Research Letter: Relationship of Blood Biomarkers of Inflammation With Acute Concussion Symptoms and Recovery in the CARE Consortium.

OBJECTIVE: Determine the association of inflammatory biomarkers with clinical measures and recovery in participants with concussion. SETTING: Multicenter study in National Collegiate Athletic Association member institutions including military service academies. PARTICIPANTS: Four hundred twenty-two participants with acute concussion. DESIGN: Clinical visits and blood draws were completed preinjury and at multiple visits postconcussion (0-12 hours, 12-36 hours, and 36-60 hours postinjury). Clinical measures included Sport Concussion Assessment Tool (SCAT) symptom severity, Balance Error Scoring System, Standardized Assessment of Concussion (SAC), Brief Symptom Inventory-18 (BSI-18) scores, time to initiation of graduated return-to-play (RTP) protocol, and time to RTP. Interleukin (IL)-6, IL-10, IL-8, IL-1 receptor antagonist (RA), tumor necrosis factor (TNF), c-reactive protein, and vascular endothelial growth factor (VEGF) were measured in serum. Prespecified analyses focused on IL-6 and IL-1RA at 0 to 12 hours; exploratory analyses were conducted with false discovery rate correction. RESULTS: For prespecified analyses, IL-1RA at 0 to 12 hours in female participants was positively associated with more errors on the SAC (B(standard error, SE) = 0.58(0.27), P < .05) and worse SCAT symptom severity (B(SE) = 0.96(0.44), P < .05). For exploratory analyses, higher levels of IL-1RA at 12 to 36 hours were associated with higher global (B(SE) = 0.55(0.14), q < 0.01), depression (B(SE) = 0.45(0.10), q < 0.005), and somatization scores on the BSI (B(SE) = 0.46(0.12), q < 0.01) in participants with concussion; Higher TNF at 12 to 36 hours was associated with fewer errors on the SAC (B(SE) = - 0.46(0.14), q < 0.05). Subanalyses showed similar results for male participants and participants who were athletes. No associations were discovered in nonathlete cadets. Higher IL-8 at 0 to 12 hours was associated with slower RTP in female participants (OR = 14.47; 95% confidence interval, 2.96-70.66, q < 0.05); no other associations with recovery were observed. CONCLUSIONS: Peripheral inflammatory markers are associated with clinical symptoms following concussion and potentially represent one mechanism for psychological symptoms observed postinjury. Current results do not provide strong support for a potential prognostic role for these markers.

The Prevalence and Influence of New or Worsened Neck Pain After a Sport-Related Concussion in Collegiate Athletes: A Study From the CARE Consortium.

BACKGROUND: Neck pain in a concussion population is an emerging area of study that has been shown to have a negative influence on recovery. This effect has not yet been studied in collegiate athletes. HYPOTHESIS: New or worsened neck pain is common after a concussion (>30%), negatively influences recovery, and is associated with patient sex and level of contact in sport. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Varsity-level athletes from 29 National Collegiate Athletic Association member institutions as well as nonvarsity sport athletes at military service academies were eligible for enrollment. Participants completed a preseason baseline assessment and follow-up assessments at 6 and 24 to 48 hours after a concussion, when they were symptom-free, and when they returned to unrestricted play. Data collection occurred between January 2014 and September 2018. RESULTS: A total of 2163 injuries were studied. New or worsened neck pain was reported with 47.0% of injuries. New or worsened neck pain was associated with patient sex (higher in female athletes), an altered mental status after the injury, the mechanism of injury, and what the athlete collided with. The presence of new/worsened neck pain was associated with delayed recovery. Those with new or worsened neck pain had 11.1 days of symptoms versus 8.8 days in those without (P < .001). They were also less likely to have a resolution of self-reported symptoms in ≤7 days (P < .001). However, the mean duration of the return-to-play protocol was not significantly different for those with new or worsened neck pain (7.5 ± 7.7 days) than those without (7.4 ± 8.3 days) (P = .592). CONCLUSION: This novel study shows that neck pain was common in collegiate athletes sustaining a concussion, was influenced by many factors, and negatively affected recovery.

Accelerating the Development of Thin Film Photovoltaic Technologies: An Artificial Intelligence Assisted Methodology Using Spectroscopic and Optoelectronic Techniques.

Thin film photovoltaic (TFPV) materials and devices present a high complexity with multiscale, multilayer, and multielement structures and with complex fabrication procedures. To deal with this complexity, the evaluation of their physicochemical properties is critical for generating a model that proposes strategies for their development and optimization. However, this process is time-consuming and requires high expertise. In this context, the adoption of combinatorial analysis (CA) and artificial intelligence (AI) strategies represents a powerful asset for accelerating the development of these complex materials and devices. This work introduces a methodology to facilitate the adoption of AI and CA for the development of TFPV technologies. The methodology covers all the necessary steps from the synthesis of samples for CA to data acquisition, AI-assisted data analysis, and the extraction of relevant information for research acceleration. Each step provides details on the necessary concepts, requirements, and procedures and are illustrated with examples from the literature. Then, the application of the methodology to a complex set of samples from a TFPV production line highlights its ability to rapidly glean significant insights even in intricate scenarios. The proposed methodology can be applied to other types of materials and devices beyond PV and using different characterization techniques.

Use of the Buffalo Concussion Treadmill Test in community adult patients with mild traumatic brain injury.

BACKGROUND: The Buffalo Concussion Treadmill Test (BCTT) is used to establish exercise tolerance for rehabilitation and identify injury subtypes for youth athletes after mild traumatic brain injury (mTBI). Its utility in adult community members is unknown. OBJECTIVE: Primary: To describe how adults with and without mTBI tolerate the BCTT. Secondary: To explore relationships between baseline factors, mTBI-related symptoms, and BCTT duration. DESIGN: Prospective, observational, longitudinal. SETTING: Academic medical center. PARTICIPANTS: Thirty-seven adults treated in a level 1 trauma center emergency department with mTBI; 24 uninjured controls (UC). INTERVENTIONS: N/A. MAIN MEASURES: Participants completed two visits 3 weeks apart (1 week and 1 month after mTBI) including a 15-minute BCTT, the Rivermead Post Concussion Symptoms Questionnaire (RPQ), and preinjury International Physical Activity Questionnaire. Analyses characterized BCTT response and associations between baseline factors, RPQ scores, and BCTT duration. RESULTS: Persons with mTBI discontinued earlier than UC at 1-week postinjury using standard discontinuation criteria for exercise intolerance. The percentage of mTBI participants with signs of possible mTBI-related intolerance was 55.6% at 1 week (36.1% for mTBI-related symptom exacerbation, 19.4% for exertion/fatigue before reaching 85% of one's age-predicted maximum heart rate [HR]) and 48.0% at 1 month (40.0% mTBI-related symptom exacerbation, 8.0% exertion without reaching the target HR). Thirty percent of UCs completed the BCTT at both assessments. UCs met discontinuation criteria for increased nonspecific symptoms (eg, pain/general discomfort and increased Visual Analog Scale ratings; 39-61%) and physical exertion (9-26%). Shorter duration was associated with higher body mass index (r = -0.42 - -0.45), shorter height (r = 0.22-0.29), female gender (r = -0.26 - -0.27), and greater RPQ symptoms (r = -0.28 - -0.47). CONCLUSION: The BCTT exacerbates mTBI-related symptoms in adult community members. Participant characteristics and noninjury factors influence performance. The findings imply the BCTT could be useful in clinical assessments of adults with mTBI. Interpretation should account for the unique characteristics of nonathletes.

Utility of Structured Oculomotor, Balance, and Exercise Testing in Civilian Adults With Mild Traumatic Brain Injury.

PURPOSE: Assessments of oculomotor, balance, and exercise function detect different responses to mild traumatic brain injury in sports-related mild traumatic brain injury. These assessments are understudied in the adult community mild traumatic brain injury population. We evaluated level 1 trauma center patients with nonsports-related mild traumatic brain injury on oculomotor functioning (near point of convergence and accommodation), balance (Balance Error Scoring System), and exercise tolerance (Buffalo Concussion Treadmill Test). METHODS: A prospective, cohort study of adults with mild traumatic brain injury ( n = 36) were assessed at 1 wk and 1-mo post-mild traumatic brain injury ( n = 26) using near point of convergence, near point of accommodation, Balance Error Scoring System, Buffalo Concussion Treadmill Test, and the Rivermead Post Concussion Symptoms Questionnaire. Prevalence of test impairment and association between performance and mild traumatic brain injury-related symptom burden (Rivermead Post Concussion Symptoms Questionnaire scores) were characterized. RESULTS: Participants demonstrated varying levels of impairment (e.g., 33.3% oculomotor, 44.1% balance, and 55.6% exercise impairment at 1 wk). Participants displayed diverse impairment profiles across assessments. We observed medium-to-large correlations between poorer near point of convergence and Buffalo Concussion Treadmill Test performance and greater mild traumatic brain injury symptom burden. CONCLUSIONS: Clinical examinations of oculomotor function, balance, and exercise adopted from sports-related concussion assessments detect impairment in adult community members with mild traumatic brain injury. While findings warrant larger-scale replication, they imply that incorporating these simple, structured examinations into the assessment of mild traumatic brain injury may facilitate more personalized management strategies.

Association of Blood Biomarkers of Inflammation With Acute Concussion in Collegiate Athletes and Military Service Academy Cadets.

BACKGROUND AND OBJECTIVES: The objective was to characterize the acute effects of concussion (a subset of mild traumatic brain injury) on serum interleukin (IL)-6 and IL-1 receptor antagonist (RA) and 5 additional inflammatory markers in athletes and military service academy members from the Concussion Assessment, Research, and Education Consortium and to determine whether these markers aid in discrimination of concussed participants from controls. METHODS: Athletes and cadets with concussion and matched controls provided blood at baseline and postinjury visits between January 2015 and March 2020. Linear models investigated changes in inflammatory markers measured using Meso Scale Discovery assays across time points (baseline and 0-12, 12-36, 36-60 hours). Subanalyses were conducted in participants split by sex and injury population. Logistic regression analyses tested whether acute levels of IL-6 and IL-1RA improved discrimination of concussed participants relative to brain injury markers (glial fibrillary acidic protein, tau, neurofilament light, ubiquitin c-terminal hydrolase-L1) or clinical data (Sport Concussion Assessment Tool-Third Edition, Standardized Assessment of Concussion, Balance Error Scoring System). RESULTS: Participants with concussion (total, N = 422) had elevated IL-6 and IL-1RA at 0-12 hours vs controls (n = 345; IL-6: mean difference [MD] (standard error) = 0.701 (0.091), p < 0.0001; IL-1RA: MD = 0.283 (0.042), p < 0.0001) and relative to baseline (IL-6: MD = 0.656 (0.078), p < 0.0001; IL-1RA: MD = 0.242 (0.038), p < 0.0001), 12-36 hours (IL-6: MD = 0.609 (0.086), p < 0.0001; IL-1RA: MD = 0.322 (0.041), p < 0.0001), and 36-60 hours (IL-6: MD = 0.818 (0.084), p < 0.0001; IL-1RA: MD = 0.317 (0.040), p < 0.0001). IL-6 and IL-1RA were elevated in participants with sport (IL-6: MD = 0.748 (0.115), p < 0.0001; IL-1RA: MD = 0.304 (0.055), p < 0.0001) and combative-related concussions (IL-6: MD = 0.583 (0.178), p = 0.001; IL-1RA: MD = 0.312 (0.081), p = 0.0001). IL-6 was elevated in male (MD = 0.734 (0.105), p < 0.0001) and female participants (MD = 0.600 (0.177), p = 0.0008); IL-1RA was only elevated in male participants (MD = 0.356 (0.047), p < 0.0001). Logistic regression showed the inclusion of IL-6 and IL-1RA at 0-12 hours improved the discrimination of participants with concussion from controls relative to brain injury markers (χ2(2) = 17.855, p = 0.0001; area under the receiver operating characteristic curve [AUC] 0.73 [0.66-0.80] to 0.78 [0.71-0.84]), objective clinical measures (balance and cognition; χ2(2) = 40.661, p < 0.0001; AUC 0.81 [0.76-0.86] to 0.87 [0.83-0.91]), and objective and subjective measures combined (χ2(2) = 13.456, p = 0.001; AUC 0.97 [0.95-0.99] to 0.98 [0.96-0.99]), although improvement in AUC was only significantly relative to objective clinical measures. DISCUSSION: IL-6 and IL-1RA (male participants only) are elevated in the early-acute window postconcussion and may aid in diagnostic decisions beyond traditional blood markers and common clinical measures. IL-1RA results highlight sex differences in the immune response to concussion which should be considered in future biomarker work.

Plasma phosphorylated tau181 as a biomarker of mild traumatic brain injury: findings from THINC and NCAA-DoD CARE Consortium prospective cohorts.

Objective: The aim of this study was to investigate phosphorylated tau (p-tau181) protein in plasma in a cohort of mild traumatic brain injury (mTBI) patients and a cohort of concussed athletes. Methods: This pilot study comprised two independent cohorts. The first cohort-part of a Traumatic Head Injury Neuroimaging Classification (THINC) study-with a mean age of 46 years was composed of uninjured controls (UIC, n = 30) and mTBI patients (n = 288) recruited from the emergency department with clinical computed tomography (CT) and research magnetic resonance imaging (MRI) findings. The second cohort-with a mean age of 19 years-comprised 133 collegiate athletes with (n = 112) and without (n = 21) concussions. The participants enrolled in the second cohort were a part of a multicenter, prospective, case-control study conducted by the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium at six CARE Advanced Research Core (ARC) sites between 2015 and 2019. Blood was collected within 48 h of injury for both cohorts. Plasma concentration (pg/ml) of p-tau181 was measured using the Single Molecule Array ultrasensitive assay. Results: Concentrations of plasma p-tau181 in both cohorts were significantly elevated compared to controls within 48 h of injury, with the highest concentrations of p-tau181 within 18 h of injury, with an area under the curve (AUC) of 0.690-0.748, respectively, in distinguishing mTBI patients and concussed athletes from controls. Among the mTBI patients, the levels of plasma p-tau181 were significantly higher in patients with positive neuroimaging (either CT+/MRI+, n = 74 or CT-/MRI+, n = 89) compared to mTBI patients with negative neuroimaging (CT-/MRI-, n = 111) findings and UIC (P-values < 0.05). Conclusion: These findings indicate that plasma p-tau181 concentrations likely relate to brain injury, with the highest levels in patients with neuroimaging evidence of injury. Future research is needed to replicate and validate this protein assay's performance as a possible early diagnostic biomarker for mTBI/concussions.

Increased brain age and relationships with blood-based biomarkers following concussion in younger populations.

OBJECTIVE: Brain age is increasingly being applied to the spectrum of brain injury to define neuropathological changes in conjunction with blood-based biomarkers. However, data from the acute/sub-acute stages of concussion are lacking, especially among younger cohorts. METHODS: Predicted brain age differences were independently calculated in large, prospectively recruited cohorts of pediatric concussion and matched healthy controls (total N = 446), as well as collegiate athletes with sport-related concussion and matched non-contact sport controls (total N = 184). Effects of repetitive head injury (i.e., exposure) were examined in a separate cohort of contact sport athletes (N = 82), as well as by quantifying concussion history through semi-structured interviews and years of contact sport participation. RESULTS: Findings of increased brain age during acute and sub-acute concussion were independently replicated across both cohorts, with stronger evidence of recovery for pediatric (4 months) relative to concussed athletes (6 months). Mixed evidence existed for effects of repetitive head injury, as brain age was increased in contact sport athletes, but was not associated with concussion history or years of contact sport exposure. There was no difference in brain age between concussed and contact sport athletes. Total tau decreased immediately (~ 1.5 days) post-concussion relative to the non-contact group, whereas pro-inflammatory markers were increased in both concussed and contact sport athletes. Anti-inflammatory markers were inversely related to brain age, whereas markers of axonal injury (neurofilament light) exhibited a trend positive association. CONCLUSION: Current and previous findings collectively suggest that the chronicity of brain age differences may be mediated by age at injury (adults > children), with preliminary findings suggesting that exposure to contact sports may also increase brain age.

A close-in giant planet escapes engulfment by its star.

When main-sequence stars expand into red giants, they are expected to engulf close-in planets1-5. Until now, the absence of planets with short orbital periods around post-expansion, core-helium-burning red giants6-8 has been interpreted as evidence that short-period planets around Sun-like stars do not survive the giant expansion phase of their host stars9. Here we present the discovery that the giant planet 8 Ursae Minoris b10 orbits a core-helium-burning red giant. At a distance of only 0.5 AU from its host star, the planet would have been engulfed by its host star, which is predicted by standard single-star evolution to have previously expanded to a radius of 0.7 AU. Given the brief lifetime of helium-burning giants, the nearly circular orbit of the planet is challenging to reconcile with scenarios in which the planet survives by having a distant orbit initially. Instead, the planet may have avoided engulfment through a stellar merger that either altered the evolution of the host star or produced 8 Ursae Minoris b as a second-generation planet11. This system shows that core-helium-burning red giants can harbour close planets and provides evidence for the role of non-canonical stellar evolution in the extended survival of late-stage exoplanetary systems.

Radiolytic degradation of dodecane substituted with common energetic functional groups.

Explosives exist in and are expected to withstand a variety of harsh environments up to and including ionizing radiation, though little is known about the chemical consequences of exposing explosives to an ionizing radiation field. This study focused on the radiation-induced chemical changes to a variety of common energetic functional groups by utilizing a consistent molecular backbone. Dodecane was substituted with azide, nitro, nitrate ester, and nitramine functional groups and γ-irradiated with 60Co in order to study how the functional group degraded along with what the relative stability to ionizing radiation was. Chemical changes were assessed using a combination of analysis techniques including: nuclear magnetic resonance (NMR) spectroscopy, gas chromatography of both the condensed and gas phases, Raman spectroscopy, and Fourier transform infrared (FTIR) spectroscopy. Results revealed that much of the damage to the molecules was on the energetic functional group and often concentrated on the trigger linkage, also known as the weakest bond in the molecule. The general trend from most to least susceptible to radiolytic damage was found to be D-ONO2 → D-N3 → D-NHNO2 → D-NO2. These results also appear to be in line with the relative stability of these functional groups to things such as photolysis, thermolysis, and explosive insults.

Mice and primates use distinct strategies for visual segmentation.

The rodent visual system has attracted great interest in recent years due to its experimental tractability, but the fundamental mechanisms used by the mouse to represent the visual world remain unclear. In the primate, researchers have argued from both behavioral and neural evidence that a key step in visual representation is 'figure-ground segmentation', the delineation of figures as distinct from backgrounds. To determine if mice also show behavioral and neural signatures of figure-ground segmentation, we trained mice on a figure-ground segmentation task where figures were defined by gratings and naturalistic textures moving counterphase to the background. Unlike primates, mice were severely limited in their ability to segment figure from ground using the opponent motion cue, with segmentation behavior strongly dependent on the specific carrier pattern. Remarkably, when mice were forced to localize naturalistic patterns defined by opponent motion, they adopted a strategy of brute force memorization of texture patterns. In contrast, primates, including humans, macaques, and mouse lemurs, could readily segment figures independent of carrier pattern using the opponent motion cue. Consistent with mouse behavior, neural responses to the same stimuli recorded in mouse visual areas V1, RL, and LM also did not support texture-invariant segmentation of figures using opponent motion. Modeling revealed that the texture dependence of both the mouse's behavior and neural responses could be explained by a feedforward neural network lacking explicit segmentation capabilities. These findings reveal a fundamental limitation in the ability of mice to segment visual objects compared to primates.

Relationship Between Neighborhood Disadvantage and Mild Traumatic Brain Injury Symptoms.

OBJECTIVE: To test the hypotheses that (1) higher neighborhood disadvantage is associated with greater injury-related symptom severity in civilians with mild traumatic brain injury (mTBI) and (2) neighborhood disadvantage remains predictive after controlling for other established predictors. SETTING: Level 1 trauma center and affiliated academic medical center. PARTICIPANTS: N = 171 individuals with mTBI. DESIGN: Prospective cohort study. MAIN MEASURES: Rivermead Post Concussion Symptoms Questionnaire (RPQ) total score assessed less than 24 hours and at 2 weeks, 3 months, and 6 months postinjury. Linear mixed-effects models were used to assess the relationship between predictor variables and mTBI-related symptom burden (RPQ score). Neighborhood disadvantage was quantified by the Area Deprivation Index (ADI), a composite of 17 markers of socioeconomic position (SEP) scored at the census block group level. RESULTS: Individuals in the upper ADI quartile of the national distribution displayed higher RPQ symptoms than those in the lower 3 quartiles ( P < .001), with a nonsignificant ADI × visit interaction ( P = .903). In a multivariable model, the effect of ADI remained significant ( P = .034) after adjusting for demographics, individual SEP, and injury factors. Other unique predictors in the multivariable model were gender (gender × visit P = .035), health insurance type ( P = .017), and injury-related litigation ( P = .012). CONCLUSION: Neighborhood disadvantage as quantified by the ADI is robustly associated with greater mTBI-related symptom burden throughout the first 6 months postinjury. That the effect of ADI remained after controlling for demographics, individual SEP, and injury characteristics implies that neighborhood disadvantage is an important, understudied factor contributing to clinical recovery from mTBI.

Salivary Cortisol Dynamics After Mild Traumatic Brain Injury.

OBJECTIVE: To assess mild traumatic brain injury (mTBI)-related alterations in baseline (resting) salivary cortisol and cortisol reactivity to cognitive and exercise stressors, which are frequently encountered during mTBI rehabilitation and recovery. SETTING: Persons with mTBI were recruited from a level 1 trauma center emergency department. Uninjured controls (UCs) were recruited from the community. PARTICIPANTS: Participants were 37 individuals with mTBI and 24 UCs. All patients with mTBI were enrolled at 7 ± 3 days post-injury, met the American Congress of Rehabilitation Medicine definition of mTBI, and had no acute intracranial findings on clinical neuroimaging (if performed). DESIGN: A prospective cohort study design was used. All participants provided saliva samples 10 times during each of 2 visits spaced 3 weeks apart (1 week and 1 month post-injury for the mTBI group). Each visit included baseline saliva sampling and sampling to evaluate reactivity to a cognitive stressor (Paced Auditory Serial Addition Test) and physical stressor (Buffalo Concussion Treadmill Test [BCTT]). MAIN OUTCOME MEASURE: Natural log-transformed salivary cortisol was measured by enzyme immunoassay. Cortisol was predicted using a linear mixed-effects model by group (mTBI and UC), visit (1 week and 1 month), and saliva sample. RESULTS: Mean salivary cortisol was higher in the mTBI group (1.67 nmol/L [95% CI 1.42-1.72]) than in controls (1.30 nmol/L [1.12-1.47]), without an mTBI × time interaction. At 1 week, the mTBI group had greater cortisol reactivity in response to the BCTT. CONCLUSIONS: Higher cortisol in individuals with mTBI at 1 week and 1 month post-injury extends previous findings into the subacute recovery period. Furthermore, the mTBI group demonstrated a greater cortisol response to mild-to-moderate aerobic exercise (BCTT) at 1 week post-injury. Given the increasing role of exercise in mTBI rehabilitation, further research is warranted to replicate these findings and identify the clinical implications, if any, of enhanced hypothalamic-pituitary-adrenal axis responses to exercise in civilians with recent mTBI.

Are EPB41 and alpha-synuclein diagnostic biomarkers of sport-related concussion? Findings from the NCAA and Department of Defense CARE Consortium.

BACKGROUND: 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. METHODS: 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 h 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. RESULTS: A total of 140 athletes with concussion (79.3% males; aged 18.71 ± 1.10 years, mean ± SD) and 21 non-concussed athletes (76.2% males; 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 (AUC) of 0.954 (95% confidence interval: 0.922‒0.986). Specifically, after 6 h of injury, the individual AUC of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein (SNCA) were 0.956 and 0.875, respectively. The combination of EPB41 and SNCA provided the best AUC (1.000), which suggests this combination of candidate plasma biomarkers is the best for diagnosing concussion in athletes after 6 h of injury. CONCLUSION: Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury.

Refinements to rodent head fixation and fluid/food control for neuroscience.

The use of head fixation in mice is increasingly common in research, its use having initially been restricted to the field of sensory neuroscience. Head restraint has often been combined with fluid control, rather than food restriction, to motivate behaviour, but this too is now in use for both restrained and non-restrained animals. Despite this, there is little guidance on how best to employ these techniques to optimise both scientific outcomes and animal welfare. This article summarises current practices and provides recommendations to improve animal wellbeing and data quality, based on a survey of the community, literature reviews, and the expert opinion and practical experience of an international working group convened by the UK's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). Topics covered include head fixation surgery and post-operative care, habituation to restraint, and the use of fluid/food control to motivate performance. We also discuss some recent developments that may offer alternative ways to collect data from large numbers of behavioural trials without the need for restraint. The aim is to provide support for researchers at all levels, animal care staff, and ethics committees to refine procedures and practices in line with the refinement principle of the 3Rs.

Proteomic Profiling of Plasma Biomarkers Associated With Return to Sport Following Concussion: Findings From the NCAA and Department of Defense CARE Consortium.

Objective: To investigate the plasma proteomic profiling in identifying biomarkers related to return to sport (RTS) following a sport-related concussion (SRC). Methods: This multicenter, prospective, case-control study was part of a larger cohort study conducted by the NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium, athletes (n = 140) with blood collected within 48 h of injury and reported day to asymptomatic were included in this study, divided into two groups: (1) recovery <14-days (n = 99) and (2) recovery ≥14-days (n = 41). We applied a highly multiplexed proteomic technique that uses DNA aptamers assay to target 1,305 proteins in plasma samples from concussed athletes with <14-days and ≥14-days. Results: We identified 87 plasma proteins significantly dysregulated (32 upregulated and 55 downregulated) in concussed athletes with recovery ≥14-days relative to recovery <14-days groups. The significantly dysregulated proteins were uploaded to Ingenuity Pathway Analysis (IPA) software for analysis. Pathway analysis showed that significantly dysregulated proteins were associated with STAT3 pathway, regulation of the epithelial mesenchymal transition by growth factors pathway, and acute phase response signaling. Conclusion: Our data showed the feasibility of large-scale plasma proteomic profiling in concussed athletes with a <14-days and ≥ 14-days recovery. These findings provide a possible understanding of the pathophysiological mechanism in neurobiological recovery. Further study is required to determine whether these proteins can aid clinicians in RTS decisions.

Left Atrial Appendage Ligation Using the AtriClip Device: Single-Center Study of Device Safety and Efficacy.

Objective: Left atrial appendage (LAA) occlusion at the time of cardiac surgery in patients with atrial fibrillation has been shown to reduce the incidence of postoperative embolic stroke. However, the optimal method for LAA occlusion is not universally accepted. We sought to examine the safety and effectiveness of LAA occlusion with the AtriClip epicardial occlusion device. Methods: Cardiac surgical patients with atrial fibrillation who underwent LAA AtriClip placement were evaluated prospectively. Clip placement and clinical outcomes were examined after 1 year of follow-up with transesophageal echocardiography (TEE). The presence of a 10 mm or greater residual pouch, presence of flow into the LAA, or device-related thrombus (DRT) were considered failures. Results: Ninety-seven patients were analyzed. The mean CHA2DS2-VASc score was 2.4 ± 1.4. The postoperative follow-up period ranged from 366 to 1,693 days (mean 685 days or 1.87 years). Seventy-four AtriClips were placed with video-assisted thoracic surgery, whereas 23 were placed via sternotomy or thoracotomy. Successful closure was found in 96% (93 of 97) of patients at follow-up. Failure occurred in 4 patients. No clip migration or DRT was seen on 3-dimensional imaging. Of all 97 patients, 76 (78%) were on presurgical oral anticoagulation, whereas 5 (5.1%) were on postprocedure oral anticoagulation. There were no postoperative thromboembolic events at the time of the study TEE. Conclusions: The AtriClip epicardial surgical occlusion device can provide an excellent rate of successful closure of the LAA during surgical ablation procedures without DRT.

Age-Group Differences and Annual Variation in Return-To-Play Practices After Sport-Related Concussion.

OBJECTIVE: To examine return-to-play (RTP) practice differences between high school and collegiate athletes, as well as the stability (ie, year-by-year) in these practices over a 5-year period. We hypothesized that similar protocols for treatment will be comparable across competition levels and that these practices will vary year-to-year. DESIGN: Prospective cohort study. SETTING: Nine high schools and 4 National Collegiate Athletic Association Division III colleges in Southeastern Wisconsin. PARTICIPANTS AND INDEPENDENT VARIABLES: Two-hundred seventy-three (N = 273) athletes with sport-related concussions (SRCs). Independent predictors included competition level (high school, n = 88 vs collegiate, n = 185) and year-of-injury. OUTCOME MEASURES: Athletes were evaluated prospectively for differences in symptom duration, symptom free waiting period (SFWP), and time to RTP, as well as longitudinal changes in management. RESULTS: High school and collegiate athletes experienced comparable median symptom duration (high school, 6.0 days, interquartile range (IQR) = 3.5-11.0; college, 6.0 days, IQR = 4.0-9.0, P = 0.95), SFWP (high school, 5.0 days, IQR = 3.0-8.0; college, 5.0 days, IQR = 3.0-7.0, P = 0.12), and total time to RTP (high school, 10.5 days, IQR = 7.0-16.0; college, 11.0 days, IQR = 8.0-14.0 days, P = 0.94). A Cox regression analysis revealed a nonsignificant trend toward longer SFWPs in high school athletes (P = 0.055; hazard ratio = 1.347, confidence interval = 0.99-1.83). Among football players, SFWPs in 2017 (Median = 3.5 days, IQR = 1.5-5.0 days) were significantly longer than those in 2014 (Median = 5.0 days, IQR = 4.0-8.5 days, P = 0.029) after correction for multiple comparisons. CONCLUSION: Similar postinjury and RTP management practices were observed at the high school and collegiate levels after SRCs. Symptom duration and time from injury to unrestricted RTP were comparable, although high school athletes may have longer SFWPs.

Wireless closed-loop optogenetics across the entire dorsoventral spinal cord in mice.

Optoelectronic systems can exert precise control over targeted neurons and pathways throughout the brain in untethered animals, but similar technologies for the spinal cord are not well established. In the present study, we describe a system for ultrafast, wireless, closed-loop manipulation of targeted neurons and pathways across the entire dorsoventral spinal cord in untethered mice. We developed a soft stretchable carrier, integrating microscale light-emitting diodes (micro-LEDs), that conforms to the dura mater of the spinal cord. A coating of silicone-phosphor matrix over the micro-LEDs provides mechanical protection and light conversion for compatibility with a large library of opsins. A lightweight, head-mounted, wireless platform powers the micro-LEDs and performs low-latency, on-chip processing of sensed physiological signals to control photostimulation in a closed loop. We use the device to reveal the role of various neuronal subtypes, sensory pathways and supraspinal projections in the control of locomotion in healthy and spinal-cord injured mice.

Temporal controls over inter-areal cortical projection neuron fate diversity.

Interconnectivity between neocortical areas is critical for sensory integration and sensorimotor transformations1-6. These functions are mediated by heterogeneous inter-areal cortical projection neurons (ICPN), which send axon branches across cortical areas as well as to subcortical targets7-9. Although ICPN are anatomically diverse10-14, they are molecularly homogeneous15, and how the diversity of their anatomical and functional features emerge during development remains largely unknown. Here we address this question by linking the connectome and transcriptome in developing single ICPN of the mouse neocortex using a combination of multiplexed analysis of projections by sequencing16,17 (MAPseq, to identify single-neuron axonal projections) and single-cell RNA sequencing (to identify corresponding gene expression). Focusing on neurons of the primary somatosensory cortex (S1), we reveal a protracted unfolding of the molecular and functional differentiation of motor cortex-projecting ([Formula: see text]) ICPN compared with secondary somatosensory cortex-projecting ([Formula: see text]) ICPN. We identify SOX11 as a temporally differentially expressed transcription factor in [Formula: see text] versus [Formula: see text] ICPN. Postnatal manipulation of SOX11 expression in S1 impaired sensorimotor connectivity and disrupted selective exploratory behaviours in mice. Together, our results reveal that within a single cortical area, different subtypes of ICPN have distinct postnatal paces of molecular differentiation, which are subsequently reflected in distinct circuit connectivities and functions. Dynamic differences in the expression levels of a largely generic set of genes, rather than fundamental differences in the identity of developmental genetic programs, may thus account for the emergence of intra-type diversity in cortical neurons.