most useful. This private infrastructure is ideal for multi-lab transdisciplinary studies that require a well-organized, scalable data commons for rapid data sharing within a closed, distributed team. As a use-case for the PDC-SCI, we demonstrate the VA Gordon Mansfield SCI Consortium, in which multimodal data from behavior, biomechanics of injury, hospital records, imaging, and histology are integrated, shared, and analyzed to facilitate insights and knowledge discovery., Competing Interests: Declaration of competing interest A.R.F. discloses Spine X Inc. DSMB, and research funding support from NIH/NINDS R01NS122888, UH3NS106899, U24NS122732, U19AR076737; VA I01RX002245, I01RX002787, I01BX005871, I50BX005878, Craig H. Neilsen Foundation, and Wings for Life Foundation. ATE: co-owner of YEG scientific, a company producing behavioral research tools for animal models of disease. All other authors have nothing to declare., (Copyright © 2024. Published by Elsevier Inc.)

Objective: The International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) assessment is the gold standard for evaluation of neurological function after spinal cord injury (SCI). Although it is an invaluable tool for diagnostic and research purposes, it is time consuming and can be impractical in acute injury settings. Clinical neurosurgery motor examinations (NMEs) could serve as an expeditious surrogate for SCI research when ISNCSCI motor examinations are not feasible. The aim of this study was to evaluate the agreement between motor examinations performed by the neurosurgery clinical team and ISNCSCI examiners., Methods: The multicenter prospective Transforming Research and Clinical Knowledge in Spinal Cord Injury (TRACK-SCI) registry was queried to identify patients with recorded neurosurgery and research motor examinations within 24 hours of each other. Pearson correlations and modified Bland-Altman analyses were performed using data from matching upper-extremity, lower-extremity, and combined examinations. Kappa analysis was used to test interrater reliability with respect to determination of American Spinal Injury Association Impairment Scale (AIS) grade., Results: There were 72 pairs of matching clinical and research examinations in 63 patients. NME scores were strongly correlated with ISNCSCI motor scores (R = 0.962, p < 0.001). Both upper- and lower-extremity NME scores were strongly correlated with upper- and lower-extremity ISNCSCI motor scores, respectively (R = 0.939, p < 0.001; and R = 0.959, p < 0.001, respectively). In modified Bland-Altman analyses, total, upper-extremity, and lower-extremity NME scores and ISNCSCI motor scores showed low systematic bias and high agreeability (total: bias = 0.3, limit of agreement [LoA] = 36.6; upper extremity: bias = -0.5, LoA = 17.6; lower extremity: bias = 0.8, LoA = 24.0). There were 66 pairs of examinations that had thorough sensory and rectal examinations for AIS grade calculation. Using kappa analysis to test the interrater reliability of AIS grade calculation using NME versus ISNCSCI motor scores, the authors found a weighted kappa of 0.883 (SE 0.061, 95% CI 0.736-0.976), indicating strong agreement., Conclusions: Overall, this study suggests that ISNCSCI motor scores and NME scores are strongly correlated and highly agreeable. When conducting SCI research, a thorough clinical motor examination may be a useful surrogate when ISNCSCI examinations are missing.

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., (© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

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.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Wai, Zdunowski, Zhong, Nielson, Ferguson, Strand, Moseanko, Hawbecker, Nout-Lomas, Rosenzweig, Beattie, Bresnahan, Tuszynski, Roy and Edgerton.)

Large animal contusion models of spinal cord injury are an essential precursor to developing and evaluating treatment options for human spinal cord injury. Reducing variability in these experiments has been a recent focus as it increases the sensitivity with which treatment effects can be detected while simultaneously decreasing the number of animals required in a study. Here, we conducted a detailed review to explore if head and neck positioning in a cervical contusion model of spinal cord injury could be a factor impacting the biomechanics of a spinal cord injury, and thus, the resulting outcomes. By reviewing existing literature, we found evidence that animal head/neck positioning affects the exposed level of the spinal cord, morphology of the spinal cord, tissue mechanics and as a result the biomechanics of a cervical spinal cord injury. We posited that neck position could be a hidden factor contributing to variability. Our results indicate that neck positioning is an important factor in studying biomechanics, and that reporting these values can improve inter-study consistency and comparability and that further work needs to be done to standardize positioning for cervical spinal cord contusion injury models., Competing Interests: ESa was employed by the ClearPoint Neuro, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Obaid, Morioka, Sinopoulou, Lomas, Salegio, Bresnahan, Beattie and Sparrey.)

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.

Human papillomavirus (HPV) infections are linked to at least six different types of cancer. The Medical University of South Carolina (MUSC) Hollings Cancer Center (HCC) and Department of Pediatrics leaders identified suboptimal rates of HPV vaccinations in rural and medically underserved communities in South Carolina (SC). To address this major public health problem in SC, they received funding from the HealthyMe/HealthySC (HMHSC) program and HCC to create a statewide community engagement-focused HPV Vaccination Van Program in October 2021. The Program provides HPV vaccinations and other childhood immunizations in school districts and HMHSC health clinics throughout SC, focusing on children aged 9-18 who are eligible for the U.S. Centers for Disease Control and Prevention's Vaccines for Children Program. As of 14 December 2022, the Program administered vaccinations in 16 counties of SC to 552 participants, 243 of whom received HPV vaccinations and were predominantly female (57.2%), aged 4-18 (95.9%), and self-identified as White (44.0%), Black (33.2%), or Hispanic/Latino (15.1%). Most had Medicaid (53.1%)/no insurance coverage (25.1%). The Program is expected to expand as the Program's relationship with SC's school districts grows. The Program provides a model for delivering mobile HPV vaccinations to rural children, thus reducing their cancer risk.

We used viral intersectional tools to map the entire projectome of corticospinal neurons associated with fine distal forelimb control in Fischer 344 rats and rhesus macaques. In rats, we found an extraordinarily diverse set of collateral projections from corticospinal neurons to 23 different brain and spinal regions. Remarkably, the vast weighting of this "motor" projection was to sensory systems in both the brain and spinal cord, confirmed by optogenetic and transsynaptic viral intersectional tools. In contrast, rhesus macaques exhibited far heavier and narrower weighting of corticospinal outputs toward spinal and brainstem motor systems. Thus, corticospinal systems in macaques primarily constitute a final output system for fine motor control, whereas this projection in rats exerts a multi-modal integrative role that accesses far broader CNS regions. Unique structural-functional correlations can be achieved by mapping and quantifying a single neuronal system's total axonal output and its relative weighting across CNS targets., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Spinal cord injuries (SCIs) frequently occur in combination with other major organ injuries, such as traumatic brain injury (TBI) and injuries to the chest, abdomen, and musculoskeletal system (e.g., extremity, pelvic, and spine fractures). However, the effects of appendicular fractures on SCI recovery are poorly understood. We investigated whether the presence of SCI-concurrent appendicular fractures is predictive of a less robust SCI recovery. Patients enrolled in the Transforming Research and Clinical Knowledge in SCI (TRACK-SCI) prospective cohort study were identified and included in this secondary analysis study. Inclusion criteria resulted in 147 patients, consisting of 120 with isolated SCIs and 27 with concomitant appendicular fracture. The primary outcome was American Spinal Injury Association (ASIA) Impairment Scale (AIS) neurological grades at hospital discharge. Secondary outcomes included hospital length of stay, intensive care unit (ICU) length of stay, and AIS grade improvement during hospitalization. Multivariable binomial logistical regression analyses assessed whether SCI-concomitant appendicular fractures associate with SCI function and secondary outcomes. These analyses were adjusted for age, gender, injury severity, and non-fracture polytrauma. Appendicular fractures were associated with more severe AIS grades at hospital discharge, though covariate adjustments diminished statistical significance of this effect. Notably, non-fracture injuries to the chest and abdomen were influential covariates. Secondary analyses suggested that appendicular fractures also increased hospital length of stay. Our study indicated that SCI-associated polytrauma is important for predicting SCI functional outcomes. Further statistical evaluation is required to disentangle the effects of appendicular fractures, non-fracture solid organ injury, and SCI physiology to improve health outcomes among SCI patients.

Artificial intelligence and machine learning (AI/ML) is becoming increasingly more accessible to biomedical researchers with significant potential to transform biomedicine through optimization of highly-accurate predictive models and enabling better understanding of disease biology. Automated machine learning (AutoML) in particular is positioned to democratize artificial intelligence (AI) by reducing the amount of human input and ML expertise needed. However, successful translation of AI/ML in biomedicine requires moving beyond optimizing only for prediction accuracy and towards establishing reproducible clinical and biological inferences. This is especially challenging for clinical studies on rare disorders where the smaller patient cohorts and corresponding sample size is an obstacle for reproducible modeling results. Here, we present a model-agnostic framework to reinforce AutoML using strategies and tools of explainable and reproducible AI, including novel metrics to assess model reproducibility. The framework enables clinicians to interpret AutoML-generated models for clinical and biological verifiability and consequently integrate domain expertise during model development. We applied the framework towards spinal cord injury prognostication to optimize the intraoperative hemodynamic range during injury-related surgery and additionally identified a strong detrimental relationship between intraoperative hypertension and patient outcome. Furthermore, our analysis captured how evolving clinical practices such as faster time-to-surgery and blood pressure management affect clinical model development. Altogether, we illustrate how expert-augmented AutoML improves inferential reproducibility for biomedical discovery and can ultimately build trust in AI processes towards effective clinical integration., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AC, SK, JF, JH, AL, RS, and CM are current or former employees of DataRobot and own shares of the company. Access to the DataRobot Automated Machine Learning platform was awarded through application and selection by the DataRobot AI for Good program. DataRobot affiliated authors provided editorial contributions during the preparation of the manuscript. All other authors have declared that they have no competing interests.

Traumatic brain injury (TBI) is a major public health problem. Despite considerable research deciphering injury pathophysiology, precision therapies remain elusive. Here, we present large-scale data sharing and machine intelligence approaches to leverage TBI complexity. The Open Data Commons for TBI (ODC-TBI) is a community-centered repository emphasizing Findable, Accessible, Interoperable, and Reusable data sharing and publication with persistent identifiers. Importantly, the ODC-TBI implements data sharing of individual subject data, enabling pooling for high-sample-size, feature-rich data sets for machine learning analytics. We demonstrate pooled ODC-TBI data analyses, starting with descriptive analytics of subject-level data from 11 previously published articles ( N  = 1250 subjects) representing six distinct pre-clinical TBI models. Second, we perform unsupervised machine learning on multi-cohort data to identify persistent inflammatory patterns across different studies, improving experimental sensitivity for pro- versus anti-inflammation effects. As funders and journals increasingly mandate open data practices, ODC-TBI will create new scientific opportunities for researchers and facilitate multi-data-set, multi-dimensional analytics toward effective translation., Competing Interests: No competing financial interests exist., (© Austin Chou et al., 2022; Published by Mary Ann Liebert, Inc.)

Objective: Previous work has shown that maintaining mean arterial pressures (MAPs) between 76 and 104 mm Hg intraoperatively is associated with improved neurological function at discharge in patients with acute spinal cord injury (SCI). However, whether temporary fluctuations in MAPs outside of this range can be tolerated without impairment of recovery is unknown. This retrospective study builds on previous work by implementing machine learning to derive clinically actionable thresholds for intraoperative MAP management guided by neurological outcomes., Methods: Seventy-four surgically treated patients were retrospectively analyzed as part of a longitudinal study assessing outcomes following SCI. Each patient underwent intraoperative hemodynamic monitoring with recordings at 5-minute intervals for a cumulative 28,594 minutes, resulting in 5718 unique data points for each parameter. The type of vasopressor used, dose, drug-related complications, average intraoperative MAP, and time spent in an extreme MAP range (< 76 mm Hg or > 104 mm Hg) were collected. Outcomes were evaluated by measuring the change in American Spinal Injury Association Impairment Scale (AIS) grade over the course of acute hospitalization. Features most predictive of an improvement in AIS grade were determined statistically by generating random forests with 10,000 iterations. Recursive partitioning was used to establish clinically intuitive thresholds for the top features., Results: At discharge, a significant improvement in AIS grade was noted by an average of 0.71 levels (p = 0.002). The hemodynamic parameters most important in predicting improvement were the amount of time intraoperative MAPs were in extreme ranges and the average intraoperative MAP. Patients with average intraoperative MAPs between 80 and 96 mm Hg throughout surgery had improved AIS grades at discharge. All patients with average intraoperative MAP > 96.3 mm Hg had no improvement. A threshold of 93 minutes spent in an extreme MAP range was identified after which the chance of neurological improvement significantly declined. Finally, the use of dopamine as compared to norepinephrine was associated with higher rates of significant cardiovascular complications (50% vs 25%, p < 0.001)., Conclusions: An average intraoperative MAP value between 80 and 96 mm Hg was associated with improved outcome, corroborating previous results and supporting the clinical verifiability of the model. Additionally, an accumulated time of 93 minutes or longer outside of the MAP range of 76-104 mm Hg is associated with worse neurological function at discharge among patients undergoing emergency surgical intervention for acute SCI.

Meta-analyses suggest that the published literature represents only a small minority of the total data collected in biomedical research, with most becoming 'dark data' unreported in the literature. Dark data is due to publication bias toward novel results that confirm investigator hypotheses and omission of data that do not. Publication bias contributes to scientific irreproducibility and failures in bench-to-bedside translation. Sharing dark data by making it Findable, Accessible, Interoperable, and Reusable (FAIR) may reduce the burden of irreproducible science by increasing transparency and support data-driven discoveries beyond the lifecycle of the original study. We illustrate feasibility of dark data sharing by recovering original raw data from the Multicenter Animal Spinal Cord Injury Study (MASCIS), an NIH-funded multi-site preclinical drug trial conducted in the 1990s that tested efficacy of several therapies after a spinal cord injury (SCI). The original drug treatments did not produce clear positive results and MASCIS data were stored in boxes for more than two decades. The goal of the present study was to independently confirm published machine learning findings that perioperative blood pressure is a major predictor of SCI neuromotor outcome (Nielson et al., 2015). We recovered, digitized, and curated the data from 1125 rats from MASCIS. Analyses indicated that high perioperative blood pressure at the time of SCI is associated with poorer health and worse neuromotor outcomes in more severe SCI, whereas low perioperative blood pressure is associated with poorer health and worse neuromotor outcome in moderate SCI. These findings confirm and expand prior results that a narrow window of blood-pressure control optimizes outcome, and demonstrate the value of recovering dark data for assessing reproducibility of findings with implications for precision therapeutic approaches., (© 2021. The Author(s).)

Background: Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients., Methods: Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods., Results: Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76-[104-117] mmHg associated with neurological recovery., Conclusions: We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention., Funding: NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB)., Competing Interests: AT, JH, RE, DT, CA, JH, AC, DM, NS, BD, CS, JN, NK, DH, JT, GM, SD, WW, JB, MB, SM, JP, AF No competing interests declared, (© 2021, Torres-Espín et al.)

Research using nonhuman primate models for human disease frequently requires behavioral observational techniques to quantify functional outcomes. The ability to assess reaching and grasping patterns is of particular interest in clinical conditions that affect the motor system (e.g., spinal cord injury, SCI). Here we explored the use of DeepLabCut, an open-source deep learning toolset, in combination with a standard behavioral task (Brinkman Board) to quantify nonhuman primate performance in precision grasping. We examined one male rhesus macaque (Macaca mulatta) in the task which involved retrieving rewards from variously-oriented shallow wells. Simultaneous recordings were made using GoPro Hero7 Black cameras (resolution 1920 x 1080 at 120 fps) from two different angles (from the side and top of the hand motion). The task/device design necessitates use of the right hand to complete the task. Two neural networks (corresponding to the top and side view cameras) were trained using 400 manually annotated images, tracking 19 unique landmarks each. Based on previous reports, this produced sufficient tracking (Side: trained pixel error of 2.15, test pixel error of 11.25; Top: trained pixel error of 2.06, test pixel error of 30.31) so that landmarks could be tracked on the remaining frames. Landmarks included in the tracking were the spatial location of the knuckles and the fingernails of each digit, and three different behavioral measures were quantified for assessment of hand movement (finger separation, middle digit extension and preshaping distance). Together, our preliminary results suggest that this markerless approach is a possible method to examine specific kinematic features of dexterous function.Clinical Relevance- The methodology presented below allows for the markerless tracking of kinematic features of dexterous finger movement by non-human primates. This method could allow for direct comparisons between human patients and non-human primate models of clinical conditions (e.g., spinal cord injury). This would provide objective quantitative metrics and crucial information for assessing movement impairments across populations and the potential translation of treatments, interventions and their outcomes.

Non-human primate (NHP) models are the closest approximation of human spinal cord injury (SCI) available for pre-clinical trials. The NHP models, however, include broader morphological variability that can confound experimental outcomes. We developed subject-specific finite element (FE) models to quantify the relationship between impact mechanics and SCI, including the correlations between FE outcomes and tissue damage. Subject-specific models of cervical unilateral contusion SCI were generated from pre-injury MRIs of six NHPs. Stress and strain outcomes were compared with lesion histology using logit analysis. A parallel generic model was constructed to compare the outcomes of subject-specific and generic models. The FE outcomes were correlated more strongly with gray matter damage (0.29 < R 2 < 0.76) than white matter (0.18 < R 2 < 0.58). Maximum/minimum principal strain, Von-Mises and Tresca stresses showed the strongest correlations (0.31 < R 2 < 0.76) with tissue damage in the gray matter while minimum principal strain, Von-Mises stress, and Tresca stress best predicted white matter damage (0.23 < R 2 < 0.58). Tissue damage thresholds varied for each subject. The generic FE model captured the impact biomechanics in two of the four models; however, the correlations between FE outcomes and tissue damage were weaker than the subject-specific models (gray matter [0.25 < R 2 < 0.69] and white matter [R 2 < 0.06] except for one subject [0.26 < R 2 < 0.48]). The FE mechanical outputs correlated with tissue damage in spinal cord white and gray matters, and the subject-specific models accurately mimicked the biomechanics of NHP cervical contusion impacts.

Diagnosis of spinal cord injury (SCI) severity at the ultra-acute stage is of great importance for emergency clinical care of patients as well as for potential enrollment into clinical trials. The lack of a diagnostic biomarker for SCI has played a major role in the poor results of clinical trials. We analyzed global gene expression in peripheral white blood cells during the acute injury phase and identified 197 genes whose expression changed after SCI compared with healthy and trauma controls and in direct relation to SCI severity. Unsupervised coexpression network analysis identified several gene modules that predicted injury severity (AIS grades) with an overall accuracy of 72.7% and included signatures of immune cell subtypes. Specifically, for complete SCIs (AIS A), ROC analysis showed impressive specificity and sensitivity (AUC: 0.865). Similar precision was also shown for AIS D SCIs (AUC: 0.938). Our findings indicate that global transcriptomic changes in peripheral blood cells have diagnostic and potentially prognostic value for SCI severity., Competing Interests: Disclosures: G.T. Manley reported grants from NIH-NINDS and grants from United States Department of Defense during the conduct of the study. S. Dhall reported personal fees from Depuy Synthes, personal fees from Globus Medical, and other from Great Circle Technologies outside the submitted work. M.S. Beattie reported that he is on the board of directors of two nonprofits that support spinal cord injury research, the American Spinal Injury Association and the Praxis Spinal Cord Institute. Only travel expenses are reimbursed. No other disclosures were reported., (© 2021 Kyritsis et al.)

Conventional MRI measures of traumatic spinal cord injury severity largely rely on 2-dimensional injury characteristics such as intramedullary lesion length and cord compression. Recent advances in spinal cord (SC) analysis have led to the development of a robust anatomic atlas incorporated into an open-source platform called the Spinal Cord Toolbox (SCT) that allows for quantitative volumetric injury analysis. In the current study, we evaluate the prognostic value of volumetric measures of spinal cord injury on MRI following registration of T2-weighted (T2w) images and segmented lesions from acute SCI patients with a standardized atlas. This IRB-approved prospective cohort study involved the image analysis of 60 blunt cervical SCI patients enrolled in the TRACK-SCI clinical research protocol. Axial T2w MRI data obtained within 24 h of injury were processed using the SCT. Briefly, SC MRIs were automatically segmented using the sct&#95;deepseg&#95;sc tool in the SCT and segmentations were manually corrected by a neuro-radiologist. Lesion volume data were used as predictor variables for correlation with lower extremity motor scores at discharge. Volumetric MRI measures of T2w signal abnormality comprising the SCI lesion accurately predict lower extremity motor scores at time of patient discharge. Similarly, MRI measures of injury volume significantly correlated with motor scores to a greater degree than conventional 2-D metrics of lesion size. The volume of total injury and of injured spinal cord motor regions on T2w MRI is significantly and independently associated with neurologic outcome at discharge after injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Objective: Traumatic spinal cord injury (SCI) is a dreaded condition that can lead to paralysis and severe disability. With few treatment options available for patients who have suffered from SCI, it is important to develop prospective databases to standardize data collection in order to develop new therapeutic approaches and guidelines. Here, the authors present an overview of their multicenter, prospective, observational patient registry, Transforming Research and Clinical Knowledge in SCI (TRACK-SCI)., Methods: Data were collected using the National Institute of Neurological Disorders and Stroke (NINDS) common data elements (CDEs). Highly granular clinical information, in addition to standardized imaging, biospecimen, and follow-up data, were included in the registry. Surgical approaches were determined by the surgeon treating each patient; however, they were carefully documented and compared within and across study sites. Follow-up visits were scheduled for 6 and 12 months after injury., Results: One hundred sixty patients were enrolled in the TRACK-SCI study. In this overview, basic clinical, imaging, neurological severity, and follow-up data on these patients are presented. Overall, 78.8% of the patients were determined to be surgical candidates and underwent spinal decompression and/or stabilization. Follow-up rates to date at 6 and 12 months are 45% and 36.3%, respectively. Overall resources required for clinical research coordination are also discussed., Conclusions: The authors established the feasibility of SCI CDE implementation in a multicenter, prospective observational study. Through the application of standardized SCI CDEs and expansion of future multicenter collaborations, they hope to advance SCI research and improve treatment.

Study Design: Retrospective analysis., Objective: To assess the impact of mean arterial blood pressure (MAP) during surgical intervention for spinal cord injury (SCI) on motor recovery., Setting: Level-one Trauma Hospital and Acute Rehabilitation Hospital in San Jose, CA, USA., Methods: Twenty-five individuals with traumatic SCI who received surgical and acute rehabilitation care at a level-one trauma center were included in this study. The Surgical Information System captured intraoperative MAPs on a minute-by-minute basis and exposure was quantified at sequential thresholds from 50 to 104 mmHg. Change in International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor score was calculated based on physiatry evaluations at the earliest postoperative time and at discharge from acute rehabilitation. Linear regression models were used to estimate the rate of recovery across the entire MAP range., Results: An exploratory analysis revealed that increased time within an intraoperative MAP range (70-94 mmHg) was associated with ISNCSCI motor score improvement. A significant regression equation was found for the MAP range 70-94 mmHg (F[1, 23] = 5.07, r 2  = 0.181, p = 0.034). ISNCSCI motor scores increased 0.039 for each minute of exposure to the MAP range 70-94 mmHg during the operative procedure; this represents a significant correlation between intraoperative time with MAP 70-94 and subsequent motor recovery. Blood pressure exposures above or below this range did not display a positive association with motor recovery., Conclusions: Hypertension as well as hypotension during surgery may impact the trajectory of recovery in individuals with SCI, and there may be a direct relationship between intraoperative MAP and motor recovery.

Objective: We sought to report the safety of implementation of a novel standard of care protocol using spinal cord perfusion pressure (SCPP) maintenance for managing traumatic spinal cord injury (SCI) in lieu of mean arterial pressure goals at a U.S. Level I trauma center., Methods: Starting in December 2017, blunt SCI patients presenting <24 hours after injury with admission American Spinal Injury Association Impairment Scale (AIS) A-C (or AIS D at neurosurgeon discretion) received lumbar subarachnoid drain (LSAD) placement for SCPP monitoring in the intensive care unit and were included in the TRACK-SCI (Transforming Research and Clinical Knowledge in Spinal Cord Injury) data registry. This SCPP protocol comprises standard care at our institution. SCPPs were monitored for 5 days (goal ≥65 mm Hg) achieved through intravenous fluids and vasopressor support. AISs were assessed at admission and day 7., Results: Fifteen patients enrolled to date were aged 60.5 ± 17 years. Injury levels were 93.3% (cervical) and 6.7% (thoracic). Admission AIS was 20.0%/20.0%/26.7%/33.3% for A/B/C/D. All patients maintained mean SCPP ≥65 mm Hg during monitoring. Fourteen of 15 cases required surgical decompression and stabilization with time to surgery 8.8 ± 7.1 hours (71.4% <12 hours). At day 7, 33.3% overall and 50% of initial AIS A-C had an improved AIS. Length of stay was 14.7 ± 8.3 days. None had LSAD-related complications. There were 7 respiratory complications. One patient expired after transfer to comfort care., Conclusions: In our initial experience of 15 patients with acute SCI, standardized SCPP goal-directed care based on LSAD monitoring for 5 days was feasible. There were no SCPP-related complications. This is the first report of SCPP implementation as clinical standard of care in acute SCI., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Spinal cord injury induces inflammatory responses that include the release of cytokines and the recruitment and activation of macrophages and microglia. Neuroinflammation at the lesion site contributes to secondary tissue injury and permanent locomotor dysfunction. Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is anti-inflammatory and neuroprotective in both preclinical and clinical trials. We investigated the effect of DEX on the microglial response, and histological and neurological outcomes in a rat model of cervical spinal cord injury., Methods: Anaesthetised rats underwent unilateral (right) C5 spinal cord contusion (75 kdyne) using an impactor device. The locomotor function, injury size, and inflammatory responses were assessed. The effect of DEX was also studied in a microglial cell culture model., Results: DEX significantly improved the ipsilateral upper-limb motor dysfunction (grooming and paw placement; P<0.0001 and P=0.0012), decreased the injury size (P<0.05), spared white matter (P<0.05), and reduced the number of activated macrophages (P<0.05) at the injury site 4 weeks post-SCI. In DEX-treated rats after injury, tissue RNA expression indicated a significant downregulation of pro-inflammatory markers (e.g. interleukin [IL]-1β, tumour necrosis factor-α, interleukin (IL)-6, and CD11b) and an upregulation of anti-inflammatory and pro-resolving M2 responses (e.g. IL-4, arginase-1, and CD206) (P<0.05). In lipopolysaccharide-stimulated cultured microglia, DEX produced a similar inflammation-modulatory effect as was seen in spinal cord injury. The benefits of DEX on these outcomes were mostly reversed by an α2-adrenergic receptor antagonist., Conclusions: DEX significantly improves neurological outcomes and decreases tissue damage after spinal cord injury, which is associated with modulation of neuroinflammation and is partially mediated via α2-adrenergic receptor signaling., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)