A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury.

A prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50 mg of riluzole PO/NG twice-daily, within 12 h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group

Mortality in ASIA Impairment Scale grade A to D Patients With Odontoid Fracture and Magnetic Resonance Imaging Evidence of Spinal Cord Injury

Odontoid fractures are common, often presenting in the elderly after a fall and infrequently associated with traumatic spinal cord injury (tSCI). The goal of this study was to analyze predictors of mortality and neurological outcome when odontoid fractures were associated with signal change on magnetic resonance imaging (MRI) at admission. Over an 18-year period (2001-2019), 33 patients with odontoid fractures and documented tSCI on MRI were identified. Mean age was 65.3 years (standard deviation [SD] = 17.2), and 21 patients were male. The mechanism of injury was falls in 25 patients, motor vehicle accidents in 5, and other causes in 3. Mean Injury Severity Score (ISS) was 40.5 (SD = 30.2), Glasgow Coma Scale (GCS) score was 13 (SD = 3.4), and American Spinal Injury Association (ASIA) motor score (AMS) was 51.6 (SD = 42.7). ASIA Impairment Scale (AIS) grade was A, B, C, and D in 9, 2, 3, and 19 patients, respectively. Mean intramedullary lesion length was 32.3 mm (SD = 18.6). The odontoid peg was displaced ventral or dorsal in 15 patients. Twenty patients had surgical intervention: anterior odontoid screw fixation in 7 and posterior spinal fusion in 13. Eleven (33.3%) patients died in this series: withdrawal of medical care in 5; anoxic brain injury in 4; and failure of critical care management in 2. Univariate logistic regression indicated that GCS score (p\u3c0.014), AMS (p\u3c0.002), AIS grade (p\u3c0.002), and ISS (p\u3c0.009) were risk factors for mortality. Multi-variate regression analysis indicated that only AMS (p\u3c0.002) had a significant relationship with mortality when odontoid fracture was associated with tSCI (odds ratio, 0.963; 95% confidence interval, 0.941–0.986)

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Comparison of \nu\mu-Ar multiplicity distributions observed by MicroBooNE to GENIE model predictions

We measure a large set of observables in inclusive charged current muon neutrino scattering on argon with the MicroBooNE liquid argon time projection chamber operating at Fermilab. We evaluate three neutrino interaction models based on the widely used GENIE event generator using these observables. The measurement uses a data set consisting of neutrino interactions with a final state muon candidate fully contained within the MicroBooNE detector. These data were collected in 2016 with the Fermilab Booster Neutrino Beam, which has an average neutrino energy of 800 MeV, using an exposure corresponding to 5E19 protons-on-target. The analysis employs fully automatic event selection and charged particle track reconstruction and uses a data-driven technique to separate neutrino interactions from cosmic ray background events. We find that GENIE models consistently describe the shapes of a large number of kinematic distributions for fixed observed multiplicity.Comment: 31 pages, 39 figures, 10 table

History and Accomplishments of the North American Clinical Trials Network (NACTN) for Spinal Cord Injury, 2004 to 2022

This is a historical account of the origin and accomplishments of the North American Clinical Trials Network (NACTN) for traumatic spinal cord injury (SCI), which was established in 2004 by Christopher Reeve and Dr. Robert Grossman. Christopher Reeve was an actor who became quadriplegic and started the Christopher and Dana Reeve Foundation, while Robert Grossman was a neurosurgeon experienced in neurotrauma and a university professor in Houston. NACTN has member investigators at university and military centers in North America and has contributed greatly to the improvement of care, primarily acute care, of patients sustaining traumatic SCI. Its accomplishments are a clinical registry database of more than 1000 acute SCI patients documenting the care pathways, including complications. NACTN determined the effectiveness of treatment, including pharmacotherapy and the role and timing of surgery, and barriers to early surgery with a focus on neurological recovery. NACTN has assessed the effectiveness of treatment, including pharmacotherapy and the role and timing of surgery, and has also identified barriers to early surgery. The principal focus has been on improving neurological recovery. It has trained many SCI practitioners and has collaborated with many other SCI networks and organizations internationally to promote the care of SCI patients

Trends in the Use of Corticosteroids in the Management of Acute Spinal Cord Injury in North American Clinical Trials Networks (NACTN) Sites

Immunomodulatory therapeutics represent a potential neuroprotective strategy for the management of acute spinal cord injury (SCI). One of the most intensely debated neuroprotective drugs has been methylprednisolone sodium succinate (MPSS). MPSS was initially investigated for its role in mitigating lipid peroxidation. More recently, the anti-inflammatory/immunomodulatory properties of MPSS have been increasingly appreciated. Over the past two decades, several systematic reviews and clinical practice guidelines related to MPSS use in SCI have been published. The goal of this study was to investigate the temporal changes in the use of steroids at North American Clinical Trials Network (NACTN) centers and to correlate these with the evolution in published literature and guidelines. Data on patients enrolled from 2008 - 2018 in the prospective, multicenter NACTN registry, and in whom information related to the use of steroids was available, were analyzed. Patients were stratified as to whether they received steroids or not. The primary outcome was the change in the rate of steroid use per year between 2008 and 2018. Secondary outcomes included cardiac, gastrointestinal & genitourinary (GIGU), pulmonary and dermatologic complications. We identified 608 patients, of whom 171 (28.1%) were given steroids. In 2008 and 2009, the prevailing paradigm across NACTN centers was in favor of steroid administration and as such 70% (n=56) of patients received steroids in 2008 and 71.9% (n=46) in 2009. An abrupt practice reversal was observed in 2010, whereby only 19.7% of patients (n=14) received steroids, a trend that continued over subsequent years. Increasing literature in the 2000s arguing against the use of steroids culminated in the 2013 CNS/AANS practice guidelines for the management of acute SCI. These guidelines recommended against the use of MPSS for the treatment of acute SCI. Over the following years (2013-2018), steroids continued to be an uncommonly used therapeutic option in NACTN centers (range 3.9-16.9%). Patients receiving steroids had significantly higher rates of pulmonary complications (87%, n=147) compared to those not receiving steroids (73%, n=265; p=0.0003). However, compared to patients receiving steroids, those who did not receive steroids had significantly higher rates of cardiac (40%, [n=146] versus 23%, [n=39]; p=0.0001) and gastrointestinal/genitourinary complications (55%, [n=189], versus 31%, [n=52]; p<0.0001). The 2013 AANS/CNS guidelines and preceding literature appeared to have an impact on dramatically lowering the rates of corticosteroid use for acute SCI in NACTN sites after 2009. Of note, this analysis may not reflect the impact of the 2017 AO Spine Clinical Practice guidelines, which suggested the use of methylprednisolone as a valid practice option for acute SCI, especially for cervical injuries. Enhanced patient involvement in the clinical decision-making process and opportunities to personalize SCI management exist in reference to the use of MPSS in acute SCI

Natural History, Predictors of Outcome, and Effects of Treatment in Thoracic Spinal Cord Injury: A Multi-Center Cohort Study from the North American Clinical Trials Network

The course, treatment response, and recovery potential after acute traumatic spinal cord injury (SCI) have been shown to differ depending on the neurological level of injury. There are limited data focused on thoracic-level injuries, however. A cohort of 86 patients from the prospectively maintained North American Clinical Trials Network SCI registry were identified and studied to characterize the patterns of neurological recovery and to determine rates of acute hospital death and pulmonary complications. Regression analyses were used to examine the relationship between timing of surgery and administration of methylprednisolone on neurologic and clinical outcomes. Neurological conversion (≥1 American Spinal Injury Association Impairment Scale [AIS] grade improvement) was poorest for AIS grade A patients; 14.3% converted at last available follow-up (mean eight months). While rates of conversion were more optimistic for AIS-B patients (54.5%) and AIS C injuries (77.8%) at the same time point, none of the AIS grade D patients converted to AIS E. At last available follow-up (mean eight months), the magnitudes of lower motor extremity score (LEMS) change were highest for AIS C injuries (21.9 points), then AIS B (17.7 points), AIS D (16.4 points), and finally AIS A (2.5 points) (p < 0.05). Early surgical intervention (<24 h post-injury) was independently associated with an additional seven points in motor recovery and a 60% decreased incidence of pulmonary events ( p  < 0.05). Methylprednisolone administration was not an independent predictor of neurological outcome or pulmonary complications. Evaluation of this cohort obtained from a modern multi-center SCI registry provides an update on the natural history, acute death, and incidence of pulmonary complications after traumatic thoracic SCI. Although small sample size limited the extent of analyses possible, early surgical treatment was associated with significantly larger motor recovery and lower rates of pulmonary complications