Role of biomarkers and emerging technologies in defining and assessing neurobiological recovery after sport-related concussion: a systematic review.

OBJECTIVE: Determine the role of fluid-based biomarkers, advanced neuroimaging, genetic testing and emerging technologies in defining and assessing neurobiological recovery after sport-related concussion (SRC). DESIGN: Systematic review. DATA SOURCES: Searches of seven databases from 1 January 2001 through 24 March 2022 using keywords and index terms relevant to concussion, sports and neurobiological recovery. Separate reviews were conducted for studies involving neuroimaging, fluid biomarkers, genetic testing and emerging technologies. A standardised method and data extraction tool was used to document the study design, population, methodology and results. Reviewers also rated the risk of bias and quality of each study. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were included if they: (1) were published in English; (2) represented original research; (3) involved human research; (4) pertained only to SRC; (5) included data involving neuroimaging (including electrophysiological testing), fluid biomarkers or genetic testing or other advanced technologies used to assess neurobiological recovery after SRC; (6) had a minimum of one data collection point within 6 months post-SRC; and (7) contained a minimum sample size of 10 participants. RESULTS: A total of 205 studies met inclusion criteria, including 81 neuroimaging, 50 fluid biomarkers, 5 genetic testing, 73 advanced technologies studies (4 studies overlapped two separate domains). Numerous studies have demonstrated the ability of neuroimaging and fluid-based biomarkers to detect the acute effects of concussion and to track neurobiological recovery after injury. Recent studies have also reported on the diagnostic and prognostic performance of emerging technologies in the assessment of SRC. In sum, the available evidence reinforces the theory that physiological recovery may persist beyond clinical recovery after SRC. The potential role of genetic testing remains unclear based on limited research. CONCLUSIONS: Advanced neuroimaging, fluid-based biomarkers, genetic testing and emerging technologies are valuable research tools for the study of SRC, but there is not sufficient evidence to recommend their use in clinical practice. PROSPERO REGISTRATION NUMBER: CRD42020164558.

Amsterdam 2022 process: A summary of the methodology for the Amsterdam International Consensus on Concussion in Sport.

The purpose of this paper is to summarise the consensus methodology that was used to inform the International Consensus Statement on Concussion in Sport (Amsterdam 2022). Building on a Delphi process to inform the questions and outcomes from the 5th International Conference on Concussion in Sport, the Scientific Committee identified key questions, the answers to which would help encapsulate the current science in sport-related concussion and help guide clinical practice. Over 3½ years, delayed by 2 years due to the pandemic, author groups conducted systematic reviews on each selected topic. The 6th International Conference on Concussion in Sport was held in Amsterdam (27-30 October 2022) and consisted of 2 days of systematic review presentations, panel discussions, question and answer engagement with the 600 attendees, and abstract presentations. This was followed by a closed third day of consensus deliberations by an expert panel of 29 with observers in attendance. The fourth day, also closed, was dedicated to a workshop to discuss and refine the sports concussion tools (Concussion Recognition Tool 6 (CRT6), Sport Concussion Assessment Tool 6 (SCAT6), Child SCAT6, Sport Concussion Office Assessment Tool 6 (SCOAT6) and Child SCOAT6). We include a summary of recommendations for methodological improvements for future research that grew out of the systematic reviews.

The Association of Saliva Cytokines and Pediatric Sports-Related Concussion Outcomes.

OBJECTIVES: This study aimed to explore cytokine alterations following pediatric sports-related concussion (SRC) and whether a specific cytokine profile could predict symptom burden and time to return to sports (RTS). SETTING: Sports Medicine Clinic. PARTICIPANTS: Youth ice hockey participants (aged 12-17 years) were recruited prior to the 2013-2016 hockey season. DESIGN: Prospective exploratory cohort study. MAIN MEASURE: Following SRC, saliva samples were collected and a Sport Concussion Assessment Tool version 3 (SCAT3) was administered within 72 hours of injury and analyzed for cytokines. Additive regression of decision stumps was used to model symptom burden and length to RTS based on cytokine and clinical features. RRelieFF feature selection was used to determine the predictive value of each cytokine and clinical feature, as well as to identify the optimal cytokine profile for the symptom burden and RTS. RESULTS: Thirty-six participants provided samples post-SRC (81% male; age 14.4 ± 1.3 years). Of these, 10 features, sex, number of previous concussions, and 8 cytokines, were identified to lead to the best prediction of symptom severity (r = 0.505, P = .002), while 12 cytokines, age, and history of previous concussions predicted the number of symptoms best (r = 0.637, P < .001). The prediction of RTS led to the worst results, requiring 21 cytokines, age, sex, and number of previous concussions as features (r = -0.320, P = .076). CONCLUSIONS: In pediatric ice hockey participants following SRC, there is evidence of saliva cytokine profiles that are associated with increased symptom burden. However, further studies are needed.

Ultrasound guided platelet rich plasma injections for post-traumatic greater occipital neuralgia following concussion: a pilot randomized controlled trial.

Background: Treatment for post-traumatic greater occipital neuralgia (GON) includes serial injections of steroid/anesthetic. While these injections can alleviate pain, effects can be transient, frequently lasting only 1 month. As a potential alternative, platelet-rich plasma (PRP) injections are an emerging biological treatment with beneficial effects in peripheral nerve disorders. We investigated the feasibility, safety, and effectiveness of a single PRP injection for post-traumatic GON in comparison to saline or steroid/anesthetic injection. Methods: In this pilot randomized, double-blinded, placebo-controlled trial, 32 adults with post-traumatic GON were allocated 1:1:1 to receive a single ultrasound-guided injection of (1) autologous PRP (2) steroid/anesthetic or (3) normal saline. Our primary outcome was feasibility (recruitment, attendance, retention) and safety (adverse events). Exploratory measures included headache intensity and frequency (daily headache diaries) and additional questionnaires (headache impact, and quality of life) assessed at pre-injection, 1 week, 1 month, and 3 months post-injection. Results: We screened 67 individuals, 55% were eligible and 95% of those participated. Over 80% of daily headache diaries were completed with 91% of participants completing the 3-month outcome questionnaires. No serious adverse events were reported. There were no significant differences between groups for headache intensity or frequency. Headache impact on function test-6 scores improved at 3 month in the PRP (ß = -9.7, 95% CI [-15.6, -3.74], p = 0.002) and saline (ß = -6.7 [-12.7, -0.57], p = 0.033) groups but not steroid/anesthetic group (p = 0.135). Conclusion: PRP is a feasible and safe method for treating post-traumatic GON with comparable results to saline and steroid/anaesthetic. Further trials with larger sample sizes are required.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT04051203.

Saliva Cortisol as a Biomarker of Injury in Youth Sport-Related Concussion.

Increasing rates of sport-related concussion (SRC) in youth impose a significant burden on public health systems and the lives of young athletes. Accurate prediction for those likely to develop persistent post-concussion symptomology (PPCS) using a fluid biomarker, reflecting both acute injury and recovery processes, would provide the opportunity for early intervention. Cortisol, a stress hormone released through the hypothalamic-pituitary-adrenal (HPA) axis following injury, may provide a missing physiological link to clinical recovery. This cohort study investigated the change in saliva cortisol following SRC and the association between cortisol and symptom burden in pediatric ice hockey players. Further, the association between cortisol levels and medical clearance to return to play was explored. In total, cortisol samples from 233 players were included; 165 athletes (23.6% female) provided pre-injury saliva and 68 athletes (19.1% female) provided post-SRC saliva samples for cortisol analysis. Quantile (median) regressions were used to compare cortisol between pre-injury and post-SRC groups, and the association between total symptoms (/22) and symptom severity scores (/132) reported on the Sport Concussion Assessment Tool (SCAT)3/SCAT5 and post-SRC cortisol (adjusting for age, sex, history of concussion, and time from injury to sample collection). Results demonstrated significantly lower saliva cortisol in post-SRC athletes compared with the pre-injury group (ß = -0.62, 95% confidence interval [CI; -1.08, -0.16], p = 0.009). Post-SRC cortisol was not significantly associated with the SCAT3/SCAT5 symptom totals or symptom severity scores; however, females were found to report more symptoms (ß = 6.95, 95% CI [0.35, 13.55], p = 0.040) and greater symptom severity (ß = 23.87, 95% CI [9.58, 38.15], p = 0.002) compared with males. Exploratory time-to-event analysis revealed a point estimate suggesting a potential association between low cortisol levels and days to medical clearance to return to play. Although preliminary, these findings suggest that the HPA axis may be dysregulated post-SRC. Further, our exploratory analysis and case presentation of post-injury outliers highlight the need to further research cortisol as a prognostic biomarker to inform individualized sex-specific care after SRC.

Nanoporous Carbon Immunosensor for Highly Accurate and Sensitive Clinical Detection of Glial Fibrillary Acidic Protein in Traumatic Brain Injury, Stroke, and Spinal Cord Injury.

Elevated glial fibrillary acidic protein (GFAP) in the blood serum is one of the promising bodily fluid markers for the diagnosis of central nervous system (CNS) injuries, including traumatic brain injury (TBI), stroke, and spinal cord injury (SCI). However, accurate and point-of-care (POC) quantification of GFAP in clinical blood samples has been challenging and yet to be clinically validated against gold-standard assays and outcome practices. This work engineered and characterized a novel nanoporous carbon screen-printed electrode with significantly increased surface area and conductivity, as well as preserved stability and anti-fouling properties. This nano-decorated electrode was immobilized with the target GFAP antibody to create an ultrasensitive GFAP immunosensor and quantify GFAP levels in spiked samples and the serum of CNS injury patients. The immunosensor presented a dynamic detection range of 100 fg/mL to 10 ng/mL, a limit of detection of 86.6 fg/mL, and a sensitivity of 20.3 Ω mL/pg mm2 for detecting GFAP in the serum. Its clinical utility was demonstrated by the consistent and selective quantification of GFAP comparable to the ultrasensitive single-molecule array technology in 107 serum samples collected from TBI, stroke, and SCI patients. Comparing the diagnostic and prognostic performance of the immunosensor with the existing clinical paradigms confirms the immunosensor's accuracy as a potential complement to the existing imaging diagnostic modalities and presents a potential for rapid, accurate, cost-effective, and near real-time POC diagnosis and prognosis of CNS injuries.

Characterizing Factors Influencing Baseline Plasma Biomarkers for Sport-Related Concussion in Adolescents.

Abstract Developing objective measures to diagnose sport-related concussion (SRC) is a top priority, particularly in the pediatric context, given the vulnerability of the developing brain. While advances in SRC blood biomarkers are being made in adult populations, less data are available for adolescents. Clinical validation of blood biomarkers post-SRC will first require investigation in a healthy uninjured state. Further, rapid pubertal changes during adolescence may implicate possible interactions with circulating sex hormones and the menstrual cycle for females. This cross-sectional study aimed to characterize pre-injury plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light (NF-L), ubiquitin C-terminal hydrolase-L1 (UCH-L1), total tau (T-tau), and phosphorylated tau-181 (P-tau-181), considering previous concussion, age, and sex in healthy adolescent sport participants. Possible associations with menstrual cycle phase and circulating sex hormone levels (i.e., progesterone, estradiol, testosterone) were also explored. Pre-injury blood samples were obtained from 149 healthy adolescents (48% female, ages 11-18) participating in a larger Surveillance in High Schools and Community Sports to Reduce Concussions and their Consequences (SHRed Concussions) multi-site longitudinal cohort study. Main outcomes were natural log (ln) transformed plasma GFAP, NF-L, UCH-L1, T-tau, and P-tau-181 concentrations, quantified on the Quanterix Simoa HD-X platform. Mixed-effects multi-variable linear regression was used to assess associations between biomarkers and self-reported previous concussion (yes/no), age (years), sex (male/female), objectively determined menstrual cycle phase (follicular/luteal), plasma progesterone, estradiol, and testosterone. Males had 19.8% lower UCH-L1 (ß = -0.221, 95% confidence interval [CI; -0.396, -0.046]), 18.9% lower GFAP (ß = -0.210, 95% CI [-0.352, -0.068]), and 21.8% higher P-tau-181 (ß = 0.197, 95% CI [0.048, 0.346]) compared with females, adjusting for age and previous concussion. GFAP decreased 9.5% with each 1-year increase in age, adjusting for previous concussion and sex (ß = -0.100, 95% CI [-0.152, -0.049]). No biomarkers were associated with a history of previous concussion. Exploratory investigations found no associations between biomarkers and menstrual cycle phase. Females displayed an age-adjusted negative association between T-tau and progesterone (ß = -0.010, 95% CI [-0.018, -0.002]), whereas males had a negative age-adjusted association between UCH-L1 and testosterone (ß = -0.020, 95% CI [-0.037, -0.002]). As such, age- and sex-specific reference intervals may be warranted for pediatric athlete populations prior to clinical validation of blood biomarkers for SRC. Additionally, hormonal associations highlight the need to consider puberty and development in adolescent studies. Overall, findings suggest these biomarkers are resilient to a history of previous concussion and menstrual cycle phase, supporting continued investigation in adolescent SRC.

Use of Biostatistical Models to Manage Replicate Error in Concussion Biomarker Research.

Importance: Advancing research on fluid biomarkers associated with sport-related concussion (SRC) highlights the importance of detecting low concentrations using ultrasensitive platforms. However, common statistical practices may overlook replicate errors and specimen exclusion, emphasizing the need to explore robust modeling approaches that consider all available replicate data for comprehensive understanding of sample variation and statistical inferences. Objective: To evaluate the impact of replicate error and different biostatistical modeling approaches on SRC biomarker interpretation. Design, Setting, and Participants: This cross-sectional study within the Surveillance in High Schools to Reduce the Risk of Concussions and Their Consequences study used data from healthy youth athletes (ages 11-18 years) collected from 3 sites across Canada between September 2019 and November 2021. Data were analyzed from November 2022 to February 2023. Exposures: Demographic variables included age, sex, and self-reported history of previous concussion. Main Outcomes and Measures: Outcomes of interest were preinjury plasma glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament-light (NFL), total tau (t-tau) and phosphorylated-tau-181 (p-tau-181) assayed in duplicate. Bland-Altman analysis determined the 95% limits of agreement (LOAs) for each biomarker. The impact of replicate error was explored using 3 biostatistical modeling approaches assessing the associations of age, sex, and previous concussion on biomarker concentrations: multilevel regression using all available replicate data, single-level regression using the means of replicate data, and single-level regression with replicate means, excluding specimens demonstrating more than 20% coefficient variation (CV). Results: The sample included 149 healthy youth athletes (78 [52%] male; mean [SD] age, 15.74 [1.41] years; 51 participants [34%] reporting ≥1 previous concussions). Wide 95% LOAs were observed for GFAP (-17.74 to 18.20 pg/mL), UCH-L1 (-13.80 to 14.77 pg/mL), and t-tau (65.27% to 150.03%). GFAP and UCH-L1 were significantly associated with sex in multilevel regression (GFAP: effect size, 15.65%; ß = -0.17; 95% CI, -0.30 to -0.04]; P = .02; UCH-L1: effect size, 17.24%; ß = -0.19; 95% CI, -0.36 to -0.02]; P = .03) and single-level regression using the means of replicate data (GFAP: effect size, 15.56%; ß = -0.17; 95% CI, -0.30 to -0.03]; P = .02; UCH-L1: effect size, 18.02%; ß = -0.20; 95% CI, -0.37 to -0.03]; P = .02); however, there was no association for UCH-L1 after excluding specimens demonstrating more than 20% CV. Excluding specimens demonstrating more than 20% CV resulted in decreased differences associated with sex in GFAP (effect size, 12.29%; ß = -0.14; 95% CI, -0.273 to -0.004]; P = .04) and increased sex differences in UCH-L1 (effect size, 23.59%; ß = -0.27; 95% CI, -0.55 to 0.01]; P = .06), with the widest 95% CIs (ie, least precision) found in UCH-L1. Conclusions and Relevance: In this cross-sectional study of healthy youth athletes, varying levels of agreement between SRC biomarker technical replicates suggested that means of measurements may not optimize precision for population values. Multilevel regression modeling demonstrated how incorporating all available biomarker data could capture replicate variation, avoiding challenges associated with means and percentage of CV exclusion thresholds to produce more representative estimates of association.

Hiding in Plain Sight: Factors Influencing the Neuroinflammatory Response to Sport-Related Concussion.

Sport-related concussion (SRC) is a major concern among athletes and clinicians around the world. Research into fluid biomarkers of SRC has made significant progress in understanding the complex underlying pathophysiology of concussion. However, little headway has been made toward clinically validating any biomarkers to improve the clinical management of SRC. A major obstacle toward clinical translation of any fluid biomarker is the heterogeneity of SRC overlapping with multiple physiological systems involved in pathology and recovery. Neuroinflammation post-SRC is one such system that may confound fluid biomarker data on many fronts. Neuroinflammatory processes consist of cell mediators, both within the central nervous system and the periphery, that play vital roles in regulating the response to brain injury. Further, neuroinflammation is influenced by many biopsychosocial variables present in most athletic populations. In this commentary, we propose that future fluid biomarker research should take a systems biology approach in the context of the neuroinflammatory response to SRC. We highlight how biological variables, such as age, sex, immune challenges, and hypothalamic-pituitary-adrenal (HPA)-axis responses to stress, may alter neuroinflammation. Further, we underscore the importance of accounting for health and lifestyle variables, such as diet, exercise, sleep, and pre-morbid medical factors, when measuring inflammatory markers of SRC. To successfully move toward clinical translation, fluid biomarker research should take a more holistic approach in study design and data interpretation, collecting information on hidden variables that may be influencing the neuroinflammatory response to SRC.

The Impact of Concussion, Sport, and Time in Season on Saliva Telomere Length in Healthy Athletes.

To date, sport-related concussion diagnosis and management is primarily based on subjective clinical tests in the absence of validated biomarkers. A major obstacle to clinical validation and application is a lack of studies exploring potential biomarkers in non-injured populations. This cross-sectional study examined the associations between saliva telomere length (TL) and multiple confounding variables in a healthy university athlete population. One hundred eighty-three (108 male and 75 female) uninjured varsity athletes were recruited to the study and provided saliva samples at either pre- or mid-season, for TL analysis. Multiple linear regression was used to determine the associations between saliva TL and history of concussion, sport contact type, time in season (pre vs. mid-season collection), age, and sex. Results showed no significant associations between TL and history of concussion, age, or sport contact type. However, TL from samples collected mid-season were longer than those collected pre-season [ß = 231.4, 95% CI (61.9, 401.0), p = 0.008], and males had longer TL than females [ß = 284.8, 95% CI (111.5, 458.2), p = 0.001] when adjusting for all other variables in the model. These findings population suggest that multiple variables may influence TL. Future studies should consider these confounders when evaluating saliva TL as a plausible fluid biomarker for SRC.

When Two Wrongs Make a Right: The Effect of Acute and Chronic Binge Drinking on Traumatic Brain Injury Outcomes in Young Adult Female Rats.

Alcohol is the most commonly abused drug by young adults across North America. Although alcohol consumption itself incurs a risk of neurological damage, it is also a significant risk factor for traumatic brain injury (TBI). TBI among young adults is described as a modern healthcare epidemic. The drastic changes occurring within their neurological networks put young adults at greater risk for developing long-term post-traumatic deficits. Contradictory findings have been indicated regarding the effects of alcohol consumption on TBI outcomes in adults, with some studies demonstrating detrimental effects, whereas others suggest neuroprotective abilities. However, little is known about the effects of alcohol consumption on TBI outcomes during the sensitive stage of early adulthood. Young adult female Sprague-Dawley rats were randomly assigned to one of six experimental conditions: Pre-injury alcohol+TBI; Pre-injury alcohol+Sham; Pre- and Post-injury alcohol+TBI; Pre- and Post-injury alcohol+Sham; No alcohol+TBI; No alcohol+Sham. Alcohol consumption groups received an amount of 10% v/v ethanol solution based on the animals' weight. Following the injury, the rats were subjected to a behavioral test battery to assess post-concussive symptomology. Overall, chronic binge drinking significantly improved TBI outcomes related to motor coordination and balance, whereas binge drinking in general significantly decreased anxiety-like behaviors. Additionally, in many cases, chronic binge drinking appears to return the TBI animal's behavioral outcomes to levels comparable to those of the no alcohol sham animals. Thus, the results suggest that alcohol may exhibit neuroprotective abilities in the context of early adulthood TBI.

Examining the Effects of Anabolic-Androgenic Steroids on Repetitive Mild Traumatic Brain Injury (RmTBI) Outcomes in Adolescent Rats.

BACKGROUND: Repetitive mild traumatic brain injury (RmTBI) is increasingly common in adolescents. Anabolic-androgenic steroid (AAS) consumption among younger professional athletes is a significant risk factor for impaired neurodevelopment. Given the increased rates and overlapping symptomology of RmTBI and AAS use, we sought to investigate the behavioural and neuropathological outcomes associated with the AAS Metandienone (Met) and RmTBI on rats. METHODS: Rats received either Met or placebo and were then administered RmTBIs or sham injuries, followed by a behavioural test battery. Post-mortem MRI was conducted to examine markers of brain integrity and qRT-PCR assessed mRNA expression of markers for neurodevelopment, neuroinflammation, stress responses, and repair processes. RESULTS: Although AAS and RmTBI did not produce cumulative deficits, AAS use was associated with detrimental outcomes including changes to depression, aggression, and memory; prefrontal cortex (PFC) atrophy and amygdala (AMYG) enlargement; damaged white matter integrity in the corpus callosum; and altered mRNA expression in the PFC and AMYG. RmTBI affected general activity and contributed to PFC atrophy. CONCLUSIONS: Findings corroborate previous results indicating that RmTBI negatively impacts neurodevelopment but also demonstrates that AAS results in significant neuropathological insult to the developing brain.

Neuroendocrine Whiplash: Slamming the Breaks on Anabolic-Androgenic Steroids Following Repetitive Mild Traumatic Brain Injury in Rats May Worsen Outcomes.

Sport-related concussion is an increasingly common injury among adolescents, with repetitive mild traumatic brain injuries (RmTBI) being a significant risk factor for long-term neurobiological and psychological consequences. It is not uncommon for younger professional athletes to consume anabolic-androgenic steroids (AAS) in an attempt to enhance their performance, subjecting their hormonally sensitive brains to potential impairment during neurodevelopment. Furthermore, RmTBI produces acute neuroendocrine dysfunction, specifically in the anterior pituitary, disrupting the hypothalamic-pituitary adrenal axis, lowering cortisol secretion that is needed to appropriately respond to injury. Some AAS users exhibit worse symptoms post-RmTBI if they quit their steroid regime. We sought to examine the pathophysiological outcomes associated with the abrupt cessation of the commonly abused AAS, Metandienone (Met) on RmTBI outcomes in rats. Prior to injury, adolescent male rats received either Met or placebo, and exercise. Rats were then administered RmTBIs or sham injuries, followed by steroid and exercise cessation (SEC) or continued treatment. A behavioral battery was conducted to measure outcomes consistent with clinical representations of post-concussion syndrome and chronic AAS exposure, followed by analysis of serum hormone levels, and qRT-PCR for mRNA expression and telomere length. RmTBI increased loss of consciousness and anxiety-like behavior, while also impairing balance and short-term working memory. SEC induced hyperactivity while Met treatment alone increased depressive-like behavior. There were cumulative effects whereby RmTBI and SEC exacerbated anxiety and short-term memory outcomes. mRNA expression in the prefrontal cortex, amygdala, hippocampus, and pituitary were modified in response to Met and SEC. Analysis of telomere length revealed the negative impact of SEC while Met and SEC produced changes in serum levels of testosterone and corticosterone. We identified robust changes in mRNA to serotonergic circuitry, neuroinflammation, and an enhanced stress response. Interestingly, Met treatment promoted glucocorticoid secretion after injury, suggesting that maintained AAS may be more beneficial than abstaining after mTBI.

A Bump on the Head or Late to Bed: Behavioral and Pathophysiological Effects of Sleep Deprivation after Repetitive Mild Traumatic Brain Injury in Adolescent Rats.

An old wives' tale, and strongly held dogma, maintains that one should be kept awake after a mild traumatic brain injury (mTBI) to prevent a coma. This, however, conflicts with the known benefits of sleep: repair and restoration. We therefore sought to examine the effects of sleep deprivation (SD) in the post-traumatic sleep period on post-concussion symptomology (PCS). Adolescent male and female rats were administered repetitive mTBIs (RmTBI) or sham injuries and were then assigned to 5 h of SD or left undisturbed. All animals were then tested using seven behavioral tasks validated to examine PCS, followed by analysis of serum cytokines, and quantitative real-time PCR for messenger RNA (mRNA) expression. Exposure to 3 SD epochs significantly impaired behavior in 4 of 7 of the measures, while RmTBI also produced dysfunction in 5 of 7 tests, but the effects of SD and RmTBI were not cumulative. SD induced long-lasting changes in serum levels of Tnf-α, IL6, and IL-1ß. mRNA expression in the pre-frontal cortex, hippocampus, hypothalamus, and anterior cingulate cortex was modified in response to SD and RmTBI; but similar to the behavioral measures, the mRNA changes were not cumulative. Consequently, we report that SD often produced impairments similar or worse than RmTBI, and sleep hygiene should become a priority for adolescent health.

Role of Nursing Competencies for Accelerating Clinical Trials in Stem Cell Clinics.

The California Institute for Regenerative Medicine has formed a group of clinics called the Alpha Stem Cell Clinics Network. Its goal is to accelerate clinical trials of stem cell-based therapies for diseases with unmet medical needs. In this report, we describe our experience in establishing an Alpha Stem Cell Clinic at City of Hope. Implementation and integration of the clinic into the existing institutional structures required collaboration and cooperation with clinical trial units, nursing administration, and creation of new positions. The highlight of this process and the centerpiece to our success has been the definition of the role of the "hybrid nurse," a person with nursing competencies in both clinical care and research. Stem Cells Translational Medicine 2018;7:6-10 Abstract Video Link: https://youtu.be/WOeZrNyXkGU.