Unintentionally intentional: unintended effects of spinal stimulation as a platform for multi-modal neurorehabilitation after spinal cord injury.

Electrical stimulation of spinal neurons has emerged as a valuable tool to enhance rehabilitation after spinal cord injury. In separate parameterizations, it has shown promise for improving voluntary movement, reducing symptoms of autonomic dysreflexia, improving functions mediated by muscles of the pelvic floor (e.g., bowel, bladder, and sexual function), reducing spasms and spasticity, and decreasing neuropathic pain, among others. This diverse set of actions is related both to the density of sensorimotor neural networks in the spinal cord and to the intrinsic ability of electrical stimulation to modulate neural transmission in multiple spinal networks simultaneously. It also suggests that certain spinal stimulation parameterizations may be capable of providing multi-modal therapeutic benefits, which would directly address the complex, multi-faceted rehabilitation goals of people living with spinal cord injury. This review is intended to identify and characterize reports of spinal stimulation-based therapies specifically designed to provide multi-modal benefits and those that report relevant unintended effects of spinal stimulation paradigms parameterized to enhance a single consequence of spinal cord injury.

Temporal expression of brainstem neurotrophic proteins following mild traumatic brain injury.

BDNF, a neurotrophic factor, and its receptors have been implicated in the pathophysiology of mild traumatic brain injury (mTBI). The brainstem houses many vital functions, that are also associated with signs and symptoms of mTBI, but has been understudied in mTBI animal models. We determined the extent to which neurotrophic protein and associated receptor expression is affected within the brainstem of adult rats following mTBI. Their behavioral function was assessed and temporal expression of the 'negative' regulators of neuronal function (p75, t-TrkB, and pro-BDNF) and 'positive' neuroprotective (FL-TrkB and m-BDNF) protein isoforms were determined via western blot and immunohistochemistry at 1, 3, 7, and 14 post-injury days (PID) following mTBI or sham (control) procedure. Within the brainstem, p75 expression increased at PID 1 vs. sham animals. t-TrkB and pro-BDNF expression increased at PID 7 and 14. The 'positive' protein isoforms of FL-TrkB and m-BDNF expression were increased only at PID 7. The ratio of t-TrkB:FL-TrkB (negative:positive) was substantial across groups and time points, suggesting a negative impact of neurotrophic signaling on neuronal function. Additional NeuN experiments revealed cell death occurring within a subset of neurons within the medulla. While behavioral measures improved by PID 7-14, negative neurotrophic biochemical responses persisted. Despite the assertion that mTBI produces "mild" injury, evidence of cell death was observed in the medulla. Ratios of TrkB and BDNF isoforms with conflicting functions suggest that future work should specifically measure each subtype since they induce opposing downstream effects on neuronal function.

An Exploratory Analysis of Physical Examination Subtypes in Pediatric Athletes With Concussion.

OBJECTIVE: Pediatric athletes with concussion present with a variety of impairments on clinical assessment and require individualized treatment. The Buffalo Concussion Physical Examination is a brief, pertinent clinical assessment for individuals with concussion. The purpose of this study was to identify physical examination subtypes in pediatric athletes with concussion within 2 weeks of injury that are relevant to diagnosis and treatment. DESIGN: Secondary analysis of a published cohort study and clinician consensus. SETTING: Three university-affiliated sports medicine centers. PARTICIPANTS: Two hundred seventy children (14.9 ± 1.9 years). INDEPENDENT VARIABLES: Orthostatic intolerance, horizontal and vertical saccades, smooth pursuits, vestibulo-ocular reflex, near-point convergence, complex tandem gait, neck range of motion, neck tenderness, and neck spasm. MAIN OUTCOME MEASURES: Correlations between independent variables were calculated, and network graphs were made. k-means and hierarchical clustering were used to identify clusters of impairments. Optimal number of clusters was assessed. Results were reviewed by experienced clinicians and consensus was reached on proposed subtypes. RESULTS: Physical examination clusters overlapped with each other, and no optimal number of clusters was identified. Clinician consensus suggested 3 possible subtypes: (1) visio-vestibular (horizontal and vertical saccades, smooth pursuits, and vestibulo-ocular reflex), (2) cervicogenic (neck range of motion and spasm), and (3) autonomic/balance (orthostatic intolerance and complex tandem gait). CONCLUSIONS: Although we identified 3 physical examination subtypes, it seemed that physical examination findings alone are not enough to define subtypes that are both statistically supported and clinically relevant, likely because they do not include symptoms, assessment of mood or cognitive problems, or graded exertion testing.

Early Identification and Management of Cervical Impairments in Pediatric Patients With Concussion May Reduce Risk of Delayed Recovery.

OBJECTIVE: Previous research, including high-quality systematic reviews, has found that cervical injury, which often accompanies concussive head injury, can delay recovery from concussion. One pilot randomized controlled trial found that focused cervical assessment and appropriate intervention in children and young adults with persisting postconcussive symptoms (PPCS) improved recovery outcomes. Our sports medicine clinics adopted this approach early (within 2 weeks) in children (aged 10-18 years) after concussion. This study describes our clinical management protocol and compares the recovery trajectories in children after concussion with and without a concomitant cervical injury. DESIGN: Prospective cohort study. SETTING: Three university-affiliated outpatient sports medicine clinics from September 2016 to December 2019. PATIENTS: One-hundred thirty-four concussed children with cervical impairment (mean age 14.9 years, 65% male, and 6.2 days since concussion) were compared with 130 concussed children without cervical impairment (mean age 14.9 years, 57% male, and 6.0 days since concussion). INDEPENDENT VARIABLES: Examination findings related to the cervical spine (range of motion, cervical spasm, and cervical tenderness). MAIN OUTCOME MEASURES: Recovery time (measured in days), concussion symptom burden (Postconcussion Symptom Scale), and incidence of PPCS. RESULTS: Children with cervical impairment reported a higher initial symptom burden; however, there were no differences in recovery time (33.65 [28.20-39.09] days vs 35.98 [27.50-44.45] days, P = 0.651) or incidence of PPCS (40.0% vs 34.3%, P = 0.340). CONCLUSIONS: We conclude that within this pediatric population, early identification and management of cervical injuries concomitant with concussion may reduce the risk of delayed recovery.

Does Physiologic Post-Concussion Disorder Cause Persistent Post-Traumatic Headache?

PURPOSE OF REVIEW: One system classifies patients with symptoms after concussion into physiologic, vestibulo-ocular, cervicogenic, and mood/cognition post-concussion disorders (PCD) based upon the preponderance of specific symptoms and physical impairments. This review discusses physiologic PCD and its potential relationship to the development of persistent post-traumatic headaches (PPTH). RECENT FINDINGS: Headache is the most reported symptom after a concussion. Headaches in physiologic PCD are suspected to be due to abnormal cellular metabolism, subclinical neuroinflammation, and dysfunction of the autonomic nervous system (ANS). These abnormalities have been linked to the development of migraine-like and neuralgia-related PPTH. Physiologic PCD is a potential cause of PPTH after a concussion. Future research should focus on how to prevent PPTH in patients with physiologic PCD.

Neural population dynamics reveal that motor-targeted intraspinal microstimulation preferentially depresses nociceptive transmission in spinal cord injury-related neuropathic pain.

The purpose of this study is to determine whether intraspinal microstimulation (ISMS) intended to enhance voluntary motor output after spinal cord injury (SCI) modulates neural population-level spinal responsiveness to nociceptive sensory feedback. The study was conducted in vivo in three cohorts of rats: neurologically intact, chronic SCI without behavioral signs of neuropathic pain, and chronic SCI with SCI-related neuropathic pain (SCI-NP). Nociceptive sensory feedback was induced by application of graded mechanical pressure to the plantar surface of the hindpaw before, during, and after periods of sub-motor threshold ISMS delivered within the motor pools of the L5 spinal segment. Neural population-level responsiveness to nociceptive feedback was recorded throughout the dorso-ventral extent of the L5 spinal segment using dense multi-channel microelectrode arrays. Whereas motor-targeted ISMS reduced nociceptive transmission across electrodes in neurologically intact animals both during and following stimulation, it was not associated with altered nociceptive transmission in rats with SCI that lacked behavioral signs of neuropathic pain. Surprisingly, nociceptive transmission was reduced both during and following motor-targeted ISMS in rats with SCI-NP, and to an extent comparable to that of neurologically intact animals. The mechanisms underlying the differential anti-nociceptive effects of motor-targeted ISMS are unclear, although they may be related to differences in the intrinsic active membrane properties of spinal neurons across the cohorts. Nevertheless, the results of this study support the notion that it may be possible to purposefully engineer spinal stimulation-based therapies that afford multi-modal rehabilitation benefits, and specifically that it may be possible to do so for the individuals most in need - i.e., those with SCI-related movement impairments and SCI-NP.

Precision neuromodulation: Promises and challenges of spinal stimulation for multi-modal rehabilitation.

Spinal cord injury results in multiple, simultaneous sensorimotor deficits. These include, but are not limited to, full or partial paralysis of muscles below the lesion, muscle spasms, spasticity, and neuropathic pain. Bowel, bladder, and sexual dysfunction are also prevalent. Yet, the majority of emerging spinal stimulation-based therapies focus on a single issue: locomotor rehabilitation. Despite the enormous potential of these translational advances to transform the lives of people living with spinal cord injury, meaningful recovery in other domains deemed critical priorities remains lacking. Here, we highlight the importance of considering the diverse patterns of neural transmission that underlie clinically similar presentations when developing spinal stimulation-based therapies. We also motivate advancement of multi-modal rehabilitation paradigms, which leverage the dense interconnectivity of sensorimotor spinal networks and the unique ability of electrical stimulation to modulate these networks to facilitate and guide simultaneous rehabilitation across domains.

Ascertainment of stroke from administrative data to support a pragmatic embedded clinical trial.

The goal of this observational study was to identify stroke hospitalizations using International Classification of Disease (ICD)-10 codes and use these codes to develop an ascertainment algorithm for use in pragmatic clinical trials, reducing or eliminating the need for manual chart adjudication in future. Using VA (Veterans Affairs) electronic medical records, 9959 patient charts with ICD-10 codes indicating stroke were screened and a sample of 304 were adjudicated by three clinical reviewers. Hospitalizations were categorized as stroke or non-stroke and positive predictive value (PPV) was calculated for each ICD-10 code that was sampled. The adjudicated codes were categorized for use in a decision tool for identifying stroke in a clinical trial. Of the 304 hospitalizations adjudicated, 192 met the definition of stroke. Of the ICD-10 codes evaluated, I61 yielded the highest PPV (100%) while I63.x yielded the 2nd highest PPV (90%) with a false discovery rate of 10%. A relatively high PPV of ≥80% was associated with codes I60.1-7, I61, I62.9 and I63, which accounted for nearly half of all cases reviewed. Hospitalizations associated with these codes were categorized at positive stroke cases. The incorporation of large administrative datasets, and elimination of trial specific data collection, increases efficiencies, while reducing costs. Accurate algorithms must be developed to allow for identification of clinical endpoints from administrative databases to offer a reliable alternative to study-specific case report form completion. This study demonstrates an example of how to apply medical record data to a decision tool for clinical trial outcomes. CSP597 or clinicaltrials.gov NCT02185417.

Motor-targeted spinal stimulation promotes concurrent rebalancing of pathologic nociceptive transmission in chronic spinal cord injury.

Electrical stimulation of spinal networks below a spinal cord injury (SCI) is a promising approach to restore functions compromised by inadequate excitatory neural drive. The most translationally successful examples are paradigms intended to increase neural transmission in weakened yet spared motor pathways and spinal motor networks rendered dormant after being severed from their inputs by lesion. Less well understood is whether spinal stimulation is also capable of reducing neural transmission in pathways made pathologically overactive by SCI. Debilitating spasms, spasticity, and neuropathic pain are all common manifestations of hyperexcitable spinal responses to sensory feedback. But whereas spasms and spasticity can often be managed pharmacologically, SCI-related neuropathic pain is notoriously medically refractory. Interestingly, however, spinal stimulation is a clinically available option for ameliorating neuropathic pain arising from etiologies other than SCI, and it has traditionally been assumed to modulate sensorimotor networks overlapping with those engaged by spinal stimulation for motor rehabilitation. Thus, we reasoned that spinal stimulation intended to increase transmission in motor pathways may simultaneously reduce transmission in spinal pain pathways. Using a well-validated pre-clinical model of SCI that results in severe bilateral motor impairments and SCI-related neuropathic pain, we show that the responsiveness of neurons integral to the development and persistence of the neuropathic pain state can be enduringly reduced by motor-targeted spinal stimulation while preserving spinal responses to non-pain-related sensory feedback. These results suggest that spinal stimulation paradigms could be intentionally designed to afford multi-modal therapeutic benefits, directly addressing the diverse, intersectional rehabilitation goals of people living with SCI.

Sensitivity and Specificity of Exercise Intolerance on Graded Exertion Testing for Diagnosing Sport-Related Concussion: A Systematic Review and Exploratory Meta-Analysis.

Abstract There is no single gold standard test to diagnose sport-related concussion (SRC). Concussion-related exercise intolerance, that is, inability to exercise to the individual's appropriate level due to exacerbation of concussion-like symptoms, is a frequent finding in athletes early after SRC that has not been systematically evaluated as a diagnostic test of SRC. We performed a systematic review and proportional meta-analysis of studies that evaluated graded exertion testing in athletes after SRC. We also included studies of exertion testing in healthy athletic participants without SRC to assess specificity. Pubmed and Embase were searched in January 2022 for articles published since 2000. Eligible studies included those that performed graded exercise tolerance tests in symptomatic concussed participants (> 90% of subjects had an SRC, seen within 14 days of injury), at the time of clinical recovery from SRC, in healthy athletes, or both. Study quality was assessed using the Newcastle-Ottawa Scale. Twelve articles met inclusion criteria, most of which were of poor methodological quality. The pooled estimate of incidence of exercise intolerance in participants with SRC equated to an estimated sensitivity of 94.4% (95% confidence interval [CI]: 90.8, 97.2). The pooled estimate of incidence of exercise intolerance in participants without SRC equated to an estimated specificity of 94.6% (95% CI: 91.1, 97.3). The results suggest that exercise intolerance measured on systematic testing within 2 weeks of SRC may have excellent sensitivity for helping to rule in the diagnosis of SRC and excellent specificity for helping to rule out SRC. A prospective validation study to determine the sensitivity and specificity of exercise intolerance on graded exertion testing for diagnosing SRC after head injury as the source of symptoms is warranted.

Adults are not older adolescents: comparing physical therapy findings among adolescents, young adults and older adults with persistent post-concussive symptoms.

OBJECTIVE: Individuals with persistent post-concussive symptoms (PPCS) may present with a myriad of physical symptoms. There is limited research available comparing the presence of examination findings among individuals with PPCS from different age groups. METHODS: Retrospective case-control chart review of 481 patients with PPCS and 271 non-trauma controls. Physical assessments were categorized as ocular, cervical, and vestibular/balance. Differences in presentation were compared between PPCS and controls as well as between individuals with PPCS in three age groups: adolescents, young adults, and older adults. RESULTS: All three PPCS groups had more abnormal oculomotor findings than their age-matched counterparts. When comparing PPCS patients from different age groups, no differences were seen in prevalence of abnormal smooth pursuits or saccades; however, adolescents with PPCS had more abnormal cervical findings and a lower prevalence of abnormal NPC, vestibular and balance findings. CONCLUSION: Patients with PPCS presented with a different constellation of clinical findings based on their age. Adolescents were more likely to demonstrate evidence of cervical injury compared to younger and older adults, and adults were more likely to present with vestibular findings and impaired NPC. Adults with PPCS were more likely to present with abnormal oculomotor findings compared to adults with non-traumatic causes of dizziness.

Adolescents With More Oculomotor and Vestibular Signs of Sport-Related Concussion Benefit from Aerobic Exercise: An Exploratory Analysis.

Abstract Early targeted heart rate (HR) aerobic exercise has been shown to reduce the duration of recovery from sport-related concussion (SRC) as well as the incidence of persistent post-concussive symptoms (PPCS). It is not known, however, if more severe oculomotor and vestibular presentations of SRC benefit from a prescription of aerobic exercise. The current study is an exploratory analysis of two published randomized controlled trials that compared aerobic exercise within 10 days of injury with a placebo-like stretching intervention. Combining the two studies yielded a larger sample size to stratify severity of concussion based on the number of abnormal physical examination signs present at the initial office evaluation, which were confirmed with self-reported symptoms and recovery outcomes. The most discriminant cut-off was between those who had ≤3 oculomotor and vestibular signs and those who had >3 signs. Aerobic exercise (hazard ratio = 0.621 [0.412, 0.936], p = 0.023) reduced recovery times even when controlling for site (hazard ratio = 0.461 [0.303, 0.701], p < 0.001), severity (hazard ratio = 0.528 [0.325, 0.858], p = 0.010) and the interaction term of intervention and severity (hazard ratio = 0.972 [0.495, 1.909], p = 0.935). Adolescents who presented with >3 signs and were assigned to the placebo-like stretching group had a PPCS incidence of 38%, which was the highest of all subgroups (aerobic exercise and ≤3 findings: 8%; stretching and ≤3 findings: 11%; aerobic exercise and >3 findings: 21%). This exploratory study provides pilot evidence that prescribed sub-symptom threshold aerobic exercise treatment early after SRC may be effective for adolescents with more oculomotor and vestibular physical examination signs and should be validated in future adequately powered trials.

Service Delivery Models for the Management of Pediatric and Adolescent Concussion: A Systematic Review.

Objective: To examine the current peer-reviewed literature on pediatric concussion and mild traumatic brain injury (mTBI) service delivery models (SDMs) and relevant cost analyses. Data Sources: PubMed, Embase (Elsevier), CINAHL Plus (EBSCO), APA PsycINFO (EBSCO), and Web of Science Core Collection, limited to human trials published in English from January 1, 2001, to January 10, 2022. Study Selection: Included articles that (1) were peer-reviewed; (2) were evidence-based; (3) described service delivery and/or associated health care costs; and (4) focused on mTBI, concussion, or postconcussion symptoms of children and adolescents. Studies describing emergency department-based interventions, adults, and moderate to severe brain injuries were excluded. Data Extraction: The initial search resulted in 1668 articles. Using Rayyan software, 2 reviewers independently completed title and abstract screening followed by a full-text screening of potentially included articles. A third blinded reviewer resolved inclusion/exclusion conflicts among the other reviewers. This resulted in 28 articles included. Data Synthesis: Each of the 28 articles were grouped into 1 of the following 3 categories: generalist-based services (7), specialist-based services (12), and web/telemedicine services (6). One article discussed both generalists and specialists. It was clear that specialists are more proactive in their treatment of concussion than generalists. Most of the research on generalists emphasized the need for education and training. Four studies discussed costs relevant to SDMs. Conclusions: This review highlights the need for more discussion and formalized evaluation of SDMs to better understand concussion management. Overall there is more literature on specialist-based services than generalist-based services. Specialists and generalists have overarching similarities but differ often in their approach to pediatric concussion management. Cost analysis data are sparse and more research is needed.

Spinal stimulation for motor rehabilitation immediately modulates nociceptive transmission.

Objective. Spinal cord injury (SCI) often results in debilitating movement impairments and neuropathic pain. Electrical stimulation of spinal neurons holds considerable promise both for enhancing neural transmission in weakened motor pathways and for reducing neural transmission in overactive nociceptive pathways. However, spinal stimulation paradigms currently under development for individuals living with SCI continue overwhelmingly to be developed in the context of motor rehabilitation alone. The objective of this study is to test the hypothesis that motor-targeted spinal stimulation simultaneously modulates spinal nociceptive transmission.Approach. We characterized the neuromodulatory actions of motor-targeted intraspinal microstimulation (ISMS) on the firing dynamics of large populations of discrete nociceptive specific and wide dynamic range (WDR) neurons. Neurons were accessed via dense microelectrode arrays implantedin vivointo lumbar enlargement of rats. Nociceptive and non-nociceptive cutaneous transmission was induced before, during, and after ISMS by mechanically probing the L5 dermatome.Main results. Our primary findings are that (a) sub-motor threshold ISMS delivered to spinal motor pools immediately modulates concurrent nociceptive transmission; (b) the magnitude of anti-nociceptive effects increases with longer durations of ISMS, including robust carryover effects; (c) the majority of all identified nociceptive-specific and WDR neurons exhibit firing rate reductions after only 10 min of ISMS; and (d) ISMS does not increase spinal responsiveness to non-nociceptive cutaneous transmission. These results lead to the conclusion that ISMS parameterized to enhance motor output results in an overall net decrease n spinal nociceptive transmission.Significance. These results suggest that ISMS may hold translational potential for neuropathic pain-related applications and that it may be uniquely suited to delivering multi-modal therapeutic benefits for individuals living with SCI.

Functional and Metagenomic Evaluation of Ibezapolstat for Early Evaluation of Anti-Recurrence Effects in Clostridioides difficile Infection.

Reduction of Clostridioides difficile infection (CDI) recurrence is an essential endpoint for CDI-directed antibiotic development that is often not evaluated until Phase III trials. The purpose of this project was to use a functional and metagenomic approach to predict the potential anti-CDI recurrence effect of ibezapolstat, a DNA polymerase IIIC inhibitor, in clinical development for CDI. As part of the Phase I ibezapolstat clinical study, stool samples were collected from 22 healthy volunteers, who were given either ibezapolstat or vancomycin. Stool samples were evaluated for microbiome changes and bile acid concentrations. Ibezapolstat 450 mg and vancomycin, but not ibezapolstat 300 mg, showed statistically significant changes in alpha diversity over time compared to that of a placebo. Beta diversity changes confirmed that microbiota were significantly different between study groups. Vancomycin had a more wide-ranging effect on the microbiome, characterized by an increased proportion of Gammaproteobacteria. Ibezapolstat demonstrated an increased proportion of Actinobacteria, including the Bifidobacteriaceae family. Using a linear regression analysis, vancomycin was associated with significant increases in primary bile acids as well as primary:secondary bile acid ratios. An overabundance of Enterobacteriaceae was most highly correlated with primary bile acid concentrations (r = 0.63; P < 0.0001). Using Phase I healthy volunteer samples, beneficial changes suggestive of a lower risk of CDI recurrence were associated with ibezapolstat compared to vancomycin. This novel omics approach may allow for better and earlier prediction of anti-CDI recurrence effects for antibiotics in the clinical development pipeline.

Multi-country surveillance of Clostridioides difficile demonstrates high prevalence of spores in non-healthcare environmental settings.

BACKGROUND: C. difficile spores are frequently isolated from hospital and non-healthcare settings but a worldwide analysis has not been done. The study objectives were to assess C. difficile spore contamination in the hospital and non-healthcare environments across a variety of countries. METHODS: Field studies assessed hospital vs. non-healthcare C. difficile spore contamination in hospitals, non-healthcare buildings, outdoor environments, and shoes. Swabs were cultured anaerobically for C. difficile and typed using PCR-fluorescent ribotyping. C. difficile contamination by swabbing area and geographic locations were compared. FINDINGS: A total of 7,857 unique samples were collected primarily from the USA (89%) in addition to 9 other countries. The global prevalence of C difficile from environmental samples was 25.3% and did not differ between countries. In USA based studies, C. difficile contamination rates were similar for healthcare buildings (23.2%), non-healthcare buildings (23.4%), and outdoor spaces (24.7%). Floor samples had significantly higher (p < 0.001) C. difficile contamination rate (46.5%) followed by non-floor samples (21.1%), and bathrooms (15.3%). In a comparison of USA to other country samples, C. difficile contamination rates were similar for USA samples (21.5%) compared to rest of world samples (22.3%; p = 0.61). The most common ribotypes included F014-020 (15.7%), F106 (12.6%), F010 (8.9%), F027 (8.8%), and F002 (8.1%) and did not differ significantly between USA and non-USA samples. Finally, 546 of 1,218 (44.8%) shoe soles swabbed from the USA were contaminated with C. difficile spores. INTERPRETATION: This large surveillance study of several countries demonstrated high prevalence of toxigenic C. difficile in non-healthcare environments with high contamination rates from floors and shoe soles.

Efficacy, Safety, Pharmacokinetics, and Microbiome Changes of Ibezapolstat in Adults with Clostridioides difficile Infection: A Phase 2a Multicenter Clinical Trial.

BACKGROUND: This study was the first human validation of the gram-positive bacterial DNA polymerase IIIC target in patients with Clostridioides difficile infection. The primary objectives were to assess clinical cure rates and adverse events (AEs). Secondary objectives were to evaluate plasma/fecal pharmacokinetics, microbiologic eradication, microbiome and bile acid effects, and sustained clinical cure (SCC) with ibezapolstat. METHODS: This single-arm, open-label, phase 2a study enrolled adults with C. difficile infection at 4 US centers. Patients received ibezapolstat 450 mg orally every 12 hours for 10 days and followed for an additional 28 days to assess study objectives. RESULTS: Ten patients with a mean (standard deviation [SD]) age of 49 [15] years were enrolled. Seven AEs were reported classified as mild-moderate. Plasma levels of ibezapolstat ranged from 233 to 578 ng/mL while mean (SD) fecal levels were 416 (494) µg/g stool by treatment day 3 and >1000 µg/g stool by days 8-10. A rapid increase in alpha diversity in the fecal microbiome was noted after starting ibezapolstat therapy, which was maintained after completion of therapy. A proportional decrease in Bacteroidetes phylum was observed (mean change [SD], -10.0% [4.8%]; P = .04) with a concomitantly increased proportion of Firmicutes phylum (+14.7% [5.4%]; P = .009). Compared with baseline, total primary bile acids decreased by a mean (SD) of 40.1 (9.6) ng/mg stool during therapy (P < .001) and 40.5 (14.1) ng/mg stool after completion of therapy (P = .007). Rates of both initial clinical cure and SCC at 28 days were 100% (10 of 10 patients). CONCLUSIONS: In this phase 2a study, 10 of 10 patients achieved SCC, demonstrated favorable pharmacokinetics, minimal AEs, and beneficial microbiome and bile acids results. These results support continued clinical development.

Practical Management: Telehealth Examination for Sport-Related Concussion in the Outpatient Setting.

ABSTRACT: This article presents the telehealth version of the Buffalo Concussion Physical Examination (BCPE) (Tele-BCPE). It is a brief, focused telehealth PE for use in the outpatient setting by sports medicine physicians, pediatricians, neurologists, and primary care physicians. It is derived from the BCPE and includes general considerations for providers performing telehealth services and instructions for adapting traditional clinical tests for virtual use. The Tele-BCPE includes an orthostatic intolerance screen, examination of the cranial nerves, and tests of the oculomotor, vestibular, and cervical systems. It is meant to be used at initial and follow-up outpatient visits for patients acutely after concussion and in those with prolonged symptoms. This telehealth PE, when combined with other assessments, can help provide direct treatment to patients at any stage after concussion and reduce barriers to healthcare access posed by the COVID-19 pandemic and for patients living in rural or underserved areas.

Development of a Telehealth Examination for Sport-Related Concussion in the Outpatient Setting.

OBJECTIVE: To develop a brief, focused telehealth physical examination for use in the outpatient setting by sports medicine physicians, pediatricians, neurologists, and primary care physicians. BACKGROUND: Telemedicine has become a key resource for addressing healthcare access limitations for individuals living in rural communities. The COVID-19 pandemic has forced physicians and other healthcare providers to adopt telemedicine practices. Published literature guiding the evaluation of patients with concussion via telemedicine is sparse. DESIGN/METHODS: The Buffalo Concussion Physical Examination (BCPE) is a practical and pertinent clinical assessment that helps to diagnose concussion and that has prognostic value when repeated over the first weeks after injury. An interdisciplinary team with experience in telemedicine services utilized a modified-Glaser approach to consensus to translate elements of the BCPE into virtual methods enabling clinicians to provide care to patients over the internet. RESULTS: The Telehealth version of the BCPE (Tele-BCPE) includes an orthostatic intolerance screen, examination of the cranial nerves, and tests of the oculomotor, vestibular and cervical systems. History and examination templates as well as detailed instructions for performance are included. The Tele-BCPE is meant to be used at initial and follow-up visits for patients acutely after concussion as well as in those with prolonged symptoms. CONCLUSIONS: We developed a telehealth physical examination to help direct treatment to patients at any stage after concussion and reduce barriers to healthcare access posed by the COVID-19 pandemic and for patients living in rural or underserved areas. Prospective evaluation of the validity and reliability of the Tele-BCPE for the diagnosis and management of patients with concussion is warranted.