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Individuals with major limb amputation(s) frequently experience phantom limb sensations, which are described as vivid impressions of either parts or entire missing limb(s). Despite the high incidence and prevalence of phantom limb pain, the underlying pathophysiology of phantom limb pain remains poorly understood. The objective of this study was to evaluate a possible role of microRNAs in the pathophysiology of phantom limb pain.Adults with acquired limb amputation and varying degrees of phantom limb pain consented to provide clinical data and blood samples. One hundred forty participants with single or multiple limb amputation(s) were enrolled. The Visual analog scale and neuropathic pain symptom inventory were administered to evaluate the pain. Serum samples were analyzed for microRNA expression and bioinformatic analysis was performed.Sixty-seven participants did not experience phantom limb pain, whereas 73 participants experienced varying severities of phantom limb pain measured on a pain scale. Linear regression analysis suggested that the time since amputation is inversely related to severity of the pain. A significantly increased expression of 16 microRNAs was observed in participants experiencing phantom limb pain. Bioinformatic analysis shows a possible role of these microRNAs in regulating genes expressed in peripheral neuropathy.This study provides the first evidence of association of microRNA in phantom limb pain.

To derive minimum detectable change (MDC) across individual Vestibular-Ocular Motor Screening (VOMS) items and VOMS overall score in 17-25 years old collegiate athletes and to examine false positive rates.Participants (n = 378) completed VOMS pre-season for two consecutive years. MDC was identified for individual VOMS symptom items and NPC distance (cm). Both total and change methods of VOMS scoring were included in analysis.Regarding total scoring, MDC for ocular VOMS symptom items was 1 and MDC for vestibular VOMS symptoms items was 2. MDC for NPC was 4 cm and for VOMS overall score was 10. Regarding change scoring, MDC for each VOMS symptom item was 1, and for VOMS overall score was 8. False positives ranged from 5.3% to 15.9%.This study presents MDCs for each VOMS item and overall VOMS score, using total and change scoring. These values can be considered true change outside measurement error with 95% confidence in a 17-25 year old collegiate athlete population.

The purpose of this study was to examine the association between sports participation history, including estimated age of first exposure (eAFE) to high-risk sports, and concussion history in first year (i.e., freshmen) collegiate athletes. Athletes increased their odds of sustaining a pre-college concussion by 5% [odds ratio(OR) = 1.05 (95%CI:1.05-1.06)] for each additional year of contact sports participation - 24% of all student athletes reported one or more pre-college concussions. When eAFE was analysed dichotomously at age 12, a greater proportion of those who started playing football before age 12 reported a positive concussion history compared to those who started playing football at age 12 or later (Х2 = 4.483, p = 0.034, Phi = 0.049). When eAFE was analysed continuously, later eAFE to women's high-risk sports was associated with a lower likelihood of sustaining a pre-college concussion [OR = 0.93 (95%CI:0.88-0.98)]. Our findings suggest that there is a relationship between eAFE to football and to women's high-risk sports and concussion history.

Rapid diagnosis of concussion is essential to effective treatment and recovery. Concussion biomarker research has focused primarily on blood-based protein assays to detect markers of brain injury. However, transcriptomic data provides insight into the complex biological response to concussion. In this study, we investigated RNA-seq transcriptome analysis of whole blood in a large cohort of concussed and control collegiate athletes who were participating in the Concussion Assessment, Research and Education (CARE) Consortium. In this multicenter prospective cohort study, blood samples were collected from collegiate athletes at preseason (baseline), post-injury (0–6 hours), 24–48 hours postinjury, time of symptom resolution, 7 days after unrestricted return to play and 6 months post-injury. RNA-sequencing was performed on samples from 230 concussed, 130 contact control and 102 non-contact control athletes. Differential gene expression analysis was performed at each timepoint relative to baseline. Deconvolution analysis was used to identify differences in immune cell types. We identified key genes and pathways that were activated in response to concussion. Cytokine and immune response signaling pathways were activated immediately after concussion, but at later time points, these pathways appeared to be suppressed relative to contact controls. RNA-seq data also revealed that the proportion of neutrophils increased and natural killer cells decreased in the blood following concussion. Transcriptome signatures in the blood reflect the known pathophysiology of concussion and may be useful for defining the immediate biological response and the time course for recovery. In addition, the identified immune response pathways and changes in immune cell type proportions following concussion could inform future treatment strategies.

ObjectiveTo examine the association between estimated age at first exposure (eAFE) to American football and clinical measures throughout recovery following concussion.MethodsParticipants were recruited across 30 colleges and universities as part of the National Collegiate Athletic Association (NCAA)–Department of Defense Concussion Assessment, Research and Education Consortium. There were 294 NCAA American football players (age 19 ± 1 years) evaluated 24–48 hours following concussion with valid baseline data and 327 (age 19 ± 1 years) evaluated at the time they were asymptomatic with valid baseline data. Participants sustained a medically diagnosed concussion between baseline testing and postconcussion assessments. Outcome measures included the number of days until asymptomatic, Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) composite scores, Balance Error Scoring System (BESS) total score, and Brief Symptom Inventory 18 (BSI-18) subscores. The eAFE was defined as participant's age at the time of assessment minus self-reported number of years playing football.ResultsIn unadjusted regression models, younger eAFE was associated with lower (worse) ImPACT Visual Motor Speed (R2 = 0.031, p = 0.012) at 24–48 hours following injury and lower (better) BSI-18 Somatization subscores (R2 = 0.014, p = 0.038) when the athletes were asymptomatic. The effect sizes were very small. The eAFE was not associated with the number of days until asymptomatic, other ImPACT composite scores, BESS total score, or other BSI-18 subscores.ConclusionEarlier eAFE to American football was not associated with longer symptom recovery, worse balance, worse cognitive performance, or greater psychological distress following concussion. In these NCAA football players, longer duration of exposure to football during childhood and adolescence appears to be unrelated to clinical recovery following concussion.

Continued participation after sport-related concussion (SRC) worsens outcomes, but it is unknown if duration of continued participation after SRC impacts recovery outcomes, and which athletes who continue to participate are at greatest risk for poor SRC outcomes. The purpose of this National Collegiate Athletic Association/Department of Defense (NCAA/DoD) Concussion Assessment, Research, and Education (CARE) Consortium study was to evaluate the association of estimated duration of continued participation after SRC with symptom severity and recovery time in collegiate athletes.Clinicians estimated if/how long athletes continued participation after SRC. Collegiate athletes who continued participation after suspected SRC (n = 195/373, 52.3%) completed the Graded Symptom Checklist to evaluate the severity of total symptoms and migraine/fatigue, cognitive/ocular, and affective symptom clusters. Linear regression analyzed the associations between estimated duration of continued participation, symptom severity, and recovery time. Binary logistic regression examined the association of estimated duration of continued participation with the odds of recovery ≥ 14 and ≥ 21 days. Statistical significance was p 0.05.Athletes who continued to participate did so for 27.9 ± 25.3 min (mean ± standard deviation; range 1-90 min). Longer estimated continued participation (1-90 min) was associated with greater symptom severity (β = 0.122, p = 0.02), affective (β = 0.171, p = 0.001) and migraine/fatigue symptoms (β = 0.104, p = 0.049), longer symptom duration (β = 0.193, p 0.001), and longer time missed (β = 0.156, p = 0.003). Longer estimated continued participation positively interacted with female sex (cognitive/ocular: female RLonger estimated duration of continued participation after SRC was associated with higher symptom severity, particularly affective and migraine/fatigue; longer symptom duration; and more time missed from sport. SRC outcomes in those who continue to play may be especially severe for female athletes, athletes with migraine history, and athletes with prior concussion(s). The findings can help clinicians and administrators to educate athletes on the importance of immediate removal following a suspected SRC.

Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion.This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the National Collegiate Athletic Association-Department of Defense Concussion Assessment, Research, and Education Consortium conducted between 2015 and 2019. The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0-6 h post-injury) and after 6 h post-injury (7-48 hours post-injury) groups. We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target 1305 proteins in plasma samples from athletes with and without sport-related concussion.A total of 140 athletes with concussion (79.3% male; aged 18.71 ± 1.10 years, mean ± SD) and 21 non-concussed athletes (76.2% male; 19.14 ± 1.10 years) were included in this study. We identified 338 plasma proteins that significantly differed in abundance (319 upregulated and 19 downregulated) in concussed athletes compared to non-concussed athletes. The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve of 0.954 (95% confidence interval: 0.922‒0.986). Specifically, after 6 h of injury, the individual area under the curve of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein were 0.956 and 0.875, respectively. The combination of EPB41 and alpha-synuclein provided the best area under the curve (1.000), which suggests this combination of candidate plasma biomarkers is best for diagnosing concussion in athletes after 6 h of injury.Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and alpha-synuclein is the most predictive biomarker of concussion after 6 h of injury.

Contact sport athletes are exposed to a unique environment where they sustain repeated head impacts throughout the season and can sustain hundreds of head impacts over a few months. Accordingly, recent studies outlined the role that head impact exposure (HIE) has in concussion biomechanics and in the development of cognitive and brain-based changes. Those studies focused on time-bound effects by quantifying exposure leading up to the concussion, or cognitive changes after a season in which athletes had high HIE. However, HIE may have a more prolonged effect. This study identified associations between HIE and concussion incidence during different periods of the college football fall season.This study included 1120 athlete seasons from six National Collegiate Athletic Association Division I football programs across 5 yr. Athletes were instrumented with the Head Impact Telemetry System to record daily HIE. The analysis quantified associations of preseason/regular season/total season concussion incidence with HIE during those periods.Strong associations were identified between HIE and concussion incidence during different periods of the season. Preseason HIE was associated with preseason and total season concussion incidence, and total season HIE was associated with total season concussion incidence.These findings demonstrate a prolonged effect of HIE on concussion risk, wherein elevated preseason HIE was associated with higher concussion risk both during the preseason and throughout the entire fall season. This investigation is the first to provide evidence supporting the hypothesis of a relationship between elevated HIE during the college football preseason and a sustained decreased tolerance for concussion throughout that season.

Sport-related concussions can result from a single high magnitude impact that generates concussive symptoms, repeated subconcussive head impacts aggregating to generate concussive symptoms, or a combined effect from the two mechanisms. The array of symptoms produced by these mechanisms may be clinically interpreted as a sport-related concussion. It was hypothesized that head impact exposure resulting in concussion is influenced by severity, total number, and frequency of subconcussive head impacts. The influence of total number and magnitude of impacts was previously explored, but frequency was investigated to a lesser degree. In this analysis, head impact frequency was investigated over a new metric called 'time delta', the time difference from the first recorded head impact of the day until the concussive impact. Four exposure metrics were analyzed over the time delta to determine whether frequency of head impact exposure was greater for athletes on their concussion date relative to other dates of contact participation. Those metrics included head impact frequency, head impact accrual rate, risk weighted exposure (RWE), and RWE accrual rate. Athletes experienced an elevated median number of impacts, RWE, and RWE accrual rate over the time delta on their concussion date compared to non-injury sessions. This finding suggests elevated frequency of head impact exposure on the concussion date compared to other dates that may precipitate the onset of concussion. National Institute of Neurological Disorders and Stroke of the National Institutes of Health [1R01NS126449]; Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium - National Collegiate Athletic Association (NCAA); Department of Defense (DOD); Office of the Assistant Secretary of Defense for Health Affairs [W81XWH-14-2-0151]; Veterans Affairs Medical Research Published version Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number 1R01NS126449. This publication was also made possible with support from the Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium, funded in part by the National Collegiate Athletic Association (NCAA) and the Department of Defense (DOD). The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Psychological Health and Traumatic Brain Injury Program under Award NO W81XWH-14-2-0151. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense (DHP funds). This study was also supported by Veterans Affairs Medical Research. The authors would also like to thank Jody Harland, MS, Janetta Matesan, BA, Michael Menser, Larry Riggen, MS (Indiana University School of Medicine); Ashley Rettmann, BS, Nicole L'Heureux, MBA (University of Michigan); Melissa Koschnitzke, MA (Medical College of Wisconsin); Michael Jarrett, MBA, Vibeke Brinck, MS and Bianca Byrne, BA (Quesgen); Melissa Baker, BS (Datalys Center for Sports Injury Research and Prevention); and the research and medical staff at each of the CARE participation sites. The team would also like to acknowledge the HIT System operators that participated in this study: Julia Ford (UNC), Philippe Gagnon-Joseph (UNC), Miranda Kruse (UNC), Gus Hendricks (UCLA), Quinn Lukens (UW), Brett Griesemer (VT), Alex Black (VT), Lewis Young (VT), Dom Calhoun (USAFA), Mike Aderman (USMA), Sean Roach (USMA), and Jeremy Ross (USMA).

COVID-19 is a novel disease with complex primary and secondary health effects that may significantly impact the functional independence and quality of life of patients and their families. While the term "rehabilitation" is often associated with exercise, the interventions employed by rehabilitation professionals in both the inpatient and outpatient setting are much more complex and very relevant in caring for individuals hospitalized with respiratory infections. Since the start of the pandemic, the Department of Rehabilitation at Walter Reed National Military Medical Center has cared for over 85% of the military beneficiaries admitted to the hospital for COVID-19. In addition to providing acute inpatient occupational, physical, and recreational therapy to help maximize each patient's functional independence, the rehabilitation team has also developed a novel program to help facilitate the safe discharge and successful recovery and social reintegration for all patients with COVID-19. Using a holistic approach, a team led by Occupational Therapy has applied a needs-based assessment of each patient and developed an individualized treatment plan, which employs home monitoring, virtual health interventions, peer support, and augmentation to case management and behavioral health care. The overall acceptance and satisfaction of this program by the patients and staff has been excellent, with early evidence to suggest improved quality of life and possible mitigation of long-term complications. This article describes the development and essential elements of this unique rehabilitation program so that other military treatment facilities may consider implementing.

Key Points Question Are plasma biomarkers associated with a return-to-sport period of less than 14 days vs 14 days or more in male and female collegiate athletes following a sport-related concussion? Findings This diagnostic study, which included 127 collegiate athletes who had sustained a sports-related concussion, found that higher total tau concentrations 24 to 48 hours after injury and at the time of symptom resolution as well as lower glial fibrillary acidic protein levels acutely postinjury were associated with return-to-sport decisions. Meaning In this study, total tau and glial fibrillary acidic protein levels were associated with return to sport in male and female collegiate athletes following a sports-related concussion., This diagnostic study examines whether plasma biomarkers can differentiate collegiate athletes who return to sport in less than 14 days vs 14 days or more following a sports-related concussion., Importance Identifying plasma biomarkers associated with the amount of time an athlete may need before they return to sport (RTS) following a sport-related concussion (SRC) is important because it may help to improve the health and safety of athletes. Objective To examine whether plasma biomarkers can differentiate collegiate athletes who RTS in less than 14 days or 14 days or more following SRC. Design, Setting, and Participants This multicenter prospective diagnostic study, conducted by the National Collegiate Athletics Association–Department of Defense Concussion Assessment, Research, and Education Consortium, included 127 male and female athletes who had sustained an SRC while enrolled at 6 Concussion Assessment, Research, and Education Consortium Advanced Research Core sites as well as 2 partial–Advanced Research Core military service academies. Data were collected between February 2015 and May 2018. Athletes with SRC completed clinical testing and blood collection at preseason (baseline), postinjury (0-21 hours), 24 to 48 hours postinjury, time of symptom resolution, and 7 days after unrestricted RTS. Main Outcomes and Measures A total of 3 plasma biomarkers (ie, total tau protein, glial fibrillary acidic protein [GFAP], and neurofilament light chain protein [Nf-L]) were measured using an ultrasensitive single molecule array technology and were included in the final analysis. RTS was examined between athletes who took less than 14 days vs those who took 14 days or more to RTS following SRC. Linear mixed models were used to identify significant interactions between period by RTS group. Area under the receiver operating characteristic curve analyses were conducted to examine whether these plasma biomarkers could discriminate between RTS groups. Results The 127 participants had a mean (SD) age of 18.9 (1.3) years, and 97 (76.4%) were men; 65 (51.2%) took less than 14 days to RTS, and 62 (48.8%) took 14 days or more to RTS. Linear mixed models identified significant associations for both mean (SE) plasma total tau (24-48 hours postinjury

Advances in combat casualty care have contributed to unprecedented survival rates of battlefield injuries, challenging the field of rehabilitation to help injured service members achieve maximal functional recovery and independence. Nowhere is this better illustrated than in the care of the multiple-limb amputee. Specialized medical, surgical, and rehabilitative interventions are needed to optimize the care of this unique patient population. This article describes lessons learned at Walter Reed National Military Medical Center Bethesda in providing advanced therapy and prosthetics for combat casualties, but provides guidelines for all providers involved in the care of individuals with amputation.

Tbe Annual Progress Report documents all research protocols, both new and continuing, reviewed during FY O3 by the Clinical Investigation Committtee (CIC) and the Human Use Committtee/Institutinal Review Board (HUCIIRB) of Walter Reed Army Medical Center (WRAMC). Continuing research review is administered by tbe Research Review Service (RRS), Department of Clinical Investigation (DCI), WRAMC. A detailed summary sheet of each protocol giving tbe objective, technical approach, and progress is presented. Personnel rosters, DCI accomplisbments, funding information, and known publications and presentations by tbe WRAMC professional staff are listed for FY 03.